BASIC AND TRANSLATIONAL MEDICINE
BASIC RESEARCH OF CARDIOVASCULAR DISEASE
GW32-e1228
Evgeny Bezsonov1,2,3, Dmitry Kashirskikh1, Veronika Myasoedova1, Alexandra Melnichenko1, Varvara Orekhova1, Alexander Orekhov1
1The Institute of General Pathology and Pathophysiology, Moscow, Russia
2Institute of Human Morphology, Moscow, Russia
3Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
OBJECTIVES Sialidases play an important role in atherosclerosis development due to modification of LDL (low density lipoproteins). The aim of this study was to explore the contribution of viral sialidases to the total sialidase activity in blood plasma. Also, we tested the possibility to change sialylation of lipoproteids in healthy mice upon an injection of immobilized sialidase.
METHODS The total sialidase activity was measured using commercially available kits. The work was carried out in accordance with the principles of good clinical practice on volunteers showing increased sialidase activity of blood plasma in preliminary screening. Immobilized sialidaze was injected in healthy mice, animals were sacrificed after certain time and a fraction of lipoproteids was purified for subsequent sialylation determination.
RESULTS There were no significant changes in the sialidase activity of plasma when measured immediately after oral administration of oseltamivir phosphate, a selective inhibitor of neuraminidases of influenza A and B viruses, after 4 hours and after 6 hours (8 volunteers). The study of neuraminidase activity during a 6-week clinical study using oseltamivir phosphate was carried out. In 6 volunteers, no significant changes in the sialidase activity of plasma measured immediately after taking the drug, on days 7, 14 and 42, were found. We found that even a single dose of the immobilized sialidaze injected into a mouse reduced the level of Sia in lipoproteids by 50% suggesting that the natural sialidase activity in the murine plasma was low enough for the usage of a higher dosage of the preparation to treat the animals.
CONCLUSIONS The data obtained indicate the possible absence of the determining role of viral neuraminidases in the appearance of modified low density lipoproteins (desialylated LDL). A new approach to study the role of sialidase as a proatherogenic factor in vivo was established. Research was supported by the Russian Science Foundation (grant#18-15-00254).
GW32-e1670
Vasily Sukhorukov1,2, Vladislav Kalmykov3, Igor Sobenin2
1Institute of Human Morphology
2National Medical Research Center of Cardiology, Institute of Experimental Cardiology
3Institute of Gene Biology
OBJECTIVES Mutant mitochondrial DNA (mtDNA) copies can accumulate in intima cells during atherogenesis and cause mitochondrial dysfunctions. Mitochondrial dysfunction can be a mechanistic factor in many pathologies, including atherosclerosis. In our previous studies, we found several mitochondrial mutations, correlated with cardiovascular diseases, and created the cybrid cell lines bearing these mutations. One of these mutations is Cytb G15059A. Mitochondria are promising organelles for the search for molecular targets for gene therapy. Mitochondrial editing is one of the desirable approaches for the therapy of mitochondrial-related diseases. The aim of our study to create an approach to delete Cytb G15059A mutation from THP-1 cells by the CRISPR/Cas9 editing.
METHODS The pMitoCas9 vector, based on CMV-T7-humanSpCas9, was created to edit mtDNA, bearing Cytb G15059A mutation. Liposomes were used to deliver this vector to THP-1 cybrid cells that carried Cytb G15059A mutation. The efficiency of mutation elimination was assessed by T7 analysis, qPCR, and drop digital PCR (ddPCR).
RESULTS The cleavage of mtDNA in the area of Cytb mutation by the pMitoCas9 vector was successfully confirmed by T7 analysis and ddPCR. The ddPCR has shown that around 92% of mtDNA were cut by Cas9 nuclease. The qPCR analysis was shown that the mutation ratio was decreased from 99% to only 3.7% after transfection of cybrid cells with the pMitoCas9 vector. Thus, the Cas9 nuclease can eliminate the Cytb G15059A mutation. This approach may help to study the role of mtDNA mutations in changing the functional properties of cells that can lead to the formation of a pathological phenotype.
CONCLUSIONS Our approach has led to the almost complete elimination of the Cytb G15059A mutation. This approach can be used to edit mitochondrial mutations to prevent atherosclerosis.
This study was supported by Russian Science Foundation, Grant#19-1500297.
GW32-e1730
Suparna Roy1, Parijat Biswas2, Dipanjan Ray2, Soumik Kundu2, Deepak Sinha2, Prasenjit Sen2
1Research Associate
2IACS, Jadavpur
OBJECTIVES 1. To study the effect of feed on regeneration.
METHODS To establish the proof of principle, we have investigated the effect of Ulva fasciata water extract on Zebrafish caudal fin regeneration at our laboratory. We purchased 2-month-old 6 male Zebrafish from local aquarium shop subsequently maintained those Zebrafish in a standard environment in an Aquaneering recirculating system in a core facility with 14 hours light and 10 hours dark cycle, air and water temperature maintained at 24–30 °C. The fresh seaweed Uf were collected from Digha coast, West Bengal. The Uf was repeatedly washed with in-situ water and distilled water and the clean Uf of 0.05 gm was pasted with mortar and pestle and dissolved with 5 mL distilled water and prepared 0.1 gm/mL seaweed solution. The group-I and group-II normal Zebrafish caudal fin were measured and cut with blade, and after amputation group-I Zebrafish was kept within normal water and group-II within 0.1 gm/mL seaweed water solution in the fish tank for 7th days. The area of regenerating caudal fin was calculated using ImageJ software.
RESULTS Our study showed that Uf water solution accelerated the regeneration rate gradually in comparison to normal water. The seaweed treated caudal fin regenerating area was 0.63 sq.mm and normal water treated caudal fin area was 0.03 sq.mm. The results represented in a table and graph; image of 7th day regenerating caudal fin. Figure1 A compares the images of regenerating fin in control and treated group of fish. Figure1 B compares the rate of fin regeneration by comparing the fin area in control and treated group of fish. Normalized % regeneration in Figure1 B is estimated by following equation %R=[1-{(A(0)-A(i))/(A(0)-A(1))/(A(0)-A(1))/(A(0)-A(1))}]*100; Ai=the area of ith day, A0=is the area of fin before cutting, A1 is the area of first day.
CONCLUSIONS It can be concluded that seaweed has accelerating effect on regeneration.
GW32-e0156
Nadiia Demikhova, Olha Prykhodko, Valentyna Bumeister, Serhii Dmytruk, Viktoria Hula, Olena Gordienko, Lyudmila Kiptenko
Sumy State University
OBJECTIVES Macrophages are mononuclear phagocytes that provide a system of non-specific immune response in various tissues and organs, including thymus. To date, morphological changes in thymus cells under various pathological conditions represent significant interest, primarily for clarifying specific pathogenetic mechanisms, as well as assessing the state of central organs of immunogenesis. Aim: Determination of features of ultrastructural changes in thymus macrophages under experimental total dehydration of the organism.
METHODS Twelve nonlinear mature male rats were involved in the experiment. The mild degree of total dehydration was simulated on six animals by keeping them on a completely anhydrous diet for 3 days. Six rats represented the control group and were in the usual drinking regimen. When animals were removed from the experiment, we selected the thymus and prepared samples for researching the organ ultrastructure by electron microscopy.
RESULTS In experimental animals, in comparison with the control ones, a greater number of thymic macrophages were revealed. Phagocytized apoptotic bodies, phagolysosomes, and numerous predominantly elongated lysosomes of various sizes with homo- and heterogeneous contents are found in the cytoplasm of macrophages. The granular endoplasmic reticulum of macrophages is represented by channels with a large number of ribosomes on the inner membrane. The Golgi complex has the appearance of little cisterns with a small amount of separately located bubbles. The density of macrophages in thymus medulla is much lower than in the cortex. In our opinion, this reflects differences in the intensity of apoptosis in these zones.
CONCLUSIONS The dynamics of the amount and ultrastructural changes of macrophages in thymus suggests that a mild degree of total dehydration of the organism is accompanied by the activation of a nonspecific immune response in thymus, which, in turn, develops as a result of the intensification of apoptosis of the thymocytes.
GW32-e0419
Elena Yaroslavskaya, Dmitrij Krinochkin, Olga Guskova, Elena Gorbatenko, Tatiana Petelina
Tyumen Cardiology Research Center, the branch of Tomsk National Research Medical Center of the Russian Academy of sciences
OBJECTIVES To explore the prevalence of cardiovascular diseases, signs of anxiety, depression, stress, and their relationship in patients with proven COVID-19 pneumonia 3 months after discharge depending of gender.
METHODS The study was carried out within the framework of “One-year Cardiac Follow-up of COVID-19 Pneumonia”. One hundred and three patients (46.6±15.8 years) were divided into groups: 52 men (50.9%) and 51 women. Anxiety and depression symptoms were measured by GAD-7 and PHQ-9, respectively. PSS-10 was used to measure stress symptoms. The minimum value of anxiety and depression presence was a total value of 5 points.
RESULTS 48.5% of patients had cardiovascular diseases, out of which arterial hypertension (AH) was the most common (44.7%). Less common was coronary artery disease (CAD) (16.5%), which in 14.6% of patients was accompanied by AH. Chronic heart failure (CHF) NYHA class I-II was found in 19.4% of patients, and severe CHF (NYHA class III–IV) – in 4.9%. Arrhythmia was detected in 11.7% of patients. According to the clinical characteristics, no significant differences were found between the groups of men and women. AH affected 21.4% of men and 23.3% of women, CAD −10.7% and 5.8%, respectively. NYHA class I-II CHF were found in 8.7% of men and 10.7% of women, and severe CHF (NYHA class III–IV) – in 2 men and 3 women. Arrhythmia had a prevalence of less than 6% among both men and women. Anxiety or depression symptoms were reported in 29.1% and 27.2%, respectively. Combination of anxiety and depression symptoms was determined in 18.4%, symptoms of stress in 8.7% of patients. Symptoms of depression were reported in women more often (P=0.023). The value of the median scores of the PHQ-9 questionnaire in the group of women is significantly higher than in the group of men (3.00 [1.00; 8.00] and 1.00 [0; 3.75], P=0.006). Depression symptoms were associated with female gender (OR 2.83; CI 95% 1.35–7.08). Despite the absence of gender differences in the prevalence of anxiety (18.4% and 10.7%, P=0.072), when comparing the values of the median scores of the GAD-7 questionnaire in the groups of men and women, the difference was statistically significant (1.00 [0; 4.00] and 3.00 [2.00; 7.00], P=0.001, respectively). Signs of stress among married people were less common in comparison with unmarried and unmarried (2.9 vs. 5.8%, P=0.037).
CONCLUSIONS Three months after discharge, no significant differences in clinical characteristics between the men and women were found. Signs of anxiety or depression were found in more than a quarter of patients who had proven COVID-19-associated pneumonia. Women experienced symptoms of depression 3 times more often than men. Unmarried patients tended to experience stress more often.
GW32-e0045
Xing Luo1,2, Bo Yu1,2, Haibo Jia1,2
1Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University
2Key Laboratory of Myocardial Ischemia, Ministry of Education
OBJECTIVES Emerging evidence indicates that pyroptosis and oxidative stress have a considerable influence on the development of atherosclerosis. Quercetin is known to possess atherosclerosis protect effects. However, the molecular mechanism is largely unclear. Here, we evaluated the effects of quercetin on macrophage pyroptosis and further investigated whether and how quercetin activates NRF2 pathway in macrophage and ApoE−/− mice.
METHODS The Carotid plaques and monocytes from atherosclerosis patients were used to evaluated the macrophage/monocytes pyroptosis level. ApoE−/− mice were divided into ND group (feed with normal diet), HD group (feed with high fat diet for 16 weeks) and Quer+HD group (feed with high fat diet supplemental with 1% quercetin for 16 weeks). Oil red, Masson and HE staining were used to evaluated the plaque area and collagen content in the plaque. The serum of MDA, GSH, SOD and IL-1β were also analyzed. To explore the molecular mechanisms, we treated the THP-1 original macrophages with oxldl (100 ng/mL) and examined the effects of quercetin on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of NRF2 signaling in quercetin functions in macrophages.
RESULTS The monocytes and carotid plaques from atherosclerosis patients shown that macrophage/monocyte pyroptosis is more frequently observed in atherosclerosis patients. Quercetin oral administration significant attenuated the progression of atherosclerosis, characterized by reduced plaque area, increased collagen content, improved oxidative stress and attenuated macrophage pyroptosis in ApoE−/− mice. In THP-1 original macrophages, quercetin suppressed the macrophage pyroptosis induced by oxldl, demonstrated by inhibiting the activation of NLRP3 inflammasome, lowering level of oxidative stress and activating NRF2/KEAP1 pathway. Mechanistically, the anti-atherosclerosis effect of quercetin appeared dependent upon effective elimination of cellular and total reactive oxygen species (ROS) and enhances NRF2 translocate into nuclear by promoting the dissociation of NRF2 and KEAP1 by competing with NRF2 to bind KEAP1.
CONCLUSIONS Taken together, there funding illustrated that quercetin protects against atherosclerosis in vivo and in vitro, partially via suppressing ROS and macrophage pyroptosis.
GW32-e0127
Guokun Wang, Hongjie Xu, Zhiyun Xu
Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University
OBJECTIVES The accelerated aging of vascular is an important risk factor for various cardiovascular diseases. The present study aimed to explore the role and mechanism of transcription factor krüppel-like factor 4 (KLF4) in vascular smooth muscle cells (VSMCs) senescence.
METHODS The vascular aging mice and VSMCs senescence models were induced by angiotensin II (Ang II). The cellular senescence was measured by senescence-associated beta-galactosidase (SA-β-gal) activity and p53 expression. Chromatin immunoprecipitation, luciferase assay, and gain- and loss-of-function experiments were used to validate the role and mechanism of KLF4 on VSMCs senescence. The autophagic activity was evaluated by autophagic flux and autophagic marker expression.
RESULTS In the vascular aging mice model, KLF4 expression was found extremely increased in aortic media after Ang II stimulation, but significantly decreased in later period. The decreased expression of KLF4 was also detected both in Ang II-induced premature senescent VSMCs and in continually passaging-replicative senescent VSMCs. Overexpression of KLF4 significantly enhanced the anti-aging ability of VSMCs. The decreased SA-β-gal-positive cells number and p53 expression could be detected in KLF4-overexpressing VSMCs. Then, telomerase reverse transcriptase (TERT) was identified as a direct genomic target downstream of KLF4. Overexpression of KLF4 in VSMCs could prevent the decline expression of TERT under Ang II-stimulation condition, in turn, contribute to enhance the autophagic activity, and ultimately improve the anti-aging ability of VSMCs.
CONCLUSIONS Our results demonstrated that overexpression of KLF4 could prevent VSMCs senescence through promoting TERT-mediated autophagy. These findings provided novel potential targets for the prevention and therapy of aging-related vascular diseases.
GW32-e0252
Bo Liang, Ning Gu
Nanjing University of Chinese Medicine
OBJECTIVES Oxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerotic coronary heart disease (CHD). NRF2 is a key transcriptional factor against oxidative stress through activation of multiple ARE-mediated genes. Z-Lig is derived from the Ligusticum species with antitumor, anti-inflammation and neuroprotection activities. However, the antioxidant potentials of Z-Lig on endothelial dysfunction and atherosclerosis have not been well elucidated. Therefore, in the present work, we appraise the cytoprotective property and anti-atherosclerosis effect of Z-Lig.
METHODS Potential NRF2 activators were screened and verified by luciferase reporter gene assay. The protein and mRNA levels of NRF2 and ARE-mediated genes, and GSH/GSSG level in EA.hy926 cells treated with Z-Lig were detected. The cytoprotective property of Z-Lig was assessed in the tert-butyl hydroperoxide (t-BHP)-evoked oxidative stress model. Cell viability and reactive oxygen species (ROS) levels in EA.hy926 cells were determined. An atherosclerosis model induced by HFD was used to determine the anti-atherosclerosis effect of ZLig in HFD-fed Ldlr-deficient mice.
RESULTS In vitro, 100 μM Z-Lig upregulated expressions of NRF2 and ARE-driven genes, promoted accumulation of nuclear NRF2 and unbound NRF2-KEAP1 complex in EA.hy926 cells. Furthermore, Z-Lig alleviated oxidative stress and cell injury caused by t-BHP via stimulation of the NRF2/ARE pathway. In vivo, intervention with 20 mg/kg Z-Lig markedly restrained atherosclerosis progression, including attenuation of HFD-induced atherosclerotic plaque formation, alleviation of lipid peroxidation and increase in antioxidant enzyme activity in aortas of HFD-fed Ldlr −/− mice. The chemopreventive effects of Z-Lig might be associated with the activation of NRF2 and ARE-driven genes.
CONCLUSIONS The present study suggested that Z-Lig is an effective NRF2 activator, which can protect vascular endothelial cells from oxidative stress and rescue HFD-induced atherosclerosis.
GW32-e0414
Yu Liang1, Wei Ou2, Yu Qing3, Wei Wu4, Tao Li1
1Laboratory of Mitochondria and Metabolism, Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu 610041, China
2Department of Anesthesiology, Nanchong Central Hospital, Nanchong 637003, China
3Department of Anesthesiology, The People’s Hospital of Jianyang City, Jianyang 641400, China
4Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu 610083, China
OBJECTIVES Myocardial ischemia-reperfusion (I/R) injury leads to irreversible cardiac dysfunction and damage of cardiovascular system. Alteration in glucose metabolism has been recognized as an important adaptive response under hypoxic conditions. However, the biological benefits underlying this metabolic phenotype remain to be elucidated. This study was aimed to investigate the impact of hypoxic acclimation (HA) on cardiac I/R injury.
METHODS Mice were acclimated to a hypoxia condition (10% oxygen [O2]) for 8 h/day for 14 days, and then subjected to cardiac I/R injury by ligation of left anterior descending coronary artery for 30 min and reperfusion for 24 h or 7 days. The infarct size, the levels of oxidative stress and antioxidant capacity, the change of glucose metabolism of hearts were measured.
RESULTS Our results revealed that HA attenuated oxidative stress and reduced infarct size in the I/R hearts. This cardioprotective effect is coupled with an elevation of protein O-linked N-acetylglucosamine (O-GlcNAc) modification partially due to inflammatory stimulation. Hyperglycosylation activated glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway, resulting in an upregulation of NADPH/NADP+ and GSH/GSSG couples and enhancement of redox homeostasis in the heart. Pharmacological suppression of O-GlcNAcylation totally abolished the influence of HA on the G6PDH activity, redox balance and post-I/R damage in the hearts and cultured cardiomyocytes, whereby augmentation of O-GlcNAcylation further enhanced the benefits, suggesting a central role of O-GlcNAcylation in HA-initiated antioxidative and cardioprotective effects.
CONCLUSIONS Our study identified HA as a promising anti-I/R strategy for the heart and revealed HA O-GlcNAc modification of G6PDH as a therapeutic target in ischemic heart disease.
GW32-e0525
Hao Ding1, Lei Gao2, Qingnian Liu1, Xiaohong Yin2, Liang Ma2, Yonghua Yang2, Xinyang Hu1, Bin Zhang2, Jian’an Wang1
1The Second Affiliated Hospital Zhejiang University College of Medicine
2School of Mechanical Engineering, Zhejiang University
OBJECTIVES To investigate the contact guidance effect of micropatterned gelatin methacryloyl hydrogel with various geometrical parameters on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs).
METHODS In this study, we utilize a micro-molding technique to develop various micropatterns on photocrosslinkable gelatin methacryloyl (GelMA) hydrogel. We fabricated various types of micropatterned GelMA substrates and seeded hiPSC-CMs atop. We quantified the contact guiding effect by analyzing the directional distribution of nuclei and cytoskeletal F-actin. Furthermore, to assess the maturation and contraction, we carried out immunofluorescence staining, RNA-sequencing, and video-based beating characterization. Finally, the optimized micropattern design for improving CMs organization, maturation, and contraction is suggested.
RESULTS Gelatin methacryloyl hydrogel has comparable mechanical properties to native cardiac tissues and good fidelity in fabricating micropatterns. 20-μm-width and 20-μm-spacing microgroove is found to be the optimal design regarding contact guidance effect. Besides, this micropattern enhances cardiomyocyte maturation, as indicated by improved expression of connecxin 43 and vinculin, and extended sarcomere length. It also improves contraction of cardiomyocytes with larger contractile amplitude and higher contractile motion anisotropy.
CONCLUSIONS Here we investigated the contact guidance effect of various micropatterned GelMA substrates on hiPSC-CMs organization, maturation, and contraction. Our data showed that by changing the geometrical parameters of micropatterns, i.e., width, spacing, and shape, we could regulate the proportion of aligned hiPSC-CMs. We conclude that the 20-μm-width and 20-μm-spacing microgrooves is the optimal design of here-investigated micropatterns. This conclusion is supported by several evidence. First, this micropattern leads to the highest degree of cell alignment, as demonstrated by orientational analysis of nuclei and F-actin. Second, hiPSC-CMs exhibit improved functional maturation on micropatterned GelMA substrates. Our finding is supported by improved connexin43 expression, vinculin expression, and extended sarcomere length. Larger contracting amplitude and anisotropy indicate the similarity of highly aligned hiPSC-CMs and native cardiac tissues. To our best knowledge, it is the first time that several geometrical parameters are systematically studied in the regard of regulating the functions of hiPSC-CMs. Since the same criteria are employed in evaluating organization, maturation, and contraction of hiPSC-CMs, our findings could provide important insights to optimizing cell-guiding micropatterns and constructing functionally mature cardiac tissues in vitro.
GW32-e0569
Zhen Guo1,2, Di Fan1,2, Fang-Yuan Liu1,2, Peng An1,2, Ming-Yu Wang1,2, Dan Yang1,2, Chen-Fei Li1,2, Qi-Zhu Tang1,2
1Department of Cardiology, Renmin Hospital of Wuhan University
2Hubei Key Laboratory of Metabolic and Chronic Diseases
OBJECTIVES To explore the effects of TLR9 on diabetic cardiomyopathy (DCM), and to focus on the specific mechanism of TLR9 on DCM.
METHODS DCM model was constructed by intraperitoneal injection of Streptozocin (STZ, 50 mg/kg/d, 5 consecutive days) in C57 mice, and neonatal rat cardiomyocytes were stimulated by high glucose to construct the model in vitro, TLR9 localization and expression were detected by immunofluorescence staining and Western Blot. In situ injection of adeno-associated virus 9 (AAV9) into myocardium was performed one week before intraperitoneal injection of STZ to overexpress TLR9. Exploring the effects of TLR9 overexpression on DCM through ultrasound data and molecular biology experiments (such as immunohistochemical staining, Tunel staining and Western Blot). Subsequently, the genetically engineered mice of PGC1α and shRNA or small interfering RNA were used to verify the mechanism of TLR9 affecting DCM in vitro and in vivo. Immunoprecipitation was used to detect Triad3A-mediated TLR9 ubiquitination.
RESULTS TLR9 expression was down-regulated in STZ-induced diabetic mice and HG-stimulated cardiomyocytes (P<0.05). Overexpression of TLR9 improved the deterioration of heart function caused by DCM, which was reflected by the improvement of ultrasound data, but did not improve blood glucose levels. In addition, TLR9 overexpression significantly reduced the levels of myocardial fibrosis, oxidative stress, and apoptosis caused by STZ. In the diabetic state or high glucose environment, after the overexpression of TLR9 in myocardial tissue or cardiomyocytes, the expression of PGC1α and Nrf2-HO1 are up-regulated, and the nuclear translocation of Nrf2 is also up-regulated. However, the expression of NOX2 and NOX4 was not affected. In the case of conditional knockout of PGC1α, even if TLR9 was overexpressed, it could not improve the fibrosis and oxidative stress levels of DCM myocardial tissue. Similarly, ultrasound and hemodynamics also showed that the knockout of PGC1α made TLR9 lose its protective effect. Overexpression of TLR9 can significantly increase the phosphorylation level of AMPK. After using shRNA to silence AMPK, even if TLR9 was overexpressed, it cannot increase the expression of PGC1α and nuclear translocation of Nrf2. When AMPK was silenced, TLR9 overexpression could not ameliorate the increase in ROS level and the decrease in cell survival rate induced by high glucose. The mRNA level of TLR9 did not change significantly in the diabetic state, but the expression of Triad3A was significantly up-regulated in heart tissue. After using Triad3A small interfering RNA, the ubiquitination degradation of TLR9 is reduced, and the expression level of TLR9 protein was high.
CONCLUSIONS In the environment of diabetes or high glucose, the expression of Triad3A in the myocardial tissue increases, which mediates the ubiquitination and degradation of TLR9, which in turn causes the phosphorylation level of AMPK to decrease. Further down-regulating the expression of PGC1α and Nrf2, the expression and nuclear translocation of Nrf2 are reduced, resulting in a reduction in the production of antioxidants, causing an imbalance between peroxides and antioxidants, causing oxidative stress and various pathological conditions.
GW32-e0837
Zhenyu Feng, Yunpeng Xie
大连医科大学附属第一医院 (The First Affiliated Hospital of Dalian Medical University)
OBJECTIVES To detect whether CDC20 is involved in DOX-induced cardiotoxicity by overexpression of CDC20, and the role of CDC20 in dox-induced cardiotoxicity.
METHODS We first established DOX-induced cardiotoxicity models in vivo and in vitro. In vivo, the recombinant adeno-associated virus serotype 9 (RAAV9) vector expressing CDC20 was injected into C57BL/6 male mice via tail vein. Two weeks later, C57BL/6 mice were intraperitoneally injected with DOX (cumulative dose of 20 mg/kg) to establish an in vivo model. In vivo, left ventricular ejection fraction (EF%) and left ventricular shortened fraction (FS%) were measured by echocardiography. After sampling, the heart tissues were stained with HE, Masson, WGA, and TDT-mediated dUTP nick end-labeling (TUNEL) staining. And CDC20 was detected by RT-qPCR to determine whether the overexpression model of CDC20 was successfully constructed. In vitro, 5 μM DOX was added into the H9C2 cells and neonatal rat cardiomyocytes (NRCMs) culture medium and incubated for 24 h to establish the cardiac cytotoxicity model. In vitro, the H9C2 cells and NRCMs were used to infect H9C2 and NRCMs with Ad-CDC20 at a 50-fold multiplex and then treated with DOX (5 μM) for 24 h. Cell proteins were extracted and western blot was performed to detect caspase3 (cleaved), Bax, and Bcl-2, and other apoptosis-related proteins.
RESULTS We found that CDC20 overexpression significantly alleviated DOX-induced cardiomyocyte apoptosis and DOX-induced cardiomyocyte miniaturization. Echocardiography showed that left ventricular systolic function was significantly reduced in DOX group mice, such as EF% and FS%, and this situation was significantly alleviated after CDC20 overexpression. HE staining showed that the overexpression of CDC20 significantly reduced the myocardial cavitation induced by DOX. Masson staining showed that CDC20 overexpression had no significant effect on myocardial fibrosis induced by DOX. WGA staining showed that overexpression of CDC20 significantly alleviated DOX-induced cardiomyocyte shrinkage. TUNEL staining showed that overexpression of CDC20 significantly reduced DOX-induced myocardial cell apoptosis. Consistent with in vivo models, in vitro models, Western blot results showed that overexpression of Cdc20 alleviated DOX-induced down-regulation of apoptosis-related proteins such as caspase3 (cleaved) and up-regulation of Bax.
CONCLUSIONS Our results show that overexpression of CDC20 can alleviate DOX-induced apoptosis of cardiomyocytes, and cdc20 is a potential therapeutic target against DOX-induced cardiotoxicity.
GW32-e0892
Rongfeng Huang, Haoran Xin, Zhihui Zhang, Min-Dian Li
Southwest Hospital, Army Medical University
OBJECTIVES Time of eating synchronizes circadian rhythms of metabolism and physiology. However, system-wide changes of circadian metabolism and physiology entrained to inverted feeding in heart remain largely unexplored. Here, we performed a 24-h global profiling of transcripts and metabolites in heart to study the transition kinetics during inverted feeding, and tested how inverted feeding entrains diurnal physiology and metabolism in heart.
METHODS Nine-week-old female mice on daytime restricted feeding (DRF)- and nighttime (control, NRF)-restricted feeding, for one week were subjected to heart collection. We first examined entrainment of heart tissue circadian clocks by feeding and discerned the impact of sex, duration of restricted feeding, and constant light on food entrainment. Next, phase analysis and pathway analysis of the heart were performed. At last, we integrated diurnal transcriptomes with metabolomes/lipidomes to explore how inverted feeding entrains diurnal physiology and metabolism in heart.
RESULTS Clock genes in heart were phase inverted under DRF in constant light-conditioned female mice and remained phase-locked to light-dark cycles under 36-day. In addition, Diurnal rhythms of clock genes showed phase shifts of 0–3 h in heart. The multi-omics analysis showed the majority (57.41%) of dual-oscillating genes were phase locked to light-dark cycles, and only 21.68% of genes were phase inverted by inverted feeding. The peak time of cardiac acylcarnitine species fell in the inactive/food-restricted period, targeted lipidomics profiling of acylCoA species showed that inverted feeding reversed the phase of cardiac acyl-CoA species in synchrony with its actions on acylcarnitines. Diurnal rhythms of major genes involved in lipolysis and fatty acid oxidation, such as Lipe, Cpt1a, Acox3, Acad11, Ehhadh, and Ucp3, were phase inverted by inverted feeding in heart.
CONCLUSIONS Integrated analysis of transcripts and metabolites demonstrated that fatty acid oxidation entrained completely to inverted feeding in heart despite the slow kinetics of the heart clock to entrainment by feeding. This systems approach sheds light on molecular and metabolic signatures of inverted feeding on circadian biology in heart and provides an integrated resource to approach clock synchronization in the body.
GW32-e0965
Linlin Zhu
Nanjing First Hospital
OBJECTIVES STATs (signal transducers and activators of transcription), constituting a family of transcription factors, were first discovered to be involved in interferon (IFN) signal transduction and were subsequently named. After STAT1 was found to be involved in the IFN-alpha/beta signalling pathway, researchers subsequently found it to be involved in regulating cell responses to cytokines, growth factors, and hormones. Many recent studies have found that STAT1 also plays a significant role in cardiovascular disease. It is involved in the de-differentiation and proliferation of VSMCs, the formation of foam cells, intimal hyperplasia, the development of atherosclerosis, the increase in chemokine expression, oxidative stress, and tissue damage. The relationship between STAT1 and LSS has rarely been studied.
METHODS The main methods used include western blot, immunofluorescence and PCR. Small interfering RNA and overexpressed plasmid were used to alter the expression of target protein.
RESULTS In our experiments, we found that, under the action of LSS, the phosphorylation level of STAT1 at tyrosine701 was significantly increased and regulated by inhibitor of nuclear factor kappa-B kinase ε (IKKε). Moreover, STAT1 was involved in LSS-induced endothelial inflammation. LSS increased reactive oxygen species (ROS) levels and decreased endogenous nitric oxide (NO) release, however, siSTAT1 reversed these adverse effects through up-regulating the antioxidant gene heme oxygenase-1(HO-1) and down-regulating endothelial nitric oxide synthase (eNOS) Thr495 phosphorylation.
CONCLUSIONS Collectively, the results from our study clearly indicate the injurious effect of STAT1 on ECs exposed to LSS. Elucidating the details of these mechanisms may provide a basis for the development of new therapies for atherosclerosis.
GW32-e1060
Huahui Yu1,2, Xiaolu Jiao1,2, Yunyun Yang1,2, Zhiyong Du1,2, Linyi Li1,2, Chaowei Hu1,2, Yunhui Du1,2, Jing Zhang1,2, Huina Zhang1,2, Qianwen Lv1,2, Fan Li1,2, Qiuju Sun1,2, Yu Wang1,2, Xiaoping Zhang1,2, Yanwen Qin1,2
1Beijing Anzhen Hospital, Capital Medical University
2Beijing Institute of Heart Lung and Blood Vessel Disease
OBJECTIVES ANGPTL8 is a secretory protein, which plays a critical role in cardiovascular diseases, including atherosclerosis and thoracic aortic dissection. However, the direct role of ANGPTL8 on Abdominal aortic aneurysm (AAA) is still unknown. Thus, we explored the contribution of ANGPTL8 to AAA formation and its underlying mechanisms.
METHODS Human specimens were used to verify the expression of ANGPTL8 in AAA tissues. The angiotensin II (Ang II) was continuously infused by a micropump for 28 days to induce AAA in mice. By using ANGPTL8 and ApoE double-knockout mice, we determined the role of ANGPTL8 on AAA in vivo. ANGPTL8 knockdown and overexpression human artery smooth muscle cells (HASMCs) were used to detect the mechanism of ANGPTL8 promoted the development of AAA.
RESULTS ANGPTL8 expression was significantly increased in aortic tissues of human AAA and Ang II (angiotensin II)–infused ApoE−/− mice developing AAA. Genetic deletion of ANGPTL8 reduced incidence and severity of AAA, with lower expression of aortic apoptosis and proinflammatory cytokines. Transcriptome analysis revealed that ANGPTL8 regulates apoptotic of HASMCs. In human artery smooth muscle cells (HASMCs), ANGPTL8 knockdown prevented Ang II-induced apoptosis. Overexpress of ANGPTL8 significantly increased the apoptosis in HASMCs while P53 pathway inhibitor pifithrin-α significantly decreased the effects of ANGPTL8 in HASMCs.
CONCLUSIONS Our study demonstrated that ANGPTL8 knockout protects against Ang II-induced AAA in ApoE−/− mice. ANGPTL8 inhibition might be a feasible strategy target for the treatment of AAA.
GW32-e1108
Zhiyi Li, Siqi Wang, Si Lv, Fang Ji, Jie Qiao, Jie Yan, Miaoling Li
Key Laboratory of Medical Electrophysiology of the Ministry of Education and Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University
OBJECTIVES Hypertensive cardiac remodeling is accompanied with fibrosis. Acacetin is a natural flavonoid compound, which plays a protective role on doxorubicin-induced cardiomyopathy. In this study, we investigated the alleviative effect and potential molecular mechanism of acacetin on hypertensive cardiac fibrosis.
METHODS In vivo, 20-week-old SHR rats were intragastric administration with Acacetin (10 mg/kg and 20 mg/kg) for 6 weeks. Echocardiography, pathological morphological and Western-bloting techniques were used to evaluate the anti-fibrosis effects. In vitro, Ang II and TGFβ1 was used to build the cellular fibrosis model in neonatal rat cardiac fibroblasts. Acacetin treatment for 48 hours was used to study the reverse effect.
RESULTS Echocardiography and hemodynamic evaluation showed that acacetin significantly alleviated hypertension induced left ventricular posterior wall (LVPW) thickening. Furthermore, acacetin also relieved cardiac fibrosis in SHR by using H&E staining and Masson’s staining. The expressions of fibrosis markers (collagen-1, collagen-III CTGF, POSTIN and αSMA) were remarkely decreased by treatment with acacetin of 10 mg/kg and 20 mg/kg. In neonatal rat cardiac fibroblasts, Wound scratch assay showed that the wound closure rate decreased obviously treatment with Acacetin (3 and 10 μmol/L) compared to the Ang II group (P<0.05). Transwell data showed that the number of migratory cells per field decreased obviously with Acacetin treatment compared with the Ang II group (P<0.05). Acacetin (10 μmol/L) inhibited both Ang II and TGFβ1 induced upregulation of collagen-1, collagen-III (P<0.05). Meanwhile, Acacetin reversed fibroblast to myofibroblast differentiation by downregulation the expression of αSMA under the Ang II treatment. Moreover, Acacetin inhibited the expression of key signal molecules of fibrosis, included TGF-β1 and the fraction of p-Smad3/Smad3, while the expression of Smad7 was increased in Acacetin treatment groups compared with those of the Ang II group (P<0.05).
CONCLUSIONS Acacetin could inhibit the hypertensive cardiac fibrosis process through regulating TGF-β/Smad3 signal transduction pathways.
GW32-e1243
Chunqiu Liu, Shuang Xiong, Jiangang Liu, Guoju Dong
Xiyuan Hospital, China Academy of Chinese Medical Sciences
OBJECTIVES Heart failure with preserved ejection fraction (HFpEF) belongs to the category of heart failure in traditional Chinese medicine. Traditional Chinese medicine believes that its pathogenesis is chronic heart disease extension does not heal and hurt the heart qi. The deficiency and inability of heart qi make it can’t promote blood circulation, which leads to blood stasis. Qi and blood also inhibit the return of body fluids. HFpEF belongs to the deficiency of root and excess of branch, so that the clinical treatment is mainly to supplement qi, invigorate blood and promote urination for the purpose of treating the root and branch simultaneously. The effective components and action targets of Linggui Qihua Fang (LGQHF) on heart failure with preserved ejection fraction (HFpEF) were discussed by using network pharmacology, and the network diagram of molecular docking and effective component-target-signal pathway was constructed. The possible action mechanism of LGQHF on HFpEF was obtained by analyzing the obtained results.
METHODS Searching the effective components and target information of various traditional Chinese medicines in LGQHF in Traditional Chinese Medicine database and analysis platform (TCMSP), and searching related genes of HFpEF in GeneCard, OMIM, PharmGkb, TTD and DrugBank gene databases. By running Cytoscape3.7.1 and JAVA software, the intersection of drug targets and disease-related genes and their corresponding LGQHF effective components are used to construct the interaction network of “effective components-disease targets” and the LGQHF protein interaction network (PPI) diagram was constructed through STRING online database. Gene oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to enrich the genes in the network. At the same time, with the help of PubChem database, ChemOffice database, Uniprot database, PDB database and PyMol, 3D structures of ligands and protein receptors were obtained. AutoDock Vina 1.12 was used to simulate molecular docking between ligands and receptors, which verified the close relationship between them, and further proved the possibility of Linggui Qihua Fang in treating HFpEF.
RESULTS The results of network pharmacological analysis showed that LGQHF contained 58 effective components, mainly including 3β-acetoxyatractylone, ellagic acid, baicalein, beta-sitosterol, stigmasterol, (+)-catechin, (2R,3R)-4-methoxyl-distylin, hederagenin, ent-Epicatechin and taxifolin. There are 45 intersections between drug targets and disease-related targets, among which the high-scoring targets are Fos protooncogene (FOS), tumor necrosis factor (TNF), vascular endothelial growth factor (VEGFA), interleukin 6 (IL6), catalase (CAT), intercellular adhesion molecule 1 (ICAM1), estrogen receptor 1 (ESR1), nitric oxide synthase 2 (NOS2), NFKB inhibitor α (NFKBIA), serine/threonine kinase 1 (AKT1), rela protooncogene (RELA) and tumor protein p53 (TP53). GO and KEGG enrichment analysis showed that LGQHF influenced HFpEF mainly involving lipid and atherosclerosis, fluid shear stress and atherosclerosis, small cell lung cancer, AGE-RAGE signaling pathway in diabetic complications, calcium signaling pathway, cAMP signaling pathway and so on. The results of molecular docking show that the core effective components of LGQHF have a good combination with the core target of LGQHF in treating HFpEF.
CONCLUSIONS LGQHF contains many effective components for treating HFpEF, and can treat HFpEF through multiple targets and signal pathways, which provides data basis for later application of LGQHF in treating HFpEF.
GW32-e1317
Chang Cui, Yike Zhang, Yanjuan Zhang, Yongping Lin, Minglong Chen
The First Affiliated Hospital of Nanjing Medical University
OBJECTIVES To characterize the atrial phenotype and possible mechanisms in a large Chinese family with LMNALMNA missense mutation in rod 2B domain (c.1003C>T p.R335W), which was reported to be associated with Heart-Hand syndrome.
METHODS Clinical characteristics were collected based on the pedigree investigation. The Computational model was used to predict the effect of the mutation on lamin dimerization, which is the structural basis for the lamin assembly. We heterologously expressed mutant lamin in rat atrial cardiomyocytes cell line (HL-1) sand zebrafish, respectively, to test the pathogenicity of this mutation in vitro and in vivo.
RESULTS In the present pedigree, 7/13 of mutation carriers showed heterogeneous cardiac phenotypes, and most carriers also showed acro-osteolysis of distal phalanges and short nails. In silicon prediction demonstrated increased binding energy of R335W mutant lamins. HL-1 cells expressing mutant lamin showed aggregates, nuclear enlargement, and cellular senescence. Adult zebrafish expressing mutant lamins showed increased P wave duration in the electrocardiogram and atrial lesion under the transmission electron microscope.
CONCLUSIONS The LMNALMNAp.R335W mutation LMNA mutation c.C1003T p.R335W leads to a familial Heart-Hand syndrome with a prominent atrial phenotype. The unstable lamin dimerization and impaired DNA repair are possible mechanisms. Our findings consolidated the genetic role in the course of atrial arrhythmias and cardiac aging, which is helpful to the diagnosis and treatment of cardiac laminopathy.
GW32-e1386
Qian Wang
Department of Cardiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
OBJECTIVES Aims To explore the effect of rapamycin on the expression of origin recognition complex 1 (ORC1) on vascular smooth muscle cells (VSMCs) of rats in vitro.
METHODS Growth curves of VSMCs were drawn by methyl-thiazolyl-tetrazolium (MTT) colorimetric assay. VSMCs were divided randomly into two groups. Control group (CG) cells were cultured in DMEM with 10% FBS, and experimental group (EG) cells were cultured in DMEM with 10% FBS plus 10 μmol/L rapamycin. Expression of ORC1 at transcriptional and protein levels were displayed respectively by RT-PCR and Western Blot during VSMCs were cultured at 0 h, 12 h, 24 h, and 48 h.
RESULTS The expression levels of ORC1mRNA in EG decreased gradually from 0 h to 12 h and reduced significantly from 24 h to 48 h compared with those of CG. The expression changes of ORC1 protein by Western Blot were similar to those of ORC1mRNA.
CONCLUSIONS Rapamycin inhibits the expression of ORC1, indicating that the target of rapamycin (mTOR) is on the upstream of ORC1 in cell cycle, which shed light on novel strategies that can be used to prevent and treat vascular proliferative disease.
GW32-e1505
Hongji Cheng, Yanling Feng, Jinlei Wu, Qinxiu Chen, Yuexing Duan, Dong Zheng, Peng Zhang, Guixiong Lin, Yufeng Zhuo
Department of Cardiology, He Xian Memorial Hospital, Guangzhou, Guangdong, China
OBJECTIVES Previous studies have shown that circ_0040414 is highly expressed in the blood of patients with heart failure, which suggests that circ_0040414 is associated with heart failure. However, the functional involvement of circ_0040414 in heart failure and its potential mechanism remains unclear. Therefore, the objective of our study is to uncovered a novel role and the mechanism of circ_0040414 in controlling chronic heart failure, enriched the molecular regulatory network in chronic heart failure, and may provide a possible strategy for the treatment of chronic heart failure.
METHODS In our study, we first compared the expression of circ_0040414 in peripheral blood of patients with chronic heart failure and healthy controls, and confirmed the diagnostic potential of circ_0040414 in patients with chronic heart failure. Then, the relationship between circ_0040414 and chronic heart failure was determined and the stability difference between circ_0040414 and linear RNA was further compared. Subsequently, we evaluated the effect of circ_0040414 on cardiomyocyte functions, including cell proliferation, inflammation and apoptosis, by overexpressing or silencing circ_0040414 in cardiomyocyte cell lines. Finally, we identified the downstream signaling molecules of circ_0040414 using Circular RNA Interactome and Starbase databases.
RESULTS We found that circ_0040414 is highly expressed in peripheral blood samples of patients with chronic heart failure. Silencing circ_0040414 promotes the proliferation of cardiomyocytes and inhibits cell apoptosis and inflammation. In terms of mechanism, circ_0040414 acts as a miR-186-5p sponge to inhibit miR-186-5p, which in turns upregulates the expression of PTEN and dampens the AKT signaling pathway activity. Since silencing circ_0040414 activates the AKT signaling pathway and alleviates the apoptosis and inflammation in cardiomyocytes, provides novel insights into the treatment strategies for the relief of heart failure by targeting circ_0040414 /miR-186-5p/PTEN/AKT axis.
CONCLUSIONS In summary, our study uncovered a functional role of circ_0040414 in chronic heart failure and its potential regulatory mechanism.
GW32-e1626
Xuewei Xia
Daping Hospital, Third Military Medical University
OBJECTIVES In recent years, the incidence of myocardial infaction (MI) death is increasing, posing a serious threat to public health. The treatment of MI is mainly based on medicine, percutaneous coronary intervention, coronary artery bypass grafting. However, these methods cannot restore the necrotic myocardium, which limits the prognosis of patients. Bone marrow mesenchymal stem cells (BMSCs) mainly refer to non-hematopoietic stem cells in the bone marrow of the body. They are characterized by capabilities of self-replication and highly proliferation, and have multidirectional differentiation potential. In addition, they are relatively easy to obtain and with low immunogenicity. However, the hypoxic and ischemic microenvironment is not conducive to the survival and differentiation of stem cells during MI, which seriously restricts the therapeutic effect of stem cells. Studies have found that MG53 has a certain myocardial protective effect and can repair damaged cells. In this study, MG53 transfected BMSC was transplanted to the injured myocardium, its effects on cardiac function and cell apoptosis in MI mice were observed.
METHODS BMSC transfected with adenovirus over-expressing MG53 were injected into the injured myocardium. Apoptosis was detected by flow cytometry and immunofluorescence staining. The angiogenesis was assessed by CD31 staining. The cardiac function was detected by echocardiography. The paracrine factors were detected by mass spectrometry.
RESULTS We found that the apoptosis rate of MG53-transfected BMSC was significantly lower than that of vector transfected group under H2O2 treatment, and the cardiac function of mice post to myocardial infarction was significantly improved after transplantation of MG53-transfected BMSC than that of vector transfected group, and the apoptosis of cardiomyocytes were significantly reduced. Analysis of MG53 transfected BMSC supernatant by mass spectrometry showed that the expression abundance of MG53 was high in the supernatant, and the apoptosis rate, scar size, and cardiac function were aggravated after the addition of MG53 neutralizing antibody.
CONCLUSIONS Transplantation of MG53 transfected BMSC can significantly increase the survival rate of BMSC in injured myocardium, improve the cardiac function, reduce the cardiomyocyte apoptosis and scar size, promote the angiogenesis by improving the survival of BMSC and secretion of MG53.
GW32-e1696
Yongqi Feng1,2,3, Di Ye1,2,3, Zhen Wang1,2,3, Jing Ye1,2,3, Menglong Wang1,2,3, Yao Xu1,2,3, Jianfang Liu1,2,3, Jishou Zhang1,2,3, Mengmeng Zhao1,2,3, Shuwan Xu1,2,3, Wei Pan1,2,3, Jun Wan1,3
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
2Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China
3Hubei Key Laboratory of Cardiology, Wuhan, China
OBJECTIVES Doxorubicin (DOX) is widely used as an anti-tumor antibiotic. But DOX-induced cardiotoxicity limited the chemotherapeutic application of DOX. The mechanisms by which DOX causes cardiotoxicity are complex, and a variety of pathological factors are involved, such as oxidative stress and cardiomyocytes apoptosis. Previous studies have shown that Interleukin-12 (IL-12) family members affect the progression of various cardiovascular diseases by regulating inflammation. IL-27 belongs to the IL-12 family. P28 is the α subunit of IL-27 and plays an anti-inflammatory role independently of IL-27. But the role of p28 on DOX-induced cardiotoxicity remains unknown. This study aimed to investigate the role of p28 in DOX-induced cardiotoxicity and explore the underlying mechanisms.
METHODS In this study, DOX was used to induce DOX-induced cardiotoxicity in mice. The mice were randomly divided into four groups: WT+saline group, WT+DOX group, p28 KO+ saline group, and p28 KO+DOX group. Five days later, we assessed the cardiac function of each group by echocardiography. Cardiac injury, oxidative stress, and apoptosis were assessed by histological analysis and western blot. And we assessed the macrophage polarization by flow cytometry.
RESULTS Compared to the WT+saline group, the mice of the WT+DOX group had worse cardiac function. The p28 KO+DOX group had an improved cardiac function compared with the WT+DOX group. P28 KO reversed the increased cardiomyocyte apoptosis, oxidative stress, endoplasmic reticulum stress, and autophagy induced by DOX. Furthermore, p28 KO increased M2 macrophage polarization but had no effect on M1 macrophage polarization by regulating the p38/MAPK pathway.
CONCLUSIONS We demonstrated that p28 KO alleviated DOX-induced cardiac injury and dysfunction by increasing M2 macrophage polarization. Inhibition of p28 might be a potential target to inhibit DOX-induced cardiotoxicity.
GW32-e1801
Naixin Wang, Weiwei Wang, Ge Mang, Xiaoqi Wang, Zhonghua Tong, Mengdi Wang, Jian Wu, Maomao Zhang
The Second Affiliated Hospital of Harbin Medical University
OBJECTIVES The timely transition of monocyte-macrophages from inflammatory to repair state act as a crucial link that affects the outcome of myocardial infarction (MI). Histone lactylation, a newly identified epigenetic regulatory mechanism that promotes immune homeostasis by facilitating repair-related genes expression during M1 macrophages polarization. However, the role of histone lactylation in MI remains unclear. This study aims to investigate whether histone lactylation could induce the expression of repair-related genes in bone marrow and circulating monocytes early and remotely, thereby regulating the post-MI inflammatory state and improving the long-term prognosis after MI.
METHODS Western blot and immunofluorescence staining were used to detect histone lactylation level of monocytes and macrophages. Cleavage under targets and tagmentation (CUT&Tag) and paired RNA sequencing (RNA-seq) were performed to identify potential downstream targets of histone lactylation. CHIP-qPCR and qRT-PCR verified modification and expression level of the target genes. EdU staining and transwell assay detected macrophages function. Mice underwent permanent LAD ligation received injections of sodium L-lactate or lactate dehydrogenase inhibitor (FX-11) intraperitoneally. HE staining, flow cytometry and ELISA were carried out to examine the cardiac inflammatory infiltration and histological damage. Masson trichrome staining, echocardiography, magnetic resonance were performed to evaluated cardiac remodeling and dysfunction.
RESULTS Single-cell transcriptome data indicated that the repair-related genes were activated early and remotely in bone marrow and circulating monocytes before reaching the infarcted heart. Meanwhile, we observed an elevated histone lacylation level of monocyte-macrophages in the early stage after MI, including the previously identified histone H3K18 lacylation (H3K18la). Through the joint analysis of CUT&Tag and RNA-seq, we identified Lrg1, Vegf-a and IL-10 as the potential H3K18la target genes. Then we proved that increased histone lactation attenuated the excessive inflammatory response and promoted angiogenesis by facilitating Lrg1, Vegf-a and IL-10 transcription both in vitro and in vivo, while inhibition of histone lactylation suppressed the repair process after MI. Mechanistically, we revealed that circulating monocytes underwent metabolic reprogramming after MI, and the elevated glycolysis level may serve as the cornerstone of histone lactylation. Finally, our study revealed that in addition to p300, GCN5 and MOF also possessed catalytic activity toward H3K18la, which indicated that they might involve in immune homeostasis re-establishing after MI as upstream regulators.
CONCLUSIONS Taken together, this study revealed the role of histone lactylation in promoting the timely transition from inflammatory to repair state after MI via upregulating Lrg1, Vegf-a and IL-10 expression, and highlighted that the metabolome-epigenome cascade may provide clues to the underlying protective effect and mechanism of histone lactylation in MI.
GW32-e1872
Weixin Sun1, Ruijie Shi2, Jun Guo2, Haiyan Wang2, Le Shen2, Haibo Shi2, Peng Yu2, Xiaohu Chen2
1Department of Cardiology, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine
2Department of Cardiology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China, 2 Department of Cardiology, Q5 Affiliated Hospital of Nanjing University of Chinese Medicine
OBJECTIVES Myocardial ischemia-reperfusion (I/R) may be the therapeutic approach for protecting acute myocardial ischemic infarction (MI). But as a direct result of blood flow restoration to ischemic tissue, myocardial I/R also leads to cell death and additional cell dysfunction. Ferroptosis is an iron-dependent, novel form of programmed cell death that is distinct from apoptosis, cell necrosis, and cell autophagy. Essentially, ferroptosis is due to the failure of the membrane lipid repair enzyme, glutathione peroxidase (GPX4), resulting in the accumulation of lipid peroxides and reactive oxygen species (ROS) on membrane lipids. Ferroptosis inhibitor is effective in treating other diseases such as I/R induced organ damage in experimental models. Although ferroptosis is strongly implicated in human myocardial I/R injury, currently the precise molecular mechanisms and biological function of ferroptosis remain poorly understood. Therefore, in this study, we will conduct an in-depth study on the specific mechanisms underlying the occurrence of ferroptosis in the context of I/R.
METHODS Since GPX4 plays a crucial role in the onset of ferroptosis, we hypothesize that there are miRNAs that can be involved in regulating the onset of ferroptosis by targeting GPX4. Through database analysis and experimental validation, we targeted the miR-135b-3p as a key target for our study and confirmed through various in vitro and in vivo experiments that the miR-135b-3p could promote ferroptosis by inhibiting GPX4 expression in myocardial I/R injury. In this study, we established an in vivo myocardial I/R rat model and an in vitro hypoxia/reoxygenation (H/R)-induced H9C2 cardiomyocyte injury model and observed that ferroptosis occurred in tissues and cells during I/R myocardial injury. We used database analysis to find miR-135b-3p and validated its inhibitory effect on the ferroptosis-related gene glutathione peroxidase 4 (Gpx4), using a luciferase reporter assay.
RESULTS Ferroptosis involved in the process of rat myocardial I/R. We used database analysis to find miR-135b-3p and validated its inhibitory effect on the ferroptosis-related gene glutathione peroxidase 4, using a luciferase reporter assay. Ferroptosis occurs in H9C2 after H/R and is accompanied by altered expression of miR-135b-3p. And miR-135b-3p promotes cell ferroptosis by reducing GPX4 expression in H9C2 after H/R. At the end, miR-135b-3p/GPX4 promotes cell ferroptosis and aggravates myocardial I/R injury in vivo.
CONCLUSIONS In summary, we demonstrated that the upregulation of miR-135b-3p in myocardial I/R rat cardiac muscle tissues and H/R myocardial cells. Moreover, increase the expression of miR-135b-3p heightened cell injury by promoting ferroptosis via targeting GPX4. Therefore, targeting miR-135b-3p might be a potential therapeutic approach for myocardial I/R injury.
GW32-e1958
Mengqi Jiang1, Yuanxiu Song2, Ming Cui2, Yun Bai1
1Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing
2Department of Cardiology, Peking University Third Hospital, Beijing
OBJECTIVES Mitochondria are the main sites of myocardial energy metabolism, which is crucial to maintain the normal function of myocardial energy metabolism. The pathogenesis of mitochondrial cardiomyopathy (MCM) is currently unclear, and it can be manifested as hypertrophic cardiomyopathy and dilated cardiomyopathy. Mitochondria rely on four complexes on the membrane surface to transfer electrons and protons to produce ATP for cellular function, of which complex IV plays a key role. The COX6A2 gene, located on chromosome 16, is one of the subunits of complex IV. Studies have reported that regulating the expression of COX6A2 gene can affect ATP synthesis. So far, no studies have been conducted on the specific physiology and pathology of COX6A2 associated with mitochondrial cardiomyopathy. In this study, iPSC myocardial differentiation combined with CRISPR/Cas9 gene editing technology was used to establish a COX6A2 homozygous knockout human cardiomyocyte model, and to explore the mechanism of COX6A2 deletion-induced mitochondrial cardiomyopathy.
METHODS Combine CRISPR/Cas9 genome editing technology and human pluripotent stem cell cardiomyocyte differentiation technology to establish COX6A2−/− cell line and differentiate into cardiomyocytes. Immunofluorescence staining, electron microscopy and flow cytometry were used to observe the effect of COX6A2 knockout on the morphology of cardiomyocytes. Mitotracker and JC-1 fluorescent probe were used to observe the effect of COX6A2 on the number of myocardial mitochondria and membrane potential. The fluo-4/AM probe was used to explore the effect of COX6A2 on the calcium signal and contractility of cardiomyocytes. The Annexin V/APC fluorescent apoptosis detection was used to compare the differences in apoptosis between WT and KO hiPSC-CMs. Western blot and qPCR were used to detect differences in the expression of genes related to heart failure, fibrosis, ion channels and energy metabolism pathways in cardiomyocytes.
RESULTS Compared with WT hiPSC-CMs, the cell volume became larger, the number of mitochondria increased, and the cross-sectional area decreased (P<0.05), indicating that the loss of COX6A2 did not affect the differentiation of hiPSCs into myocardium, but the cell morphology and number of mitochondria changed. COX6A2−/− (KO) hiPSC-CMs have decreased mitochondrial membrane potential and impaired mitochondrial function. QPCR results showed that the expression of KO hiPSC-CMs ion channel-related genes (SCN5A, KCNH2, KCNQ1) was significantly reduced, and the expression of energy metabolism-related genes (CPT1B, CD36, PPARGC1A, PPARGC1B, PDK4, GFPT1) was significantly reduced (P<0.05); COX6A2 lacked Caused myocardial calcium activity disorder and weakened myocardial contractility (P<0.05). Apoptosis detection results show that the loss of COX6A2 promotes the apoptosis level of cardiomyocytes.
CONCLUSIONS cytochrome c oxidase subunit 6A2 (COX6A2) is involved in maintaining the morphology and function of mitochondria, and plays an important role in maintaining the energy metabolism of cardiomyocytes. Loss of COX6A2 can lead to impaired mitochondrial function, unable to maintain the normal level of energy metabolism of cardiomyocytes, leading to premature aging and apoptosis of cardiomyocytes. This study helps to clarify the pathogenesis of mitochondrial cardiomyopathy, and provides new targets and directions for the prevention and treatment of mitochondrial cardiomyopathy.
GW32-e0051
Pan Gao, Mengying Cao, Xueli Jiang, Yunzeng Zou
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University
OBJECTIVES Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus with inflammatory cell death as a critical contributing factor. Necroptosis is a novel type of inflammatory cell deaths. This study aims to investigate the role and detailed molecular mechanism of cannabinoid receptor 2 (CB2R) in diabetes-induced myocardial necroptosis.
METHODS Type 2 diabetic mouse models were established to assess the expression and location of CB2R in DCM. Specific agonist and antagonist of CB2R and adeno associated virus 9 (AAV9)-delivered expression plasmid of Cb2r were respectively injected into the diabetic mice to investigate effects of CB2R on cardiomyocyte necroptosis. RNA-seq was performed to uncover transcription factors that were recruited by CB2R. Cardiomyocyte-restricted knockout of potential transcription factor was constructed to investigate the signaling mechanism underlying CB2R-modulated cell necroptosis. Western blot, qRT-PCR, co-IP, ChIP, site-specific mutagenesis and luciferase reporter assays were performed to uncover the regulatory mechanism of CB2R in necroptosis.
RESULTS In DCM, CB2R was translocated to plasma and its expression was suppressed which contradicted with the time- and dose-dependent activation of myocardial necroptosis. Re-expression of CB2R by its specific agonist or an AAV9 expression system significantly suppressed cardiomyocyte necroptosis both in vivo and in vitro. Mechanistically, Bach2 was identified as a core transcription factor, which was recruited by CB2R to specific sites on the promoter of necroptosis initiator gene Rip1 and directly inhibited Rip1 transcription. Knockout of Bach2 blunted CB2R-mediated protection against cardiomyocyte necroptosis both in diabetic mice and in the cultured primary cardiomyocytes. Mutation of the binding site of Bach2 on Rip1 promoter also abolished the CB2R-mediated protection against necroptosis in cultured myocardial cells.
CONCLUSIONS CB2R transcriptionally repressed necroptosis in DCM through interaction with Bach2. Upregulation of CB2R or Bach2 represents a promising strategy as to ameliorate the development of DCM.
GW32-e0133
Chan Li, Ruizheng Shi
Xiangya Hospital, Central South University
OBJECTIVES Cellular senescence is a state of stable cell cycle arrest which participates in a variety of physiological and pathological processes, including age-related diseases, cancer, etc. This study aimed to analyze the landscape of investigations related to cellular senescence over the past three decades by machine learning.
METHODS Publications indexed under the Medical Subject Headings (MeSH) term “cellular senescence” from 1990 to 2020 were downloaded from PubMed in January, 2021. Information including publication data, abstract and MeSH terms were extracted by R language for bibliometric analyses. Latent Dirichlet allocation (LDA) was applied to the abstracts for more specific research topics and a topic network was established subsequently using Louvain algorithm.
RESULTS Nineteen thousand and five hundred and sixty four publications were included in this study, most of which were experimental study. USA, China and Germany were the top 3 countries with most publications. Among the MeSH terms of these publications, cell proliferation was the leading theme and telomere shortening has increased rapidly over the past decade. In LDA analyses, research topics were recognized and divided into three clusters, including physiological function, pathological function and molecular mechanism. Topics in the cluster of physiological function accounted for a relatively small proportion of the network.
CONCLUSIONS Publications related to cellular senescence has been increased rapidly in the past 30 years. These studies mainly focus on three areas, among which the pathological function and molecular mechanism are most concerned. Moreover, further studies are demanded to investigate the physiological function of cellular senescence.
GW32-e0275
Zhen Meng, Erli Zhang, Yongjian Wu
State Key Laboratory of Cardiovascular, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Calcific aortic valve stenosis (CAVS) is characterized by inflammation-mediated valvular calcification. Porphyromonas gingivalis, a keystone pathogen for periodontitis, has been associated with chronic inflammatory diseases. The purpose of this study was therefore to test the hypothesis that intravenous inoculation of P. gingivalis can cause the progression of CAVS.
METHODS Firstly, we tested P. gingivalis in human aortic valve tissues by using 16S rRNA gene sequencing and real-time quantitative polymerase chain reactions (qPCR). Secondly, Intravenous or oral inoculation of P. gingivalis in either wild-type (WT) or ApoE deficient (ApoE−/−) mice was performed to build an CAVS model. The animal model was evaluated by von kossa staining and echocardiography. Finally we performed realtime-qPCR and mRNA sequencing on P. gingivalis challenged valvular interstitial cells (VICs) to determine the molecular mechanisms.
RESULTS We found that P. gingivalis was the most significantly enriched bacterial species in aortic valves from CAVS patients compared with controls. Morphometric assays showed predominant P. gingivalis infiltration inside of human aortic valves. Intravenous or oral inoculation of P. gingivalis in either wild-type (WT) or ApoE deficient (ApoE−/−) mice resulted in increased bacterial infiltration in aortic valves, irrespective of chow- or high-fat diet (HFD). Von kossa staining and echocardiographic evaluation further revealed that P. gingivalis bacteremia markedly enhanced valvular calcification, leading to hemodynamically significant aortic stenosis in the murine models. RNA sequencing and qPCR validation showed that the gene expression of IL1B, RUNX2, and BMP2 was upregulated in P. gingivalis-stimulated VICs. Similar changes on IL1B were observed in aortic valves form P. gingivalis-challenged WT and ApoE−/− mice, and in valvular specimens from CAVS patients.
CONCLUSIONS We reported, for the first time, that P. gingivalis infiltration in aortic valves promoted IL-1β-mediated local inflammation and valvular calcification, thus resulting in the progression of CAVS.
GW32-e0441
Zhishan Lin
The Second Affiliated Hospital of Shantou University Medical College
OBJECTIVES To explore whether Notch1-RBP-Jk/Msx2 signaling pathway is involved in the osteogenic differentiation of human vascular smooth muscle cells (hVSMCs) induced by high uric acid.
METHODS hVSMCs were cultured by establishing different gradients of uric acid concentration and time gradients. The optimal time and optimal concentration were confirmed by measuring the markers of osteogenic differentiation, OPN and α-sma. Expressions of the markers of Notch1-RBP-Jk/Msx2 signaling pathway, Notch1 and RBP-Jk, and markers of osteogenic differentiation, OPN and α-sma, were determined by western blot, quantitative real-time polymerase chain reaction and immunohistochemical analysis.
RESULTS (1) The osteogenic differentiation process of hVSMCs was closely related to the concentration of uric acid, and the osteogenic differentiation of hVSMCs was concentration-dependent at different gradient concentrations of uric acid; 0, 300, 600, 900 and 1200 μmol/L in culture for 48 h. However, at 1500 μmol/L concentration uric acid culture, the osteogenic differentiation of hVSMCs decreased. (2) Osteogenic differentiation of hVSMCs was closely related to the culture time of uric acid, and the degree of osteogenic differentiation of hVSMCs was time-dependent under 0, 6, 12, 24, 36, and 48 hours cultures. (3) The expression of Notch1 and RBP-Jk, signaling protein associated with the Notch1-RBP-Jk/Msx2 pathway, were significantly upregulated under a uric acid concentration of 1200 μmol/L incubation for 48 h. This trend was mitigated by DAPT, an inhibitor of this pathway. (4) Osteoblast cells markers OPN expression was significantly upregulated and α-sma expression was decreased in uric acid concentration of 1200 μmol/L for 48 h. This trend was mitigated by the Notch1-RBP-Jk/Msx2 pathway inhibitor DAPT.
CONCLUSIONS Uric acid induced human vascular smooth muscle cells osteoblast differentiation via Notch1-RBP-Jk/Msx2 pathway.
GW32-e0537
Ning Zhang, Xiaojie Xie
Department of Cardiology, The Second Affiliated Hospital Zhejiang University College of Medicine
OBJECTIVES The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing rapidly worldwide, lacking effective therapeutic strategies. Macrophage plays a critical role in the pathogenesis of HFpEF. The C-X-C chemokine receptor 4 (CXCR4) is a regulator of the macrophage-mediated immune response. In this study, we aim to investigate the role and underlying molecular mechanisms of CXCR4-positive macrophages in HFpEF.
METHODS SAUNA (unilateral nephrectomy and a continuous infusion of 0.30 μg/h d-aldosterone through osmotic minipumps and provision of 1% NaCl drinking water) was administrated to wild-type (WT) mice, myeloid-specific CXCR4-deficient (MKO) mice, and adoptive bone marrow transfer mice for 30 days. On the other hand, the in vitro experiments first detected CXCR4-mediated inflammatory cytokines secretion in macrophage. Then we evaluated the paracrine effect from activated macrophages on fibroblasts through co-culturing with macrophages and fibroblasts.
RESULTS We found circulatory CXCR4+ inflammatory cells, mainly monocytes, markedly elevated in HFpEF patients and mice. During the progression of HEpEF, CXCR4 is abundantly expressed in macrophages but not neutrophils infiltrated in the myocardial. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in HEpEF heart tissue, ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, CXCR4 loss in macrophages exhibited a less inflammatory transcriptional signature, dampening the secretion of pro-inflammatory cytokines. Notably, Chemokine (CXC) motif ligand (CXCL3) was identified as one of the top down-regulated genes after CXCR4 ablation, promoting myofibroblast differentiation and cardiac fibrosis in HEpEF mice by interaction with its receptor CXCR2. Further, PPARγ was found to be a critical downstream molecular in CXCR4-mediated pro-inflammatory cytokine secretion of macrophages.
CONCLUSIONS Altogether, macrophage-specific CXCR4 ablation ameliorated cardiac function in HEpEF. Our data supported the possibility of using CXCR4 antagonists or CXCL3 neutralizing antibodies in clinical therapy of HFpEF.
GW32-e0574
Yiming Ding1,2, Yuanming Xing1,2, Chen Wang1,2, Datian Gao2, Yuzhi Jia3, Tao Fu3, Enqi Liu2, Liang Bai1,2, Zuyi Yuan1
1Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, China
2Institute of Cardiovascular Science, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi 710061, China
3Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611
OBJECTIVES Mediator 1 (MED1), a key transcription co-activator subunit of the Mediator complex, serves as a transcriptional nexus by integrating diverse signaling pathways through its interactions with sequence specific transcription factors, transcriptional coactivators, proteins that induce epigenetic alterations and RNA polymerase II. The role of MED1 in cholesterol metabolism and the relevant cardiovascular diseases remains to be investigated.
METHODS To study the molecular mechanism by which MED1 regulates the cholesterol metabolism and the effect on hypercholesterolemia and atherosclerosis, we generated MED1/low-density lipoprotein receptor (LDLR) double-deficient (MED1ΔLiv/ LDLR−/− ) mice and challenged with chow diet or western diet.
RESULTS Normal mice with conditional ablation of MED1 in hepatocytes (LDLR+/+/MED1ΔLiv) did not display obvious abnormalities but became hypercholesterolemic when fed a western diet. LDLR−/− /MED1ΔLiv mice displayed hypercholesterolemia and atherosclerosis that was significantly more severe than in LDLR−/− mice, even when the animals were maintained on a chow diet. The hypercholesterolemia observed in MED1ΔLiv mice is caused by a defect in the removal of LDL from circulation. MED1ΔLiv mice had a marked decrease in the hepatic expression of the LDL-binding low-density lipoprotein receptor-related protein 6 (LRP6).
CONCLUSIONS Our data indicate that the augmented hypercholesterolemia and atherosclerosis observed in LDLR−/− /MED1ΔLiv mice is caused by a defect in the removal of LDL from circulation, superimposed on the LDL-removal defect caused by the absence of LDL receptors. We suggest that the MED1ΔLiv-related hypercholesterolemia is caused by the down-regulation of LRP6 in the liver.
GW32-e0845
Kun Zhao, Yong Li, Peng Li
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
OBJECTIVES Epidemiological studies reported that high-salt intake can lead to chronic comorbidities such as hypertension. Evidence also implied that high salt diet (HSD) may adversely impact the vascular wall—regardless of blood pressure. The present study was to explore whether HSD could cause cardiac fibrosis regardless of blood pressure in rats, and to determine the effects of microRNA (miR)-210-5p on sodium chloride (NaCl)-induced fibrosis in neonatal rat cardiac fibroblasts (NRCFs) and its target.
METHODS The rats received 8% HSD, and NRCFs were treated with NaCl in vitro. The levels of cardiac fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods.
RESULTS The levels of collagen I, alpha smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) were increased in the heart of hypertension (HTN), hypertension-prone (HP) and hypertension-resistant (HR) rats on HSD. NaCl increased the levels of collagen I, α-SMA and TGF-β in NRCFs. The level of miR-210-5p was reduced in NaCl-treated NRCFs by miR high-throughput sequencing. The NaCl-induced increases of collagen I, α-SMA and TGF-β were inhibited by miR-210-5p agomiR in vitro and in vivo, and further enhanced by miR-210-5p antagomiR. Bioinformatics analysis and luciferase reporter assays demonstrated that TGF-β type I receptor (TGFβRI) was a direct target gene of miR-210-5p.
CONCLUSIONS These results indicated that HSD resulted in cardiac fibrosis regardless of blood pressure. The upregulation of miR-210-5p could attenuate NRCF fibrosis via targeting TGFβRI. Thus, upregulating miR-210-5p to inhibit TGF-β signaling pathway might be a strategy for the treatment of cardiac fibrosis.
GW32-e0896
Haoran Xin1, Fang Deng2, XiaoGen Ma1, Min-Dian Li1, Zhihui Zhang1
1Southwest Hospital, Army Medical University
2Army Medical University
OBJECTIVES Liver circadian clock regulates lipid homeostasis through epigenetic and transcriptional mechanisms, which limits the occurrence and development of metabolic cardiovascular diseases. Circular RNA (circRNA) is a novel epigenetic mechanism affecting organ homeostasis and metabolism in recent years. However, the role of circRNA in regulating circadian clock remains unclear. We screen circRNA and its enrichment pathway from circRNA group of nutrition-rhythm disturbance liver. So as to further study the mechanism of circRNA regulating circadian clock and lipid homeostasis.
METHODS Eight-week-old female C57/B6J mice were subjected to time-restricted feeding (DRF for daytime-restricted, NRF for nighttime-restricted) for 7 days. The mice in DRF group fed during the day received food from 9 A.M. to 9 P.M., whereas mice in NF group fed during the night received food from 9 P.M. to 9 A.M. Livers were dissected every 4 hours across the 24 h (n=4 per time point, per group), and subjected to long non-coding. Rhythmicity was determined by MetaCycle with meta2d FDR of 0.05. Oscillating circRNAs were further analyzed and visualized in R.
RESULTS From 13,132 detected circRNAs in liver, we find 79 circRNAs oscillate in a circadian manner in at least one feeding condition and DRF induced 5-fold more de novo oscillation of circRNAs than NRF. In addition, the de novo oscillation of RNA splicing genes may contribute, at least partially, to de novo oscillation of circRNAs in liver. Oscillating circRNAs may function as sponges of miRNAs or origins of regulatory peptides.
CONCLUSIONS DRF induced more de novo oscillation of circRNAs than NRF. DRF-induced de novo oscillating circRNAs may derive from de novo oscillation of RNA splicing genes and gain potential functions such as sponges of miRNAs or origins of regulatory peptides. These results provide an impetus for further investigating the roles of circRNAs in circadian clock.
GW32-e0988
Haozheng Yu1, Mujun Yu2, Wenhua Jiang3, Zihui Zhang3, Chan Zhang3, Heng Ma4
1Shaanxi University of Chinese Medicine
2Yan’an University
3Northweastern Polytechnical University
4Fourth Military Medical University
OBJECTIVES Irisin, mainly secreted by muscles after exercise training, is closely related to metabolic diseases and cardiovascular diseases. However, whether irisin can inhibit the ferroptosis in myocardial ischemia/reperfusion (MI/R) is still unknown. The present study aims to investigate whether irisin could protect against MI/R induced ferroptosis in mice.
METHODS Eighty healthy male C57 mice aged 5 weeks were randomly divided into a normal control group (40 mice) and an exercise training group (40 mice). After the exercise training, the two groups of mice were further divided into sham group and MI/R group (20 in each group). The in vivo mouse models of myocardial I/R injury were used. After 30 min ischemia and 24 h reperfusion period, heart tissues were excised. The levels of irisin in serum and tissues of each group, the expression of iron death-related signals, and the area of myocardial infarction were measured. Myocardial function was also evaluated. In cytology experiments, in vitro hypoxia/reoxygenation (H/R) injury model for H9C2 cardiomyocytes with irisin treatment were used to detect the expression of ferroptosis-related signals.
RESULTS The ferroptosis inhibitor ferrostatin-1 (Fer-1) can significantly reduce the MI/R myocardial infarction area and decrease the levels of cardiac Ptgs2 mRNA and MDA, suggesting that myocardial ferroptosis is involved in MI/R injury. Compared with the control group, aerobic exercise training can effectively increase the level of irisin in skeletal muscle and myocardium (P<0.05). In addition, the degree of myocardial ferroptosis in the exercise MI/R group was significantly inhibited, manifested as myocardial Ptgs2mRNA, MDA and lipid peroxidation were significantly reduced (P<0.05), while cardiac function was significantly improved (P<0.05). Exogenous supplementation of irisin can effectively increase the level of GPX4 in MI/R myocardium, inhibit myocardial ferroptosis, and reduce the area of myocardial infarction (P<0.05). Cytological experiments found that irisin induced ferroptosis inhibition was effectively blocked by knockdown of integrin aV/b5 receptor using siRNA.
CONCLUSIONS Irisin inhibits MI/R myocardial ferroptosis through the integrin aV/b5-GPX4 signaling pathway. Aerobic exercise training can achieve cardioprotection by increasing the level of endogenous irisin.
GW32-e1061
Xiaobo Yao, Yunli Shen, Qizheng Lu
Shanghai East Hospital
OBJECTIVES Recently, superparamagnetic iron oxide nanoparticles (SPION) as target carriers are widely used in the cardiovascular field. However, SPION may increase a risk of ferroptosis of hypoxia/reoxygenation cells, which is a serious obstacle for clinical transformation. In this study, we explored the underlying cytotoxic mechanisms of SPION and whether the mitochondrial targeted antioxidant SS-31 loaded on magnetic nanoparticles can improve the cardiotoxicity of SPION.
METHODS SS-31 was chemically loaded onto SPION. H9c2 hypoxia/reoxygenation cardiomyocyte model was incubated with SPION orSS-31 loaded SPION (SPION@SS-31) for 24 hours. To explore the main molecular mechanism of SPION cytotoxicity, ferroptosis inhibitor ferritin-1, autophagy inhibitor 3-MA, necrosis inhibitor Nec-1 and apoptosis inhibitor ZVAD were co-incubated with SPION for 24 hours. Non heme iron content of cytoplasm and mitochondria was detected by inductively coupled plasma mass spectrometry (ICP-MS). The mitochondrial ROS levels and the mitochondrial membrane potential (MMP) was measured by Mito-Sox and JC-1. The lipid peroxidation products (MDA), cytoplasm ATP, ferroptosis markers (GSH, GPX4) were detected by ELASA and biochemical methods. The inhibition of cell proliferation was analyzed by CCK-8.
RESULTS The results demonstrated that SPION not only induced mitochondrial iron overload (P<0.0001), which in turn caused mitochondrial membrane potential (MMP) loss (P<0.001) and mitochondrial oxidative stress (P<0.0001), but also provoked downregulation of GSH (P<0.001) and GPX4 (P<0.0001) expression and upregulation of lipid peroxidation products (MDA) (P<0.001), eventually leading to ferroptosis of cardiomyocytes. Interestingly, SS-31 mitigated SIONP-induced ferroptosis evidenced by reduced production of MDA (P<0.001) and maintained concentration of GSH (P<0.001) and GPX4 (P<0.0001), indicating that SS-31 has a potential to reverse SIONP-induced ferroptosis by exerting a mitochondrial targeted antioxidant effect. Furthermore, the cell viability of H9c2 cells incubated with SPION could be significantly reversed after treatment with ferroptosis inhibitor ferritin-1 (P<0.05), but couldn’t be neutralized by inhibitors of apoptosis, autophagy or necrosis respectively, indicating that ferroptosis may be main mechanism of SPION cytotoxicity.
CONCLUSIONS Mitochondria play a crucial role in SPION-induced ferroptosis. Iron over-loaded along with lipid peroxidation in mitochondria may be the main mechanism of SPION-induced ferroptosis. SS-31 loading has a potential to reverse SIONP-induced ferroptosis of hypoxia/reoxygenation cardiomyocytes, suggesting that co-loading mitochondrial targeted antioxidants may be a novel strategy to improve the myocardial toxicity of SPION.
GW32-e1156
Lu Huang1, Jiahua Hou1, Zengmei Hu1, Yu Wang1, Wangxiao Tan1,2, Xiaoying Wang1
1Tianjin University of Traditional Chinese Medicine, Tianjin, China
2GeneNet Pharmaceuticals Co. Ltd., Tianjin, China
OBJECTIVES Atherosclerosis is characterized by disordered lipid metabolism and inflammatory injury, the primary step of which is endothelial dysfunction. Berberine (BBR) is the main active component of the Chinese medicine Coptidis Rhizoma (Huanglian), which has been shown to have anti-atherosclerotic effects. In our previous study, we found that BBR could restore aortic endothelium-dependent vasodilatation in vivo and in vitro, thus ameliorating endothelial dysfunction and protecting against atherosclerosis. However, the specific mechanism of BBR improving endothelial function needs to be further explored. Thus, we investigated the effects of BBR improves endothelial function via PI3K/Akt/eNOS pathway in apolipoprotein E-deficient (ApoE−/− ) mice.
METHODS In vitro, the aortic rings isolated from wild-type (WT) C57BL/6J mice and ApoE−/− mice were incubated with BBR (10−6 mol/L) in the present of LY294002 (PI3K inhibitor) or L-NAME (eNOS inhibitor) or not to explore the mechanism of BBR improving endothelium-dependent vasodilatation. In vivo, ApoE−/− mice fed with western-type diet were randomly divided into three groups: the vehicle group (ApoE−/−, saline), the atorvastatin group (2.6 mg/Kg) and the BBR group (156 mg/Kg). The WT mice fed with normal chow diet were used as the control group (WT, saline). After 12 weeks of administration, the expression of inflammatory factors and PI3K, Akt, eNOS mRNA in mice aortic tissues were determined by RT-PCR.
RESULTS The aortic ring assay showed that BBR could restore ApoE−/− mice aortic endothelium-dependent vasodilatation, while PI3K inhibitor LY294002 and eNOS inhibitor L-NAME blocked BBR induced vasodilatation. Furthermore, the PI3K and eNOS mRNA expression were significantly down-regulated in ApoE−/− mice aorta compared with WT mice, and BBR significantly up-regulated the expression of PI3K and eNOS mRNA after 12 weeks of administration. However, there was no significant change of Akt mRNA expression in ApoE−/− mice, but BBR had a tendency to up-regulated the expression of Akt mRNA. The mRNA expressions of inflammatory factors ICAM-1 and VCAM-1 were up-regulated significantly in ApoE−/− mice. BBR down-regulated VCAM-1 mRNA expression significantly, but down-regulated ICAM-1 mRNA expression without significant difference.
CONCLUSIONS BBR can improve endothelial function through PI3K/Akt/eNOS signaling pathway and attenuate inflammation.
GW32-e1244
Mengwen Wang, Xiaodan Zhong, Hongjie Wang, Hesong Zeng
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
OBJECTIVES Previous studies showed Inhibiting immunoproteasome activity could reduce inflammation and ameliorate the progression of metabolic disorders. However, whether immunoproteasome is involved in the development of diabetic cardiomyopathy is still unclear. The aim of this study is to demonstrate that inhibiting immunoproteasome subunit LMP7 can alleviate diabetic cardiomyopathy.
METHODS Diabetic mice were induced by streptozotocin (STZ) at 60 mg/kg on 5 successive days in 8-week-old wild type C57BL/6 mice and confirmed by blood glucose. Cardiac function was measured by echocardiogram examination and hemodynamic measurement. Hematoxylin-eosin staining, and wheat germ agglutinin were used to detect cardiac histopathological changes. LMP7 expression levels was measured by immunohistochemistry and western blot. ONX0914 (10 mg/kg), a small molecule inhibitor of LMP7, was injected to diabetic mice every two days for 6 weeks to evaluate therapeutic effect. The protein levels of NLRP3, IL1β and IL18 was measured by immunoblotting to reflect inflammation status. High glucose challenged H9c2 cells were used to further confirmed the protective effect of ONX0914.
RESULTS Blood glucose levels in STZ-induced mice were obviously elevated compared to controls. Immunohistochemistry and western blot results showed the expression level of LMP7 was increased in diabetic mice heart. ONX0914 improved cardiac function and alleviated myocardial hypertrophy in diabetic mice reflected by increased ejection fraction, fraction shortening and maintaining normal size of cardiomyocytes. Besides, the protein levels of collagen1, α-SMA and TGF-β were all reduced by ONX0914 treatment. NLRP3 inflammasome was elevated in diabetic mice, as well as cleaved caspase1, IL1β and IL18. After ONX0914 treatment, NLRP3 inflammasome expression level was decreased, and the protein levels of inflammatory factors (IL1β, IL18) were also reduced. In H9c2 cells, we also observed that high glucose could increase LMP7 expression, while ONX0914 could reduce it. In addition, ONX0914 could inhibit NLRP3 inflammasome activation, then decreased the expression levels of IL1β and IL18 in H9c2 cells.
CONCLUSIONS Our study demonstrated immunoproteasome was dysregulated in diabetic cardiomyopathy with highly expressed LMP7. This was correlated with reduced cardiac function and myocardial hypertrophy. Inhibition of LMP7 with ONX0914 could ameliorate diabetic cardiomyopathy. The protection effect of ONX0914 was at least in part via inhibiting NLRP3 inflammasome activation and reducing the maturation and secretion of inflammatory factor. Therefore, LMP7 may be a potential therapeutic target for the treatment of diabetic cardiomyopathy.
GW32-e1331
Yizhou Feng1,2,3, Yuan Yuan1,2,3, Zhefu Hu4, Hongxia Xia1,2,3, Haiming Wu1,2,3, Xiaofeng Zeng1,2,3, Shasha Wang1,2,3, Qizhu Tang1,2,3
1Department of Cardiology, Renmin Hospital of Wuhan University
2Cardiovascular Research Institute of Wuhan University
3Hubei Key Laboratory of Metabolic and Chronic Diseases
4Department of Intensive Care Unit, Renmin Hospital of Wuhan University
OBJECTIVES Trillium tschonoskii maxim (TTM), a traditional Chinese medicine, has been reported to possess anti-inflammatory and antioxidant activities, but the effect of TTM saponin (major bioactive component in TTM) on pressure overload-induced cardiac remodeling remains inconclusive. In this study, we investigated the effect of TTM saponin on cardiac remodeling in in vivo and in vitro models, and to clarify the underlying mechanisms.
METHODS C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with TTM saponin (20 mg/kg, ig) three times a week (1 week in advance and continued until the end of the experiment). Four weeks after TAC surgery, the mice were subjected to echocardiography, and then sacrificed to harvest the hearts for analysis. For in vitro study, neonatal rat cardiomyocytes and cardiac fibroblasts were used to validate the protective effects of TTM saponin in response to phenylephrine (PE) and transforming growth factor-β (TGF-β) challenge.
RESULTS We showed that TTM saponin administration protected against pressure overload-induced cardiac hypertrophy, fibrosis, inflammation, and dysfunction in TAC mice. In the in vitro study, we showed that treatment with TTM saponin (20 μM) blocked PE-induced-cardiomyocyte hypertrophy and TGF-β-induced cardiac fibroblast activation. Furthermore, TTM saponin treatment significantly decreased mitogen-activated protein kinase p38 (p38) phosphorylation in response to pressure overload in vivo and extracellular stimuli in vitro, which was upregulated in the absence of TTM saponin treatment. Moreover, transfection with mitogen-activated protein kinase 6 expressing adenoviruses (Ad-MKK6), which specifically activated p38, abolished the protective effects of TTM saponin in both in vitro and in vivo models.
CONCLUSIONS TTM saponin improves cardiac function and alleviates cardiac remodeling induced by pressure overload in a p38-dependent manner, and provide a reference for the development and utilization of natural products in the intervention of pathological cardiac remodeling.
GW32-e1527
Yuan Fang, Shu-Lin Wu, Fang Rao
广东省心血管病研究所, 广东省人民医院 (Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital)
OBJECTIVES To investigate the role and possible mechanism of mechanosensitive ion channel Piezo1 in regulating electrical remodeling of atrial myocytes induced by hypertension and leading to atrial fibrillation.
METHODS Spontaneously hypertensive rats (SHR) aged 30–32 weeks were treated with or without valsartan (30 mg/kg/d). Wistar rats were used as control. Rapid atrial pacing was used to observe the atrial fibrillation inducibility. Western blot was used to detect the protein expression of Piezo1, Src and Cav1.2 in atrial appendages of rats and in atrial myocytes (HL-1 cells) exposed to different levels of high hydrostatic pressure (20 and 40 mmHg), Piezo1 inhibitor (GsmTx4) and agonist (Yoda1) in vitro. L-type calcium current (ICa,L) and action potential duration (APD) of atrial myocytes were detected by whole-cell patch clamp technique.
RESULTS Compared with Wistar rats, the protein expression of Piezo1 and Src was significantly increased, the expression of Cav1.2 was decreased (P<0.05), AF inducibility was significantly higher in SHR (P<0.01) while the above changes could be reversed in SHR treated with valsartan (P<0.05). Higher hydrostatic pressure (40 mmHg) could increase the expression of Piezo1 and Src in HL-1 cells (P<0.05), accompanied by a shortened APD and a decrease in ICa,L and Cav1.2 proteins (P<0.05). GsmTx4 could significantly reverse the above changes. In addition, Piezo1 agonist Yoda1 can simulate the changes of electrical remodeling and related signal molecules in atrial myocytes induced by the high hydrostatic pressure.
CONCLUSIONS Mechanosensitive ion channel Piezo1/Src kinase signaling pathway is activated during hypertension, leading to the decrease of ICa,L, the shortened APD and the electrical remodeling of atrial myocytes.
GW32-e1640
Cuimei Hu, Chunyu Zeng
Daping Hospital, The Third Military Medical University
OBJECTIVES To determine if paternal exposure to PM2.5 programs offspring hypertension.
METHODS Male Sprague-Dawley rats (SD) were divided into control group and PM2.5 group according to the absence or presence of PM2.5 treatment, male rats were mated with normal SD female rats, and two groups of offspring were obtained, respectively. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of G-protein–coupled receptor kinase type 4 (GRK4) and angiotensin type 1 receptor (AT1R) were determined by Real-time (RT) quantitative PCR and immunoblotting. Renal malondialdehyde and superoxide dismutase levels were also measured in the offspring. To confirm the role of ROS in the paternal PM2.5 exposure-induced hypertension in the offspring, a SOD mimetic tempol, as an antioxidant, was administered in combination with fine particulate matter to paternal rats.
RESULTS It revealed that paternal exposure to PM2.5 significantly increased hypertension and decreased 24-hour urine volumes and sodium excretions in offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposured paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol, an antioxidant, in paternal rats for 4 months restored the increased blood pressure and decreased sodium excretion in the offspring of PM2.5-exposured paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring.
CONCLUSIONS Our present study verified that paternal PM2.5 exposure causes hypertension in the male offspring. The mechanism may be involved that PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in the male offspring.
GW32-e1707
Wenxu Pan, Ying Wang, Guiquan Zhou, Meiling Hu, Gaoshan Li, Jun Jin
Department of Cardiology Xinqiao Hospital, Army Medical University
OBJECTIVES Many studies have shown that coenzyme Q10 (CoQ10) protects against cardiac damage from myocardial infarction (MI). Macrophage mediated inflammation plays a critical role in determining the prognosis post MI. However, the effect of CoQ10 on macrophage and its potential role in MI prognosis remains unknown. This study sought to determine whether CoQ10 has an impact on macrophage mediated inflammatory response and thereby improves the prognosis of heart post-MI.
METHODS The patients with acute myocardial infarction (AMI) and healthy volunteers were randomly enrolled with age and gender matched, and randomly assigned into either CoQ10 (30 mg/day) or placebo groups. The plasma of participants was obtained at both pre- and 1-month post-treatment to determine the CoQ10 levels by LC-MS/MS, and plasma concentration of inflammatory cytokines were determined by Bio-Plex suspension chip. MI in C57BL6/J male mice (8–12-week-old) was induced by permanent ligation of left anterior descending artery (LAD). All the mice were randomly assigned to MI or sham groups and treated with either CoQ10 (600 mg/kg/day) or coin oil (isotype control) by oral gavage for four weeks. Echocardiography was applied weekly to evaluate the cardiac function. Triphenyl tetrazolium chloride (TTC) and immunohistochemical staining were used to assess the myocardial infarction area and myocardial fibrosis. Flow cytometry was employed to analyze the recruitment of immune cells into heart tissue. RNA sequence was performed on sorted cardiac macrophages of mice at 3-day post-MI either treated with CoQ10 or isotype control.
RESULTS We found that CoQ10 level was significantly lower in AMI patients compared to healthy controls at baseline, and CoQ10 plasma level was robustly elevated at 1-month post CoQ10 treatment. Of note, Bio-Plex suspension chip analysis showed that CoQ10 treatment notably reduced the plasma expression of inflammation related genes (IL6, IL8 etc.). Experimental study showed that CoQ10 treatment attenuated myocardial infarction injury and cardiac remodeling, as demonstrated by significant reduction in infarction size, decrease in myocardial fibrosis, and restoration of cardiac function. Consequently, the survival rate of CoQ10-treated mice was significantly higher than that of control mice at 14-day post-MI. Mechanistically, flow cytometrical analysis showed that CoQ10 treatment suppressed recruitment of inflammatory neutrophils and macrophages into infarct myocardium at 3-day post MI. Specifically, bone marrow derived inflammatory macrophage subtype (MHCII+CCR2+) was significantly suppressed by CoQ10. RNA sequence on sorted cardiac macrophages showed that innate immune response related genes and oxidative stress related genes were downregulated by CoQ10 treatment.
CONCLUSIONS Plasma level of CoQ10 in AMI patients was significantly decreased compared to healthy controls, and CoQ10 could significantly downregulate the plasma expression of inflammation related genes. CoQ10 could significantly improve survival rate and attenuate cardiac remodeling after MI in mice partially by regulating oxidative stress response in macrophages and its downstream inflammatory response.
GW32-e1803
Shuwan Xu, Jun Wan
Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology
OBJECTIVES Cardiac hypertrophy is associated with the imbalance between excessive sympathetic activity and weak parasympathetic control. Pyridostigmine (PYR), a reversible acetylcholinesterase inhibitor, can exert toxicine-like (M) and nicotinic (N) cholinergic receptor excitatory effects. However, whether PYR play a beneficial role in the progression of pathological cardiac hypertrophy remains not clear. This study was designed to explore the effect of PYR on cardiac hypertrophy and the possible mechanism in animal model.
METHODS Cardiac hypertrophy was induced by transverse aortic constriction (TAC) and angiotensin II, respectively. Echocardiography, Western blotting, quantitative real-time-PCR, and histological analysis were used to evaluate cardiac function, oxidative stress, fibrosis and inflammation.
RESULTS Compared with Ang II or TAC group, the PYR-treated group showed improved cardiac function, alleviated fibrosis and oxidative stress in the myocardial tissues. Pyridostigmine attenuated cardiac hypertrophy illustrated by significantly reduce of heart weight/body weight, cardiomyocyte cross-sectional area and mRNA expression of hypertrophic markers. Obvious interstitial fibrosis in the mice subjected to Ang II administration or TAC surgery was observed, and this impairment was attenuated by PYR treatment. Besides, the levels of oxidative stress and inflammation in the myocardial tissues were also significantly alleviated. In terms of the underlying mechanism, inflammation and oxidative stress were down-regulated after PYR treatment and NF-κB signaling pathways were involved according to the results.
CONCLUSIONS Pyridostigmine can prevent the progression of cardiac hypertrophy and improve cardiac function via reducing inflammation and attenuating oxidative stress. These findings suggest that pyridostigmine may be a potential therapeutic drug for cardiac hypertrophy and fibrosis.
GW32-e1874
Peng An, Qizhu Tang
Renmin Hospital of Wuhan University
OBJECTIVES To investigate the effect and mechanism of BMP9 on Doxorubicin-induced myocardial cardiotoxicity in mice.
METHODS DOX was intraperitoneally injected to induce cardiotoxicity in adult male C57/BL6 mice, and rhBMP9 was administered to detect the effects of BMP9 on cardiotoxicity and cardiac function. PGC1α-cKO mice were used to clarify the crucial role of PGC1α in the treatment of DOX-induced cardiotoxicity by rhBMP9. In order to prove that ALK1 is necessary for BMP9, C57/BL6 mice received AAV9 carrying shALK1 via myocardial injection. We performed cell experiments with Neonatal rat cardiac myocytes (CMs) and cardiac fibroblasts (CFs). To notify the paracrine interplay between CMs and CFs, CMs were incubated with the supernatant from CFs, then cells were treated with DOX while receiving BMP9 neutralizing antibody. Similar to animal experiments, CMs were transfected with shPGC1α or shALK1 to testify the pivotal role of PGC1α and ALK1. The echocardiography and hemodynamic evaluation of mice in each group were detected. TUNEL staining was used to detect cardiomyocyte apoptosis, DHE staining and ELISA were performed to detect the level of oxidative stress. Molecular changes of oxidative stress/apoptosis markers and signaling pathways were detected by RT-PCR and western blotting.
RESULTS We found that BMP9 expression was down-regulated in DOX-treated murine hearts and cardiacfibroblasts, and rhBMP9 treatment attenuated DOX-induced cardiac oxidative stress and apoptosis, then improve cardiac function. Pretreatment of CFs supernatant attenuated DOX-induced CMs apoptosis and oxidative, which eliminated after the addition of BMP9 neutralizing antibody. Mechanistically, we identified that BMP9 activated PGC1α/Nrf1 signaling to decreased DOX-induced cardiotoxicity. Cotreatment of rhBMP9 up-regulated the PGC1α and its downstream signaling (Nrf1, UCP2 and TFAM) expression compared with DOX group. Similarly, the levels of PGC1α, Nrf1, UCP2 and TFAM were decreased in cardiomyocytes exposed to DOX, and were rescued in rhBMP9 co-treatment group. Further study found that PGC1α knockout or silencing counteracted the therapeutic effect of rhBMP9. Meanwhile, shALK1 completely eliminated the effect of rhBMP9 on alleviating cardiotoxicity in vivo and in vitro.
CONCLUSIONS BMP9 secreted by cardiacfibroblasts activated PGC1α by binding to cardiomyocyte ALK1 receptor, then up-regulate downstream Nrf1 gene expression, so as to reduce ROS production and cardiomyocyte apoptosis, ultimately alleviate DOX-induced cardiotoxicity and improve cardiac function.
GW32-e0062
Shuai Zhao, Chenxiang Li, Kun Lian
Department of Cardiology, Xijing Hospital, The Air Force Medical University
OBJECTIVES Studies have reported that elevated plasma branched-chain amino acids (BCAA) level was associated with the increased risk of cardiovascular diseases (CVD). However, it still remains largely unknown whether elevated plasma BCAA level is causally related to atherosclerosis (AS), which is the main pathogenesis of CVD, as well as the mechanism involved.
METHODS The plasma BCAA level of 258 atherosclerotic cardiovascular disease (ASCVD) patients and 188 normal people was measured. They were divided into two groups based on median and logistic regression analysis was performed. Next, we changed plasma BCAA level of AS mice and plaque volume, stability and inflammation were evaluated. Then, we assayed BCAA level, catabolism-promoting genes and inflammation in the abdominal macrophages of AS mice and circulating monocytes of ASCVD patients. Next, inflammatory response, macrophage polarization, glycolysis capacity and pyruvate dehydrogenase complex (PDH) activity were detected in BCAA catabolic deficient RAW 264.7 cells by knocking down BCKDHA (BCKDHAKD). Finally, we upregulated PDH activity of BCKDHAKD RAW 264.7 cells by knocking down pyruvate dehydrogenase kinase-1 (PDK-1) to detect the effect of inhibiting glycolysis on macrophage polarization.
RESULTS First, we found that plasma BCAA level was an independent risk factor of ASCVD (OR: 4.115; 95% CI: 2.075–8.161; P<0.01). Second, we also found elevated plasma BCAA level in AS mice, which led to the increase of plaque volume and instability, as well as inflammation. The growth of plaque instability was characterized by increased macrophage amounts and decreased smooth muscle cells (SMCs) and collagen contents. Conversely, when plasma BCAA level was lowered, the above phenomena could be reversed. Third, elevated plasma BCAA level resulting from BCAA catabolic defect occurred in abdominal macrophages of AS mice and monocytes of ASCVD patients, which increased inflammatory response by promoting the polarization of macrophages toward M1 phenotype. Fourth, elevated plasma BCAA level promoted the expression of PDK-1, which inhibited PDH activity. This resulted in the increase of glycolysis, leading to the polarization of RAW 264.7 cells toward M1 phenotype. Finally, the improvement of BCAA catabolism of macrophages alleviated AS progression in mice.
CONCLUSIONS Our data demonstrates that elevated plasma BCAA level is an independent risk factor of ASCVD and promotes AS progression, indicating that plasma BCAA level might be a therapeutic target for ASCVD.
GW32-e0137
Huan Sun, Yi Gao, Ping Yang
China Japan Union Hospital of Jilin University
OBJECTIVES Myocardial hypertrophy is an important process of myocardial remodeling, which is the pathological basis of many cardiovascular diseases. Pimobendan, a combination of a phosphodiesterase 3 (PDE3) inhibitor and a calcium sensitization agent, has been widely used in heart failure, but its effect on myocardial hypertrophy remains controversial. This study aims to evaluate the therapeutic effect of pimobendan on myocardial hypertrophy induced by stress-overload in mice and phenylepenephrine (PE) induced cardiomyocyte hypertrophy, and to explore its potential mechanism.
METHODS Myocardial hypertrophy model was established by transverse aortic constriction (TAC) in C57BL/6 mice, oral pimobendan (1 mg/kg/d) or vehicle drugs were given after the operation. Four weeks after operation, cardiac ultrasound, hemodynamic examination, histology, myocardial hypertrophy marker detection and RNA sequencing were performed, and western blot was used to verify the key proteins of the MAPK pathway that was significantly changed in RNA sequencing.
RESULTS The treatment of pimobendan significantly reduced TAC-induced myocardial hypertrophy. It manifested as decreased heart/body ratio, heart weight/tibia length ratio, ventricular wall thickness, myocardial fibrosis, area of myocardial cells, relative expression of myocardial hypertrophy markers, and ventricular pressure, while it showed no effect on heart function. RNA sequencing showed that gene transcription of HIF-1 pathway, MAPK pathway and apoptosis pathway were regulated by pimobendan. Among them, the changes of MAPK pathway were significant. Western-blot showed that pimobendan can reduce the phosphorylation of key proteins in the MAPK pathway, PI3K-AKT pathway, and calcineurin signaling pathway.
CONCLUSIONS Pimobendan may attenuates myocardial hypertrophy through the MAPK pathway.
GW32-e0289
Xiaoxiang Tian, Lianqi He, Chenghui Yan, Yaling Han
Department of Cardiology, General Hospital of Northern Theater Command
OBJECTIVES Skeletal muscle can be repaired by regeneration in response to various acute and chronic injuries, thus skeletal muscle regeneration is essential for maintaining skeletal muscle homeostasis. However, the molecular mechanism of skeletal muscle regeneration has not yet been elucidated. CREG is a recently discovered secreted small molecule glycoprotein that plays a key role in regulating cardiomyocyte differentiation. However, whether CREG regulates skeletal muscle regeneration has not been reported. Therefore, this study aimed to investigate the role and mechanism of CREG in skeletal muscle regeneration.
METHODS The regeneration model of skeletal muscle injury was established by injecting cardiac toxin (CTX) into mouse skeletal muscle. Quantitative PCR, Western blot and immunohistochemical staining were used to detect CREG, myogenic regulatory factors (Myf5, MyoD, Myogenin) and skeletal muscle marker MyHC. Mouse myoblast C2C12 was induced to differentiate into myotubes in vitro using 2% horse serum. Cell differentiation was evaluated by using a creatine kinase activity ELISA kit, and cell proliferation was evaluated by using a BrdU kit. Overexpression or knock down of CREG was performed by either adenovirus infection or RNA interference respectively. Immunoprecipitation and mass spectrometry was used to determine protein interacting with CREG.
RESULTS In vivo, expression of CREG, myogenic regulatory factors and MyHC were significantly increased during skeletal muscle regeneration. In vitro, CREG was increased during C2C12 differentiation in a time dependent manner. CREG over-expression promoted C2C12 cell differentiation, while CREG knock down inhibited C2C12 cell differentiation, with no apparent effect on cell proliferation. Immunoprecipitation and mass spectrometry revealed that CREG interacted with c-Cbl. Western Blot showed that the expression of c-Cbl was decreased after overexpression of CREG, and increased after knock down of CREG. Over-expression of c-Cbl abrogated the accelerated C2C12 differentiation induced by CREG over-expression, while interference with c-Cbl expression rescued the retarded differentiation of C2C12 cells induced by CREG knock down.
CONCLUSIONS CREG promotes skeletal muscle cell regeneration by inhibiting c-Cbl, which may provide a new target for the treatment of skeletal muscle regeneration disorder.
GW32-e0513
Rongrong Wu1, Wangxing Hu1, Huan Chen2, Yingchao Wang1, Qingju Li1, Jinghai Chen1, Jianyi Zhang3, Xinyang Hu1, Jian’an Wang1
1The Second Affiliated Hospital Zhejiang University College of Medicine
2Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province
3Department of Biomedical Engineering, University of Alabama at Birmingham
OBJECTIVES Angiogenesis is essential for tissue development and homeostasis. Enhancing angiogenesis is regarded as an important therapeutic target for the salvage of stressed myocardium to reduce adverse remodeling and preserve cardiac function by restoring sufficient blood supply to the heart. However, the roles of regulatory long noncoding RNAs (lncRNAs) in mediating angiogenesis remain under-explored. Pursuant to our observations that cardiac ischemia is preferably rescued by human embryonic stem cell-derived mesenchymal stem cells (hES-MSCs) through enhanced neovascularization compared with MSCs from human bone marrow (hBM-MSCs), we use hES-MSCs as a model to search for novel and functionally important proangiogenic lncRNAs, and investigate their biological roles and prevalence in human cardiovascular tissues.
METHODS Highly enriched lncRNAs in hES-MSCs were searched by RNA sequencing compared to hBM-MSCs. Molecular mechanisms were investigated by RNA sequencing, RNA pull-down and immunoprecipitation, mass spectrometry, several loss- and gain-of-function approaches, chromatin immunoprecipitation and luciferase assays in hES-MSCs. Human endothelial cells, and aorta tissues from dilated cardiomyopathy (DCM) patients were studied for lncRNA expression and function. Left ventricular (LV) tissues from DCM patients were studied for the involvement of lncRNAs in the compensatory vascularization/angiogenesis.
RESULTS We described a previously unannotated lncRNA AC103746.1, here termed SCDAL, as one of most highly expressed intergenic lncRNAs in hES-MSCs. SCDAL knockdown significantly impaired proangiogenic potential and myocardial reparative functions of hES-MSCs, while elevated expression of SCDAL in either hES-MSCs or hBM-MSCs exhibited augmented angiogenesis and cardiac function recovery. Mechanistically, SCDAL functionally interacted with and recruited a chromatin-remodeling protein SNF5 [the core subunit of SWItch/Sucrose NonFermentable (SWI/SNF) adenosine triphosphate (ATP)-dependent chromatin-remodeling complexes] to the growth differentiation factor 6 (GDF6) promoter, thereby initiating GDF6 expression. GDF6 secretion from hES-MSCs promoted endothelial angiogenesis by triggering non-canonical vascular endothelial growth factor receptor 2 (VEGFR2) activation and downstream Akt/endothelial nitric synthase (eNOS) signaling. Furthermore, we found that SCDAL was also expressed in human endothelial cells. SCDAL overexpression directly enhanced endothelial angiogenic function via up-regulating GDF6, indicating the biological prevalence of SCDAL-GDF6 function in mediating proangiogenesis/angiogenesis.
CONCLUSIONS We uncover a novel lncRNA-involved regulatory mechanism for proangiogenesis/angiogenesis. Our findings support further research into the therapeutic potential of the SCDAL-GDF6 pathway for ischemic cardiovascular diseases. The insights obtained from this study further advance our understanding of the physiological roles of lncRNAs in general and the growing importance of these molecules in angiogenesis.
GW32-e0538
Kaixiang Yu, Xianbao Liu, Jian’an Wang
Department of Cardiology, The Second Affiliated Hospital Zhejiang University College of Medicine
OBJECTIVES Calcified aortic valvular disease (CAVD) is a common valve disease worldwide. As the population ages, the incidence rate is increasing year by year. Currently, there are no especially effective drug therapies to this kind of diseases, and the main treatment for severe aortic stenosis patients is arterial valve replacement (AVR). Bioprosthetic heart valve (BHV) is the most commonly used replacement valve which is mainly made of porcine pericardium. Due to the presence of xenogenic cells in the porcine pericardium and its traditional cross-linking method with certain toxicity, this kind of valves are easily calcification and have poor durability. Decellularization can reduce calcification partially by removal of xenogenic cells, but it also bring new problems such as thrombosis, which raise the necessity of further surface modification. As a natural sulfated polysaccharide, ulvan possesses antithrombotic and anti-inflammatory properties and behaviors as a heparinoid to immobilize proteins through their heparin binding sites. VE cadherin antibody and REDV can facilitate selective endothelial cell attachment, adhesion and proliferation. In this study, we designed a ulvan mediated decellularized biological valve functionally modified with endothelial cell cadherin antibody and REDV polypeptide to promote the endothelialization of the decellularized biological valve and improve its durability.
METHODS After the porcine pericardium is decellularized and cross-linked with glutaraldehyde, ulvan is covalently grafted, and then antibodies and polypeptides are grafted through its active groups to prepare a functional decellularized biological valve. Then, XPS, fluorescence, and FTIR were conducted to confirm successfully modification on valve scaffold. After it, we assessed the affinity of the bioprosthesis to endothelial cells by measuring the adhesion, migration and proliferation of HUVECs, and verified the biocompatibility and antiplatelet ability of the valve scaffolds in vitro via hemolysis test and platelet adhesion test. ELISA assays were conducted to measure the level of inflammatory factors released by RAW macrophages on the surface of the valve to evaluate the anti-inflammatory ability of the valve scaffolds. The anti-calcification ability of the valve scaffold in vitro was evaluated by measuring the calcium content after alternating immersion in the calcificated solution. Rat subcutaneous implantation was conducted to evaluate regeneration and biocompatibility of valve scaffolds in vivo.
RESULTS In the biological valve characterization experiment, FTIR and XPS proved the group changes and the successful grafting of Ulvan on the surface of the biological valve, and the fluorescence imaging proved the successful grafting of antibodies and peptides. In the biological function experiment of the valve scaffolds, we found that compared with the control group (unmodified group), Ulva polysaccharide, REDV polypeptide and VE-cadherin antibody modified decellularized biological valve can selectively promote endothelialization in vitro (Adhesion, proliferation and growth of cells (HUVECs)) and endothelialization (promoting the infiltration of CD31-positive endothelial cells) in vivo, which can effectively reduce platelet adhesion, anti-calcification in vitro and anti-inflammatory in vivo/in vitro.
CONCLUSIONS Ulvan, REDV polypeptide and VE-cadherin antibody modified decellularized bioprostheses have good anti-thrombosis, anti-inflammatory and endothelialization potential, and have potential for clinical application.
GW32-e0597
Xiaokang Li1, Lin Liu2, Yishi Wang3, Heng Ma3, Nan Mu3, Haiyan Wang1
1Department of Cardiology, Tangdu Hospital, Fourth Military Medical University
2Department of Dermatology, Tangdu Hospital, Fourth Military Medical University
3Department of Physiology and Pathophysiology, School of Basic Medicine, Fourth Military Medical University
OBJECTIVES Impaired autophagic flux induces ischemia vulnerability, which is the hallmark pathology in cardiac aging. Charged multivesicular body protein 2B (CHMP2B), as a subunit of the ESCRT-III complex, is a necessary factor for autophagy. However, the potential harmful effects of CHMP2B accumulation in aging heart remain unclear and contradictory. Sirtuin6 (SIRT6) has been implicated as a key factor in aging and aging-related diseases, but whether SIRT6 controls CHMP2B stability in heart has not been established. The aim of this study was to investigate the effect of SIRT6 on age-related myocardial ischemia vulnerability and autophagy deficits.
METHODS Male C57BL/6 mice at 3–4-(young) and 22–24 months of age (aged) and myocardial specific SIRT6 heterozygous knocked-out (SIRT6+/- mice) were used to investigate aging-related myocardial ischemia/reperfusion (MI/R) injury in vivo. H9c2 myocardial cell lines were used to evaluate hypoxia/reoxygenation (H/R) injury in vitro. SIRT6 specific activator-MDL800 was used to treat mice or cardiomyocyte, respectively.
RESULTS MI/R-induced myocardial injury was exaggerated in aged mice, which correlated with autophagy defects. A significant accumulation of CHMP2B was accompanied by SIRT6 decrease in aged hearts. In vitro experiments were shown that excessive accumulation of CHMP2B disrupts autophagy flux and leading intolerance to H/R injury. Newly, we found that specific activation of SIRT6 suppressed CHMP2B accumulation and ameliorated autophagic function in aged heart. Compared to control flox mice, inducible cardiac specific SIRT6 knockout mice (SIRT6 iCKO) gradually increased myocardial CHMP2B accumulation with age and induced autophagy deficit with ischemia vulnerability. Rescue experiment revealed that SIRT6 upregulation by AVV-SIRT6 myocardial injection in SIRT6 iCKO mice could reverse the CHMP2B accumulation and relief MI/R injury. At the molecular level, SIRT6 activation upregulated the mRNA expression and protein levels of atrogin-1, a muscle-specific ubiquitin ligase, in the myocardium, subsequently enhanced the interaction between atrogin-1 and CHMP2B, therefore promoting CHMP2B degradation. Of note, we demonstrate that SIRT6 regulates atrogin-1 transcriptional regulation in a FoxO1-dependent manner. SIRT6 decreased the acetylation of FoxO1 to promote its transcriptional role on Atrogin-1 and then degrade CHMP2B.
CONCLUSIONS CHMP2B clearance impairment induces autophagic flux blocking and myocardial ischemic intolerance in aged hearts. SIRT6 activation degrades CHMP2B through the FoxO1-atrogin-1-dependent pathway to improve autophagic flux. This is a novel mechanism that SIRT6 could delay myocardial senescence against MI/R injury, especially prevents excessive accumulation of autophagy key factors.
GW32-e0847
Kun Zhao1, Jing Shi1, Bin Zhou2, Xiangqing Kong2
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
2Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
OBJECTIVES Myocardial infarction (MI), one of the most severe types of heart attack, exerts a strong negative effect on heart muscle by causing a massive and rapid loss of cardiomyocytes. However, the existing therapies do little to improve cardiac regeneration. Due to the role of methyltransferase-like 3 (METTL3) in the physiological proliferation of cardiomyocytes, we aimed to determine whether METTL3 could also promote cardiomyocyte proliferation under pathological conditions and to elucidate the underlying mechanism.
METHODS The effects of METTL3 on cardiomyocyte proliferation and apoptosis were investigated in an in vivo rat model of MI and in an in vitro model of neonatal rat cardiomyocytes (NRCMs) exposed to hypoxia.
RESULTS We found that METTL3 expression was downregulated in hypoxia-exposed NRCMs and MI-induced rats. Furthermore, METTL3 pretreatment enhanced cardiomyocyte proliferation and inhibited cardiomyocyte apoptosis under hypoxic or MI conditions, and silencing METTL3 had the opposite effects. Additionally, METTL3 overexpression upregulated miR-17-3p expression. The miR-17-3p agomir mimicked the pro-proliferative and anti-apoptotic effects of METTL3 in hypoxia-exposed cells or rats with MI, while the miR-17-3p antagomir blocked these effects. Additionally, pretreatment with the RNA-binding protein DGCR8 also hampered the protective role of METTL3 in hypoxia-exposed cells.
CONCLUSIONS Overall, the current study indicated that METTL3 could improve cardiomyocyte proliferation and subsequently ameliorate MI in rats by upregulating proliferation-related miR-17-3p in a DGCR8-dependent pri-miRNA-processing manner.
GW32-e0912
Yuanting Cui1,2, Chengkang He2, Hexuan Zhang2, Zhiming Zhu2
1Department of Cardiology, Southwest Hospital, Army Medical University
2Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University
OBJECTIVES Excessive salt intake is a common problem in the world. Long-term high-salt diet can lead to hypertension and cardiovascular target organ damage. It has been proved that bitter melon extracts (BMEs) has cardiovascular protective effects such as anti-hypertension and anti-hyperlipidemic effects. The aim of this study is to explore whether long-term dietary BMEs intervention could play a role in cardiovascular protection by reducing salt intake.
METHODS C57BL/6J mice were randomly divided into three groups and fed with normal diet (0.25% NaCl, ND), high salt diet (8% NaCl, HSD) or high salt with BMEs (8% NaCl and 0.1% BME, HSB) for 6 months. The blood pressure was tested monthly. After dietary intervention, the aversion to high salt solutions was compared by gustometer licking response test. The food intake and urinary sodium excretion were measured to estimate salt intake. The cardiac structure and function of mice in each group were compared by echocardiography, and the molecular expression of myocardial cells in each group was examined through immunoblotting analysis.
RESULTS After 6 months dietary intervention, the systolic blood pressure of HSD group was significantly higher than ND group, while that of HSB group was significantly lower than HSD group. The aversion level to high salt solutions above 150 mmol/L of HSB group was significantly higher than that of HSD group. When fed with fodder containing different salt contents (0.25%, 1%, 4% and 8% NaCl), the HSB group showed increased preference for 1% NaCl and decreased preference for 4% NaCl than HSD group. Consequently, the actual salt intake and of HSB group was significantly lower than HSD group, so was the urinary sodium excretion. Compared with HSD group, the mice in HSB group had larger left ventricle (LV) internal diameter, lower interventricular septum thickness and LV posterior wall thickness at the end of systole, and higher LV ejection fraction as well as LV fractional shortening, but there was no significant difference in heart rate between the two groups. Furthermore, the expression of apoptosis related molecules such as Bax, Caspase 3 and fibrosis related molecules such as TGF-β1, Collagen III and fibronectin were significantly down-regulated in HSB treated cardiomyocytes than HS treated ones.
CONCLUSIONS These results indicate that long-term intake of BMEs enhances the aversion to high salt, thus reducing excessive salt intake, lowering blood pressure, and improving myocardial hypertrophy and cardiac dysfunction induced by high salt intake. The mechanistic evidence demonstrated the reduction of myocardial cell apoptosis and fibrosis by BMEs. Thus, dietary BMEs may be a promising approach for the prevention of high salt-induced cardiovascular dysfunction.
GW32-e0996
Dilare Adi, Yi-Tong Ma
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES Excessive increase of low-density lipoprotein cholesterol (LDL-C) is an important indicator of dyslipidemia, which is the main risk factor for the formation of atherosclerosis (AS). The main reason of dyslipidemia is the imbalance in the absorption of extracellular LDL-C endocytosis by the LDL receptor (LDLR). DMOC2 (cargo-specific endocytic adaptor protein) is the one of the most important protein which mediates endocytosis of LDLR and regulator of LDL-C levels in blood.
METHODS In our previous work using whole-exome sequencing, we identified a nonsynonymous V544I variant in DMOC2 from a Chinese Uygur high LDL-C (the proband was 16 years old and LDL-C levels was 13.6 mmol/L) family. At the cellular level, by overexpressing the DMOC2-V544I variant and investigate its molecular mechanisms in terms of gene/protein expression, protein stability, subcellular localization, interaction with proteins related to endocytic pathways, and LDL-C endocytosis.
RESULTS Using whole-exome sequencing, we identified a nonsynonymous V544I variant in DMOC2 from a Chinese Uygur family. Large cohort analysis (normal LDL-C: N=519; low LDL-C: N=515) revealed the +/V544I carriers displayed predominantly higher LDL-C levels than the DMOC2-WT (4.39±1.09 mmol/L vs. 3.04±1.09 mmol/L). On the basis of above findings, the DMOC2-V544I variant expression cell model was used to reveal the molecular mechanism of DMOC2 in regulating LDLR/LDL-C endocytosis, we found that mechanistically the DMOC2-V544I variant exhibited reduced protein levels and protein stabilities. At the same time, compared to DMOC2-WT, the DMOC2-V544I variant significantly reduced the LDLR protein levels and binding ability to the LDLR was also reduced, but the specific molecular mechanism is unclear.
CONCLUSIONS Our study demonstrates that DMOC2-V544I is a gain-of-function variant responsible for high LDL-C in humans. These results suggest that DMOC2 is a key player regulating cholesterol level in humans and required for metabolic homeostasis. Further we need to construct transgenic mouse model in order to analyze the function of DMOC2-V544I variant in the pathological process of AS formation. Implementation of the study not only will reveal the new pathogenic gene mutants and mechanisms of hypercholesterolemia, but also provide individualized therapy guidance and new insights into the diagnosis and treatment of hypercholesterolemia and the prevention of arteriosclerotic vascular disease (ASCVD).
GW32-e1062
Kai Wang, Zhongming Li, Yan Sun, Xianling Liu, Wenjie Ma, Yinzhang Ding, Di Xu
The First Affiliated Hospital of Nanjing Medical University
OBJECTIVES Sodium-glucose cotransporter 2 inhibitors (SGLT2I) are known to be used to reduce cardiovascular mortality in patients with diabetes mellitus, while its protective mechanism remains unknown. The aim of this study was to investigate the performance of dapagliflozin (DAPA), the SGLT2 inhibitor, on cardiac function and its potential mechanism in mice with myocardial infarction (MI).
METHODS C57BL/6 mice were subjected to left artery coronary artery descending ligation to induce MI or Sham-operation. One week after surgery, mice cardiac function was assessed by echocardiography. After that, mice were randomly divided into the Sham group, the MI group, and the MI+DAPA group. On a daily basis, the MI group received saline, and the MI+DAPA group received DAPA (1.5 mg/kg/day) by oral gavage for 4 weeks. At the end of the 5th week, echocardiography was performed on mice to assess its cardiac structure and function. Also, the blood pressure, heart rate, and blood glucose level were measured from each mouse. After sacrifice, cell apoptosis was analyzed by western blot and immunofluorescence. The inflammatory cytokines were measured by RT-PCR, and the cardiac fibrosis was analyzed by using Masson’s trichrome stain.
RESULTS One-week post MI, echocardiography revealed that ejection fraction (EF) and fractional shortening (FS) were significantly decreased in mice with MI, compared to the sham group. At the end of the 5 weeks period, comparing to the MI group, the MI+ DAPA group showed that DAPA improved the mice cardiac function and reduced cardiac fibrosis, as well as attenuated myocardial inflammatory factors and apoptosis. In addition, phospho-the protein kinase B (p-AKT)/AKT ratios were remarkably lower in the MI+DAPA group than the MI group. However, there was no significant difference observed in blood pressure, heart rate and blood glucose level among these three groups.
CONCLUSIONS In summary, dapagliflozin could improve cardiac function by inhibiting cells apoptosis and inflammatory cytokines in mice with myocardial infarction. Results indicate that dapagliflozin is a promising agent for MI patients without diabetes.
GW32-e1158
Jingjiang Pi1, Tao Zhuang1, Xiaoli Chen1, Jiu Liu1, Yu Cheng2, Edward Morrisey3, Yuzhen Zhang2
1Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
2Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
3Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
OBJECTIVES Angiogenesis is a critical process required for tumor progression. Newly formed blood vessels provide nutrition and oxygen to the tumor contributing to its growth and development. Due to the dysfunctional vasculature associated with large areas of some cancers, sections of these tumors continue to develop in hypoxic environments. Crucial to drug development, a robust understanding of the significance of these metabolism changes will facilitate our understanding of cancer cell survival.
METHODS Vascular endothelial cell specific Foxp1 loss-of-function mouse models. Generation of vascular endothelial cell specific Foxp1 loss-of-function mouse was obtained by crossing a conditional gain-of-function Foxp1−/− mouse line with VE-cadherin (Cdh5) promoter-driven Cre recombinase expression line.
RESULTS Foxp1 is highly expressed in vascular endothelial cells and loss of endothelial Foxp1 increases xenography tumor angiogenesis and accelerates tumor growth. Loss of endothelial Foxp1 promotes in vivo retinal angiogenesis and exerts in vitro proangiogenic effects under hypoxi. EC-Foxp1 gain of function reduces retinal angiogenesis during hypoxia. Hif1α is identified as Foxp1 direct downstream target gene and Hk2 as Hif1a downstream target gene.
CONCLUSIONS Normal tissue uses glycolysis to generate approximately 10% of the cell’s ATP, with mitochondria accounting for 90%. In tumor sections, however, over 50% of the cellular energy is produced by glycolysis with the remainder being generated at the mitochondria. The reliance of tumor cells on glycolysis for energy production causes them to consume more glucose because of the low of glycolysis in generating ATP. Targeting endothelial cell metabolism is a missing piece to revolutionize cancer therapy.
GW32-e1246
Wenjun Zhang
Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
OBJECTIVES Aortic dissection (AD) is a rare but catastrophic disorder and it is associated with significant morbidity among survivors. This study aimed to targeted IRE1α-XBP1s pathway in the pathogenesis of AD and inhibition of XBP1 splicing will protect against AD formation and progression by preserving VSMC homeostasis.
METHODS Eight-week-old male ApoE−/− mice were given β-aminopropionitrile at a concentration of 0.1% for 3 weeks and infused via osmotic mini pumps with either saline or 2500 ng/min/kg angiotensin II (Ang II) for 14 days. To evaluate the effect of XBP1 inhibitor MKC-3946 treatment on AD initiation and progression, treatment was initiated 2 weeks during Ang II infusion. MKC-3946 was freshly prepared in PBS and administered to mice at a dose of 100 mg/kg every day through intraperitoneal injection. After Ang II infusion, we evaluated remodeling in the aorta by echocardiography, histological and immunohistochemical analysis.
RESULTS To explore the role of XBP1s in acute aortic dissection (AD), we determined the relative XBP1s protein expression with Western Blot in the human aorta samples. We found that XBP1s was significantly increased in aortic vascular smooth muscle cells of acute aortic dissection patient. In vitro study confirmed that Ang II results in ER stress and further induces XBP1s expression. Subsequently, XBP1s translocate into the nucleus, evoking numerous gene transcription, including CHOP, gp91, Cleaved-caspase3, Bax, and Bcl-2, which play important role in VMSCs apoptosis in the middle layer of the aorta. Pharmacological inhibition of IRE1α endoribonuclease domain by a novel small molecular inhibitor MKC-3946 could reduce the expression of XBP1s and protect against AD in an Ang II induced mouse model by suppressing XBP1s associated ROS production and apoptosis in VSMCs.
CONCLUSIONS The current study revealed the relevant role of IRE1α-XBP1s signaling pathway in AD formation and progression. The IRE1α endoribonuclease domain inhibitor MKC-3946 could be a novel therapeutic agent for AD patient.
GW32-e1333
Guanhua Li
Sun Yat-sen Memorial Hospital
OBJECTIVES Extracorporeal membrane oxygenation (ECMO) plays a vital role in the treatment for severe COVID-19 patients. ECMO-related thrombosis is one of the leading challenges owing to foreign surface induced coagulation disturbance during prolonged ECMO support. Recently, we found that has_circ_0001177, a circular RNA (circRNA), was markedly upregulated during the pathogenesis of ECMO-related thrombosis. In this work, we investigated the biological function of hsa_circ_0001177 and explored the therapeutic effects of hsa_circ_0001177 silencing using a triblock dendritic nanocarrier.
METHODS In vitro studies were applied to determine the function of has_circ_0001177 in platelets with respect to platelet activation and aggregation. A dendritic triblock nanocarrier, polyamidoamine-polyethylene glycol-cyclic RGD peptide (PAMAM-PEG-cRGD) was constructed, with small interfering RNA (siRNA) targeting hsa_circ_0001177 encapsulated. Anti-thrombotic effects of PAMAM-PEG-cRGD-si-hsa_circ_0001177 was measured in ex-vivo ECMO circuits. Luciferase reporter assay and Western blotting are used to confirm the ceRNA network for hsa_circ_0001177 predicted by bioinformatics analysis.
RESULTS Compared with controls, the expression of hsa_circ_0001177 is upregulated in whole blood samples, platelet-rich plasma, and ECMO circuit thrombi from animal models with ECMO-related thrombosis. Platelet activation and aggregation is significantly promoted when hsa_circ_0001177 is over-expressed in platelets. The self-constructed dendrimer-based nanocarrier that delivers siRNA silencing hsa_circ_0001177 inhibits thrombosis in ex-vivo ECMO circuits. Compared to the unmodified PAMAM nanocarrier, the uptake of the triblock nanocarrier is significantly enhanced in activated platelets via the “cRGD-integrin αvβ3” recognition mechanism. Moreover, hsa_circ_0001177 acts as a miRNA sponge for miR-140-3p in platelets, increases the production of THPO through a hsa_circ_0001177/miR-140-3p/THPO ceRNA axis, and activating PI3K/Akt signaling pathway as well.
CONCLUSIONS Our data support the hypothesis that hsa_circ_0001177 may function as a miR-140-3p sponge and suppress ECMO-related thrombosis via the hsa_circ_0001177/miR-140-3p/THPO axis. PAMAM-PEG-cRGD-si-hsa_circ_0001177 triblock nanocarrier could be a promising platform in future application for the prevention of ECMO-related thrombosis.
GW32-e1447
Kai Wang, Zhongming Li, Wenjie Ma, Yan Sun, Xianling Liu, Jing Zhang, Di Xu
The First Affiliated Hospital of Nanjing Medical University
OBJECTIVES Acute myocardial infarction (AMI) is a severe cardiovascular disease. This study aimed to identify crucial miRNAs and mRNAs in AMI by establishing a miRNA-mRNA network.
METHODS The microarray datasets GSE31568, GSE148153, and GSE66360 were downloaded from the GEO database. We identified differentially expressed miRNAs and mRNAs in AMI samples compared with control groups. The consistently changing miRNAs in both the GSE31568 dataset and GSE148153 dataset were selected as the candidate with differentially expressed miRNAs. The analyses of interactions were between candidates with differentially expressed miRNAs (DE-mRNAs) and differentially expressed mRNAs (DE-mRNAs). Then, a miRNA-mRNA network and the protein-protein interaction network were constructed, along with functional enrichment and pathway analyses.
RESULTS A total of 209 DE-miRNAs in the GSE31568 dataset, 857 DE-miRNAs in the GSE148153 dataset, and 51 DE-mRNAs in the GSE66360 dataset were identified. There were 18 candidate DE-miRNAs observed in both GSE31568 and GSE148153 datasets. In the miRNA-mRNA network, miR-646, miR-127-5p, miR-509-5p, miR-509-3-5p, and miR-767-5p were shown to have a higher degree. Genes in the miRNA-mRNA network were mainly involved in the regulation of TNF and FOXO signal pathways. It was found that THBS-1 served as an important regulator in the miRNA-mRNA network; FOS was a significant regulator in the PPI network; while CDKN1A was of importance in both miRNA-mRNA and PPI network.
CONCLUSIONS We established a miRNA-mRNA network in AMI and identified five miRNAs and three genes, which might be used as biomarkers and potential therapeutic targets for patients with AMI.
GW32-e1577
Wei Shang
The Ninth People’s Hospital of Chongqing
OBJECTIVES Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects.
METHODS THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining.
RESULTS The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1.
CONCLUSIONS Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.
GW32-e1646
Liangpeng Li, Yu Huang, Ken Chen, Chunyu Zeng
Department of Cardiology, Army Medical Center (Daping Hospital), Army Medical University, Chogqing, P.R China
OBJECTIVES Physical exercise is an effective non-pharmacological therapy to lower blood pressure and has been recommended as the cornerstone therapy for hypertension. Since skeletal muscle has been identified as an endocrine organ, the endocrine factors derived from skeletal muscle, termed myokines, might play the key roles in the crosstalk between skeletal muscle and remote organs and tissues, and might mediate the exercise associated protective effects. Previous studies showed a novel myokine, irisin, lowers blood pressure immediately after bolus injections by enhancing vasodilation in normotensive and hypertensive rats. Whether irisin governs the long-term control of blood pressure is still unclear.
METHODS Irisin homozygous knockout (irisin−/−) and Human GRK4γ wild-type (hGRK4γWT) or 142V (hGRK4γ142V) transgenic mice were used in this study and induced hypertension by Ang-II infusion. The exercise was performed by the treadmill training. Exogenous irisin was subcutaneously administered for mice or rats (1 μg/kg/day) for 28 days as long-term treatment or 3 days as short-term treatment with micro-osmotic pump. Moreover, the immortalized RPT cells from WKY and SHRs were also used for further researches. The immunoblotting, real-time quantitative PCR, chromatin immunoprecipitation and LC-MS were used for the mechanism analyses.
RESULTS Physical exercise by treadmill training reduced the blood pressure levels in Ang II-induced hypertensive mice. The decreased sodium excretion in Ang II-induced hypertensive mice was recovered to some degrees by treadmill training. The lowering blood pressure effect, mediated by physical exercise, was encapsulated in the irisin overexpression mice; in contrast, the anti-hypertensive effects, induced by treadmill training, were disappeared in the irisin−/− mice, accompanied with disappeared improvement of sodium excretion. Moreover, exogenous irisin administration also decreased the blood pressure and increased sodium excretion in SHRs, but not in WKY rats. Since GRK4 plays an important role in the regulation of blood pressure, irisin lowered renal GRK4 protein and mRNA expressions in both WKY and SHRs. And the confocal microscopy and immunoblotting found the exogenous irisin in both cytosol and the nucleus. And irisin treatment reduced the c-myc-mediated GRK4 transcriptional activation in SHR RPT cells. Irisin treatment significantly reduced c-myc protein expression, but not affected c-myc mRNA expression, indicating the regulation of irisin on c-myc occurred in the post-transcriptional levels. Then we treated SHR RPT cells with cycloheximide (CHX) to inhibit protein synthesis and found irisin increased c-myc degradation as shortening the half lifetime indicating that, at least in part, irisin affect c-myc expression via regulation of c-myc degradation.
CONCLUSIONS In conclusion, the present study indicates the role of irisin in blood pressure and shows that irisin, via inducing c-myc degradation, down-regulates GRK4 transcription and expression, which may be involved in the increasing sodium excretion and lowering blood pressure. The results imply that the inhibition of GRK4 expression or activity, based on the therapeutic benefits of irisin, may be an effective therapeutic approach for essential hypertension.
GW32-e1722
Jiang He, Yumin Qiu, Bin Dong, Zhe Zhou, Wenhao Xia
Department of Hypertension and Vascular Disease, The First Affiliated Hospital of Sun Yat-sen University
OBJECTIVES Inflammatory microenvironment is attributable to age-related pathological alterations of the endothelium. Exosomes (Exos) from M1-polarized macrophages are increasingly recognized as important mediators in inflammatory microenvironment. Our study intends to decode the effects of exosomes derived from M1-polarized macrophages on endothelial senescence and their underlying mechanism.
METHODS Accumulation of M1-polarized macrophages and endothelial function in aortas from young and aged C57BL/6 mice were compared. Polarized M1 macrophages were induced from RAW264.7 cell lines by LPS and IFN-γ, from which exosomes were collected and identified. Mice aortic endothelial cells (MAECs) were treated with M1-Exos, followed by evaluations of SA-β-gal, senescent marker proteins, cell cycle, mitochondrial ROS and mitochondrial respiratory function. miRNA profile, quantitative reverse transcription-polymerase chain reaction, western blotting, and luciferase reporter assays were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of M1-Exos on endothelial senescence and vascular dysfunction in mice.
RESULTS Aged mice presented impaired endothelium-dependent vasodilatation, accompanied by abundant M1-polarized macrophages accumulated in aortas. M1-Exos significantly increased levels of SA-β-gal and senescent markers and promoted G0/G1 cell cycle arrest in MAECs. In addition, M1-Exos strikingly resulted in accumulation of reactive oxygen species (ROS) and inhibited mitochondrial oxidative phosphorylation. Through microRNA expression profiling, miR-22-3p was identified as the most upregulated miRNA in MAECs treated with M1-Exos. Further functional analysis showed that M1-Exos aggravated mitochondrial oxidative damage and induced the acquisition of a senescent phenotype by transferring miR-22-3p. Mechanistically, exosomal miR-22-3p directly suppressed SIRT1, the major deacetylase responsible for catalyzing NFκB and Foxo3a. Exosomal miR-22-3p-mediated deficiency of SIRT1 led to senescence process by activation of NFκB/p21-p27 signaling and induced mitochondrial oxidative damage by downregulation of Foxo3a/SOD2-CAT signaling. Furthermore, intravenous administration of M1-Exos into young mice significantly attenuated endothelium-dependent vascular relaxation, elevated ROS and senescent markers in aortas.
CONCLUSIONS M1-polarized macrophages exosomes facilitates endothelial senescence via, at least partially, transferring miR-22-3p to MAECs, thus inducing the cell cycle arrest and mitochondrial oxidative damage. Our work indicates that exosomal miR-22-3p derived from M1-polarized macrophages play important roles in distant communication between inflammatory microenvironment and endothelial senescence. This mechanism can be used as a novel potential therapeutic approach for the prevention and treatment of age-related vascular diseases.
GW32-e1821
Jishou Zhang, Wei Pan, Jun Wan
Wuhan University Renmin Hospital
OBJECTIVES The failure resolution of inflammation after acute myocardial infarction (AMI) could resulted in the deterioration of cardiac remodeling. Neogenin (Neo1), as a multifunctional transmembrane receptor of the immunoglobulin superfamily, has been reported to regulate inflammatory response in several immune microenvironment. However, whether Neo1 has a critical role in cardiac remodeling post AMI remains unknown.
METHODS AMI animal model was performed by the permanent ligation of the left anterior descending (LAD) coronary artery. Two hours before AMI, anti-Neo1 antibody (2 μg per mouse) was injected via tail vein to complete the inhibition of Neo1.
RESULTS The inhibition of Neo1, performed by the administration of anti-Neo1 neutralizing antibody, aggravated cardiac function, cardiac fibrosis and myocardiocyte apoptosis after AMI. In addition, the inhibition of Neo1 enhanced inflammation response in cardiac tissue illustrated by the increased infiltration of monocytes/macrophages, T lymphocytes and neutrophils and the increased production of proinflammatory cytokines, 3 days post AMI. Immunofluorescence co-localization suggested that Neo1 was abundantly located in macrophage. The inhibition of Neo1 could promote M1 polarization and inhibit M2 polarization, respectively, in vivo and vitro. Nevertheless, the over-expression of Neo1 in macrophages could promote M2 polarization and reverse M1 polarization in vitro. Besides, anti-Neo1 neutralizing antibody could regressed the expression of several specific pro-resolving receptors, including ChemR23, GPR18 and GPR37, and reduced neutrophil apoptosis.
CONCLUSIONS The inhibition of Neo1 aggravated cardiac remodeling post AMI via mediating macrophage polarization and enhancing the resolution of inflammation.
GW32-e1895
Long Zeng1,2, Sheng-Huan Yu1,2, Hai-Yin Xiao2, Fei-Fei Xiao1,2, Rui Zhu2, Pan-Yue Liu1,2, Wei Wei2
1School of Medicine, South China University of Technology Guangzhou
2Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences
OBJECTIVES Kv1.5 potassium channel was regard as a promising target in the treatment of atrial fibrillation. The present study aimed to investigate whether coactivator p300 participates in the regulation of Kv1.5 expression in Angiotensin II-treated HL-1 cell.
METHODS HL-1 cell was treated with Angiotensin II (0.1 μmol⋅L−1, 1 μmol⋅L−1, 10 μmol⋅L−1) for 24 hours. Western Blot was used to determine the expression levels of Kv1.5 and p300. Whole-cell-patch-clamp was to record the current density of atrial-specific ultra-rapid delayed rectifier K(+) current (Ikur) and action potential duration (APD). Based on the treatment of Angiotensin II (10 μmol⋅L−1), curcumin, an inhibitor of p300, as well as p300-siRNA was used to investigate its functional effect on expression of Kv1.5 and current density of Ikur. Adenovirus-mediated over-expression of p300 was also applied to determine its downstream effect.
RESULTS Expression of p300 and Kv1.5 was significantly increased in Angiotensin II-treated HL-1 cell compared with control group (1.20±0.21 vs. 0.38±0.28, n=4, P<0.01) (0.83±0.10 vs. 0.52±0.21, n=5, P<0.05). The results of Whole-cell-patch-clamp showed that Angiotensin II-treated HL-1 had higher Ikur current density and shorter APD compared with control group (Ikur: 10.05±1.50 pA/pF vs. 4.73±1.82 pA/pF, n=10, P<0.01) (APD90: 36.89±9.41 ms vs. 67.69±14.91 ms, n=10, P<0.01). However, p300 inhibitor curcumin could restored Ikur, APD and expression of Kv1.5 induced by Angiotensin II (Ikur: 5.90 pA/pF±1.11 vs. 10.05±1.50 pA/pF, n=10, P<0.01) (APD90: 69.40±17.97 ms vs. 36.89±9.41 ms, n=10, P<0.01) (Kv1.5: 0.45±0.28 vs. 1.01±0.34, n=5, P<0.05). The same results were also founded when p300 was gene-silenced with siRNA. Furthermore, over-expression p300 by Adenovirus could increase the expression of Kv1.5 (AD: 1.70±0.91 vs. NC: 0.43±0.22, n=4, P<0.05).
CONCLUSIONS Angiotensin II induces Kv1.5 upregulation via coactivator p300 in HL-1 cell. Inhibition of p300 would be beneficial for Atrial fibrillation treatment by abrogate the upregulation of Kv1.5 induced by Angiotensin II.
GW32-e0069
Pengsheng Chen, Jia Liu, Bing Han
Xuzhou Central Hospital
OBJECTIVES To investigate whether Schisandrin B (Sch B) could improve cardiac structure and function and attenuate myocardial remodeling after myocardial infarction (MI) in mice with diabetes.
METHODS Mice model of MI with diabetes was established by permanent ligation of the left anterior descending (LAD) coronary artery. In the sham operation group, only the chest was open (n=8). Then the MI mice were randomly treated with Sch B (n=24, 80 mg⋅kg–1⋅d–1) or vehicle alone (n=24). After treatment for 4 weeks, cardiac function was detected by echocardiography measurement. Infarction size was detected by Evans blue and TTC staining. H&E and Masson trichrome staining were used. TNF-α, TGF-β1, IL-1β were detected by ELISA. The apoptosis index of ischemic myocardial cells was detected by immunofluorescence. NF-κB, Bcl-2, Bax, Akt, phosphorylated akt, eNOS, phosphorylated eNOS were detected by Western Blot.
RESULTS Four weeks after operation, Sch B treatment could increase survival rate, improve LVEDD, LVESD, LVEF, LVFS, and decrease the heart weight/body weight ratio and infarct size compared with MI group. In MI group, HE staining showed a large number of inflammatory cells in the peripheral region, and the permutation structure was very disorganized. While the Sch B group was significantly better than that of MI group. Masson staining results showed that the degree of myocardial fibrosis in Sch B group was significantly smaller than that of MI group. Moreover, Sch B could down-regulate some inflammatory cytokines, like NF-κB, TGF-β, TNF-α and IL-1β, activate Akt-eNOS pathway, upgrade Bcl-2 and downgrade Bax and inhibit cell apoptosis compared with MI group.
CONCLUSIONS Our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after MI. It represents a potential novel therapeutic approach for treatment of ischemic heart disease with diabetes.
GW32-e0150
Mingming Zhang
Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University
OBJECTIVES Sepsis is a serious systemic inflammatory reaction with high mortality caused by bacterial infection. The main causes of sepsis include serious complication of severe infection, severe trauma, and major surgery. Further development of this condition can lead to septic shock, serious damage to many organs and finally death. Hence, sepsis is a serious disease that endangers human health. High morbidity and mortality are the most typical characteristics of septic cardiomyopathy. We aimed to reveal the role of miR-22 in septic cardiomyopathy and to explore the underlying mechanisms.
METHODS miR-22 cardiac-specific knockout (miR-22cKO) mice and miR-22 cardiac-specific transgenic (miR-22cOE) mice were subjected to a cecal ligation and puncture (CLP) operation, while a sham operation was used in the control group. The cardiac function, cardiomyocytes apoptosis, mitochondrial function and autophagic flux were detected.
RESULTS The echocardiogram results suggested that miR-22cKO CLP mice cardiac dysfunction was alleviated. The serum LDH and CK-MB were reduced in the miR-22cKO CLP mice. As expected, there was reduced apoptosis, increased autophagy and alleviated mitochondrial dysfunction in the miR-22cKO CLP mice, while it had contrary role in the miR-22cOE group. Inhibiting miR-22 promoted autophagy by increasing the LC3II/GAPDH ratio and decreasing the p62 level. Additionally, culturing primary cardiomyocytes with lipopolysaccharide (LPS) simulated sepsis-induced cardiomyopathy in vitro. Inhibiting miR-22 promoted autophagic flux confirmed by an increased LC3II/GAPDH ratio and reduced p62 protein level under bafilomycin A1 conditions.
CONCLUSIONS Knocking out miR-22 may exert a cardioprotective effect on sepsis by increasing autophagy and decreasing apoptosis via sirt1. Our results revealed that targeting miR-22 may become a new strategy for septic cardiomyopathy treatment.
GW32-e0314
Yunyun Yang, Xiaolu Jiao, Huahui Yu, Linyi Li, Juan Li, Yunhui Du, Huina Zhang, Jing Zhang, Chaowei Hu, Xiaoping Zhang, Yanwen Qin
Beijing Anzhen Hospital
OBJECTIVES Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening cardiovascular disorder. It has been reported that ANGPTL8 was associated with the aortic diameter and rupture rate of TAAD. However, the direct role of ANGPTL8 on TAAD is still unknown.
METHODS β-aminopropionitrile monofumarate (BAPN) was used to induce TAAD in C57BL/6 mice. ANGPTL8 knockout mice were used to detect the effects of ANGPTL8 on the development of TAAD. Ultrasound was used to measure the diameter of the aorta. Elastic staining of aortic tissue revealed elastic fiber degradation. Immunohistochemistry staining and western blot were used to detect the expression of ANGPTL8, matrix metalloproteinases (MMPs), endoplasmic reticulum stress (ERS) protein and inflammatory factors. In vitro study, ANGPTL8 knockdown was used to observe the role of ANGPTL8 on ERS. In addition, in ANGPTL8 over expression VSMCs, PERK inhibitor was as used to detect the effect of ANGPTL8 on pathway of PERK-ATF4-CHOP in VSMCs.
RESULTS ANGPTL8 expression was increased in TAAD aortic wall and abundantly expressed in VSMCs in BAPN-induced TAAD mouse model. ANGPTL8 knockout significantly reduced the rupture rate of TAAD, compared with BAPN treated wild-type mice, and the rupture rate was 0%. The number of elastic fiber breaks was significantly reduced, and the protein expression of proinflammatory cytokines and MMP-9 was decreased in ANGPTL8 knockout mice compared with BAPN treated wild-type mice. In addition, ANGPTL8 knockout mice demonstrated decreased expression of ERS protein in aorta wall. In in vitro, ANGPTL8shRNA decreased MMP-9 and ERS protein expression in VSMCs. Overexpression of ANGTL8 significantly increased the expression of ERS protein and increased the expression of MMPs, while PERK inhibitor significantly decreased the effects of ANGPTL8 in VSMCs.
CONCLUSIONS ANGPTL8 contributed to TAAD development by inducing ERS activation and degradation of extracellular matrix in the aorta wall, suggesting that inhibition of ANGPTL8 represents a new strategy for TAAD therapy.
GW32-e0514
Pingping Xiang1, Andrew V. Schally2,3, Hong Yu1
1The Second Affiliated Hospital Zhejiang University College of Medicine
2Departments of Medicine and Pathology, Miller School of Medicine, University of Miami
3Veterans Affairs Medical Center
OBJECTIVES By binding to its receptor (GHRH-R) on the pituitary cellular membranes, GHRH stimulates the production of growth hormone (GH) and consequently insulin-like growth factor 1 (IGF-1). Synthetic GHRH agonists with much higher activity and increased stability compared to native GHRH peptide have been utilized to treat experiment myocardial infarction (MI), vascular calcification, diabetes mellitus, and lung damage in animal models. Agonists of growth hormone-releasing hormone (GHRH) exhibit several favorable effects on heart function and remodeling. However, the GHRH agonists’ effect on aging-related heart failure has not be tested.
METHODS Here we assessed whether GHRH agonist MR409 can modulate heart function and systemic parameters in old mice. Starting at the age of 15 months, mice were injected subcutaneously with MR409 (10 μg/mouse/day, n=8) or vehicle (n=7) daily for a total of 6 months. Echocardiography and body weights were measured at baseline and 5 months after treatment. Cardiac function, exercise capability and chronic inflammation in vivo and beta-gal staining and senescence-related protein P21 and reactive oxygen species in vitro were tested.
RESULTS Mice treated with MR409 showed improvements in exercise activity, cardiac systolic and diastolic function, survival rate, immune function, and hair growth in comparison with controls. More stem cell colonies could be grown out of the bone marrow recovered from the MR409-treated mice. In addition, there are fewer CD68+ macrophages in the heart of old mice treated with MR409 than those in the control mice. Mitochondrial oxidative phosphorylation functions of the hearts of mice treated with MR409 were also significantly improved with more mitochondrial fusion proved by electron microscope. The ratio of L-OPA1 to S-OPA1 was increased in MR409 treated mice. In vitro, fewer β-gal positive cells were observed in endothelial cells (ECs) after 10 passages with MR409. In Doxorubicin (DOX)-treated H9C2 cardiomyocytes, cell senescence marker p21 and reactive oxygen species were significantly reduced after cultured with MR409 in in Dox-treated H9C2, neonatal mouse CMs after one passage, and HUVECs after 10 passages. MR409 also improved cellular ATP production and oxygen consumption rate in Dox-treated H9C2 cells. Mitochondrial protein OPA1 long isoform was significantly increased after treatment with MR409. Such effect could be blocked by GHRH antagonist MIA602 or PKA inhibitor H89, indicating the involvement of GHRH-R/cAMP/PKA pathway.
CONCLUSIONS In short, GHRH agonist MR409 can reverse the aging-associated changes with respect of heart function, mobility, hair growth, cellular energy production and senescence biomarkers. The improvement of heart function may be related to a better mitochondrial functions through GHRH receptor/cAMP/PKA/OPA1 signaling pathway and relieved cardiac inflammation.
GW32-e0546
Yayu You, Ning Zhang, Xiaojie Xie
Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine
OBJECTIVES Peripheral arterial disease (PAD) is an atherosclerosis disease characterized by impaired circulation to the lower extremities, commonly results from vascular occlusion or narrowing. Noteworthy, severe PAD leads to critical limb ischemia (CLI), characterized by high mortality and significant amputation rates. Currently, interventions aimed at enhancing angiogenesis and restoring blood flow in CLI are essential. Bone marrow-derived endothelial progenitor cells (EPCs) are a subset of circulating endothelial cells responsible for vascular and tissue repair processes after ischemia. Delta-like non-canonical Notch ligand 1 (DLK1) is a member of the epidermal growth factor-like family of homeotic proteins, typically involved in endothelial cell function. However, its role in angiogenesis remains controversial. Therefore, the present study aimed to determine whether DLK1 could affect angiogenesis and blood flow recovery after CLI.
METHODS Mouse model of hindlimb ischemia (HLI) created by femoral artery ligation was performed on 6–8 weeks old male C57BL/6 mice. From Day 0, Mice were injected intravenously with recombinant DLK1 (rDLK1) (0.1 mg/kg) or vehicle every 3 days for 14 days. Hindlimb blood flow was sequentially measured before and at 0, 3, 7, and 14 days after surgery. Angiogenesis was detected by CD31 staining, and mature blood vessel was assessed by α-SMA staining. In addition, flow cytometry was used to evaluate the EPC (CD34+/KDR+) mobilization from bone marrow to ischemic muscles.
RESULTS rDLK1-treated mice showed better recovery than vehicle control-treated mice at days 3 and 7 post-surgery. This result was further supported by increased CD31+ and a-SMA+ vessels in the ischemic muscles of rDLK1-treated mice compared to the vehicle group. In addition, the rDLK1 group exhibited significantly enhanced EPC mobilization from bone marrow to ischaemic tissue during the progression of hindlimb ischemia.
CONCLUSIONS These findings suggested that rDLK1 repletion may inhibit ischemia-induced damage by promoting EPC mobilization, thus improve angiogenesis and tissue repair. This benefit of rDLK1 may lead to a new therapeutic approach for critical hindlimb ischemia.
GW32-e0600
Zuyi Yuan, Zeyu Dong
The First Affiliated Hospital of Xi’an Jiaotong University
OBJECTIVES Cholesterol 25-hydroxylase (Ch25h), converting cholesterol to 25-hydroxycholesterol (25-HC), is critical in modulating cellular lipid metabolism and anti-inflammatory and antiviral activities. However, its role in non-alcoholic fatty liver disease (NAFLD) remains unclear.
METHODS We found that Ch25h expression was decreased in livers of ob/ob mice and E3 rats fed a high-fat diet (HFD).
RESULTS Ch25h knockout (Ch25h−/−) mice fed an HFD showed aggravated fatty liver and decreased level of CYP7A1 and CYP27A1, in comparison with their Ch25h+/+ (WT) littermates. RNA-seq analysis revealed that differentially expressed genes in livers of HFD-fed Ch25h−/− mice were involved in pathways of positive regulation of lipid metabolic process, steroid metabolic process, cholesterol metabolic process, and bile acid biosynthetic process. As gain-of-function experiments, WT mice receiving AAV8-Ch25h or 25-HC showed alleviated NAFLD, when compared with control group receiving AAV8-control or vehicle control. Mechanistically, Ch25h overexpression significantly elevated the levels of primary and secondary bile acids and CYP7A1 but decreased those of Shp and FGFR4.
CONCLUSIONS Elevated level of Ch25h and its enzymatic product 25-HC protect rodent models from an HFD-induced hepatic steatosis via regulating enterohepatic circulation of bile acids. The underlying mechanism involves 25-HC activation of CYP7A1 via LXR. These data suggests that targeting Ch25h or 25-HC may have therapeutic advantages for NA.
GW32-e0848
Kun Zhao, Wei Sun, Peng Li, Xiangqing Kong
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
OBJECTIVES Cardiac fibrosis and hypertrophy, as the major hallmarks of cardiac remodeling involved in the pathophysiological process of hypertensive heart diseases, can result in disturbed function and structure of the myocardium. Alamandine (Ala), a ligand of Mas-related G protein-coupled receptor, member D (MrgD), was reported to improve hypertension. However, the specific physiological and pathological role of MrgD in hypertension is not yet elucidated.
METHODS The recombinant adenovirus-MrgD (AD-MrgD) or adenovirus-shRNA-MrgD (shRNA-MrgD) was intravenously injected in Wistar-Kyoto rats (WKY) or Spontaneous Hypertension rats (SHR), respectively. The vascular smooth muscle cells (VSMCs) was induced by Ang II to mimic the cell culture model of hypertension in vitro. Then, low-intensity pulsed ultrasound (LIPUS) irradiation (0.5 MHz, 77.20 mW/cm2) was applied for 20 minutes every other day in mice received chronic Ang II infusion in vivo.
RESULTS We found that MrgD overexpression increased blood pressure and induced mesenteric vascular remodeling in WKY rats, while silencing MrgD promoted hypertension and mesenteric vascular remodeling in SHR rats. The same trends were observed in Ang II-induced VSMCs. Further results indicated that shRNA-MrgD, like Ala, downregulated Ang II-induced protein and mRNA expression of Cav1.2 in vitro, while Cav1.2 activator Bay-K-8644 could reversed the protective effects of silencing MrgD. Moreover, LIPUS, a novel and safe apparatus, improved Ang II-induced vascular remodeling in vivo and VSMCs phenotypic switch in vitro via inhibiting MrgD expression.
CONCLUSIONS Taken together, our current study unveiled the promising protective effects of silencing MrgD expression on improving hypertension and ameliorating hypertension-associated mesenteric vascular remodeling by downregulating Cav1.2 channels, paving the way to develop novel therapeutic apparatus, LIPUS, in the clinical practice of lowering hypertension in the future.
GW32-e0935
Xiaomin Jiang, Jing Dong, Dujiang Xie, Jie Luo, Hong Ran, Lin Li, Miao Li, Pingyang Zhang, Ling Zhou
Nanjing First Hospital, Nanjing Medical University
OBJECTIVES The aim of this study was to assess the characteristic of right ventricular longitudinal strain (RVLS) in a group of beagles with dehydromonocrotaline-induced pulmonary hypertension and to identify the exact changes of RV function after pulmonary artery denervation (PADN) process.
METHODS A total of 30 beagle dogs (body weight 8–10 kg) were enrolled and randomly assigned to 3 groups: control (n=10, intra-atrial injection of N-dimethylacetamide after first RHC, 3 mg/kg ), sham (n=10, intra-atrial injection of dehydromonocrotaline [DHMCT], 3 mg/kg after first RHC and PADN catheter was positioned in the PA but without ablation at 8th week) and PADN group (n=10, intra-atrial injection of dehydromonocrotaline [DHMCT], 3 mg/kg after first RHC and PADN procedure was performed at 8th week). The transthoracic echocardiography and hemodynamic measurements were performed at the beginning, 8th week and 14th week. Images of the RV-focused apical four-chamber view were obtained for 2D strain analysis. The conventional echocardiographic RV parameters (such as RV diameter, RV wall thickness, RV ejection fraction, Tei index and TAPSE et al.) were evaluated. In 2D strain analysis, RVLS and the strain rate were reported. All heart tissues were isolated at 14th week for morphometric and western blot analysis.
RESULTS The RV size enlarged in sham group and shrunk in PADN group. RVEF, TAPSE and Tei index significantly decreased in sham group while improved in PADN group. RVLS decreased remarkably from −20.76±1.85% to −13.85±1.94%, but improved significantly to −16.49±1.57% after PADN. RVLS correlated strongly with invasive hemodynamic data, exhibiting a positive correlation with RVSP (R=0.71), PASP (R=0.73), mPAP (R=0.72) and PVR (R=0.66). Meanwhile, RVLS correlated modestly with RVHI (R=0.46, P=0.018). In terms of molecular biological analysis, the expression of AT1R, TGF-β and p-ERK 1/2 were upregulated in sham group compared with control group. PADN was associated with significant decreased phosphorylation of ERK 1/2 in animal RV tissues.
CONCLUSIONS RVLS measured by 2D-STE can be a better way to evaluate RV function in PH compared with conventional echocardiography. In addition, it is confirmed though 2D strain that percutaneous PADN is feasible and effective for improving RV function, the mechanism is that modulating Ras-MAPK/ERK-TGF-β1 pathway signaling.
GW32-e1007
Jichun Wang, Lang Wang, Li Lu, Sisi Chen, Jing Xie, Yanli Zhou, Hong Jiang
Renmin Hospital of Wuhan University
OBJECTIVES It has been reported that the induction of heme oxygenase-1 (HO-1) mediated by b1-adrenergic receptor inhibits high mobility group box 1 protein (HMGB1) release and increases the survival rate in cecal ligation and puncture-induced septic mice. The present study aimed to investigate whether dobutamine, a selective b1-adrenergic receptor agonist, could inhibit HMGB1 release via b1-adrenergic receptor-mediated HO-1 induction and attenuate myocardial ischemia/reperfusion (I/R) injury in rats.
METHODS Anesthetized male rats were pretreated with dobutamine (5 or 10 mg⋅kg−1⋅min−1, intravenous) before ischemia in the absence and/or presence of LY294002 (0.3 mg/kg), a phosphatidylinositol 3-kinase (PI3K)<inhibitor; SB203580 (1 mg/kg), a p38 mitogen-activated-protein kinase (P38 mitogen-activated-protein kinase [p38 MAPK]) inhibitor, and zinc protoporphyrin IX ([ZnPPIX], 10 mg/kg), a HO-1 inhibitor, respectively, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. The myocardial I/R injury and oxidative stress were assessed. Likewise, the expressions of HO-1 protein, nuclear factor kappa B (NF-kB) p65, and HMGB1 were measured by Western blot analysis.
RESULTS Dobutamine significantly and dose-dependently attenuated myocardial I/R injury, reduced oxidative stress, and caused the induction of HO-1, the reduction of NF-kB activation and HMGB1 over expression. However, all the effects caused by dobutamine were significantly reversed by the presence of LY294002, SB203580, and ZnPPIX, respectively.
CONCLUSIONS The present study demonstrated that dobutamine mediated the induction of HO-1 by selectively stimulating b1-adrenergic receptor via PI3K and p38 MAPK, which inhibited HMGB1 release and attenuated rat myocardial I/R injury in vivo.
GW32-e1075
Liyuan Zhu1,2,3,4, Ling Liu1,2,3,4
1Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University
2Research Institute of Blood Lipid and Atherosclerosis, Central South University
3Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province
4Cardiovascular Disease Research Center of Hunan Province
OBJECTIVES Obesity is caused by hypertrophy or hyperplasia of white adipocytes. Obesity is usually accompanied by hypertriglyceridemia. It was reported that the concentration of interleukin-1β (IL-1β) in patients with central obesity was significantly increased after a high-fat meal, accompanied by postprandial hypertriglyceridemia that represents the increased number of triglyceride-rich lipoproteins (TRLs). However, the source of IL-1β was not fully elucidated. To explore the effect of postprandial TRLs on the expression and secretion of IL-1β and other inflammatory cytokines in subcutaneous white adipocytes of mice and investigate the possible mechanism.
METHODS 1. The subcutaneous adipose mesenchymal stem cells of mice and 3T3-L1 cells were induced to white adipocytes with adipogenic reagents. The differentiated adipocytes after 8 d were used as the intervention objects. 2. The density-gradient centrifugation was used to separate TRLs from the blood samples of hypertriglyceridemic patients at 4 h after a high-fat meal. 3. Effects of TRLs on the inflammatory response of white adipocytes of mice: white adipocytes were incubated with different concentrations of TRLs for 24 h or with 100 μg/mL of TRLs for different times. Intracellular lipid droplets were detected by Oil Red O staining. Cell viability was detected by CCK 8 assay. Real-time quantitative PCR was used to detect gene expressions of inflammatory cytokines. Western blot was used to detect protein expression of IL-1β of white adipocytes and the supernatants. The co-culture system was applied to detect migration and adhesion of white adipocytes to macrophages. Western blot was used to detect protein expressions of inflammasome-related makers and autophagy/lysosome-related makers. Lyso-tracker was used to detect the location of lysosomes within white adipocytes.
RESULTS 1. Lipid droplets and gene expressions of IL-1β, IL-18, IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 were significantly increased in white adipocytes treated by TRLs at high concentration (P<0.05). TRLs also promoted the secretion of IL-1β from white adipocytes, and induced the migration and adhesion of macrophages to white adipocytes. 2. Incubating with TRLs at high concentration, the protein expressions of NOD-like receptor protein 3 (NLRP3), Caspase-1, IL-1β, microtubule-associated protein 1A/1B-light chain 3 (LC3), P62 and Cathepsin B (CTSB) were significantly increased (P<0.05). While the protein expressions of lysosome-associated membrane proteins (LAMP-1) and Cathepsin L (CTSL) were significantly reduced (P<0.05), so was the number of intracellular lysosomes. 3. CTSB inhibitor CA074, NLRP3 inhibitor MCC950 and transcription factor EB (TFEB) agonist significantly improved cellular autophagy/lysosome dysfunction, inhibited the activation of NLRP3/Caspase-1 pathway and the protein expression of IL-1β induced by TRLs (P<0.05). 4. The protein expression of phosphorylated mTOR was increased by TRLs at high concentration. Rapamycin, an mTOR inhibitor, obviously improved cellular autophagy/lysosome dysfunction, inhibited the activation of NLRP3/Caspase-1 pathway, and downregulated the protein expression of IL-1β induced by TRLs.
CONCLUSIONS 1. Postprandial TRLs induced inflammatory responses in white adipocytes through impairing autophagy/lysosomes function and then activating NLRP3/Caspase-1 pathway, related to the activation of mTOR. 2. Inhibiting phosphorylation of mTOR, activating TFEB or inhibiting NLRP3 can improve the autophagic dysfunction and alleviate inflammatory response induced by TRLs at high concentration.
GW32-e1160
Jie Qiao1, Fang Li1, Jie Yan1, Dan Luo1, Miaoling Li1, Lin Wu2
1Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University
2Department of Cardiology, Peking University First Hospital
OBJECTIVES A-kinase anchoring protein 9 (AKAP9) is involved in the regulation of cardiac potassium channels by sympathetic nervous system. The gene mutations of AKAP9 may cause long QT syndrome type 11 (LQT11). We find a new mutation of a patient with long QT syndrome in the carboxyl terminus of AKAP9 located at 3712 residue. The aim of this study is to prove the molecular mechanism of the new mutation of AKPA9 caused the patient’s long QT syndrome.
METHODS In mice carrying human AKAP9 mutation gene, Ultrasonic Doppler and electrocardiogram were used to study the cardiac function and electrocardiogram changes of mice. The changes of protein expression of AKAP9 gene was detected by western blot. Optical mapping technology was used to study electrical activity of isolated mice heart.
RESULTS The novel mutation of AKAP9 was detected in proband and her daughter. Two patients were genotyped with LQT11. Forty eight-year-old mother clinically showed with a number of episodes of syncope due to polymorphic ventricular tachycardia. Nevertheless, 32-year-old daughter showed no significantly symptom of syncope. No structural changes were found in the heart of the mice. ECG showed no significant difference between mutation mice and wild-type mice at normal, but QT interval and PR interval were prolonged induced by isoproterenol. The protein of AKAP9 expression decreased significantly compared with wild-type mice.
CONCLUSIONS The new gene mutation of AKPA9 leads to abnormal cardiac electrical activity and decrease the expression of AKAP9 protein. There is correlation between the new gene mutation of AKAP9 and long QT syndrome 11, but the detailed mechanism needs further study.
GW32-e1255
Yuanxiu Song1, Hongxia Li2, Ming Cui1, Feng Lan3
1Department of Cardiology, Peking University Third Hospital
2The Affiliated Zhuzhou Hospital, Xiangya Medial College
3National Center for Cardiovascular Diseases, Fuwai Hospital
OBJECTIVES Alcoholic cardiomyopathy (ACM) is a myocardial injury caused by long-term heavy drinking. In this study, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to establish an ACM model in vitro to explore the role of angiotensin II (Ang II) and its type 1 receptor (AT1R) in the development of ACM and the internal relationship between the two and oxidative stress injury. In addition, this study intends to explore whether the AT1R blocker Losartan has a protective effect on ACM and provide a potential therapeutic agent for the treatment of ACM.
METHODS In this study, human induced pluripotent stem cells (hiPSCs) were differentiated into hiPSC-CMs by small molecular differentiation technique, and an ACM model was established by treated with alcohol in vitro. The effect of alcohol on myocardial activity was detected by CCK8. The real-time cell analysis system (RTCA) was used to monitor the changes of cardiac electrophysiological function caused by alcohol treatment. The myocardial oxidative stress injury caused by alcohol treatment was detected by CM-H2DCFDA probe. Real-time quantitative PCR and Western blot were used to observe the changes in the expression levels of Ang II, AT1R and a class of NADPH oxidase (NOX), which can cause oxidative stress, in cardiomyocytes after alcohol exposure. The effects of losartan on the above damage effects and the expression of related proteins were detected by the above methods. PRISM6 software was used for data processing. T-test was used for the comparison of measurement data conforming to normal distribution between two groups, and one-way analysis of variance was used for the comparison between multiple groups. P<0.05 was considered statistically significant.
RESULTS The ACM model of hiPSC-CMs was successfully established in this study. Losartan was found to be able to alleviate the dose-dependent decrease of hiPSC-CMs cell viability induced by alcohol treatment and can also improve the damage of cell electrophysiological functions such as cell index, vibration amplitude, and beating frequency caused by alcohol treatment. The upregulation of Ang II/AT1R and NOX4 expression and the oxidative stress injury induced by alcohol treatment of hiPSC-CMs can be rescued by losartan.
CONCLUSIONS Alcohol causes a decrease in myocardial cell viability, an increase in oxidative stress levels, an up-regulation of Ang II/AT1R levels, and lead to electrophysiological dysfunction. Ang II/AT1R participates in alcohol damage to cardiomyocytes by regulating NOX to activate the oxidative stress system. Losartan can recover the myocardial damage caused by alcohol treatment, which provides a direction for the treatment of ACM.
GW32-e1334
Lei Dai, Yang Xie, Hongjie Wang, Hesong Zeng
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
OBJECTIVES Diabetic cardiomyopathy (DbCM) is characterized by initial impairment of left ventricular relaxation followed by contractile dysfunction. Despite intensive research, the exact mechanism remains so far unsolved.
METHODS Based on the GSE 5606 dataset, we constructed weighted gene co-expression network analysis (WGCNA) to screen gene modules that were highly co-regulated and closely related with DbCM. The enrichment analysis was performed to identify the biological function of essential module genes. We used the protein-protein interaction (PPI) network and differentially expressed genes (DEGs) to identify hub genes. The most related gene was selected for functional ex vivo and in vitro assays.
RESULTS A total of 14 modules were identified via the average linkage clustering. The yellow and green modules were most positively or negatively correlated with DbCM. The top hub genes, including ANGPTL4, ACOT1, HMGCS2, PDK4, DECR1, SLC2A4, and HK2, were identified and verified by qPCR. The expression of ANGPTL4, ACOT1, HMGCS2, and PDK4 was significantly up-regulated in DbCM. Here, we further investigated the effects and mechanisms of ANGPTL4 in the pathogenesis of DbCM. The mouse models of STZ-induced DbCM, compared with control models, had increased phosphorylation of focal adhesion kinase (p-FAK), upregulated NADPH oxidase activation, and enhanced apoptosis in the diabetic heart. Accordingly, siRNA-mediated knockdown of ANGPTL4 in cardiomyocytes inhibited p-FAK, NADPH oxidase, and apoptosis under high-glucose conditions.
CONCLUSIONS ANGPTL4, ACOT1, HMGCS2, and PDK4 may play critical roles in the pathogenesis of DbCM. ANGPTL4 may induce apoptosis in the DbCM heart via the FAK/NADPH oxidase pathway.
GW32-e1454
Junyi Yu1,2,3, Gengze Wu1,2, Ye Zhang1,2, Jining Yang4, Xue Gong1,2, Hao Luo1,2, Zaicheng Xu1,2, Qiao Liao1,2, Zhi Chen1,2, Miao Tian1,2, Peili Yang1,2, Chen Gao3, Christoph Rau3, Bing Zhang5, Yibin Wang3, Chunyu Zeng1,2
1Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, P.R. China
2Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, P.R. China
3Division of Molecular Medicine, Departments of Anesthesiology, Physiology and Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA
4Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, The Third Military Medical University, Chongqing, P.R. China
5Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China
OBJECTIVES Vascular smooth muscle cells (VSMCs) undergo significant reprogramming under pathological stresses from contractile to proliferative phenotype. While gene regulation associated with this process is well recognized, the underlying mechanisms remain to be fully elucidated. Long non-coding RNAs (lncRNAs) are potential players in the regulation of VSMCs phenotypic switch, however, a subset of mammalian lncRNAs may produce both polypeptides as well as functional regulatory transcripts. Therefore, the functional impact and regulatory mechanisms for lncRNA mediated gene regulation in VSMCs remain to be fully explored.
METHODS We analyzed lncRNA expression profiles in normal and diseased vascular tissues following VSMC reprogramming. Molecular analysis was performed to uncover the underlying mechanisms and gain- and loss-of-function in intact rats were conducted to establish the functional significance in response to vascular injury.
RESULTS We identified a VSMCs enriched gene called Phenotype-Switching-Regulator (PSR), which was markedly altered in expression during vascular remodeling. Although the PSR gene was annotated as a lncRNA, we demonstrated that the PSR gene also encoded a peptide (Arteridin). In VSMCs, both Arteridin and lncPSR were necessary and sufficient to induce a significant transition from contractile to proliferative phenotype. In addition, we found Arteridin and lncPSR regulated downstream genes through direct interaction with a transcription factor YBX1 by modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by Arteridin. Most relevantly, loss of PSR gene or Arteridin protein significantly attenuated vascular remodeling induced by carotid arterial injury. Finally, the expression of lncPSR and Arteridin protein was also significantly altered in human mesenteric arteries specimens with pathological remodeling, and human Arteridin interacted with YBX1 and was sufficient to induce phenotype switching in rat VSMCs.
CONCLUSIONS A single VSMC enriched gene PSR produces two functional entities including a regulatory lncRNA and a peptide. They coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, involving both coding and non-coding products from a single gene.
GW32-e1579
Wei Shang
The Ninth People’s Hospital of Chongqing
OBJECTIVES It has been found that funny current (If) plays an important role in the occurrence and development of atrial fibrillation (AF), and ivabradine, a specific blocker, can reduce the incidence of arrhythmia by inhibiting If. This study intends to establish a rapid pacing model based on the atrial myocytes of neonatal rats, and to investigate the effect of ivabradine on hyperpolarization-activated cyclic nucleotide-gated channel (HCN).
METHODS The atrial myocytes of primary neonatal Sprague Dawley (SD) rats were isolated and cultured, a rapid pacing model was established, and then drug intervention was performed. mRNA and microRNA expression in each group were detected using real-time PCR. The expression of HCN2 and HCN4 proteins in each group were detected by Western blotting. If was recorded by whole-cell patch-clamp experiment.
RESULTS Real-time PCR results showed that the mRNA expression of HCN2 and HCN4 was significantly down-regulated, while the expression of microRNA-1 and microRNA-133 was significantly up-regulated in the pacing+iva group. Western blotting results revealed that the expression of HCN2 and HCN4 proteins in the pacing+iva group was significantly down-regulated. Whole-cell patch-clamp experiment demonstrated that the density of Ifin the pacing+iva group reduced significantly.
CONCLUSIONS Ivabradine can inhibit the occurrence of acute AF by inhibiting the gene and protein expression of HCN2 and HCN4, If amplitude and the electrical remodeling of atrial tissue.
GW32-e1655
Liangpeng Li, Chunyu Zeng, Wei Wang
Daping Hospital, Third Military Medical University
OBJECTIVES Exploring potential therapeutic target is of great significance for myocardial infarction (MI) and post-MI heart failure. Transcription factor Yin-Yang 1 (YY1) is an essential regulator of apoptosis and angiogenesis, but its role in MI is unclear.
METHODS The expression of YY1 was assessed in C57BL/6J mouse heart post MI. Over-expression or silencing of YY1 in mouse heart was achieved by adeno-associated virus 9 injection. The survival, cardiac function, scar size, as well as the apoptosis, angiogenesis, cardiac fibrosis, Th2 lymphocyte (Th2) cytokines production and macrophage polarization were assessed respectively. The effects of YY1 on Akt phosphorylation and vascular endothelial growth factor (VEGF) production were also investigated.
RESULTS The expression of YY1 in heart was significantly stimulated by MI. The survival rate, cardiac function, reduced scar size and left ventricle volume of mice were improved by YY1 over-expression but impaired by YY1 silencing. YY1 alleviated cardiac apoptosis and fibrosis, promoted angiogenesis, Th2 cytokines production and M2 macrophage polarization in post MI heart, it also enhanced the tube-formation and migration ability of endothelial cells. Enhanced Akt phosphorylation, along with the increased VEGF levels were observed in presence of YY1 over-expression.
CONCLUSIONS YY1 ameliorates cardiac injury and remodeling after MI by repressing cardiomyocyte apoptosis and boosting angiogenesis, which might be ascribed to the enhancement of Akt phosphorylation and the subsequent VEGF up-regulation. Increased Th2 cytokine production and M2 macrophage polarization may also be involved in YY1’s cardio-protective effects. These findings supported YY1 as a potential target for therapeutic investigation of MI.
GW32-e1732
Yanan Zhao, Daoyuan Si, Ping Yang
China-Japan Union Hospital of Jilin University
OBJECTIVES The mortality and rehospitalization rates remain high in patients with heart failure (HF) following acute myocardial infarction. Cardiacryanodine receptor type2 (RyR2) dysfunction, which leads to increased diastolic Sarcoplasmic reticulum (SR) calcium leak, is reported to involved in the progress recently. The purpose of this study is to determine the improvement of RyR2 receptor regulation on rat model of ischemic heart failure and the potential mechanism.
METHODS Thirty male Sprague-Dawley rats were randomly divided into a sham group (n=10) and the HF group (n=20). HF model was established by myocardial infarction which was induced by occlusion of the left anterior descending coronary artery. Twenty rats in HF group were randomly divided into experimental group (HF+DAN, n=10) and control group (HF n=10). The experimental group rats were treated with dantrolene i.p. (DAN, 15.4 mg/kg/day) once a day for eight weeks. Ten rats of the sham group and the control group were given the same volume of normal saline. The echocardiography were performed in each group at four weeks and eight weeks respectively. After eight weeks, we measured the hemodynamic parameters in vivo and the electrophysiological indexes in isolated heart by Langendorff setup. The total RyR2 and phosphorylated RyR2 at S2808 and S2814 of myocardial tissue were assessed in by Weston blot analysis.
RESULTS Compared with the sham group, the cardiac function of the experimental group and the control group decreased significantly. But compared with the control group, the Left Ventricular (LV) end-diastole pressure was significant low, while the LV end-systolic pressure, LV dp/dt max, LV dp/dt min, ejection fraction (EF) and Left ventricular short-axis shortening rate are high in rats treated with RyR2 regulation by DAN. Heart rates were not significantly different among the 3 groups. The action potential duration (APD90) of experiment and control group were significant prologated compared with the sham. DAN treatment significantly reduced this prologation and the incidence of VF. There was no significant difference expression of RyR2 among the 3 groups. Compared to the sham group, the expression of RyR2 phosphorylation at S2808 and S2814 were significant higher in both DAN and control group. However, a significant reduction in the phosphorylation of RyR2 at S2814 was observed in the DAN treatment hearts in comparison with control (P<0.05 vs. control group).
CONCLUSIONS In the HF rat model following myocardial infarction, RyR2 regulation treatment improved cardiac function and hemodynamics, as well as ventricular electrical stability. Our results suggest that decreased phosphorylation of RyR2 plays a role in the ischemic forms of HF such as MI rats. It may provide a novel therapeutic strategy for the treatment of ischemic forms of heart failure.
GW32-e1822
Menglong Wang, Jishou Zhang, Jun Wan
Wuhan University Renmin Hospital
OBJECTIVES Sympathetic hyperactivity contributes to the pathological remodeling after myocardial infarction (MI). However, the mechanisms underlying the activation of sympathetic nervous system remain unknown. Microglia are the predominant immune cells in the central nervous system, which can regulate the neuron activity through neuroinflammation response. The present study aimed to investigate whether central microglia can regulate the sympathetic activity and cardiac remodeling after MI.
METHODS PLX3397 (40 mg/kg/day, oral gavage) was used to deplete central microglia. After treatment with PLX3397 for 21 days, MI was induced by the ligation of left anterior descending coronary artery.
RESULTS Our study found that MI resulted in the activation of central microglia, which could be significantly depleted by PLX3397. Microglia depletion could suppress MI induced cardiac dysfunction, infarction size, myocardial injury and cardiac fibrosis. In addition, microglia depletion attenuated MI-induced cardiac apoptosis, oxidative stress, neutrophil infiltration, M1 macrophage polarization and the migration of monocytes/macrophages to the infarct heart. Furthermore, the increased QT interval and QTc interval and decreased CX43 expressions were attenuated by microglia depletion in mice with MI. Mechanically, these protective effects of microglia depletion were associated with the attenuated neuroimmune response in the hypothalamic paraventricular nucleus, which contributed to the decrease of sympathetic activity and sympathetic remodeling in the heart.
CONCLUSIONS Microglia depletion in central nervous system could attenuated cardiac pathological remodeling and improve cardiac function after MI through inhibiting the sympathetic activity. Targeting the neuroinflammation response mediated by microglia may be a promising approach for the treatment of MI.
GW32-e1908
Jianbing Wang1,2, Jun Zhang1,3
1Tianjin Medical University
2General Hospital of Huabei Petroleum Administration Bureau
3Cangzhou Central Hospital
OBJECTIVES Atherosclerosis (AS) is caused by lipid-driven inflammatory response. The objective of this study was to clarify the mechanisms of the effect of Helianthus Annuus L. (HAL) on AS.
METHODS In this study, AS mouse lacking apolipoprotein E (Apoe−/− ) model which was induced by high-fat diet (HFD) received feed containing 5% HAL for 24 weeks. After administration, the analysis of plaque on aortic was conducted, then the possible mechanisms were further explored.
RESULTS HAL reduced the size of atherosclerotic lesion in HFD-induced AS model. HAL adjusted the serum lipid and decreased LDL/HDL ratio. HAL up-regulated concentrations of superoxide dismutase (SOD), nitric oxide (NO) and glutathione peroxidase (GSH-Px) and down-regulated concentrations of malondialdehyde (MDA) in the aorta. In addition, HAL also reduced diversity of the intestinal microbiota and regulated the relative abundance of Akkermansia, Lactobacillus, unidentified_Enterobateriaceae, Sphingomonas, and Methylobacterium. In the end, HAL decreased the permeability of intestine by increasing the levels of occludin and tight junction protein 1 (ZO-1) in the colon, consequently decreasing concentration of interleukin (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α) in serum and mRNA expressions in the aorta.
CONCLUSIONS Data showed that HAL alleviates AS by inhibiting inflammation, restraining oxidative stress and regulating intestinal microbiota. Our findings provided novel insights into the role and mechanistic of anti-atherogenic potential of HAL.
GW32-e0083
Qiong-Dan Zhang, Li Fang*
Department of Cardiology, The First Hospital of Changsha, Changsha 410008, China
OBJECTIVES This study intends to explore the role of nucleolin in the proliferation of VSMCs induced by Ang II and its molecular mechanism from the perspective of protein-mRNA interaction.
METHODS Brdu labeling, protein quantification, and MTT were used to evaluate Ang II induces the proliferation of VSMCs, and the mRNA, protein and secretion expression of TGF-β1 and VEGF were detected. Gene transfection, RNA interference technology and nucleolin mutants were used to analyze the regulation of nucleolin on the expression of TGF-β1 and VEGF and its mRNA stability. Finally, immunoprecipitation, RNA-EMSA and luciferase reporter gene were used to analyze the binding of nucleolin to the 3′-UTR of TGF-β1 and VEGF mRNA.
RESULTS The results showed that Ang II could increase the DNA synthesis capacity, total cell protein content and cell survival rate of VSMCs. After stimulating VSMCs with different concentrations and time of Ang II, the expression of TGF-β1 and VEGF gradually increased. Nucleolin overexpression could promote the expression and secretion of TGF-β1 and VEGF, while nucleolin RNA interference could significantly inhibit the expression and secretion of TGF-β1 and VEGF, nucleolin mutant (Nucl-309) loses its regulatory effect on the expression of TGF-β1 and VEGF. Moreover, the combination of nucleolin with TGF-β1 and VEGF mRNA 3′UTR could up-regulate the stability and expression of TGF-β1 and VEGF mRNA.
CONCLUSIONS Therefore, nucleolin can increase the stability of TGF-β1 and VEGF mRNA and up-regulate its protein expression by binding to the 3′UTR of TGF-β1 and VEGF mRNA, thereby promoting the proliferation of VSMCs induced by Ang II.
GW32-e0151
Mingming Zhang
Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University
OBJECTIVES Doxorubicin (DOX) has been a widely used chemotherapy drug since the 1960s, but its widespread use is limited given its dose-dependent cardiotoxicity. In a retrospective study, congestive heart failure (CHF) occurred in 5% of patients who received DOX treatment at a dose of 500–550 mg/m2. The incidences of CHF in DOX-treated patients at doses of 551–600 and >601 mg/m2 were 16 and 26%, respectively. DOX cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro.
METHODS Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. The cardiac function, cardiac fibrosis, cardiomyocytes apoptosis, mitochondrial function and mitophagy were detected.
RESULTS Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22.
CONCLUSIONS miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.
GW32-e0379
Shaoheng Zhang, Ji Zhou Ji, Songsheng Chen, Jin Cui, Weiguang Huang, Rui Zhang, Jianrui Wei
GuangZhou Red Cross Hospital Medical College of Ji-Nan University
OBJECTIVES The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). However, their poor survival and potential in the ischemic environment limits their therapeutic efficacy for heart repair after MI. The purpose of this study was to investigate the influence of FoxC1-induced vascular niche on the activation of octamer-binding protein 4 (Oct4) and the fate of MSCs under hypoxic/ischemic conditions.
METHODS Vascular microenvironment/niche was induced by efficient delivery of FoxC1 transfection into hypoxic endothelial cells (ECs) or infarcted hearts. MSCs were cultured or injected into this niche by utilizing an in vitro coculture model and a rat MI model. Survival and neovascularization of MSCs regulated by Oct4 were explored using gene transfer and functional studies.
RESULTS Here, using gene expression heatmap, we demonstrate that cardiac ECs rapidly up-regulated FoxC1 after acute ischemic cardiac injury, contributing to an intrinsic angiogenesis. In vitro, FoxC1 accelerated tube-like structure formation and increased survival of ECs, resulting in inducing a vascular microenvironment. Overexpression of FoxC1 in ECs promoted survival and neovascularization of MSCs under hypoxic coculture. Overexpression of Oct4, a FoxC1 target gene, in MSCs enhanced their mesenchymal-to-endothelial transition (MEndoT) while knockdown of Oct4 by siRNA altering vascularization. In a rat MI model, overexpression of FoxC1 in ischemic hearts increases post infarct vascular density and improves cardiac function. Transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhances vascularity and further improves cardiac function. Consistently, these cardioprotective effects of FoxC1 was abrogated when Oct4 was depleted in the MSCs and was mimicked by overexpression of Oct4.
CONCLUSIONS Together, these studies demonstrate that the FoxC1/Oct4 axis is an essential aspect for survival and neovascularization of MSCs in the ischemic conditions and represents a potential therapeutic target for enhancing cardiac repair.
GW32-e0515
Qi Liu1, Yi Luo1, Yun Zhao1, Pingping Xiang1, Jinyun Zhu1, Wangwei Jing1, Wenjing Jin2, Mingyao Chen1, Ruikang Tang2, Hong Yu1
1The Second Affiliated Hospital Zhejiang University College of Medicine
2Department of Chemistry, Zhejiang University
OBJECTIVES To clarify the specific role of nano-sized hydroxyapatite (nHAp) in the occurrence and development of vascular calcification, and provide a new idea for the prevention and control of vascular calcification.
METHODS Human calcified aorta specimens were collected and the characteristics of calcified aorta were identified by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and immunofluorescence techniques. nHAp was synthesized and extracted from human calcified plaques respectively, and identified and compared by SEM, XRD and FT-IR. The Alizarin Red staining, calcium content, the expressions of osteogenic genes Runx2 and OPN, and alkaline phosphatase (ALP) activity were detected to demonstrate the role of nHAp in SMCs. TEM, immunofluorescence staining and Western blot analysis were used to determine the mechanism of nHAp-induced smooth muscle cell calcification. nHAp was implanted subcutaneously and smeared on the surface of abdominal aorta respectively in C57BL/6J mice. Micro-CT scanning and pathological section staining were performed to determine the effect of nHAp on smooth muscle cell calcification in vivo.
RESULTS We found nanoscale HAp in human calcification specimens, nHAp adhered to the surface of vascular cells, and nHAp was found in intracellular lysosomes. Synthetic nHAp and nHAp extracted from human specimens were similar in morphology, size and chemical composition, which provided support for the subsequent experimental study to replace human nHAp with synthetic nHAp. In vitro, nHAp induced osteogenic transformation of SMCs, resulted in a large amount of calcium deposition extracellularly, which was significantly higher than that in the normal calcification medium group. In vivo, nHAp induced calcium deposition in subcutaneous grafts and abdominal aorta and increased Runx2 expression in SMCs. TEM showed that both human origin and synthetic nHAp increased the number of autophagosomes compared with the control group in vitro. LC3 dual fluorescent adenovirus confirmed that nHAp induced the blockage of autophagy flux in SMCs. However, nHAp did not affect the fusion of autophagosomes and lysosomes. After nHAp treatment, acidizing capacity of lysosomes decreased. EGFR degradation experiments showed that nHAp affected the degradation of EGFR in lysosome, suggesting that the lysosome dysfunction affected autophagy degradation. The co-localization rate of lysosomal pump V-ATPase and LAMP1 decreased, suggesting that the damage of proton pump may be the reason for the decreased capacity of lysosomal acidification. nHAp promoted the release of exosomes, and calcium content in exosomes was significantly increased. Moreover, LC3 and LAMP1 in exosomes were significantly increased in nHAp treatment group. Exosome release inhibitor GW4869 can down-regulate exosome release induced by nHAp and inhibit calcium deposition.
CONCLUSIONS Blockage of autophagy flux participates in nHAp-accelerated calcification. Our results suggest that targeting this novel autophagy-lysosome-exosome pathway may help to control vascular calcification development.
GW32-e0549
Heng Ma, Tian Li, Yue Yin, Yishi Wang, Nan Mu
School of Basic Medicine, Fourth Military Medical University
OBJECTIVES Cardiac autophagic flux is impaired during myocardial ischemia/reperfusion (MI/R). Impaired autophagic flux may exacerbate MI/R injury. Charged multivesicular body protein 2B (CHMP2B) is a subunit of the endosomal sorting complex required for transport (ESCRT-III) complex that is required for autophagy. However, the reverse role of CHMP2B accumulation in autophagy and MI/R injury has not been established. The objective of this article is to elucidate the roles of AMPK/Atrogin-1 pathways in inhibiting CHMP2B accumulation in ischemia–reperfusion injury.
METHODS Male C57BL/6 mice (3–4 months) and H9c2 cardiomyocytes were used to evaluate MI/R and hypoxia/reoxygenation (H/R) injury in vivo and in vitro, respectively. MI/R was built by a left lateral thoracotomy and occluded left anterior descending artery. H9c2 cells were firstly treated in 95% N2 and 5% CO2 for 15 h and reoxygenation for 1 h. Metformin (100 mg/kg/d) and CHMP2B (Ad-CHMP2B) transfected adenoviruses were administered to the mice. The H9c2 cells were treated with metformin (2.5 mM), MG-132 (10 μM), bafilomycin A1 (10 nM), and Compound C (20 μM).
RESULTS Autophagic flux was found to be inhibited in H/R-treated cardiomyocytes and MI/R mice, with elevated cardiac CHMP2B accumulation. Upregulated CHMP2B levels in the in vivo and in vitro experiments was shown to inhibit autophagic flux leading to the deterioration of H/R-cardiomyocytes and MI/R injury. This finding implies that CHMP2B accumulation increases the risk for myocardial ischemia. Metformin suppressed CHMP2B accumulation and ameliorated H/R-induced autophagic dysfunction by activating AMPK. Activated AMPK up-regulated the mRNA expression and protein levels of Atrogin-1, a muscle-specific ubiquitin-ligase, in the myocardium. Atrogin-1 significantly enhanced the interaction between Atrogin-1 and CHMP2B, therefore, promoting CHMP2B degradation in the MI/R myocardium. Finally, this study revealed that Metformin inhibited CHMP2B accumulation induced autophagic impairment and ischemic susceptibility in vivo through the AMPK-regulated CHMP2B degradation by Atrogin-1.
CONCLUSIONS Impaired CHMP2B clearance in vitro and in vivo inhibits autophagic flux and weakens the myocardial ischemic tolerance. Metformin treatment degrades CHMP2B through the AMPK-Atrogin-1 dependent pathway to maintain the homeostasis of autophagic flux. This is a novel mechanism that enriches the understanding of cardioprotection.
GW32-e0604
Jinyun Zhu, Ning Zhang, Yayu You
Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University.
OBJECTIVES Recent studies have shown that innate response can exert adaptive features building immunological memory. This process has been termed ‘trained immunity’. Recurrent myocardial ischemia is common in patients with coronary artery disease, which predicts adverse outcome and high mortality in patients with unstable angina. Since HIF-1a is a major player in monocytes activation and also targets some epigenetic enzymes, we hypothesize that repeated hypoxia/ischemia can lead to “trained immunity” in macrophages and inflammation in a mouse model of recurrent myocardial ischemia. Our study aims to elucidate the effect and mechanism of recurrent transient myocardial ischemia on macrophages and cardiac inflammation.
METHODS We developed a surgical mouse model of recurrent transient myocardial ischemia, which was induced by ligating the left anterior descending coronary artery for 5 min followed by resting 1 week. Mice were divided in trained and sham groups. The trained mice were subjected to the first, second and third insult of transient ischemia. Before and after the first, second and third ischemia insult, heart function was examined by echocardiography. Heart tissues from all groups were investigated for cardiac fibrosis, inflammation, and oxidative stress markers. Cardiac immune cell filtration and inflammation were examined by flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. For an in vitro assay, monocytes were isolated and placed in normoxia (21% O2) and hypoxia (2% O2) for 24 h followed by a resting period of 3 days after the training, both groups were replaced in normoxia for the last 24 h. Several cytokines were then quantified by ELISA. Blood leukocyte count and IL-6 were retrospectively analyzed from patients with stable angina and unstable angina.
RESULTS Recurrent ischemia (third ischemia) triggers significant cardiac fibrosis and aggravated cardiac dysfunction in mice as compared to sham, first and second ischemia insults. There are more macrophages (CD11b+Ly-6G−F4/80+) in the recurrent ischemia myocardium, whereas no difference of neutrophils (CD11b+Ly-6G+). Intriguingly, cardiac macrophages are basically CCR2+ (C-C chemokine receptor 2) cells, suggesting that vast majority of them are derived from bone marrow. In vitro assay, hypoxia training results in significantly increased mRNA level and production of proinflammatory cytokines, such as IL-6, IL-8, TNF-α, and IL-1β, compared with normoxia and only once hypoxia insult. The underlying mechanisms is that hypoxia training in macrophages leads to activate mTOR-HIF1α pathway and increased ROS and lactate production. There are no differences in peripheral blood leukocytes in stable angina, except for patients with recurrent angina who had increased number of white blood count compared with their first episode of chest pain. A positive correlation between peripheral leukocyte count and recurrent angina was discovered.
CONCLUSIONS The data suggested that monocyte-derived macrophages can be trained and ignited by preceding recurrent ischemia/hypoxia insult, cause cardiac inflammation, and predict outcome of ischemia in angina.
GW32-e0849
Kun Zhao, Wei Sun, Peng Li, Xiangqing Kong
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
OBJECTIVES Cardiac fibrosis and hypertrophy, as the major hallmarks of cardiac remodeling involved in the pathophysiological process of hypertensive heart diseases, can result in disturbed function and structure of the myocardium. Alamandine (Ala), a ligand of Mas-related G protein-coupled receptor, member D (MrgD), alleviates angiotensin II (Ang II)-induced cardiac hypertrophy. However, the specific physiological and pathological role of MrgD is not yet elucidated.
METHODS We used Ang II to mimic the animal or cell culture models of cardiac hypertrophy and fibrosis. Pretreatment or intra-myocardial injection of recombinant adenovirus-MrgD (AD-MrgD) or adenovirus-shRNA-MrgD (shRNA-MrgD) were further used to verify the pathophysiological function of MrgD in vivo and in vitro. Then, low-intensity pulsed ultrasound (LIPUS) irradiation (0.5 MHz, 77.20 mW/cm2) was applied for 20 minutes every other day in mice received chronic Ang II infusion in vivo. Following that, the levels of cardiac hypertrophy and fibrosis were evaluated by echocardiographic, histopathological, and molecular biological methods.
RESULTS Here, we found MrgD expression increased under various pathological conditions. Then, MrgD knockdown reversed Ang II-induced hypertrophy in NRCM and fibrosis in NRCF via inactivating Gai-mediacted downstream signaling pathways, including the phosphorylation of p38 mitogen-activated protein kinase and protein kinase A, while MrgD overexpression induced pathological cardiac remodeling. Next, Ala, like silencing MrgD, exerted its cardioprotective effects by inhibiting Ang II-induced nuclear import of MrgD. Further, LIPUS, a novel and safe apparatus, improved Ang II-induced cardiac remodeling in vivo, and alleviated NRCM hypertrophy and NRCF fibrosis in vitro via inhibiting nuclear import of MrgD and oxidative stress.
CONCLUSIONS Taken together, our current study unveiled the promising cardioprotective effect of silencing MrgD expression on alleviating Ang II-induced cardiac hypertrophy and fibrosis by reducing its nuclear import, paving the way to develop novel therapeutic apparatus, LIPUS, in the clinical practice of cardiac remodeling in the future.
GW32-e0940
Dongchen Wang
Nanjing First Hospital
OBJECTIVES Diabetic cardiomyopathy (DCM) is characterized by cardiac hypertrophy and fibrosis, and G protein-coupled receptor kinases 2 (GRK2) is an important target in regulating various kinds of cardiac damage. Polymerase-δ interacting protein 2 (Poldip2), a mitochondrial protein, regulates many cellular functions. Here, we decide to study whether GRK2 has an effect in regulating Poldip2 signaling pathway in DCM.
METHODS C57BL/6J mice were induced to diabetes by intraperitoneal injection of streptozotocin and were injected with adeno-associated virus containing ShGRK2 (AAV-ShGRK2) to inhibit GRK2 expression for 12 weeks. We used H9C2 cell line and neonatal rat cardiomyocytes (NRCMs) with small interfering RNA (SiGRK2) and adenovirus (Ad-GRK2) to decrease or increase GRK2 protein level prior to high glucose (HG) exposure to carry out the experiment in vitro. Echocardiography and histological analysis evaluated cardiac structure and function. Mitochondria function was detected by scanning electron microscope, seahorse analytic system and immunofluorescent staining. The GRK2 and Poldip2 expression and mitochondria localization were determined in cells and cardiac tissues.
RESULTS GRK2 deficiency attenuated HG-induced cardiac injury through inhibiting cardiac hypertrophy and fibrosis. In vitro, GRK2 induces mitochondria dysfunction, ROS accumulation and Calcium overload in NRCMs exposed to HG. In contrary, knock-down of GRK2 with siGRK2 in H9C2 cells improves myocardial apoptosis and mitochondria function. Also, increasing binding between GRK2 and Poldip2 induced by HG promotes Poldip2 mitochondria translocation and ROS production. Loss of GRK2 inhibits Poldip2 expression and mitochondria translocation to improve mitochondria morphological structure and function.
CONCLUSIONS The study provides more evidence of the therapeutic potential of GRK2 inhibitors in DCM.
GW32-e1008
Jichun Wang, Lang Wang, Li Lu, Sisi Chen, Jing Xie, Yanli Zhou, Hong Jiang
Renmin Hospital of Wuhan University
OBJECTIVES Ischemia-reperfusion (I/R) injury, which leads to additionally cardiac tissue damage, is a severe adverse effect of reperfusion therapeutics used for the treatment of acute myocardial infarction. Agents capable of alleviating I/R-induced myocardial injury are urgently needed. In this study, we investigated whether up-regulation of PERK/Nrf2/HO-1 axis provided protective roles for murine myocardium suffering I/R intervention.
METHODS The in vivo I/R model was formed by ligation of the left anterior descending (LAD) coronary artery of C57BL/6J mice. All animals were assigned into the following groups at random: sham, I/R, rAAV9-PERK + I/R, rAAV9-Nrf2 + I/R, rAAV9-HO-1 + I/R, siRNA-HO-1 + rAAV9-PERK + I/R. The ligation of LAD was released after 30 min of ischemia, which was followed by reperfusion of LAD for 4 h. Then the cardiac tissues and blood serum were collected. TUNEL staining, ELISA assay, TTC staining, Western blotting and real-time PCR were used to determine I/R injury-related indicators.
RESULTS Our results showed that I/R administration triggered cardiomyocytes apoptosis and LDH and CK-MB release, yet overexpression of PERK decreased cellular apoptosis index in the cardiac tissue and reduced levels of LDH and CK-MB in the serum. We further found that the protective actions of PERK against I/R-evoked cardiac damage might be attributed to up-regulation of Nrf2/HO-1 signaling transduction, given that overexpression of Nrf2 and HO-1 ameliorated cardiac cell apoptosis and reduced the size of infarction and ischemia in the myocardial tissue, yet gene silencing of HO-1 invalidated the beneficial roles of PERK overexpression in improving I/R-induced cardiac injury. Then, we investigated whether PERK-activated Nrf2/HO-1 cascade affected endoplasmic reticulum stress (ERS), considering the crucial roles of ERS-associated apoptosis in the development of I/R damage. Our findings indicated that up-regulation of PERK-mediated Nrf2/HO-1 pathway induced the expression reduction of GRP78, CRT, CHOP and caspase-12 both at the transcriptional and translational level.
CONCLUSIONS We, for the first time, discovered that up-regulation of PERK/Nrf2/HO-1 axis improved I/R-induced myocardial injury via reducing ERS-related signal molecules and downstream pro-apoptotic factors.
GW32-e1078
Jiahe Xie
Gannan Medical University
OBJECTIVES A woman’s age at final pregnancy is correlated with post-reproductive longevity, and we previously reported a phenomenon termed myocardial hypertrophic preconditioning. Based on these data, we investigated whether myocardial hypertrophic preconditioning during pregnancy created anti-hypertrophic memory and cardiac resistance to subsequent pathological hypertrophic stress, as well slowing progression to heart failure.
METHODS In C57BL/6 mice, cardiac hypertrophy was induced by either transverse aortic constriction (TAC) or infusion of angiotensin II (Ang II). In addition, hypertrophy of cultured neonatal rat ventricular cardiomyocytes (NRVCs) was induced by exposure to Ang II. To assess the influence of preconditioning, mice at 3 weeks postpartum received Ang II infusion or TAC for the same period as the control group, or NRVCs were cultured with Ang II for 12 h and without it for 24 h, followed by re-exposure to Ang II for 48 h like control cultures.
RESULTS In C57BL/6 mice, the heart weight/body weight ratio and expression of fetal genes (ANP and β-MHC) were significantly lower after preconditioning. In addition, the lung weight/body weight ratio was significantly lower in the preconditioned group at 4 weeks after TAC. Consistent results were obtained with cultured NRVCs after Ang II treatment. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice and in preconditioned NRVCs, and this change persisted after re-exposure to the hypertrophic stimulus. Silencing of FoxO3a attenuated the anti-hypertrophic effect of pregnancy preconditioning in mice with Ang II infusion and increased cardiomyocyte growth and apoptosis, while overexpression of FoxO3a prevented such changes.
CONCLUSIONS Myocardial hypertrophic preconditioning induced by pregnancy confers resistance to subsequent hypertrophic stress and slows progression to heart failure. FoxO3a is involved in cardiac protection by pregnancy hypertrophic preconditioning.
GW32-e1172
Aiqun Chen, Xiaofei Gao
Nanjing First Hospital
OBJECTIVES In-stent restenosis (ISR) still remains an Achilles heel of drug-eluting stents in spite of the technical advances in devices and procedural techniques. The present study is to map normal arteries and stenotic arteries to explain the mechanism of ISR by single-cell RNA sequencing.
METHODS We performed balloon injury surgery (Fogarty, 12A0602F) on the right cartoid arteries of rats, and selected the left ones of the same rats as a control. Single cells isolated from the carotid arteries underwent single-cell sequencing (10× Genomics platform, database available as GSE174098). The raw sequencing data was analyzed by Seurat R package (3.1.1) for single-cell genomics.
RESULTS By comparing left (control) and right (balloon injury) carotid arteries of rats, we mapped 11 clusters in normal arteries and 11 mutual clusters in both control and experimental groups. Different clusters were categorized into 6 cell types, including vascular smooth muscle cells (VSMCs), fibroblasts, endothelial cells (ECs), macrophages, unknown cells and others. A new cell type (unknown cells), expressing both VSMC and fibroblast markers at the same time, was termed as transitional-cell via the pseudotime analysis. The proportion of different cell types changed obviously between case and control groups especially VSMCs. Therefore, we highlighted VSMCs and divided them into 6 clusters and analyzed their relationship with VSMC phenotype switching. We used previously reported contractile and synthetic phenotype markers to identify VSMCs. Meanwhile, N-myristoyltransferase 1 (NMT1) was verified as a credible VSMC synthetic phenotype marker among these synthetic VSMCs.
CONCLUSIONS Maps of heterogeneous cellular landscape in carotid artery were defined by single-cell RNA sequencing and revealed several cell types with their internal relations in the ISR model. In fact, single-cell sequencing could be a reliable means of defining cell types. We have found the path of disease evolution from the changes in the proportion of various cell types especially the role of transitional-cell between VSMC and fibroblast. The specific key genes of transitional-cells were also picked out by heat map and dynamic change trend graph of pseudotime analysis. The reduction of transitional-cells and increase of fibroblasts indicated the fibrosis among VSMCs. Since VSMCs accounted for the largest proportion and changed obviously, this study highlighted the crucial role of VSMC phenotype switching in the progression of ISR. Filtering by contractile-synthetic markers, VSMCs were classified as contractile-VSMCs and synthetic-VSMCs. In restenoic arteries, the proportion of synthetic-VSMCs increased, while contractile-VSMCs was the opposite. On the basis of this classification, more contractile-synthetic markers were predicted among differentially expressed genes such as NMT1. Unless the confirmation of our database we also proposed several novel related target genes, such as Cyp7a1 and Cdk4, which should be validated in the further study. Receptor-ligand analysis revealed that integrins and CD44/74 were activated differentially. Our study provided evidence for the existence of transitional-cell and the phenotype switching of VSMCs during ISR. Furthermore, our database clearly mapped the differences among all clusters, all cell types, and all functional subsets at gene level. New clues for in-depth study of the mechanism of ISR were shown and we are looking forward to the in-depth study immediately.
GW32-e1261
Xiying Wang, Xuan Zhang, Yuxiao Chen
The First Affiliated Hospital, College of Medicine, Zhejiang University
OBJECTIVES Heart failure is a clinical syndrome characterized by insufficient cardiac output or elevated intracardiac pressure, which increases patients’ hospitalization and mortality to a large extent. Continuous pathological stimulation leads to cardiomyocytes hypertrophy and loss, fibroblast proliferation, pathological heart dilation and mechanical dysfunction, and ultimately leads to heart failure. This continuous response is defined as heart remodeling. The mevalonate pathway is a classic cholesterol synthesis pathway, which is related to the prenylation of proteins in addition to participating in cholesterol synthesis. Prenylation is a crucial process for the activation of small GTP–binding proteins, which regulate a wide range of cellular processes, such as proliferation, differentiation, metabolism and apoptosis, by participating in intracellular signaling pathways. It has been proved that small GTP-binding proteins are involved in pathological cardiac hypertrophic pathway. Previous studies have suggested that the key enzyme farnesyl diphosphate synthase (FDPS) in this pathway has a regulatory effect on cardiovascular system. To clarify the role of FDPS in cardiac homeostasis, and provide more evidence for cardiovascular effects of the mevalonate pathway, we knocked out FDPS in mouse cardiomyocytes and explored the relevant mechanisms.
METHODS We used human samples and cardiac-specific FDPS knockout mice as models. Cardiac function was assessed by echocardiography at different age stages of mice and molecular biomarkers of cardiac remodeling was detected by real-time PCR. HE staining was used to observe structural changes in the heart, as well as sirius red staining for fibrosis. The contents of geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) in cardiomyocytes were determined by high performance liquid chromatography (HPLC). The activity of small G protein in the heart of mice was detected by pull-down method, and the changes of protein levels in the downstream pathways were detected by Western Blot. One-month-old FDPS knockout mice were randomized to receive FTI-277 (inhibitor of farnesyltransferase) or vehicle treatment for 4 weeks, six male age- and weight-matched wild type mice were housed as normal control, given an intraperitoneal injection of vehicle in same volume. Prior to tissue collection, cardiac function was assessed via echocardiography.
RESULTS The results showed that FDPS protein levels were downregulated in samples from cardiomyopathy patients. FDPS knockout mice exhibited spontaneous hypertrophy, fibrosis and develop cardiac dysfunction, along with enlargement of cardiomyocytes. This effect was associated with activation of Ras and Rheb, as well as their downstream extracellular signal-related kinase 1/2 (ERK1/2) and mTOR expression. Additionally, FDPS knockout led to deletion of FPP and accumulation of GPP which may be the reason about increased Ras and Rheb activity. Furthermore, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in FDPS knockout mice.
CONCLUSIONS These results indicated that FDPS plays a role in cardiac remodeling. The deletion of FDPS will activate the downstream complex signaling pathways and cause cardiac remodeling and dysfunction. From the perspective of clinical application, FDPS may be an important molecule to maintain cardiac homeostasis. We have observed changes in FDPS levels in patients with heart failure. For these patients, correcting their FDPS levels may have potential therapeutic significance.
GW32-e1335
Yizhou Feng1,2,3, Yuan Yuan1,2,3, Zhefu Hu4, Saiyang Xie1,2,3, Hongxia Xia1,2,3, Nan Zhang1,2,3, Haiming Wu1,2,3, Xiaofeng Zeng1,2,3, Qizhu Tang1,2,3
1Department of Cardiology, Renmin Hospital of Wuhan University
2Cardiovascular Research Institute of Wuhan University
3Hubei Key Laboratory of Metabolic and Chronic Diseases
4Department of Intensive Care Unit, Renmin Hospital of Wuhan University
OBJECTIVES Oncostatin M (OSM) is a secreted cytokine mainly involved in inflammatory and cardiovascular diseases through binding to OSM receptor β (OSMR). The effect and underlying mechanism of OSM/OSMR on the development of sepsis-induced myocardial injury remains unclear. This study aimed to investigated effect of OSMR deficiency on myocardial injury and identifying the possible mechanism in the mouse model of sepsis.
METHODS C57BL/6 wild-type (WT) and OSMR-knockout (OSMR-KO) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical and immunological analyses in the myocardium. Furthermore, WT mice underwent bone marrow transplantation (BMT) of OSMR-KO hematopoietic cells. In vitro study, bone marrow-derived macrophage (BMDM) was isolated and cultured followed by stimulating with Lipopolysaccharide (LPS).
RESULTS OSMR expression was up-regulated in the septic mouse myocardium and was mainly located in macrophages. We found that OSMR deficiency offered protection against myocardial injury and cardiac dysfunction in a mouse model of sepsis and significantly attenuates sepsis-mediated inflammation, oxidative stress and apoptosis in the myocardium relative to WT mice. Moreover, bone marrow transplantation of OSMR-KO hematopoietic cells to WT mice displayed a consistent phenotype. Additionally, we observed a relatively reduced level of JAK2 and signal transducer and activator of transcription (STAT)3 in vivo and under LPS stimulation in vitro, whereas OSM stimulation can activate the signaling pathway.
CONCLUSIONS OSMR-deficiency in macrophages improved sepsis-induced myocardial injury through inhibition of the JAK2/STAT3 activation in macrophages. Hence, inhibition of OSMR in macrophages may be a potential candidate strategy for septic cardiac dysfunction treatment.
GW32-e1456
Xiaoli Luo, Jie Zhang, Jue Li
Tongji University School of Medicine
OBJECTIVES Work stress and its contribution to cardiovascular diseases are well documented in recent years, but its molecular mechanisms are still not clear. In this study, we aimed to explore the potential pathophysiological mechanisms of stress-induced heart injury in mouse model.
METHODS The RNA- and miRNA-sequencing profiles from five stress-treated mice and five control mice were performed. After normalization, differently expressed genes (DEGs) and miRNAs (DEmiRs) were identified using the edgeR method. Then, based on the functional enrichment analysis and protein-protein interaction (PPI) network, as well as miRNA-mRNA interactome, the core DEGs and DEmiRs associated with stress-induced heart injury were marked and validated by qPCR, and the DEmiR targets were validated in vitro.
RESULTS A total of 293 genes and 29 miRNAs were identified as DEGs and DEmiRs respectively, and Alb, Stat1, C3, Irf7, Usp18 were hub genes in the PPI network. The enrichment pathways were related to inflammation and immune, coagulation, oxidative phosphorylation, vascular development, cell cycle and extracellular matrix (ECM), which likely mediate the biological injury processes or reflect the results of damage. The target DEGs of DEmiRs were clustered in angiogenesis, cell migration and protein phosphorylation. After the validation in vitro, we found that miR-29b-3p mimics can down-regulate the expression of its predicted target, Pxdn and Col15a1.
CONCLUSIONS The findings revealed a molecular basis from genes and miRNA levels for the heart injury associated with stress. miR-29b-3p, as a potential target to repair stress-induced ECM disorder in heart, deserves further study.
GW32-e1593
Wenbin Fu
Department of Cardiology, Daping Hospital, The Third Military Medical University
OBJECTIVES The role of long non-coding RNAs (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief window of time after birth, and this fact allows us to explore critical lncRNAs in the regulation of cardiac regeneration.
METHODS RNA sequencing was performed in a cardiac regeneration model of neonatal mouse apex resection (AR). Quantitative PCR, in situ hybridization, and single-cell-sequencing database retrieval were performed to determine the lncRNAs expression patterns. Gain- and loss-of-function assays were conducted to detect the role of lncRNAs in cardiomyocyte proliferation. LncRNA deletion mice were generated by the CRISPR genome-editing system and used to determine the role of lncRNAs in cardiac repair after myocardial infarction (MI). Computational analysis, RNA immunoprecipitation, and pull-down and were used to study the binding targets of lncRNA.
RESULTS In the AR regeneration model, we identified a novel lncRNA, named NPPA-AS1, which possessed a negative effect in regulating cardiomyocyte proliferation. NPPA-AS1 deletion unaffected normal heart development but was sufficient to prolong the postnatal window of regeneration capacity after AR injury. In adults, NPPA-AS1 deletion improved cardiac function and reduced infarct size in post-MI hearts, which was associated with significant improvement of cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule SFPQ. SFPQ-NONO heteromer is required for double-strand break repair, while its binding was competed by NPPA-AS1 due to the overlapping of binding sites. NPPA-AS1 deletion promoted the binding of SFPQ-NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell-cycle re-entry.
CONCLUSIONS Loss of NPPA-AS1 promoted cardiomyocyte proliferation through stabilizing SFPQ-NONO heteromer induced DNA repair and exerted therapeutic effect against MI in adults. Thus NPPA-AS1 might be a novel target for stimulating cardiac regeneration to treat MI.
GW32-e1656
Cong Xue, Ling Yang, Fang Jia
The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University
OBJECTIVES To explore the mechanism of miRNA-29b in sexual dimorphism in myocardial remodeling.
METHODS Adult cardiac fibroblasts (CFs) and adult cardiac myocytes (CM) were isolated from 2-month-old male and female SD rats through enzymatic digestion. They were classified as M-CFs, M-CM, F-CFs and F-CM. Total RNA was obtained and reverse transcribed to perform qPCR was performed to determine the expression of miR-29b. CFs were stimulated with TGF-β1 at an end concentration of 10 ng/mL, which were divided into M-CFs+TGF-β1 group and F-CFs+TGF-β1 group. CM were stimulated with Ang II at an end concentration of 10 ng/mL, which were divided into M-CFs+ Ang II group and F-CFs+ Ang II group. The mRNA and protein levels of fibrosis index (collagen I, III and α-SMA) and cardiac hypertrophy markers (ANP, αMHC, βMHC) were detected by means of reverse transcriptional polymerse chain reaction (RT-PCR) and Western blotting.
RESULTS miR-29b in F-CFs and F-CM were significantly less than M-CFs and M-CM (P<0.05). After induction by TGF-β1, the expression of fibrosis index include collagen I, III and α-SMA in F-CFs+TGF-β1 group was significantly increased. After induction by Ang II, the expression of cardiac hypertrophy markers including ANP and β-MHC were significantly increased in female rats. However, the expression of α-MHC in F-CM+Ang II group were significantly less than M-CM+Ang II group.
CONCLUSIONS Significant sex-related differences in miR-29b expression were identified and linked to sexual dimorphism in myocardial remodeling.
GW32-e1746
Weimin Yu1, Xiaoyong Tong2
1Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences
2School of Pharmaceutical Sciences, Chongqing University
OBJECTIVES Angiotensin II (Ang II) is commonly used to induce aortic aneurysm and atherosclerosis in animal models. Ang II upregulates NADPH oxidase isoform Nox4 in aortic smooth muscle cells (SMCs) in mice. However, whether smooth muscle Nox4 is directly involved in Ang II-induced aortic aneurysm and atherosclerosis is unclear.
METHODS To address this, we used smooth muscle-specific Nox4 dominant-negative (SDN) transgenic mice, in which Nox4 activity is constitutively inhibited.
RESULTS In non-transgenic (NTg) mice, Ang II increased the expression of proteins known to contribute to both aortic aneurysm and atherosclerosis, namely osteopontin (OPN), collagen type I&III (Col I&III), matrix metalloproteinase 2 (MMP2), and vascular cell adhesion molecule 1 (VCAM1), which were all significantly downregulated in SDN mice. The number and size of Ang II-induced aorta collateral aneurysms and atherosclerotic lesions in the renal artery and aortic root of SDN mice were significantly decreased compared to NTg mice, and directly correlated with a decrease in OPN expression. Replenishing OPN in SDN SMCs, increased the expression of Col I&III, MMP2, and VCAM1, and promoted SMC proliferation, migration, and inflammation.
CONCLUSIONS Our data demonstrate that smooth muscle Nox4 directly promotes the development of Ang II-induced aortic aneurysm and atherosclerosis, at least in part, through regulating OPN expression.
GW32-e1823
Nan Zhang, Shanqi Mou, Haihan Liao, Qizhu Tang
Renmin Hospital of WuHan University
OBJECTIVES Cardiac hypertrophy and the resulting heart failure are among the leading causes of death around the world. The evolution of cardiac hypertrophy is related to mitochondrial dysfunction. Histidine triad nucleotide-binding2 (HINT2) belongs to the histidine triad superfamily of nucleotide hydrolase and transferase enzymes, which containing the Histidine triad (HIT) domain and locating on the outer membrane of mitochondria. The roles and mechanisms of HINT2 have not been reported in pathological cardiac hypertrophy. Whether HINT2 plays an important role in pathological cardiac hypertrophy through mitochondria deserves exploration.
METHODS Firstly, we evaluated the levels of cardiac HINT2 mRNA and protein expression in hearts of heart failure patients, in hearts of aortic banding (AB) induced cardiac hypertrophy mice, and in cardiomyocytes treated with Ang II. Then, we constructed cardiac-special HINT2 overexpression transgenic mice and cardiac-special HINT2 deletion mice and challenged them with AB surgery. The cardiac function of mice was evaluated by echocardiography and hemodynamics. The morphological and pathological changes of the heart were observed by hematoxylin and eosin (HE) and Picric-Sirius Red staining (PSR). We used western blot, microarray, quantitative real-time polymerase chain reaction (RT-PCR), and transcriptome sequencing to discover the targets of HINTs and the underlying mechanisms in cardiac hypertrophy. Based on that, we further verified our findings by NAD+/NADH assay kit with WST-8, western blot, and ATP assay kit. In addition, NADH supplements were used in HINT2 deletion mice to investigate whether the deterioration effects of HINT2 on cardiac hypertrophy were NADH dependent. Finally, the effect of HINT2 was evaluated by lentivirus-mediated HINT2 overexpression or knockout in NRCMs stimulated by Ang II.
RESULTS The expression of HINT2 was dramatically downregulated in both cardiac tissues and cardiomyocytes in response to hypertrophic stimuli. The cardiac hypertrophy induced by AB was exacerbated when HINT2 was silenced, and HINT2 overexpression attenuated this effect and preserved cardiac function. The results of transcriptome profiling showed that NAD+/NADH-related signaling was seriously impacted. Then, we did reverse validation experiments by NAD+/NADH assay kit with WST-8, western blot, and ATP assay kit. We found that the effects of HINT2’s on cardiac hypertrophy were done dependent on NAD+/NADH, which affects the activity of electron transfer, oxidative phosphorylation, citrate cycle, and mitochondrial function further. Next, we found that NADH supplements alleviated the deterioration of cardiac function caused by stress load, improves hypertrophy and fibrosis in AB-induced HINT2 knockout mice. In vitro, the results were consistent with those of animal experiments. Overexpression of HINT2 alleviated Ang II-induced cardiomyocyte hypertrophy. And silencing cardiac HINT2 aggravated Ang II-induced cardiomyocyte hypertrophy. The mechanisms were related to NAD+/NADH and mitochondrial function.
CONCLUSIONS This study firstly demonstrated that HINT2 specific knockout in mouse cardiomyocytes could aggravate pressure overload-induced cardiac hypertrophy and affect cardiac function via affecting NAD+/NADH and regulating the function of mitochondrial. Our findings reveal the central role of HINT2 in the progression of pathological cardiac hypertrophy. Thus, targeting at HINT2 might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.
GW32-e1911
Jianbing Wang1,2, Jun Zhang1,3
1Tianjin Medical University
2General Hospital of Huabei Petroleum Administration Bureau
3Cangzhou Central Hospital
OBJECTIVES Coronary artery ligation to induce myocardial infarction (MI) and ischemia injury in mice is typically performed in normal mice, but this is not consistent with disease progression. There should be atherosclerosis (AS) first, followed by MI. We tried a novel model to induce MI that was established on atherosclerosis in mice. This approach is much more consistent with disease progression than the classical method of MI model.
METHODS In this study, Mice lacking apolipoprotein E (Apoe−/− ) were randomly divided into four groups. The mice of the control and MI groups were fed normal diet for 24-weeks, while the mice of AS and AS+MI groups were fed high-fat diet (HFD). After 23 weeks, the mice of MI and AS+MI groups were ligated with coronary arteries. A week later, after echocardiography, analysis of plaque and myocardium were conducted on aortic and heart, then the serum, aorta and heart tissues were further detected.
RESULTS Our results showed that AS model mice exhibited significant body weight gain, dyslipidemia and atherosclerotic lesions formation which were in accordance with the pathological changes of AS. Co-treatment with AS and MI led to higher operative mortality and heart pathological were in accordance with the pathological changes of MI. In addition, Echocardiography and NT pro-BNP revealed co-treatment with AS and MI led to deterioration of cardiac function. AS also aggravated inflammatory cell infiltration and myocardial fibrosis in heart post-MI.
CONCLUSIONS Together, it is feasible to establish myocardial infarction model based on atherosclerosis model.
GW32-e0092
Guojian Fang, Yingze Li, Jiali Yuan, Qunshan Wang
Department of Cardiology, Xinhua Hospital Affiliated To Shanghai Jiaotong University School of Medicine, Shanghai, China
OBJECTIVES Cadherin-11, as a member of cadherin family, is expressed in multiple tissues, including the heart. The occurrence of AF is closely associated with obesity. Previous studies have shown that cadherin-11 could make a contribution to diet-induced obesity and it would be informative to know whether cadherin-11 exerts its potential effects on atrial remodeling and AF vulnerability in a diet-induced obesity model.
METHODS Cadherin-11−/− and WT mice were subjected to normal or High-Fat Diet feeding at the age of 8 weeks. Multi-level studies on gene expression, biochemistry, histology, echocardiography and electrophysiology were carried out after 16 weeks of HFD feeding.
RESULTS Our data demonstrated that the expression of cadherin-11 were significantly up-regulated in the left atrium of AF patients with obesity and mice following 16 weeks HFD feeding. The increased level of cadherin-11 was mostly contributed to atrial fibroblasts and it was involved in the production of inflammatory cytokines by atrial fibroblasts. Using loss-of-function method, we demonstrated that although there were a lack of statistical difference in body weight, cadherin-11−/− mice could markedly improve glucose tolerance and hyperlipidemia. Adverse atrial structural remodeling, including atrial enlargement, fibrosis and inflammation caused by HFD-feeding were mitigated in cadherin-11−/− mice. Furthermore, the consequences of alterations in gap junction and vulnerability to atrial fibrillation (AF) showed similar with above. Mechanistically, cadherin-11−/− mice alleviated atrial remodeling caused by a high fat diet, partly by inhibiting the activation of MAPK and NF-κB signaling pathways.
CONCLUSIONS Our results demonstrated that cadherin-11 deficiency played a protective role in ameliorating HFD-induced atrial remodeling and vulnerability to atrial fibrillation, suggesting cadherin-11 might be a new therapeutic target for obesity-related atrial fibrillation.
GW32-e0225
Dan Zhang1, Xiang Ma2
新疆医科大学第一附属医院 (The First Affiliated Hospital of Xinjiang Medical University)
2Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES Acute Aortic Dissection (AAD) is an aortic disease that progresses rapidly due to untimely early diagnosis, delayed treatment, and rapid progression of the disease. MicroRNAs (miRNAs) in exosomes (EXs) are important participants in intercellular communication. The extent to which miRNAs are elevated in AD and whether miRNAs can distinguish AD from other causes of sudden severe chest pain are unclear. The purpose of this study was to evaluate the expression and significance of serum exosome miRNAs in AAD patients.
METHODS Twelve cases of male patients who were diagnosed and diagnosed as AAD in our hospital from January to September 2019 were selected as the case group, and 6 healthy male patients who were examined in our hospital as the control group, and fasting serum was collected. Isolation, identification and quantification of serum exosome miRNAs were performed, and the exosome-derived miRNAs with significant expression differences were screened for further biological information analysis.
RESULTS Compared with the control group, AAD serum exosome-derived miRNAs were differentially expressed. Compared with healthy controls within the time of chest pain within 24 hours, there were 61 miRNAs that expressed significant differences (P<0.05), of which 39 expressions were up-regulated and 22 were down-regulated; chest pain occurred within 24 hours and chest pain occurred within 48 hours. Among them, there were 98 miRNAs with significantly different expressions (P<0.05), of which 42 were up-regulated and 56 were down-regulated; compared with healthy controls within 48 hours of chest pain, there were 170 miRNAs with significantly different expressions (P<0.05), 91 of them were up-regulated and 79 were down-regulated.
CONCLUSIONS There are differential expressions of serum exosome miRNAs in AAD patients. According to the results of biological information analysis, nine miRNAs related to AD pathogenesis signaling pathways were screened out, which provided new ideas and clues for further exploration of AAD diagnostic markers and pathogenesis.
GW32-e0380
Shaoheng Zhang, Pengzhen Wang, Aiguo Li, Huang Huang, Jin Cui, Songsheng Chen
GuangZhou Red Cross Hospital Medical College of Ji-Nan University
OBJECTIVES β-Catenin is essential for survival of leukemic stem cells; however, the effects of β-catenin in the self-renewal and survival of peripheral blood mesenchymal stem cells (PBMSCs) are unclear. Octamer 4 (Oct4) signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. Here, we aimed to elucidate the roles of β-catenin/Oct4 signaling axis in regulating and survival of PBMSCs.
METHODS PBMSCs were obtained from abdominal aortic blood of rats. We compared the survival and capabilities of PBMSCs with β-catenin or Oct4 overexpression and β-catenin or Oct4 deficiency induced by transfecting the cells with vectors encoding β-catenin or Oct4, or β-catenin and Oct4 siRNAs in vitro. We also investigated the effects of the PBMSCs with overexpression of β-catenin/Oct4 on myocardial repair after induction of MI in rats.
RESULTS We show that β-catenin promotes PBMSC self-renewal, antiapopotosis, and long-term survival by activation of the Oct4 pathway through up-regulating the expression of anti-apopototic factors bFGF, Bcl2 and survivin, and suppressing the expression of Bax and Cleaved-caspase-3, two key members of apopotosis. β-Catenin overexpression increased Oct4 expression. β-Catenin knockdown suppresses Oct4 expression in PBMSCs. However, the β-Catenin expression was not affected by Oct4 overexpression or knockdown. Chromatin immunoprecipitation assays proved that β-catenin directly regulates Oct4 transcription in PBMSCs. In vivo, PBMSCs overexpressing β-catenin showed high survival in infarcted myocardiocytes and correlated with better myocardial repair. Further functional analysis identified Oct4 to be the direct upstream regulator of bFGF, Bcl2, and survivin, which cooperatively drive anti-apoptosis in engrafted PBMSCs.
CONCLUSIONS These findings uncover the noncanonical regulation of Wnt/β-catenin in PBMSCs by the Oct4-mediated anti-apoptotic signaling axis, and also provide a novel breakthrough point for improving the long-term survival as well as therapeutic effects for PBMSCs.
GW32-e0516
Cuiping Xie1, Feiming Ye1, Ning Zhang1, Yuxue Huang1, Yun Pan2, Xiaojie Xie1
1The Second Affiliated Hospital Zhejiang University College of Medicine
2College of Information Science and Electronic Engineering, Zhejiang University
OBJECTIVES Chemokine-mediated monocyte/macrophage recruitment contributes to the pathogenesis of the abdominal aortic aneurysm (AAA). Due to the capacity to bind with multiple leukocyte receptors, the chemokine C-C motif ligand 7 (CCL7) has been demonstrated to play a role in cardiovascular diseases via attracting and regulating monocytes/macrophage function. However, the potential mechanisms of CCL7 in AAA have not yet been explained. Our study focused on the role of CCL7 in the angiotensin II (Ang II)-induced AAA formation.
METHODS ApoE−/− male mice were subcutaneously implanted with Alzet osmotic micropump and continuously given Ang II or saline for 28 days. At the end of the experiment, the plasma and aorta tissues of the mice were collected respectively. Bone marrow derived macrophages (BMDM) were obtained and co-cultured with recombinant CCL7 (rmCCL7) for 24 hours to observe the effects of CCL7. BMDM cells were co-cultured with CCR1 antagonist (BX471), JAK2 inhibitor (Fedratinib) and STAT1 inhibitor (Fludrabine) for 1 hour, respectively. Then rmCCL7 was added into the culture medium to explore the possible intracellular mechanism of CCL7. ApoE−/− mice were randomly divided into three groups with 10 mice in each group: CCL7-nAb group, control IgG group, PBS group.
RESULTS Compared with the saline group, the mRNA, protein levels of CCL7 in aortic tissue and plasma concentration of CCL7 of Ang II group were significantly increased. Among the CCRs of CCL7, the expression of CCR1 receptor was significantly different. Transwell assay showed that rmCCL7 could promote the migration of BMDM which could be inhibited by CCR1 antagonist (BX471). rmCCL7 significantly increased the mRNA levels of M1 markers such as iNOS, IL-6, IL-12A, IL-12B and TNF-α in BMDM. Western blot showed that rmCCL7 upregulated JAK2/STAT1 protein in BMDM cells. The expression levels of iNOS, JAK2 and STAT1 in AAA tissues induced by Ang II were also significantly increased. Pretreatment of BMDM with BX471, Fedratinib or Fludarabine inhibited rmCCL7-induced upregulation of M1 type markers. In addition, BMDM pretreated with BX471 significantly inhibited the increase of JAK2/STAT1 expression induced by rmCCL7. The incidence of AAA in CCL7-nAb group was significantly lower than that in PBS groupand Control IgG group. Compared with PBS group and Control IgG group, CCL7-nAb mice had significant reduction in the maximum luminal diamete, the maximum luminal area (P<0.01), and the increase of the maximum external diameter. Macrophage infiltration in aneurysmal lesion of CCL7-nAb group was also significantly reduced.
CONCLUSIONS In conclusion, this study found that CCL7 promoted Ang II-induced AAA formation, which may play a role through CCR1/JAK2/STAT1 pathway in mediating macrophage infiltration into aortic wall and differentiation into pro-inflammatory phenotype. CCL7-nAb significantly reduced the incidence of AAA. The possible protective mechanism of CCL7-nAb is to inhibit the infiltration of macrophages in aortic wall and delay vascular remodeling. Our results suggest that CCL7 may be a potential molecular target for the prevention and treatment of AAA, which has important clinical value.
GW32-e0558
Xiaofei Gao, Junjie Zhang, Shaoliang Chen
Nanjing First Hospital, Nanjing Medical University
OBJECTIVES Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in the occurrence and development of in-stent restenosis (ISR), the underlying mechanism of which remains a key issue needing to be urgently addressed. This study is designed to investigate the role of plasma small extracellular vesicles (sEV) in VSMC phenotypic modulation.
METHODS sEV were isolated from the plasma of patients with ISR (ISR-sEV) or not (Ctl-sEV) 1 year after coronary stent implantation using differential ultracentrifugation.
RESULTS Plasma sEV in ISR patients are elevated markedly, and decrease the expression of VSMC contractile markers α-SMA and calponin, and increase VSMC proliferation. miRNA sequencing and qRT-PCR validation identified that miRNA-501-5p was the highest expressed miRNA in the plasma ISR-sEV compared with Ctl-sEV. Then we found that sEV-carried miRNA-501-5p level was significantly higher in ISR patients, and the level of plasma sEV-carried miRNA-501-5p linearly correlated with the degree of restenosis (R2=0.62). Moreover, miRNA-501-5p inhibition significantly increased the expression of VSMC contractile markers α-SMA and calponin, and suppressed VSMC proliferation and migration; in vivo inhibition of miRNA-501-5p could also blunt carotid artery balloon injury induced VSMC phenotypic modulation in rats. Mechanically, miRNA-501-5p promoted plasma sEV-induced VSMC proliferation by targeting Smad3. Notably, endothelial cells might be the major origins of miRNA-501-5p.
CONCLUSIONS Collectively, these findings showed that plasma sEV-carried miRNA-501-5p promotes VSMC phenotypic modulation-mediated ISR through targeting Smad3.
GW32-e0612
Niannian Liu
南京医科大学第四附属医院 (The Fourth Affiliated Hospital of Nanjing Medical University)
OBJECTIVES To investigate the suppressive effects of miR-133a in exosomes secreted by cardiac fibroblasts (CFs) on cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury.
METHODS Myocardial fibroblasts are isolated from the neonatal mouse. H9C2 cells, 293T cells and CFs were cultured in DMEM. The cardiomyocyte model of ischemia/reperfusion injury was established, LPS acted as a positive control. CFs and H9C2 cells were co-cultured. Exosome inhibitor GW4869 was used to treat cultured CFs. CFs exosomes were stained by green fluorescent linker PKH67 (Sigma-Aldrich, USA). Cell viability was determined using Cell Counting Kit-8 (CCK-8). RT-PCR was performed by using SYBR Premix Ex Taq (Sigma-Aldrich, USA). The whole process of protein extraction was kept on ice and the quantity of total protein was determined by BCA assay (Thermo Scientific). MiR-133a-3p mimic, mimic control, miR-133a-3p inhibitor or inhibitor negative control (Synthgene, China) were transfected into H9C2 cells. MiR-133a-3p mimic or mimic control were transfected into CFs. The entire 3′-UTR of ELAVL1 that containing the predicted binding sites for miR-133a-3p and the binding sequences mutant ELAVL1 3′-UTR was amplified and inserted into a luciferase reporter plasmid. Luciferase signals were measured using a luciferase assay kit according to the manufacture’s protocol (Promega, USA). Male Sprague-Dawley rats were obtained and were randomly divided into four groups before the operation: sham, I/R, I/R added exosomes, I/R added exosomes that from overexpressed miR-133a-5p CFs cells. The methods of myocardial I/R model building: Rats were anesthetized and the left coronary artery (LCA) was exposed using left thoracotomy at the fifth intercostal space. Following LCA ligation with 7-0 silk sutures, a smooth catheter was applied on the artery to achieve ischemia for 30 min, and then rats were sacrificed after reperfusion 120 min. The sham group rats underwent similar surgery, but without the LCA I/R, and were treated with saline. Other groups rats were injected with PBS or same volume PBS that containing 200 μg exosome into myocardium after I/R injury. Tissues were fixed with 4% paraformaldehyde for 24 hours and then paraffin-embedded after excising. The hearts of rats were isolated and fixed in 4% paraformaldehyde and were then embedded in paraffin, and TUNEL staining was processed using a Colorimetric TUNEL Apoptosis Assay Kit (Beyotime, China).
RESULTS 1. In comparison with control group without treatment, a significant cardiomyocyte death was observed in I/R group and LPS group. 2. Cardiomyocytes treated with I/R underwent significantly lowered cell death upon incubation with CFs. 3. Positive expression of exosome markers, including CD9, CD81 and TSG101, confirmed the successful isolation of exosomes. 4. Six miRNAs were predicted that can target ELAVL1 by 3 computational METHODS including TargetScan, miRWalk and miRDB. 5. The MI/R injury rat models were developed and treated with exosomes secreted from CFs or CFs with miR-133a overexpression.
CONCLUSIONS Exosomes derived from CFs can reduce pyroptosis of cardiomyocytes and protect MI/R injury both in vitro and in vivo. This effect was related to the axis of CFs-exosome/miRNA-133a/ELAL1.
GW32-e0850
Kun Zhao1, Dong Zhang2, Xiangqing Kong1, Bin Zhou3, Wei Sun1
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
2Key Laboratory of Modern Acoustics, Department of Physics, Collaborative Innovation Center of Advanced Microstructure, Nanjing University, Nanjing, Jiangsu 210093, China
3Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA
OBJECTIVES Vascular events can trigger a pathological phenotypic switch in vascular smooth muscle cells (VSMCs), decreasing and disrupting the plasticity and diversity of vascular networks. The development of novel therapeutic approaches is necessary to prevent these changes. We aimed to investigate the effects and associated mechanisms of low-intensity pulsed ultrasound (LIPUS) irradiation on the angiotensin II (Ang II)-induced phenotypic switch in VSMCs.
METHODS In vivo, Ang II was infused subcutaneously for 4 weeks to stimulate vascular remodeling of the whole wall artery in C57/Bl6 mice, and LIPUS irradiation (0.5 MHz, 77.20 mW/cm2) was applied for 20 minutes every 2 days for 4 weeks. In vitro, cultured rat aortic VSMCs (RAVSMCs) were pretreated once with LIPUS irradiation for 20 minutes before 48-hour Ang II stimulation. MiR-17-5p agomir and antagomir, and peroxisome proliferator-activated receptor gamma (PPAR-γ) activator (rosiglitazone) and inhibitor (GW9662) were used to treat the cells with or without LIPUS treatment.
RESULTS LIPUS irradiation prevents Ang II-induced vascular remodeling of the whole wall artery without discriminating between adventitia and media in vivo and RAVSMC phenotypic switching in vitro. LIPUS irradiation downregulated miR-17-5p expression and upregulated PPAR-γ expression. The PPAR-γ activator rosiglitazone could mimic the favorable effects of LIPUS irradiation on Ang II-treated RAVSMCs. In contrast, GW9662 and the miR-17-5p agomir could impede the LIPUS-mediated downregulation of RAVSMC proliferation and inflammation under Ang II stimulation conditions, respectively. The inhibitory effects of GW9662 against the anti-remodeling effects of LIPUS irradiation in Ang II-induced RAVSMCs could be blocked by pretreatment with the miR-17-5p antagomir.
CONCLUSIONS LIPUS irradiation prevents Ang II-induced RAVSMCs phenotypic switching through hampering miR-17-5p and enhancing PPAR-γ, suggesting a new approach for the treatment of vascular disorders.
GW32-e0959
Shiyu Zhang, Jing Zhang, Shijie Li, Lin Cui, Shiyang Xie, Yuan Gao, Mingjun Zhu, Youping Wang
First Affiliated Hospital, Henan University of Traditional Chinese Medicine
OBJECTIVES Endothelial inflammation, triggered by oxidized low-density lipoprotein (ox-LDL), is recognized as the crucial mechanism for atherosclerosis. Triptolide, a primary active ingredient of traditional Chinese medicine Tripterygium wilfordii Hook F., possesses anti-inflammatory and anti-oxidant properties in vitro and in vivo. However, limited information is available for these effects on endothelial inflammation occurring in the process of atherosclerosis. This study investigated the effects and possible mechanisms of triptolide on ox-LDL-mediated inflammatory responses in human umbilical vein endothelial cells (HUVECs).
METHODS HUVECs were pre-treated with triptolide at concentrations of 25, 50 or 100 nM for 1 h, and then treated with ox-LDL (50 μg/mL) for the indicated times. The effects of triptolide on ox-LDL-induced production and expression of inflammatory molecules, monocyte adhesion, oxidative stress-related parameters, and activation of nuclear factor (NF)-κB pathway were investigated using an ELISA assay, cell-based ELISA assay, co-culture cellular adhesion assay, biochemical analysis, lucigenin-enhanced chemiluminescence (ECL) assay, and a dual luciferase reporter assay system.
RESULTS Compared with the control group, treatment with ox-LDL (50 μg/mL) for 6 h enhanced the production and expression of pro-inflammatory cytokines (TNF-α: 57.8±3.6 vs. 124.8±13.9 pg/mL, and IL-6: 8.5±3.5 vs. 29.2±3.4 pg/mL) and chemokines (MCP-1: 159.5±61.7 vs. 869.7±128.9 pg/mL), adhesion molecules (ICAM-1: 0.9±0.2 vs. 3.6±0.4, and VCAM-1: 1.1±0.2 vs. 3.4±0.3), and the number of monocytes that adhered to HUVECs (98±4 vs. 396±46) (P<0.05). Pre-treatment with triptolide dose-dependently inhibited ox-LDL-induced cytokine and chemokine production, adhesion molecule expression, and monocyte adhesion (P<0.05). We also found that ox-LDL treatment for 6 h increased the production of 8-isoprostane (97.6±8.0 vs. 31.3±5.3 pg/mL), MDA (0.9±0.1 vs. 0.4±0.1 nM/mg protein), and superoxide (11.6±1.7 vs. 4.6±0.9 counts/min/mg protein) compared with the control group (P<0.05), which were associated the decreased activities of total SOD (40.6±5.8 vs. 87.4±6.0 U/mg protein) and its isoenzyme (CuZn-SOD: 24.9±5.6 vs. 69.9±7.6 U/mg protein) except for the activity of Mn-SOD (15.7±1.7 vs. 17.5±2.0 U/mg protein) (P<0.05). Pre-treatment with triptolide reversed the ox-LDL-induced effects in all events. Moreover, ox-LDL treatment for 30 min-1 h enhanced NF-κB reporter activity (7.6±0.8 vs. 0.3±0.1) with the increases in IκBα phosphorylation (3.6±0.3 vs. 1.0±0.3) and DNA binding activity of NF-κB p65 (7.1±0.8 vs. 1.0±0.1) compared with the control group (P<0.05). The ox-LDL-mediated effects were dose-dependently attenuated by pre-treatment with triptolide.
CONCLUSIONS Our data for the first time indicate that triptolide inhibits ox-LDL-induced endothelial inflammation possibly via suppression of the oxidative stress-dependent activation of NF-κB, which provides a potential therapeutic candidate for atherosclerosis. [This work was supported by grants from the National Natural Science Foundation of China (No. 82074194 & 81673734). Corresponding author: Youping Wang].
GW32-e1031
Fei Luo1,2, Eriks Smagris2, Justin Fletcher2, Shawn Burgess2, Helen Hobbs2, Jonathan Cohen2
1The Second Xiangya Hospital, Central South University
2University of Texas Southwestern Medical Center
OBJECTIVES A variant in Transmembrane 6 Superfamily Member 2 [TM6SF2 (E167K)] is strongly associated with lower plasma lipid levels, hepatic steatosis, and protection from coronary artery disease. Tm6sf2−/− mice replicate the phenotype of individuals with TM6SF2-167K variant: hepatic steatosis accompanied by hypocholesterolemia. These mice had a reduced rate of secretion of very low-density lipoprotein (VLDL)-TG, but not VLDL-Apolipoprotein B (ApoB). Thus, TM6SF2 is required for normal lipidation of VLDL. To determine where in the secretory pathway TM6SF2 promotes lipid addition to nascent VLDL, we performed liver perfusion and electron microscopy studies in wildtype (WT) and Tm6sf2−/− mice. We also generated Tm6sf2−/− rats, which have the advantage of being used extensively to purify various intracellular vesicular compartments.
METHODS Two lines of Tm6sf2−/− rats were established using CRISPR/Cas9 technology. Tissue lipids were quantified using enzymatic assays and mass spectrometry. Neutral lipids were visualized in tissue sections using Oil Red O staining. Rates of dietary TG absorption and hepatic VLDL-TG and -ApoB secretion, and composition of newly-secreted VLDL captured by isolated liver perfusion were compared in Tm6sf2−/− and WT rats. Electron microscopy was performed on liver sections that had been stained with imidazole/osmium tetroxide to visualize lipoproteins. TM6SF2 localization studies using cell fractionation were performed. Finally, TM6SF2 was immunoprecipitated from tissues to identify interacting proteins.
RESULTS Tm6sf2−/− rats had a 6-fold higher mean hepatic TG content (9.8±3.9 vs. 56.1±28.9 mg/g, P<0.0001) and lower plasma cholesterol levels (110.6±14.0 vs. 99.0±10.5 mg/dL, P=0.0294) than littermate WT controls. Rates of absorption of dietary TG and secretion of VLDL-TG were significantly reduced in Tm6sf2−/− rats (P<0.001 and 0.01, respectively). Mean TG and cholesterol per ApoB were decreased 53% and 62% (P=0.005 and P=0.01, respectively) in nascent VLDL secreted from livers of Tm6sf2−/− rats without any reduction in VLDL-ApoB and -ApoE. TM6SF2 localized to the smooth endoplasmic reticulum (ER) and the ER-Golgi intermediate compartments, but was not present in the Golgi. Analysis of the lipid profile of the Golgi apparatus in the KO rat revealed that the majority triglyceride (TG) and fatty acids (FA) subclasses were decreased by one to two folds compared to WT in terms of TG or FA to ApoB48 ratios. Electron microscopy showed that the VLDL particles in the secretory pathway of Tm6sf2−/− mice were smaller than those in the WT animals. Both ApoB-48 and Long Chain Fatty Acid-CoA Ligase 5 (ACSL5) physically interacted with TM6SF2.
CONCLUSIONS Taken together these findings are consistent with TM6SF2, located in the smooth ER, playing a key role in lipidation of VLDL and in absorption of dietary lipids.
GW32-e1079
Zihui Zhang1,2, Xinya Xie1, Lei Xiao1, Nanping Wang3
1Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710061, PR China
2Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, PR China
3The Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, PR China
OBJECTIVES Vascular endothelial dysfunction is the key pathological process of many cardiovascular diseases and vascular complications in metabolic diseases. Nitric oxide (NO) which is catalyzed by endothelial nitric oxide synthase (eNOS), is the most important vasodilator produced by vascular endothelial cells, and plays important roles in regulating endothelial function. Tetrahydrobiopterin (BH4) is an essential cofactor for eNOS. When BH4 level is insufficient, eNOS catalyzes substrate to produce superoxide anions instead of NO, which is called “eNOS uncoupling”. BH4 can be synthesized by dihydrofolate reductase (DHFR) through salvage pathway. Peroxisome proliferator–activated receptor δ (PPARδ) is a member of nuclear receptor superfamily and protects against endothelial dysfunction, while the underlying mechanisms remained largely unknown. The aim of this study was to investigate whether activation of PPARδ could increase the expression of DHFR to synthesize BH4, thus inhibited eNOS uncoupling and improve vascular endothelial function.
METHODS Quantitative real-time PCR, western blot and immunofluorescence were used to detect the gene and protein expression of DHFR. Low temperature SDS-PAGE was used to detect the ratio of eNOS dimer to monomer in endothelial cells. The levels of total biopterin, BH4 and oxidized biopterin in endothelial cells were determined by high performance liquid chromatography. Bioinformatics was used to predict the potential PPARδ binding response elements (PPREs) in the promoter region of DHFR gene. Chromatin immunoprecipitation (ChIP) were conducted to verify whether PPARδ could bind to these PPRE. The DHFR luciferase reporter plasmids and truncated mutants were cloned to detect the effects of PPARδ agonist GW501516 on the promoter activity. The aortas of endothelium-specific PPARδ knockout mice (PpardEC−/− ) were isolated and vasodilation was measured by myograph system. The NO levels in endothelial cells were measured by using NO specific probe DAF-FM DA and electron paramagnetic resonance spectroscopy. DHE and L-012 probes were used to detect the level of reactive oxygen species (ROS) in endothelial cells.
RESULTS PPARδ agonist GW501516 increased DHFR mRNA and protein levels in endothelial cells. Meanwhile, GW501516 increased BH4 levels, and decreased BH2 levels in a PPARδ-dependent manner. ChIP identified several PPREs within the 5′-flanking region of the human DHFR gene. GW501516 increased the promoter activity in deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid), but induced by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). The activation of PPARδ eliminated the inhibition of DHFR expression by PA, and increased the ratio of eNOS dimer to monomer. PPARδ agonist GW501516 improved PA-induced endothelial dysfunction in wild type mice, but not in PpardEC−/− mice. However, inhibiting DHFR blocked the improved endothelial relaxation by PPARδ activation. GW501516 inhibited PA-induced NO reduction and ROS production, but not in the presence of PPARδ antagonist GSK0660 or DHFR inhibitor MTX.
CONCLUSIONS PPARδ mitigated endothelial dysfunction by inducing DHFR and activating BH4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARδ against vascular diseases.
GW32-e1202
Yanfei Li1, Baoyu Duan2, Zhongping Ning1, Junwei Shen3, Xiaoli Luo3, Xin Li4
1Zhoupu Hospital Affiliated to Shanghai University of Health and Medicine science
2Shanghai University of Health and Medicine Science
3Tongji University
4East Hospital Affiliated to Tongji University
OBJECTIVES Cardiac diseases caused by overwork stress are becoming more and more serious in China, but its pathogenesis is unknown. The purpose of this study is to study the effect of overwork on heart and its molecular mechanism.
METHODS The overworked mice model was established by swimming with weight and sleep deprivation. Echocardiography is used to detect cardiac function. The changes of heart rate and rhythm were detected by electrocardiograph. H&E staining was used to detect the damage and nuclear changes of myocardial cells. Vsnl1 conditional knockout mice were prepared by crisper/cas9 technique. The transcriptome expression in cardiomyocytes was detected by RNA sequencing.
RESULTS The results of echocardiography showed that compared with the control group (Ctrl), the left ventricular ejection fraction (LVEF) and systolic ratio (FS) were significantly reduced; the systolic left ventricular inner diameters (LVIDs) were significantly shortened, and the diastolic left ventricular inner diameter did not change significantly. There was no significant difference in the thickness of the interventricular septum (IVS) and the thickness of the left ventricular posterior wall (LVPW) between the three groups. Electrocardiogram showed that no obvious changes in heart rate and arrhythmia in the overworked model mice, but the phenomenon of voltage enhancement exists in both models. The results of H&E staining showed that cardiomyocytes of overworked mice have myocardial damage such as edema and nuclear lysis. Further research found that Visinin-like protein 1 gene (Vsnl1) is highly expressed in myocardial tissue. We prepared vsnl1 conditional knockout mice by injecting fertilized eggs with cas9/sgRNA. Vsnl1 knockout mice and wild-type mice were treated with sleep deprivation for 5 days. Echocardiography showed that there was no significant abnormality in all indicators of wild-type mice. LVEF of Vsnl1-deficient mice decreased significantly in both systolic and diastolic stages, and LVPW was markedly thickened. The electrocardiogram showed that wild-type mice did not change significantly, while the Vsnl1-deficient mice showed arrhythmia such as increased heart rate, ST segment elevation, and “M” wave. RNA expression profile results showed by principal component analysis, the difference of total RNA expression increased significantly between Vsnl1-deficient and wild mice with the extension of overwork time. Cluster analysis showed that there were significant changes in the expression of more than 20 signaling pathways, especially in the immune pathway. Analysis of the types of immune cells showed that there was a significant difference in the proportion of different immune cells.
CONCLUSIONS Over stress can cause abnormal heart function and damage of myocardial cells in wild-type mice, but there was no significant effect on electrocardiographic conduction during the same period. However, the absence of Vsnl1 can lead to abnormal electrocardiographic conduction. The loss of Vsnl1 can cause great changes in the expression pathway of cardiac tissue.
GW32-e1263
Guang-Feng Zuo, Xiao-Fei Gao, Zhen Ge, Jun-Jie Zhang
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006
OBJECTIVES Our previous study indicated that cardiomyocytes apoptosis, which plays a critical role in the progression of diabetic cardiomyopathy (DCM), were significantly inhibited in diabetic mice by administration of ivabradine. However, the underlying mechanisms remain unknown. Our study investigated the role played by ivabradine during DCM and explored the potential mechanisms for underlying anti-apoptotic effect.
METHODS High-glucose (HG) cultured rat neonatal cardiomyocytes (NRCM) and streptozotocin (STZ)-induced diabetic mice were administrated with or without ivabradine. Signaling pathway was verified through gene silencing and western blot in both vivo and vitro. The cardiac structures and functions were determined by histopathological analysis and echocardiography.
RESULTS TGF-β-activated kinase (TAK-1) and NF-κB signaling activation along with subsequent apoptosis were significantly attenuated by administration of ivabradine in HG-stimulated NRCMs and STZ-induced diabetic mice, whereas tumor necrosis factor (TNF)-α and TNF receptor 1 (TNFR1), which mediate the death receptor pathway inducing canonical nuclear factor (NF)-κB signaling, were not inhibited ivabradine treatment both in vitro and in vivo. Interestingly, the anti-apoptotic effect and inhibition of ivabradine on NF-KB signaling were significantly mitigated by over-expression of TAK-1 both in vitro and in vivo. Additionally, ivabradine significantly improved histological abnormalities, fibrosis, and cardiac dysfunction in diabetic mice. These effects were alleviated by virus-mediated over-expression of TAK-1, but enhanced by knockdown of TAK-1.
CONCLUSIONS Ivabradine inhibited TAK1-NF-κB signaling, with no effect on TNF-α-induced canonical NF-kB signaling, leading to the attenuation of apoptosis and subsequently exerting cardio-protective effects in DCM.
GW32-e1337
Lei Dai, Jinhua Wu, Hongjie Wang, Hesong Zeng
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
OBJECTIVES Pulmonary arterial hypertension (PAH) is a progressive disorder in which endothelial dysfunction and vascular remodeling result in small pulmonary arteries occlusion, leading to right heart failure and death. Despite advances in our understanding of the pathophysiology and the management of PAH, effective treatment for this life-threatening disease is still lacking. In the current study, we aimed to explore how complement system gets involved in the pathophysiological process of PAH and test the effect of CP40-KK, a newly identified analog of selective complement C3 inhibitor CP40, on a monocrotaline (MCT) induced rat PAH model.
METHODS After MCT with or without CP40-KK treatment, right ventricle systolic pressure (RVSP) of the experimental rats was assessed by a pressure transducer system, then the animals were euthanized and lungs and hearts were dissected for further evaluation. The dry weights of the right ventricle (RV) and left ventricle (LV)+septum (S) were measured to calculate the RV/LV+S ratio and the RV/body weight ratio (RV/BW). The morphological indices were evaluated by hematoxylin and eosin (H&E) and immunohistochemical staining. The levels of NLRP3 inflammasome complexes and inflammatory cytokines were determined using western blotting, immunohistochemical staining and enzyme-linked immunosorbent assay. Survival was evaluated by Kaplan–Meier analysis.
RESULTS Complement component C3 deposition increased significantly in the pulmonary small artery of the MCT group in compared with the control group, and it is associated more perivascular monocyte/macrophage infiltration, elevated NLPR3 inflammasome activation and proinflammatory cytokines (IL-1β, IL-6 and IL-18) release, augmented vascular smooth cell proliferation and worsened hemodynamic and morphological indices, such as RVSP, RV/LV+S ratio, RV/BW ratio and pulmonary parietal wall thickness index, finally reduced survival rate, whereas CP40-KK treatment could significantly reverse these indices in an established rat PAH model.
CONCLUSIONS Our results indicated that complement component C3 could activate the NLRP3 inflammasome and promote subsequent release of the downstream proinflammatory cytokines, contributing to the pathophysiological process of PAH. Moreover, we found that CP40-KK treatment was protective in an established PAH rat model, which might serve as a therapeutic option for PAH.
GW32-e1461
Shuang Qu
Daping Hospital
OBJECTIVES Cardiomyocyte proliferation is vital for functional repair after cardiac injury. The mechanisms involved in the postnatal loss of cardiomyocyte proliferation ability are not fully understood. We aim to figure out the role of LKB1 in cardiac regeneration and find out underlying mechanism.
METHODS The function of LKB1 and its mechanism of cardiomyocytes proliferation were investigated using siRNA-mediated knockdown and plasmid-mediated overexpression techniques combined with immunofluorescence, western blot, and other molecular methods. Yes-associated protein (YAP) was knocked down to demonstrate its role in pro-proliferative effect of LKB1. DNA pull down assay was conducted to certified LKB1 can regulate the expression of GATA4 and then promote the expression of YAP. Neonatal mice were injected with AAV9 LKB1 shRNA and then adult mice were subjected to myocardial infarction, and then, effects of LKB1 on adult cardiac regeneration were analysed.
RESULTS Knockdown of LKB1 by small interfering RNA can promote cardiomyocyte proliferation. The decreased expression of LKB1 up-regulated YAP expression and knockdown of YAP reduced LKB1 siRNA-mediated cardiomyocyte proliferative effect. LKB1 can regulate YAP transcription through up-regulating GATA4. AAV9 LKB1 shRNA injection promoted adult cardiomyocyte proliferation and improved cardiac function in myocardial infarction.
CONCLUSIONS Our data uncover that the decreased of LKB1 can promote both neonatal and adult cardiomyocyte proliferation by up-regulating YAP expression.
GW32-e1606
Liang Hou1, Yanchun Ding2
1General Hospital of The Yangtze River Shipping
2The Second Affiliated Hospital of Dalian Medical University
OBJECTIVES To explore the effects of RIP2 siRNA on macrophage inflammatory activation and phenotypic variation were observed by the human monocytic cell line THP-1.
METHODS THP-1 cells were differentiated into macrophages by the addition of 160 nmol/L PMA for 24 h. Macrophages were incubated with different concentrations of OX-LDL for 24 h. The expression of RIP2 was detected by real-time PCR and Western blot. ELISA was used to detected the Tumor Necrosis Factor-α (TNF-α) and monocyte chemotactic protein 1 (MCP-1). The RIP2 siRNA was designed and transfected into macrophages by hiperfict transfection reagent. The most efficient siRNA was selected by real-time PCR and Western blot. After transfection, cells was treated with OX-LDL. TNF-α and MCP-1 was detected by ELISA. FACS was used to detect membrane molecule CD86. The expression of IL-10/IL-12 was detected by real-time PCR.
RESULTS The expression of RIP2 mRNA was up-regulated by the increasing concentrations of OX-LDL (control: 1±0.1; 10 mg/L: 3.45±0.98; 25 mg/L: 7.62±0.92; 50 mg/L: 10.21±1.13, P<0.01)). OX-LDL could also up-regulate the expression of RIP2 protein (control: 0.2±0.02; 10 mg/L: 0.21±0.01; 25 mg/L: 0.85±0.07; 50 mg/L: 1.52±0.09, P<0.01) The expression of TNF-α (control: 18.51±0.77 pg/mL; 8 h: 27.01±0.95 pg/mL; 16 h: 44.71±2.05 pg/mL; 24 h: 71.53±2.35 pg/mL, P<0.01) and MCP-1 (control: 49.10±4.03 pg/mL; 8 h: 74.51±3.93 pg/m; 16 h: 77.76±7.24 pg/mL; 24 h: 163.4±7.22 pg/mL, P<0.01) increased with the increasing time of OX-LDL. After transfection, real-time PCR showed that 50 nmol/L was the most efficient concentration (0.22±0.08 vs. 1±0, P<0.01). The most efficient siRNA was selected by Western blot (0.38±0.05 vs. 2.22±0.08, P<0.01). The most efficient siRNA was transfected into macrophages. After transfection, cells was treated with 50 mg/L OX-LDL. Compared with control, the group incubate with OX-LDL increased the expression of TNF-α (30.68±1.31 pg/mL vs. 12.77±0.68 pg/mL, P<0.01) and MCP-1 (53.42±2.99 pg/mL vs. 18.06±2.11 pg/mL, P<0.01). Compared with the the group incubate with OX-LDL, the group siRNA+ OX-LDL decreased the expression of TNF-α (30.68±1.31 pg/mL vs. 12.77±0.68 pg/mL, P<0.01) and MCP-1 (28.62±0.88 pg/mL vs. 53.42±2.99 pg/mL, P<0.01). Real-time PCR and FACS was used to detect IL-10/IL-12/membrane molecule CD86. Compared with control, the group incubate with OX-LDL decreased the expression of CD86 (15,821±525.8 vs. 20,415.9±389.3, P<0.01)/IL-12 (0.3±0.07 vs.1±0, P<0.01), and increased the expression of IL-10 (4.26±0.22 vs. 1±0, P<0.01). Compared with the group incubate with OX-LDL, the group siRNA + OX-LDL did not change the expression of CD86 (16,064.2±631.8 vs. 15,821±525.8, P>0.05)/IL-12 (0.3±0.07 vs. 0.3 1±0.08, P>0.05) /IL-10 (4.31±0.28 vs. 4.26±0.22, P>0.05).
CONCLUSIONS RIP2 can regulate the inflammatory activation of macrophages induced by OX-LDL, but it has no significant effect on macrophage phenotypic variation induced by OX-LDL.
GW32-e1684
Liujun Jiang, Ting Chen, Qingbo Xu
The First Affiliated Hospital, Zhejiang University School of Medicine
OBJECTIVES Endothelial cells (EC) play a critical role in multiple cardiovascular diseases. Circulating CD34+ cells are believed to be endothelial progenitors that have been used to treat cardiovascular disease. However, the exact identity and the role of CD34+ cells in vascular regeneration remains unclear. We aimed to investigate the exact identity and the role of CD34+ cells in vascular regeneration.
METHODS Expression of CD34 was compared between healthy and diseased arteries of patients with /without vascular diseases. Using a genetic Cd34-lineage tracing mouse model, we combined histological examination and single-cell RNA sequencing analyses of mouse femoral artery under physiological and pathological conditions. Bone marrow transplantation was performed to identify origins of lesional CD34-lineage cells, and CD34+ cell depletion model was used to delineate contribution of CD34+ cell to neointima formation. Vessel wall CD34+ cells were isolated and cultivated in vitro to study underlying mechanism of CD34+ cell differentiation into endothelial cells.
RESULTS Compared with healthy arteries, CD34 expression percentage was significantly increased in diseased femoral arteries from patients. Using a guide-wire induced endothelial denudation model, we reported the transcriptional profiling of over 30,000 cells by single-cell RNA sequencing analysis and provided a cell atlas of normal and lesioned arteries in mouse, in which a heterogeneous population of CD34+ cells were revealed. Combining the inducible lineage tracing Cd34-CreERT2;R26-tdTomato mouse model and bone marrow transplantation experiments, we showed that non-bone marrow CD34+ mesenchymal cells acquired endothelial cell fate in the injured femoral artery rather than pre-exiting ECs, while bone marrow-derived CD34+ cells differentiated into immune cells locally after vessel injury. Depletion of non-bone marrow CD34+ cells using a diphtheria toxin induced cell ablation model, exacerbate neointimal lesions of the injured vessel. Furthermore, isolated vascular adventitia CD34+ cells displayed endothelial differentiation, in which microRNA-21-Smad7-pSmad2/3 pathway regulated endothelial gene expression and function during differentiation.
CONCLUSIONS Our study provides a transcriptional and cellular landscape of vessels after endothelial denudation. Our findings suggest heterogeneous CD34+ cells serve as a contributor not only to endothelial regeneration but also an inflammatory response that may provide therapeutic insights into vascular diseases.
GW32-e1749
Qingyao Liao
The Second Affiliated Hospital of Chongqing Medical University
OBJECTIVES The relationship between treatment efficacy and safety of high intensity focused ultrasound based (HIFU-Based) renal sympathetic denervation (RDN) and the applied acoustic energy dosage have not been fully studied and may provide important understanding of the mechanism leading to the failure of the WAVE IV. The purpose of this study was to externally deliver different HIFU dosages to canines for RDN treatment, and to investigate an ideal energy for HIFU-based RDN.
METHODS Thirty canines were divided into 5 RDN groups according to the acoustic energy applied, and a sham control group consisted of 4 canines was used for comparison. All animals in RDN group underwent RDN procedure with different acoustic energy dosage while the sham control group were only obtained Color Doppler flow image (CDFI) of renal arteries. BP was recorded and blood samples were collected before RDN procedure and at 28 days after RDN procedure. Histological examinations and kidney tissue norepinephrine concentration were conducted on all retrieved samples.
RESULTS BP suppression was significantly obvious in 300 W (15.17/8.33±1.47/1.21 mmHg), 250 W (14.67/9.33±1.21/1.37 mmHg), 200 W (13.17/9.17±2.32/1.84 mmHg) groups. Semiquantitative histological assessment of periarterial nerves around the kidney revealed that target nerves in 300 W (9.77±0.63), 250 W (9.42±0.67) and 200 W (9.58±0.54) group acquired the greatest nerve injury score, followed by 150 W group (5.29±0.62). Furthermore, decreased renal tissue norepinephrine concentration, together with the lower expression of tyrosine hydroxylase in 300 W, 250 W and 200 W group demonstrated an effective sympathetic depression after enough acoustic energy deposition. However, renal artery injury score in 300 W group (0.93±0.13) was notably higher than the other groups (P<0.001).
CONCLUSIONS This study provides evidences that 200–250 W is an efficacy and safety acoustic energy range when conduct HIFU-based RDN procedure in canines.
GW32-e1828
Nan Zhang, Hong Feng, Haihan Liao, Qizhu Tang
Renmin Hospital of WuHan University
OBJECTIVES Sestrin2 (Sesn2), a member of the Sestrin (Sesn) family, is a stress-induced protein. Previous studies demonstrated that Sesn2 participated in various diseases by regulating apoptosis, oxidative stress, and toxicity. However, the effects and underlying mechanisms of Sesn2 in adult mouse cardiac hypertrophy have not been clearly elucidated. Therefore, this study intended to investigate whether Sesn2 over-expression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2.
METHODS Firstly, we investigated cardiac Sesn2 protein and mRNA expression levels in samples from mice with aortic banding (AB)-induced cardiac hypertrophy, patients with heart failure, and cardiomyocyte with Ang II-induced cardiomyocyte hypertrophy. Next, we generated cardiac-specific sesn2 over-expression transgenic mice (Sesn2-TG) and then challenged them with AB surgery. The cardiac function of mice was evaluated by echocardiography and hemodynamics. The morphological and pathological changes of the heart were observed by hematoxylin and eosin (HE) and Picric-Sirius Red staining (PSR). Western blot was used to detect AMPKα/mTORC1 and oxidative stress-related pathways. Based on that, AMPKα2 knockout mice (AMPKα2−/−) and AMPKα2−/− crossed with Sesn2-TG transgene mice (Sesn2-TG+AMPKα−/−) were generated to investigate whether the effects of Sesn2 on cardiac hypertrophy were AMPKα dependent. Finally, we verified our findings in vitro, neonatal rat cardiomyocyte (NRCM) was extracted and incubated with adenoviruses of Sesn2 (Ad-Sesn2) or a similar adenovirus vector expressing the GFP protein (Ad-GFP) for 24 h and subsequently, the cardiomyocytes were stimulated with Ang II (1 nM) for 24 hours to induce cardiomyocyte hypertrophy. To further investigate the precise molecular mechanism of Sesn2 in cardiac hypertrophy, Ad-shAMPKα targeting AMPKα was used to clarify the role of AMPKα in the protective role of Sesn2 in cardiomyocytes.
RESULTS Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after AB surgery but decreased to 60–70% of the baseline at 8 weeks. Sesn2 over-expression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgene mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 over-expression. HE and PSR staining exhibited that Sesn2 over-expression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 over-expression markedly suppressed angiotensin II-induced neonatal rat cardiomyocytes hypertrophy in vitro. Mechanistically, Sesn2 over-expression activated AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protection of Sesn2 over-expression was also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with Sesn2-TG+AMPKα−/− transgene mice, since Sesn2 over-expression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout.
CONCLUSIONS This study uniquely revealed that Sesn2 over-expression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress for protecting against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.
GW32-e1914
Dan Yang, Di Fan, Qizhu Tang
Renmin Hospital of Wuhan University
OBJECTIVES Cardiac hypertrophy, characterized by the enlargement of cardiomyocytes (CMs) and deterioration of cardiac function, occurs when CMs are continuously stimulated by injury or cell stress. Sentrin/SUMO-specific proteases (SENPs), through de-conjugation of SUMO proteins, have emerged as significant modulators involved in the pathogenesis of a variety of diseases. Previous studies have demonstrated SENP1 upregulation in the diseased heart. However, the role of SENP1 in cardiovascular biology and disease are largely uncharacterized. Our current study aims to investigate the function and regulation of SENP1 in the progression of pressure overload-induced cardiac remodeling and dysfunction.
METHODS We utilized a preclinical mouse model of left ventricle (LV) pressure overload coupled to in vitro studies in neonatal rat cardiomyocytes (NRCMs) to study the roles of SENP1 on pathological cardiac hypertrophy. SENP1 overexpression and deficiency in mice were achieved by intramyocardial injection of adeno-associated virus serotype 9 encoding SENP1 (AAV9-SENP1) and AAV9-shSENP1, respectively. Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence were performed for functional, molecular and histological analysis. Cardiomyocyte-specific STAT3 knockout (STAT3 cKO) mice were also used for the investigation of the potential mechanisms.
RESULTS We observed that SENP1 levels were significantly upregulated following pressure overload-induced cardiac hypertrophy. Similarly, stimulation of NRCMs with phenylephrine (PE) markedly increased SENP1 expression. In vivo experiments revealed that SENP1 deficiency led to deteriorated cardiac hypertrophy, systolic function, cardiac inflammation and apoptosis following chronic pressure overload. In contrast, mice receiving exogenous SENP1 were protected from cardiac dysfunction and hypertrophy. Similarly, SENP1 inhibition in NRCMs aggravated CM pathological hypertrophy but SNEP1 overexpression prevented PE-induced CM hypertrophy. Importantly, results from immunoprecipitation and immunofluorescent staining suggested that signal transducer and activator of transcription 3 (STAT3) acted as a new interacting partner of SENP1. We discovered that the upregulated SENP1 closely combined with STAT3 and subsequently prevented the phosphorylation of STAT3, ultimately resulting in suppression of pathological cardiac hypertrophy. Knockdown of STAT3 reversed SENP1 deficiency-induced myocardial injury.
CONCLUSIONS Taken together, our results revealed that SENP1 exerted cardio-protective roles in response to pressure overload through a STAT3-dependent manner. Cardiac gene therapy with SENP1 might constitute a new promising approach to protect against pathological cardiac hypertrophy.
GW32-e0024
Xiaonan He1, Yingchen Bai2
1Beijing Anzhen Hospital, Capital Medical University
2State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing, 10012, China
OBJECTIVES Atherosclerosis (AS) is a chronic inflammatory disease related with endothelial dysfunction. Polycyclic aromatic hydrocarbons (PAHs) may induce an inflammatory atherosclerotic plaque phenotype. Pyroptosis has been reported to implicate in the progression of atherosclerosis. However, whether pyroptosis induced by PAHs contributes to endothelial dysfunction in AS remained unexploited. Thus, this study aimed to investigate whether PAHs modulated pyroptosis of endothelium in vivo and vitro.
METHODS The AS apoE−/−mice model treated with or without PAHs was established. The immunofluorescence, ELISA and western blot assays were utilized to detect the effect of PAHs on expression levels of pyroptosis-related genes and the inflammatory cytokines in vivo and vitro.
RESULTS The administration of PAHs for weeks remarkedly enhanced the atherosclerotic plaque in aorta. In AS mice, NLRP3 (a pyroptosis marker) and CD31 (an endothelial cell marker) co-expressed in the aortic endothelium. PAHs treatment significantly increased the expression level of NLRP3 in aortic endothelium of AS mice, and expression levels of IL-1βand IL-18 in serum. Moreover, In PAHs-treated endothelial cells (ECs), mRNA and protein expression levels of pro-caspase-1 and NLRP3 also upregulated compared to PAHs-untreated cells. Among the down-regulated miRNAs selected by miRNA PCR array, only hsa-miR-6882-5p expression significantly decreased with time in PAHs-treated ECs.
CONCLUSIONS The administration of PAHs led to the pyroptosis of endothelium and promoted the atherosclerotic plaque in AS. Our findings expand our knowledge about the risk of PAHs in AS progress.
GW32-e0093
Guojian Fang, Yingze Li, Jiali Yuan, Qunshan Wang
Department of Cardiology, Xinhua Hospital Affiliated To Shanghai Jiaotong University School of Medicine, Shanghai, China
OBJECTIVES Cadherin-11, one of the members of cadherin family, is closely associated with inflammatory response and it is highly expressed in mammal heart. It’s role in heart failure induced ventricular remodeling and the underlying mechanisms are largely unknown.
METHODS Cadherin-11−/− and WT mice were subjected to transverse aortic constriction at the age of 8 weeks. After 4 weeks challenge, multi-level studies were carried out to investigate how cadherin-11 is involved in heart failure-induced ventricular remodeling.
RESULTS Our results demonstrated that IL (interleukin)-6 production increases following transverse aortic constriction in wild-type mice; this effect is inhibited in cadherin 11 gene knockout (cadherin 11−/−) mice. IL-6 production also increases in cultured cardiac fibroblasts adding hCad-11-Fc and neutralizing IL-6 with an anti-IL-6 antibody prohibits hCad-11-Fc-induced cardiac fibroblasts activation. Furthermore, conditioned medium from hCad-11-Fc-stimulated cardiac fibroblasts can promote cardiomyocyte hypertrophy and electrophysiological remodeling. Again, neutralizing IL-6 prevented cardiomyocyte activation. Finally, the MAPK (mitogen-activated protein kinase) and CaMKII (Ca2+/ calmodulin-dependent protein kinase II)–STAT3 (signal transducers and activators of transcription 3) pathways are activated in hCad-11-Fc-stimulated cardiac fibroblasts and conditioned medium-stimulated cardiomyocytes, this effect can be inhibited on neutralizing IL-6.
CONCLUSIONS These data showed that cadherin-11 is engaged in heart failure induced ventricular remodeling via a cardiac fibroblast-to-cardiomyocyte paracrine effect. IL-6 is a downstream signal of cadherin-11 and has a central role in myocardial fibrosis, cardiomyocyte hypertrophy as well as electrophysiological remodeling that is mediated by activating the MAPK and CaMKII-STAT3 pathways.
GW32-e0234
Mengmeng Wang
The First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES The cell-based therapy can improve the cardiac function but is limited by the survival within the ischemic tissues. The injectable cardiac tissue engineering aims to support cell-based therapies and enhance their efficacy for cardiac diseases.
METHODS In this study, Matrigel was used as an injectable scaffold to provide three-dimensional and extracellular matrix for the ADSCs in the ischemic myocardium to avoid the leakage of the adipose-derived stem cell out of the injection site and the host attack to the transplanted cell.
RESULTS The results showed that three weeks after the operation of adipose isolation, MI was induced by the left anterior descending coronary artery (LAD) permanent ligation method. SD rats with one-week-old myocardial infarction were injected with 2×106 labeled ADSCs into the border area of the ischemic heart. Its heart function was determined using echocardiography and hemodynamics and cardiac structure and graft characteristics were assessed four weeks after transplantation. The results demonstrated that the engineered cardiac tissues injected by co-transplanting ADSCs with Matrigel could improve the morphology and the function of the heart of myocardial infarction in rat model.
CONCLUSIONS The lab work demonstrated that co-transplanting ADSCs with Matrigel could improve the morphology and the heart function in rat model of myocardial infarction.
GW32-e0402
Xiaolu Jiao, Huahui Yu, Qianwen Lv, Fan Li, Qiuju Sun, Yu Wang, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Angiopoietin-like protein8 (ANGPTL8), which is a novel hormone produced in liver and adipose tissue, plays important roles in various vascular disease, including atherosclerosis and thoracic aortic dissection. Recently, it is reported that plasma and adipose tissue levels of ANGPTL8 were increased in patients with hypertension. However, the role of ANGPTL8 in hypertension has not been explored. The current study explored the role and mechanism of ANGPTL8 in regulating blood pressure and hypertensive cardiovascular remodeling.
METHODS In the present study, 312 subjects with hypertension and 163 controls were enrolled. Circulating ANGPTL8 levels were determined by ELISA. Two hypertensive animal models were used in this study: mice treated with Ang II for 14 days and spontaneously hypertensive rats (SHR). Human artery smooth muscle cells (HASMCs) were used to explore the mechanism of ANGPTL8 in hypertension.
RESULTS The levels of circulating ANGPTL8 were significantly increased in hypertensive patients compared with controls and ANGPTL8 levels were positively correlated with carotid arteries Intima-media thickness (r=0.792 P=0.001). In the media layer of hypertensive mice, ANGPTL8 expression was increased and expressed predominantly in vascular smooth muscle cell (VSMC). Deletion of ANGPTL8 reduced blood pressure levels in mice. Moreover, deletion of ANGPTL8 attenuated Ang II-induced vascular contractility and remodeling, and cardiac hypertrophy in mice. Consistent with the results of hypertensive mice model, ANGPTL8 knockdown also reduced hypertension and vascular remodeling in SHR. Transcriptome analysis revealed that the PI3K-Akt genes exhibited greatest enrichment among the pathways in ANGPTL8−/− vascular tissues. In HASMCs, ANGPTL8 knockdown prevents Ang II-induced proliferation and migration of HASMCs and decreases the cellular calcium levels. LY294002-mediated PI3K-Akt pathway inhibition abolish ANGPTL8 overexpression induced HASMCs proliferation and migration and higher cellular calcium levels.
CONCLUSIONS This study provides the first evidence that deletion of ANGPTL8 decreases blood pressure and protects against cardiovascular remolding. It is suggesting that ANGPTL8 may be a novel therapeutic target against pathologic hypertension and hypertensive cardiovascular hypertrophy.
GW32-e0517
Jiabing Rong, Yinchuan Xu, Jian’an Wang
The Second Affiliated Hospital Zhejiang University College of Medicine
OBJECTIVES Sepsis combined with cardiac dysfunction leads to a significant increase in mortality. The renin-angiotensin system (RAS) plays an important role in the development of sepsis induced myocardial dysfunction (SIMD). Angiotensinogen (AGT) is the only known precursor and substrate of the RAS, and its effects on SIMD has not been illuminated. Meanwhile, locally synthesized AGT which was independent of systemic AGT was detected in end-organs, like kidney, heart, and adipose tissue. Here we investigated whether circulated or cardiac locally synthesized AGT was responsible for myocardial function during sepsis process and explored its potential mechanism, and then tried to provide a novel theoretical basis and potential intervention target to protect heart function after sepsis.
METHODS Male C57BL/6 mice were intraperitoneally injected by either lipopolysaccharide (LPS) or an equal volume of PBS and taken down 6 hours later. Cardiac function pre-and post-injection was evaluated by Vevo 2100 imaging system. The survival rate was monitored every hour for a 72-h period. Plasma AGT and angiotensin II (Ang II) levels were measured by ELISA while hepatic and cardiac AGT expression was determined by Western Blot. Cardiac hypertrophic markers expression and proinflammatory cytokine production were assessed by RT-qPCR while plasma levels of proinflammatory cytokines were detected by ELISA. Cardiomyocytes and cardiac fibroblasts were isolated by an enzymatic dissociation method. Combination of AGT and its receptor, low density lipoprotein receptor related protein1 (LRP1), was confirmed by ligand blotting. Furthermore, RNA sequencing of cardiac tissue was performed to uncover the role of hepatic AGT on hearts after LPS challenge.
RESULTS Intraperitoneal injection of LPS significantly activated AGT expression both in liver and heart. We further generated hepatocyte-specific AGT-deficient (hepAGT−/−) mice and cardiomyocyte-specific AGT-deficient (carAGT−/−). Interestingly, we found that hepatic conditional AGT deletion in mice triggered resistance to septic cardiac dysfunction. Contrarily, cardiac deficiency of AGT in mice had a similar phenotype as carAGT+/+ littermates. Depressed plasma AGT and Ang II concentrations accompanied with less Interleukin-1β (IL-1β) level hinted hepatic elimination of AGT may functioned via circulated Ang II-dependent manner. However, hepAGT+/+ mice infused with an AT1R antagonist, losartan, partially protected from cardiac dysfunction compared to hepatic AGT deficiency, which implied that liver-secreted AGT may have another effects on heart via an Ang II-independent pathway. Furthermore, we found cardiac Ang II content of hepAGT−/− mice was comparable with hepAGT+/+ littermates while IL-1β mRNA level in heart was lower, which proved there exited a pathway which IL-1β was involved in while Ang II was not. Then, we discovered that hepatic AGT knock-out heart showed a remarkably decreased AGT protein level. These facts implied that cardiac AGT is mainly derived from circulation rather than synthesized locally. Furthermore, we identified liver derived AGT entered cardiac fibroblast rather than cardiomyocytes via LRP1 mediated endocytosis, which in turn activated NLRP3 inflammasome and improved IL-1β production.
CONCLUSIONS Hepatocyte-specific deficiency of AGT ameliorates SIMD via preventing cardiac fibroblastic LRP1-dependent endocytosis and then decreasing NLRP3 inflammasome assembly, which alleviates IL-1β releasing. These findings provide potential therapeutic targets in liver to treat SIMD.
GW32-e0566
Chen Wang1, Yuanming Xing1, Jiao Zhang1, Haoyu Wu1, John Y-J. SHYY2, Zuyi Yuan1
1Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
2Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
OBJECTIVES Dysregulated bone morphogenetic protein (BMP) or transforming growth factor b (TGF-β) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. Mediator 1 (MED1) is a key transcriptional coactivator and Krüppel-like factor 4 (KLF4) is a master transcription factor in endothelium. To elucidate the epigenetic and transcriptional regulations of the BMP/TGF-b axes in pulmonary endothelium, we studied the MED1 regulation of BMP receptor type II (BMPR2), ETS-related gene (ERG), and TGF-b receptor 2 (TGFBR2) and their involvement in the pathogenesis of PH.
METHODS High throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, KLF4 ATAC-seq, and high-throughput chromosome conformation capture (HiC) together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (PAECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic pulmonary arterial hypertension (IPAH), animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1−/−) were used to study the PH-protective effect of MED1.
RESULTS Levels of MED1 were decreased in lung tissue or PAECs from IPAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1−/− mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents.
CONCLUSIONS A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-b pathway are pathogenic in the development of PAH/PH.
GW32-e0663
Xin Zhang1,2, Qi-Zhu Tang1,2
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
2Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan 430060, China
OBJECTIVES The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to promote O-linked GlcNAc (O-GlcNAc) protein modification and cell survival under different stresses, including the cardiac ischemia/reperfusion (I/R) injury. Transcript induced in spermiogenesis 40 (Tisp40, also known as AIbZIP and CREB3L4) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. The present study aims to elucidate the role and underlying molecular basis of Tisp40 in cardiac I/R injury.
METHODS Global Tisp40 knockout (KO) and cardiac-specific transgenic (cTG) mice were generated and subjected to cardiac I/R injury, and neonatal rat cardiomyocytes were isolated to further validate the role of Tisp40 in vitro. The potential downstream targets of Tisp40 in cardiac I/R injury were screened by bioinformatics approaches, and chromatin immunoprecipitation and luciferase reporter assays were performed to validate the direct binding of Tisp40 to the promoter of glutamine-fructose-6-phosphate transaminase 1 (GFPT1), a rate-limiting enzyme of the HBP.
RESULTS Tisp40 expression, cleavage and nuclear accumulation were increased in I/R-stimulated murine hearts, cardiomyocytes and human ischemic hearts. Tisp40 KO significantly exacerbated I/R-induced oxidative stress, apoptosis and cardiac injury, and facilitated cardiac remodeling and impairment following long-term observations, which were rescued by adeno-associated virus serotype 9-aided cardiac overexpression of a cleaved Tisp40 lacking the transmembrane domain (Tisp40ΔM). Conversely, I/R-induced cardiac injury and dysfunction were ameliorated in Tisp40 cTG mice. In addition, overexpression of the Tisp40ΔM alleviated, while Tisp40 silence aggravated oxidative stress, apoptosis and cardiomyocyte injury upon I/R stimulation. Tisp40 bound to the Gfpt1 promoter, and potentiated GFPT1-mediated HBP and O-GlcNAc modification. Inhibition of GFPT1 or O-GlcNAc modification with either genetic or pharmacologic methods dramatically abrogated the deleterious phenotype in Tisp40 KO mice or cardiomyocytes.
CONCLUSIONS We demonstrate that Tisp40 upregulation in the hearts upon I/R stimulation is required to prevent cardiac injury and dysfunction by inducing GFPT1-mediated HBP and O-GlcNAc modification.
GW32-e0853
Hualu Zhang, Zhelong Xu
Tianjin Medical University
OBJECTIVES Whereas elimination of damaged mitochondria by mitophagy is proposed to be cardioprotective, the regulation of mitophagy at reperfusion and the underlying mechanism remain elusive. Since mitochondrial Zn2+ may control mitophagy by regulating mitochondrial membrane potential (MMP), we aimed to test if the zinc transporter ZIP7 that controls Zn2+ levels within mitochondria contributes to reperfusion injury by regulating mitophagy.
METHODS Mouse hearts were subjected to ischemia/reperfusion in vivo. Mitophagy was evaluated by detecting mitoLC3II, mito-Keima, and mitoQC. ROS were measured with DHE and mitoB. Infarct size was measured with TTC staining. The cardiac-specific ZIP7 conditional knockout mice (ZIP7 cKO) were generated by adopting the CRISPR/Cas9 system. Human heart samples were obtained from donors and recipients of heart transplant surgeries.
RESULTS KO or cKO of ZIP7 increased mitophagy under physiological conditions. Mitophagy was not activated at the early stage of reperfusion in mouse hearts. ZIP7 is upregulated at reperfusion and ZIP7 cKO enhanced mitophagy upon reperfusion. cKO of ZIP7 led to mitochondrial depolarization by increasing mitochondrial Zn2+ and, accumulation of PINK1 and Parkin in mitochondria, suggesting that the decrease in mitochondrial Zn2+ in response to ZIP7 upregulation resulting in mitochondrial hyperpolarization may impede PINK1 and Parkin accumulation in mitochondria. Notably, ZIP7 is markedly upregulated in cardiac mitochondria from patients with heart failure (HF), whereas mitochondrial PINK1 accumulation and mitophagy were suppressed. Furthermore, ZIP7 cKO reduced mitochondrial ROS generation and myocardial infarction via a PINK1-dependet manner.
CONCLUSIONS Our findings identify upregulation of ZIP7 leading to suppression of mitophagy as a critical feature of myocardial reperfusion injury. A timely suppression of cardiac ZIP7 upregulation or inactivation of ZIP7 is essential for the treatment of reperfusion injury.
GW32-e0962
Feng Wang, Junjie Zhang
Nanjing First Hospital
OBJECTIVES Compared with the well-studied classic MAPK family, little is known about the regulation of the atypical MAPK ERK3 signaling cascade and its role in the progression of coronary atherosclerosis. The purpose of our study was to explore the influence of non-classical MAPK signaling on the progression of atherosclerosis and its internal mechanisms.
METHODS In the study, we found that the total amount of ERK3 decreased under the action of low shear stress. Under the action of oxidized LDL, the total amount increased. But in both cases, the same change happens to ERK3, which is an increase in the nucleus. We then validated it in human tissue. In the bifurcation area of human coronary arteries, ERK3 mainly exists in the nucleus, while in the non-bifurcation area, ERK3 is mainly distributed in the cytoplasmic area of endothelial cells. To verify the origin of ERK3 in the nucleus, RNA was extracted from cells treated with low shear stress. The results of real-time-PCR showed that low shear stress did not change ERK3 mRNA levels in endothelial cells. In the following experiments, we designed three different plasmids: ERK3 1-365, ERK3 1-600, ERK3 365-721. Overexpressing different subclones respectively. After the transfection efficiency was tested, immunofluorescence experiments showed that significant nucleation was observed in the experimental group ERK3 1–600 under the stimulation of low shear stress and oxidized LDL, but not in the other two groups. In APOE mice, ERK3 overexpressed virus was injected into the tail vein. After two weeks, they were given a high cholesterol diet, and after 7 weeks, they were harvested. Then we compared the plaque area and intima-media ratio of the aortic arch and descending aorta between the control group and the experimental group.
RESULTS Low shear stress and oxidized LDL stimulated ERK3 nuclear translocation in endothelial cells and the key sites were between 365 and 600 ERK3 nucleotides, Endothelial inflammation caused by low shear stress and oxidized LDL could be significantly reduced by blocking nuclear translocation of ERK3. Interestingly, the inflammatory and apoptosis-related indicators of endothelial cells were significantly reduced with ERK3si. In animal experiments, compared with the control group, the experimental group had significantly increased plaque area and intima-media ratio.
CONCLUSIONS Nuclear translocation of ERK3 was found in the bifurcation area of the human coronary artery. Our study confirms that low shear stress and oxidized LDL promote nuclear translocation of ERK3 to promote endothelial inflammation and accelerate atherosclerosis progression. Furthermore, the potential location of nucleotide sites for ERK3 nuclear translocation was identified. As such, ERK3 protein kinase may be an attractive therapeutic target for coronary atherosclerosis.
GW32-e1035
Lu Li1,2, Ai-Ling Wang1,2, Hong Yang1,2, Xi Jie1,2, Li-Guo Yang1,2, Hui-Ping Zhao1,2, Bao Li1,2, Fu-Zhong Qin1,2, Rui-Fang Chi2
1Shanxi Medical University
2The Second Hospital of Shanxi Medical University
OBJECTIVES Programmed necrosis (necroptosis) in cardiac myocytes is increased in heart failure. Oxidative stress plays an important role in myocardial remodeling and failure. In cardiac myocytes in vitro, hydrogen peroxide induces necroptosis. However, little is known whether oxidative stress mediates necroptosis in myocytes in heart failure. In this study, we tested the hypothesis that antioxidants prevent myocyte necroptosis in pressure overload-induced heart failure.
METHODS Heart failure was induced by chronic pressure overload produced by abdominal aortic constriction (AAC) in rats. Rats with AAC or sham operation were randomized to orally receive an antioxidant N-acetylcysteine (NAC, 500 mg/kg/day) or placebo for 4 weeks. Echocardiography was performed for the assessments of left ventricular (LV) structure and function. Oxidative stress was assessed by myocardial level of 8-hydroxydeoxyguanosine. RIP1, RIP3 and MLKL protein expression was assessed by immunohistochemistry and Western blot.
RESULTS Compared with sham-operated rats, LV end-diastolic dimension (EDD) was increased and LV fractional shortening (FS) was decreased in AAC rats 4 weeks after surgery (FS %, 39.1±2.1 vs. 48.9±3.6 in Sham placebo, P<0.05). NAC treatment attenuated the alterations in LV EDD and FS in AAC rats (FS%, 48.3±1.5 vs. AAC placebo, P<0.05). Immunohistochemical staining demonstrated that myocardial level of 8-hydroxydeoxyguanosine, indicative of oxidative stress, and RIP1 expression, reflective of necroptosis were increased in AAC rats, and the increases were attenuated by the NAC treatment. Western blot further showed that RIP1, RIP3 and MLKL protein expression was markedly increased in AAC rats, and NAC treatment prevented the changes. AAC rats exhibited increased myocyte cross-sectional area and myocardial fibrosis, which were attenuated by the NAC treatment.
CONCLUSIONS Antioxidant NAC prevented the increases in oxidative stress and necroptosis in cardiac myocytes and attenuated LV dilation and systolic dysfunction in pressure-overload induced heart failure. These results suggest that enhanced oxidative stress mediates myocyte necroptosis, leading to LV remodeling and dysfunction, and antioxidants may be of value to prevent heart failure through inhibition of myocyte necroptosis.
GW32-e1081
Xing Liu
Gannan Medical University
OBJECTIVES Because of the high morbidity and mortality of related patients, cardiovascular disease (CVD) has become a major health problem. Although pharmacological and non-pharmacological treatments can delay disease progression, there are difficulties and complications in CVD. Terms, such as myocardial hypertrophy (MH). In recent years, with the development of evidence-based medicine, the concept of “heart bowel axis” has gradually become popular Known, and more and more studies suggest that the intestinal flora is closely related to cardiovascular disease. This paper will investigate changes and mechanisms of intestinal flora in mice with myocardial hypertrophy.
METHODS Here, we used 16S rRNA sequencing to explore the mouse gut microbiota. The mouse MH model was completed and constructed as an experimental group, and wild-type mice were used as a control group. Fecal specimens were collected on the 28th day after surgery and stored at −80 °C until DNA extraction. We used the 16S rRNA amplicon metabolome code to determine the relative abundance of the bacterial taxonomic group, and combined the analysis with the parent software and UPARSE for sequence analysis. At the same time, the indicators and items for sample analysis were: α diversity of samples, β diversity of samples, Principal component (PCoA) analysis, which also includes different analyses of related intestinal flora such as LEfSe.
RESULTS Through the identification of the flora, we found a phenomenon that the intestinal flora of MH mice showed very different results compared with the control group: in the MH mice, the intestinal flora was rich, uniform, and scattered. The degree, proportion of bacteria, diversity and differences showed significant differences, and Alistipes, Alloprevotella, Odoribater, Rikenella were significantly reduced in the intestinal flora of MH mice compared with the control group, and the thick-walled mycoplasma The ratio of (F) and Bacteroides (B) has changed: in the intestinal flora of MH mice, the F/B ratio increases, and the flora is out of balance; therefore, we consider that the intestinal flora of MH mice has occurred Changes, and the above-mentioned changed flora in MH mice may be closely related to the occurrence and development of MH and HF.
CONCLUSIONS Intestinal microbiological disorders in MH mice, intestinal flora Alistipes, Alloprevotella, Odoribater, Rikenella may be closely related to myocardial hypertrophy; in this way, another important point can be pointed out: the intestinal flora may be considered as MH and HF Potential goals are significant.
GW32-e1205
Aiqun Chen, Xiaofei Gao, Junjie Zhang
Nanjing First Hospital
OBJECTIVES In-stent restenosis (ISR) still remains an Achilles heel of drug-eluting stents in spite of the technical advances in devices and procedural techniques. The present study is to reveal the mechanism by which PFN1 affects vascular smooth muscle cell (VSMC) phenotype switching and then leads to neointimal hyperplasia.
METHODS We performed single-cell RNA sequencing on rat carotid arteries (balloon injury vs. uninjured) and identified VSMC. We screened out the differentially expressed genes and verified them with RT-PCR. To explore the relationship between N6-Methyladenosine (m6A) and mRNA-profilin1, MeRIP-sequencing was performed on murine-VSMC (si-METTL3 vs. NC).
RESULTS Single-cell RNA sequencing and RT-PCR revealed the critical role of profilin1 (PFN1) in neointimal hyperplasia. In vitro cell experiments based on primary murine-VSMC suggested that PFN1 promotes VSMC proliferation, migration and phenotypic switching. In vitro experiments suggested that knocking down PFN1 could delay neointimal hyperplasia. Besides, IHC/IF and RT-PCR/FCM of restenotic vessels indicated that there is a difference in the expression abundance of PFN1 between the protein level and the RNA level. Combined with the results of methylation sequencing, we confirmed that m6A methylation affects the translation efficiency of PFN1 transcripts. Meanwhile, METTL3/YTHDF2 reduced the stability of mRNA-PFN1 by loading and identifying m6A methylation modifications. The final additive effect was still to promote the increase of the protein level of PFN1.
CONCLUSIONS Hence, we reported the critical role of PFN1 in VSMC phenotype switching and neointimal hyperplasia. Then our study revealed the overall effect of m6A methylation-related METTL3/YTHDF2 signal axis on PFN1 at the mRNA level.
GW32-e1283
Bin Li1, Quanwei Pei1, Xuexin Jin2, Jiaxin Wang1, Weifa Wang1, Junpei Zhang1, Jingjie Li1, Xiufen Qu1,3, Dechun Yin1,3
1Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
2Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China
3This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
OBJECTIVES The purpose of this study was to determine whether verapamil decreases ventricular arrhythmias and intracellular calcium concentration during therapeutic hypothermia.
METHODS Optical mapping was performed in rat hearts with hypothermic (25.0 °C) and normal hearts before and after verapamil infusion. APD at 80% repolarization (APD80) and arrhythmia inducibility were determined. Additional studies with verapamil were performed in isolated ventricular cardiomyocytes using patch clamp and confocal calcium imaging.
RESULTS APD was homogeneous at baseline. Hypothermia heterogeneously prolonged APD80 at all pacing cycle lengths (PCLs) [51.0+2.9 ms vs 66.2+1.6 ms, P<0001, n=5]. Subsequent verapamil addition shortened APD80, reduced APD heterogeneity, These Hypothermic effects on APD in whole hearts were supported by patch clamp in isolated ventricular cardiomyocytes [23.3+6.6 ms vs 71.2+10.2 ms, P<0.015, n=3]. We further investigated the properties of ventricular arrhythmias induced by Hypothermia. At baseline, there was no spontaneous or pacing-induced TdP with an burst pacing protocol. After hypothermia, either spontaneous, pacing-induced TdP, or EADs and DADs were observed, these were eliminated by subsequent verapamil addition. Hypothermia significantly lengthened Cai transient duration (CaiTD50) at all PCLs. These effects on calcium transient in whole hearts were supported by confocal calcium imaging in fluo-4AM–loaded isolated ventricular cardiomyocytes, showing increased time to peak and decreased decay time after Hypothermia, which were shortened after verapamil infusion.
CONCLUSIONS Hypothermia heterogeneously prolonged APD80, verapamil may shorten APD80, reduced APD heterogeneity, and decrease intracellular calcium concentration during therapeutic hypothermia, which increases the vulnerability to ventricular arrhythmias.
GW32-e1354
Xiaodan Zhong, Hongjie Wang, Hesong Zeng
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
OBJECTIVES Our recent data revealed that YB-1 functioned as a transcript factor in diabetic cardiomyopathy (DCM) protection. In this study, we aimed to investigate the mechanism of YB-1 phosphorylation regulation and evaluate the effectiveness of related blockade U0126 intervention on cardiac function in DCM.
METHODS Mice DCM animal model was induced by continuous STZ intraperitoneal injection and verified by blood glucose, cardiac morphology, echocardiography, hemodynamic measurement and among other things. YB-1 expression and YB-1 phosphorylation levels were determined by immunoblotting and immunohistochemical. Then, Co-immunoprecipitation was used to evaluate the effect of YB-1 phosphorylation on YB-1 ubiquitination, especially K48 linked ubiquitination, and the interaction between YB-1 and deubiquitination enzyme OTUB1, which indicated the ubiquitin-degradation degree of YB-1. Upstream regulation of YB-1 was determined by corresponding pharmacological inhibitors, including SL-0101 and U0126. Effects of pharmacological inhibitors on high glucose (HG) stimulated H9c2 cells were determined by western blot. Afterwards, MEK inhibitor U0126 was administrated to DCM mice at the dose of 1 mg/kg/d for 8 weeks to assess the therapeutic effect on DCM.
RESULTS Blood glucose in STZ administrated mice were significantly elevated. Cardiac function which indicated by ejection fraction, fraction shortening, and hemodynamic parameters were markedly decreased. YB-1 phosphorylation was elevated in DCM mice heart while YB-1 expression was reduced. In high glucose incubated H9c2 cells, YB-1 phosphorylation modification was increased in a time dependent manner. The in vitro study demonstrated that YB-1 phosphorylation accelerated YB-1 ubiquitination degradation and destroyed the interaction between YB-1 and OTUB1, thus leading a decreased YB-1 protein level. Subsequent investigations reveal that activation of p90RSK was markedly increased in DCM mouse hearts and high glucose incubated H9c2 cells. Moreover, pharmacological inhibitor SL-0101 alleviated YB-1 phosphorylation in high glucose incubated H9c2. Notably, MEK inhibitor U0126 can lead to a significant decrease of YB-1 phosphorylation both in vivo and in vitro, preserving the YB-1 protein expression and protecting DCM.
CONCLUSIONS This work brought to light the beneficial effects of U0126 on cardiac dysfunction in a mouse model of STZ induced DCM. Those cardioprotective effects may be explained on account of the regulation of YB-1 expression by YB-1 phosphorylation via ERK/RSK/YB-1 pathway.
GW32-e1482
Jianfang Liu, Di Ye, Menglong Wang, Zhen Wang, Jishou Zhang, Yao Xu, Mengmeng Zhao, Cheng Wei, Jun Wan
Renmin Hospital of Wuhan University
OBJECTIVES Ventricular arrhythmia after myocardial ischemia-reperfusion (I/R) injury affects the prognosis of acute myocardial infarction (AMI) patients after revascularization. I/R injury results in the generation of free radicals and accumulation of peroxidation-derived unsaturated aldehydes. Transient receptor potential ankyrin 1 (TRPA1) is highly sensitive to peroxides and can be activated by a variety of harmful stimuli. Therefore, the aim of this study was to investigate the effect of TRPA1 on ventricular arrhythmia after myocardial I/R injury.
METHODS In vivo, myocardial I/R model was established by ligating left anterior descending branch for 30 minutes and then reperfusing 120 minutes in TRPA1 knockout (TRPA1-KO) and wild type (Control) rats. Heart rate (HR) and occurrence of ventricular arrhythmia (VA) during I/R injury were recorded. Langendorff perfused heart model was used to explore the electrophysiological characteristics and mechanisms post-I/R ex vivo, including the induction rate of VA, the occurrence rate of sustained VA, VA duration time, epicardial monophasic action potential duration (APD), APD alternans, effective refractory period (ERP) and ERP dispersion.
RESULTS In vivo, the ECG parameters at baseline and the occurrence of VA after I/R injury had no difference between TRPA1-KO and control groups. However, compared with control group, the occurrence rate of sustained VA (which identified as last longer than 30 seconds) and total duration time of VA were reduced in TRPA1-KO group. Ex vivo, sustained VA was also attenuated in TRPA1 deficient heart. However, the induction rate of VA induced by high-frequency electrical stimulation was not affected by TRPA1 deficiency. In addition, although the average APD and ERP were similar between the two groups, the threshold of APD alternans and the dispersion of ERP were attenuated after TRPA1 deficiency, indicating that TRPA1 ablation may affect the homogeneity of electrical activity.
CONCLUSIONS The ablation of TRPA1 channel attenuated sustained VA after myocardial I/R both in vivo and ex vivo. The attenuated threshold of APD alternans and ERP dispersion may contribute to the electrophysiological stability after I/R injury.
GW32-e1620
Mengmeng Zhao, Menglong Wang, Jun Wan
Renmin Hospital of Wuhan University
OBJECTIVES Obesity is often accompanied by hypertension. Although a large number of studies have confirmed that NLRP3 inhibitors can improve cardiac remodeling in mice with normal diet, it is still unclear whether NLRP3 inhibitors can improve heart failure induced by pressure load in obese mice. The purpose of this study was to explore the role of NLRP3 inhibitor MCC950 on heart failure in obese mice and its metabolic mechanism.
METHODS 10-week high-fat diet (HFD)-induced obesity mice were used in this study. After 4 weeks of HFD, transverse aortic constriction (TAC) surgery were performed to induce heart failure model mice. MCC950 (10 mg/kg, once/day) was injected intraperitoneally from 2 weeks after TAC and continued for 4 weeks. After echocardiography examination, we harvested mouse tissues and performed molecular experiments.
RESULTS In obese mice, MCC950 can significantly improve cardiac hypertrophy and fibrosis caused by pressure overload. At the same time, MCC950 can improve cardiac metabolism disorders, and its mechanism may be related to the regulation of AKT/FOXO1 and PPARγ/NRF2 signaling pathways. In addition, MCC950 can significantly attenuate glucose and lipid metabolism disorders in metabolism-related tissues, including liver and brown adipose tissue, which contributes to the improved cardiac function after pressure overload in obese mice.
CONCLUSIONS MCC950 can alleviate heart failure induced by pressure overload in obese mice via improving cardiac and system metabolism, providing a basis for clinical application in obese patients with heart failure.
GW32-e1691
Zhi Chen, Junyi Yu, Gengze Wu, Chunyu Zeng
Department of Cardiology, Daping Hospital, The Third Military Medical University
OBJECTIVES Angiogenesis involving endothelial cell (EC) homeostasis is indispensable for normal growth, and tissue repair. While pathological angiogenesis takes essential role in diseases including diabetic retinopathy as well as cancer. We recently identified a conserved, vascular tissue-dominant protein, named Arteridin, whose function in EC or angiogenesis remains unclear.
METHODS Using quantitative real time PCR and western blot, retinal whole mount immunostaining, PH3 staining, CCK8 as well as bioinformatics analysis and studies in vitro and in vivo.
RESULTS Using specific antibodies targeting rat or human Arteridin, we identified Arteridin to be significantly reduced in the glioma tissues than in normal brain tissue. In addition, Arteridin was significantly decreased in the retinas and carotid arterial of diabetic rats as well as in human umbilical vein endothelial cells (HUVECs) treated with pro-angiogenic factors, including vascular endothelial growth factor (VEGF), hypoxia and high glucose. In HUVECs, Arteridin knock-down increases while Arterdin overexpression decreases the proliferation, migration, and tube formation. We constructed the Arteridin global transgenic rats. Compared with WT rats, Arteridin transgenic rats showed a significantly reduced retinal vessel growth as well as aortic ring sprouting, indicating an anti-angiogenesis role of Arteridin in vivo. To further dissect the molecular mechanism, we performed RNA-sequencing in HUVECs with Arteridin overexpression or knock-down, finding ITGB3 gene to be positively regulated by Arteridin at transcription level. The well-set pro-angiogenetic transcription factor YAP was reported to be downstream of ITGB3 gene. In both retinal tissue of Arteridin transgenic rats and HUVECs transfected with Arteridin plasmid, ITGB3 was significantly up-regulated, and the phosphorylation of YAP was increased, leading to a cytoplasmic retention of YAP. In HUVECs, ITGB3 knockdown abolished the Arteridin overexpression-reduced proliferation, migration, tube formation as well as the phosphorylation of YAP, suggesting ITGB3 to be necessary for the anti-angiogenetic function of Arteridin. Finally, using an orthotopic C6 glioma model, tumor growth and angiogenesis was significantly attenuated in Arteridin overexpression rats compared with WT rats.
CONCLUSIONS In endothelial cell, novel protein Arteridin activates the transcription of ITGB3, leading to an increased phosphorylation and cytoplasmic retention of YAP, thus preventing the angiogenesis. Targeting Arteridin protein may provide ultimate therapeutic solution for angiogenesis-related diseases.
GW32-e1761
Chuannan Zhai, Hongliang Cong
Tianjin Chest Hospital, NanKai University School of Medicine
OBJECTIVES MicroRNAs are engaged in the progression of atherosclerosis which is a chronic inflammatory disease. The endothelial damage plays a critical role in promoting development of atherosclerotic plaques. We aimed to investigate the molecular mechanisms of microRNA miR-195-5P related to atherogenesis using in vitro and further explore how it is regulated.
METHODS Using a Human umbilical vein endothelial cell (HUVEC) line and in vitro gene silencing method, we detected cell proliferation by CCK8 assay and the expression of SM22α by immunofluorescence (IF) assay, as well as cell apoptosis by TUNEL assay. Chromatin Immunoprecipitation (ChIP) assay was performed to determine the association of KLF5 and miR-195-5P.
RESULTS Following KLF5 silencing, the influence of KLF5 on miR-195-5P function was further evaluated by these main methods. We found that miR-195-5P was upregulated in HUVECs stimulated with oxidized LDL (ox-LDL) in time-dependent manner. miR-195-5P inhibition reduced inflammatory markers levels (TNF-a, IL-1β, IL-6 and MCP-1), cell apoptosis and EndMT in HUVECs with ox-LDL treatment. In turn, KLF5 was responsible for the effects of miR-195-5P overexpression on inflammatory markers, apoptosis and EndMT.
CONCLUSIONS We identify increase of miR-195-5P to convey pro-inflammatory pro-apoptotic signals and EndMT, which was induced by KLF5 at transcription levels. Therefore, stimulation of miR-195-5P/ KLF5 is a candidate direct anti-atherosclerotic therapy.
GW32-e1841
Di Fan, Zheng Yang, Qi-Zhu Tang
Renmin Hospital of Wuhan University
OBJECTIVES Cardiac rupture is the second most common cause of death after ventricular failure in acute myocardial infarction. Successful repair prevents cardiac rupture after acute myocardial infarction. CDKN1A is a central regulator of innate and adaptive immunity. This study evaluates the potential therapeutic treatment with CDKN1A to induce cardiac repair after MI.
METHODS Cardiac repair was analyzed in mice deficiency of CDKN1A and challenged with acute myocardial infarction. MI was induced by surgical ligation of the left anterior descending coronary artery. Echocardiographic measurements in mice were performed at the indicated times after sham or MI surgery to evaluate mouse cardiac structure and function. The mice were checked daily for survival. Infarct area evaluation by TTC staining. Bone marrow (BM) cells were obtained by flushing tibiae and femora of donor mice.
RESULTS In the infarct region, CDKN1A expression was increased at days 3 and 7 post-MI. The number of monocytes peaked in the infarct areas at days 3 post-MI. The increase in CDKN1A was consistent with the pattern of monocytes infiltrate. CDKN1A colocalizes with the macrophage marker CD68 after MI. These findings indicate an increase in macrophage-derived CDKN1A post-MI. Infarct areas were similar between WT and CDKN1A−/− mice, demonstrating that CDKN1A deficiency had no effect on the acute ischemia response. CDKN1A deletion decreased survival and increased cardiac rupture rates. By day 7, the end-systolic and end-diastolic volumes in CDKN1A−/− mice were higher, respectively, compared with WT. The increases in volumes translated to a reduced ejection fraction with CDKN1A deletion, compared with day 7 post-MI WT. CDKN1A deletion exacerbates cardiac dysfunction, suggesting an important role of CDKN1A functions in the post-MI setting. Collagen volume fraction detected by picrosirius red staining in the infarct and border areas was significantly higher in WT mice than in the CDKN1A−/− mice 7 days after MI. M1 macrophages promote ECM degradation, whereas anti-inflammatory M2 macrophages facilitate the ECM reconstruction and reparative response. Our quantitative real-time PCR data showed that at day 7 post-MI, IL-1β was the only M1 marker significantly increased with CDKN1A deletion. In vitro study, CDKN1A−/− macrophages showed reduced response to IL-4 stimulation. Compared with WT, CDKN1A−/− macrophages stimulated with IL-4 showed reduced expression of M2 markers. Co-culture of CFs with CDKN1A−/− macrophages had the lowest expression of α-SMA after Ang II stimulated. Similarly, either the protein levels or the mRNA levels of α-SMA, collagen I, collagen III, or TGF-b1 were remarkably lower in co-culture of CFs with CDKN1A−/− macrophages after Ang II treatment, but higher in co-culture of CFs with CDKN1A overexpress macrophages. Moreover, CDKN1A deletion in cardio-fibroblasts did not display any different with WT cardio-fibroblasts with TGF-β stimulated.
CONCLUSIONS CDKN1A deletion led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired as a result of decreased expression. CDKN1A deletion aggravated MI-induced LV dysfunction and rupture as a result of defective inflammatory response and scar formation by suppressing M2 macrophage activation.
GW32-e1936
Gulinazi Yesitayi, Qianru Yuan
First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES Aortic Dissection (AD) is a serious life-threatening cardiovascular emergency with rapid onset, rapid progress and high mortality. In recent years, with the continuous in-depth research on the Gut microbiome (GM), the potential role of GM in cardiovascular disease has been revealed, but it is still unknown whether GM disorders are involved in the development of AD. This study explored the role of the innate immune inflammatory response caused by the damage of the intestinal barrier in the pathogenesis of aortic dissection.
METHODS 1. Use proteomics technology to detect the blood samples and tissue of the healthy control group, screening the differential genes and proteins when AD occurs, and through the gene ontology On (Gene oncology, GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases carry out enrichment analysis of the important biological processes and key signal pathways involved in differential genes and proteins in the occurrence of AD, revealing The key mechanism of AD occurrence. 2. We collected blood samples from 50 healthy controls, 50 hypertensive patients, and 50 AD patients, and tested lipopolysaccharide (LPS), which is the component of the outer wall of gram-negative bacteria, also known as endotoxin; interleukin-6 (Interleukin-6, IL-6), a marker protein of inflammation; serum lipopolysaccharide binding protein (LBP) and soluble CD14 (soluble-CD14, s-CD14). 3 Fecal samples of the above population were collected and used 16S sequencing to analyze the diversity of the floor and further screen for different bacteria Group 4. The feces of AD patients were extracted into bacterial solution and transplanted into sterile C57/BL mice for 4 weeks as the experimental group, and sterile mice were used as the control group, BAPN), combined with 24 hours Ang II induced AD mice. And compares the modeling rate of the two groups of mice. At the same time, the expression levels of serum IL-6, LBP, and sCD14 in sterile mice before fecal bacteria transplantation, fecal bacteria transplanted mice after transplantation, and AD model mice were detected.
RESULTS 1. Proteomics analysis results show that differential proteins are enriched in the Toll-like receptor signaling pathway. 2. Compared with healthy controls and hypertensive patients, AD patients have higher levels of serum LPS, IL-6, LBP, and sCD14, the difference is statistically significant (P<0.05). 3. The composition of the intestinal microbiome was analyzed, and α-diversity and β-multiplicity were evaluated. The results show that compared with healthy controls and hypertensive patients, the intestinal flora of AD patients tends to be more inclined It produces LPS type. 4. Compared with mice without fecal bacteria transplantation, fecal bacteria transplanted mice have a higher AD model rate. And compared with those without fecal bacteria transplantation, serum LPS, LBP, and sCD14 of fecal bacteria transplanted mice increased with fecal bacteria transplantation and model construction.
CONCLUSIONS After the intestinal barrier function is impaired, LPS-mediated low-grade endotoxemia causes the activation of immune inflammation in the blood vessels and participates in the occurrence and development of aortic dissection
GW32-e0027
Jianxin Huang1,2, Yi Feng1,2, Xing Luo1,2, Xiuzhu Weng1,2, Xiaoxuan Bai1,2, Xiaoyi Bao1,2, Ying Lv1,2, Shan Zhang1,2, Chen Zhao1,2, Ming Zeng1,2, Xi Chen1,2, Sining Hu1,2, Bo Yu1,2, Haibo Jia1,2
1Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China
2Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin 150001, PR China
OBJECTIVES Cardiovascular disease (CVD) is known to be the major public health issue across the world. There is accumulating evidence indicated that pyroptosis played a vital role in the development of CVD. Therefore, it is significant to study anti-pyroptosis drugs for the prevention and therapy of CVD.
METHODS LPS and ATP were used to established a macrophage pyroptosis model, Cell counting kit (CCK8) and scanning electron microscope (SEM) were used to evaluate the cell viability and cell shape; PCR and western blot were used to evaluate the mRNA and protein of NLRP3, caspase1, IL-1β and N-GSDMD. Immunofluorescent staining was used to evaluate the level of reactive oxygen and the translation of P65.
RESULTS In this study, we showed the protective effect of quercetin on the pyroptosis of THP1 macrophage and elucidated the underlying mechanism for the first time. Different concentrations of quercetin were used for the pretreatment of THP1 macrophage before LPS/ATP induction. The results of CCK8 assay combined with SEM demonstrated that the pyroptosis of THP1 macrophages was obviously reversed by quercetin pretreatment. Furthermore, it was observed that quercetin dose-dependently ameliorated LPS/ATP-induced macrophage pyroptosis by inhibiting the gene and protein expression of NLRP3, caspase1, IL-1β and N-GSDMD. DCFDA assay indicated that, like NAC, quercetin suppressed the activation of NLRP3 inflammasome by inhibiting ROS overproduction. The results of western blot and immunofluorescence showed that quercetin inhibited the phosphorylation of P65 and its’ translocation from cytoplasm into nuclear.
CONCLUSIONS Our results indicated that quercetin had a protective effect on macrophage pyroptosis via ROS/AMPK/NF-κB axis. Therefore, we suggested quercetin could be a potential therapeutic agent for CVD.
GW32-e0121
Weizhong Huangfu2, Zhuqing Kang1
1The People’s Hospital Affiliated of Inner Mongolia Medical University
2The Affiliated Hospital of Inner Mongolia Medical University
OBJECTIVES To analyze the difference between intestinal flora of hypertension patients and healthy people in Mongolian, and to explore the correlation between Mongolian hypertension and intestinal flora, and to provide new ideas for the pathogenesis of Mongolian hypertension from the perspective of intestinal flora, and to seek new targets for the prevention and treatment of Mongolian hypertension.
METHODS Twenty-one Mongolian hypertensive patients who met the inclusion criteria and 15 Mongolian healthy people were selected. All individuals were from the pastoral area around Siziwang Banner, Wulanchabu City, Inner Mongolia Autonomous Region. Blood and fecal samples of all subjects were collected, and the biochemical indexes of the blood samples were determined. At the same time, the fecal samples were sequenced by 16SrDNA sequencing technology, to analyze the difference of intestinal flora between hypertension and healthy people in Mongolian.
RESULTS 1. The Mongolian hypertension group’s sobs index decreased compared with the Mongolian healthy control group, but the difference was not statistically significant. By comparing 17 Alpha indexes such as Shannon, simpson, chao, ace, coverage, it was found that there was no significant difference in Alpha diversity between the hypertension group and the control group (P>0.05); through principal component analysis (PCA), there was no significant difference in Beta diversity of intestinal flora between the two groups (P>0.05). 2. At the phylum level, the abundance of Firmicutes and Bacteroidetes in the Mongolian hypertension group was higher than that in the Mongolian healthy control group, but the difference was not statistically significant (P>0.05); while the abundance of Patescibacteria in the Mongolian hypertension group was significantly lower than that in the Mongolian healthy control group (P<0.05). 3. At the genus level, compared with the Mongolian healthy control group, the number of Bifiobacterium, Lactobacillus, Escherichia-Shigella and Weissella decreased while the number of Prevotella_2 increased in the Mongolian hypertension group, and there was significant difference of Lactobacillus between the Mongolian hypertension group and the Mongolian healthy control group (P<0.05). 4. At the species level, compared with the Mongolian healthy control group, the number of Bacteroides vulgatus in the Mongolian hypertension group increased, while the number of Lactobacillus ruminis and Escherichia Shigella decreased in the Mongolian hypertension group, but there was no significant difference between the two groups (P>0.05). The number of a new strain from the genus Subdoligranulum of coccidiaceae in the Mongolian hypertension group was significantly lower than that in the control group, and the difference was statistically significant (P<0.05).
CONCLUSIONS 1. There was no statistical difference in community diversity, richness, evenness and coverage between Mongolian hypertensive patients and Mongolian healthy people, and there was no significant difference in species composition and structure between the two groups. 2. The number of intestinal Patescibacteria and Lactobacillus in Mongolian hypertensive patients is significantly lower than that in Mongolian healthy people, and the number of a new bacteria from Subdoligranulum in the intestinal tract of Mongolian hypertensive patients is significantly reduced. The reduction of these colonies may participate in and affect the occurrence and development of Mongolian hypertension.
GW32-e0251
Bo Liang, Ning Gu
Nanjing University of Chinese Medicine
OBJECTIVES Accumulating evidence indicates that oxidative stress plays a critical role in cardiovascular disease, which stands as a major cause of morbidity and mortality worldwide. Guanxin V, a traditional Chinese medicine, has a significant effect on cardiovascular disease. However, the deeper biological mechanisms remain unclear. Here, our study investigated the anti-apoptotic and anti-oxidative effects of Guanxin V on oxidative stress damage to cardiomyocytes.
METHODS We used hydrogen peroxide to stimulate reactive oxygen species production in cardiomyocytes. Cell viability was evaluated by CCK-8 assay, cell apoptosis was assessed via Annexin V-FITC/PI Apoptosis Detection Kit and Hoechst 33342 stain. We used Transmission electron microscopy to captured ultrastructural mitochondria. TGF-β1, Collagen Type I, and Collagen Type III were determined by ELISA kits. We also used RT-qPCR and immunoblotting to detect important markers.
RESULTS Our findings revealed that treatment with Guanxin V significantly decreased hydrogen peroxide-induced cell damage, inhibited oxidative stress damage and apoptosis, and enhanced mitochondrial dynamic balance. Furthermore, Guanxin V attenuated oxidative stress damage induced TGF-β/Smads pathway activation.
CONCLUSIONS In conclusion, our results demonstrated that Guanxin V effectively alleviated hydrogen peroxide-induced oxidative stress damage and apoptosis though down-regulating TGF-β/Smads signalling pathway, which increases our understanding of the molecular biological mechanism of Guanxin V in treating cardiovascular disease.
GW32-e0413
Shenjie Sun
Beijing Tsinghua Changgung Hospital
OBJECTIVES Telomeric Zinc finger-associated Protein (TZAP) directly binds to telomeric TTAGGG repeats via zinc finger domains and triggers the initiation of the telomere trimming process, which is closely related to mitochondrial metabolism and premature senescence. Telomere length is highly related to cardiovascular diseases. However, proteomics analysis of TZAP in cardiomyocytes is little unknown.
METHODS In our study, TZAP was overexpressed by adenovirus transfection in cultured H9c2 cardiomyocytes, then mass spectrometry-based quantitative proteomics research strategies, including Gene Ontology (GO) analysis, KEGG pathway analysis, subcellular localizations, predicted functional domains and protein-protein interaction analysis were performed to explore the potential pathogenesis of TZAP overexpressing cardiomyocytes.
RESULTS 184 up-regulated and 228 down-regulated differentially expressed proteins (DEPs) were identified among identified 5693 quantifiable proteins in TZAP-overexpressed H9c2 cardiomyocytes. Among them, 11 key DEPs were involved in 5 cellular processes pathways, including “Cellular process”, “Biologic lation”, “Metabolic process”, “Response to stimulus”, and “Cellular component organization or biogenesis”. The top five with the largest number of enriched DEPs were “Cell”, “Organelle”, “Membrane-enclosed lumen”, “Membrane”, “Macromolecular complex”, and “Cell part” in the cellular component category were identified in TZAP-overexpressed H9c2 cells.
CONCLUSIONS Our results provided fundamental data for identification of candidate proteins and enrichment pathways in cardiomyocytes overexpressing TZAP. Considering the results above, TZAP may be involved in cell senescence, myocardial fibrosis, mitochondrial metabolism, and cell apoptosis in cardiovascular diseases.
GW32-e0518
Shuhan Zhong1, Shiyuan Hua2, Arami Hamed3, Jian He2, Danni Zhong2, Dongxiao Zhang2, Xiaoying Chen1, Jun Qian2, Xinyang Hu1, Min Zhou2
1The Second Affiliated Hospital Zhejiang University College of Medicine
2Institute of Translational Medicine Zhejiang University
3Department of Radiology Stanford University Stanford
OBJECTIVES To better enable tracking of the stem cells in heart regenerative applications, multi-modal, positive-contrast imaging probes with sufficient tissue penetration and precision imaging capabilities are highly demanded.
METHODS We developed a hybrid nanostructured substrate consisting of gold nanostars and Ag2S QDs. Stem cells were labeled with our SERS/NIR-II contrast agents, then transmission electron microscopy was used to evaluate the composition and nanostructure of the GDS NPs as well as investigate the cellular uptake of GDS NPs. And MTT assay was used to measure cell viability of MSCs, after their incubation with different concentrations of GDS NPs for 24 or 48 h. We evaluated the migration and repair ability of the GDS-MSCs by scratch-wound healing assay. Colony-forming assay was used to evaluate the proliferation ability of the GDS-MSCs. The differentiation ability of GDS-MSCs assessed by oil red O staining, alizarin red staining, and toluidine blue staining, respectively. The paracrine function of GDS-MSCs was tested by tube formation assay and western blot. At last, we evaluated this dual-modal imaging system for tracking the GDS-MSCs in a MI model and the therapeutic effects of GDS-MSCs.
RESULTS In this study, we prepared GDS NPs for combined SERS and NIR-II fluorescence imaging and dual-modal tracking of mesenchymal stem cells (MSCs) in MI. The gold nanostar (Au-Star)-DTTC compartment enabled high-resolution Raman imaging. Star-like GDS NPs were observed in the cytoplasm of the MSCs, which verified the cellular uptake of GDS NPs. And also, we could observe a strong Raman signal even at the single-cell level. The SERS/NIR-II signals could be clearly detected and their intensities were increased with the population of the MSCs. It has no apparent toxicity or effects to MSC after their incubation with GDS NPs. NIR-II fluorescence imaging enabled us to evaluate in vivo distribution of the labeled stem cells dynamically, and Raman imaging enabled precise localization of the labeled stem cells in the heart tissues. We observed transplanted MSCs were mainly distributed near the injection point, and then MSCs migrated to adjacent areas during the next days, as it can be seen by sparse Raman signals around the injection site. And the surviving MSCs in the heart could be clearly detected before day 6, but the signal was almost disappeared by day 8. Our results revealing mechanistic details about the distribution and migration pattern of the stem cells, as well as exact borders between normal tissues and the areas injected with cells. Monitoring the cardiac function and analysis of the infarcted myocardial tissue sections showed that our nanoparticles did not diminish the therapeutic efficacy of the labeled stem cells.
CONCLUSIONS Au-Star based NIR-II/SERS dual-modal imaging probes were developed to monitor the cellular behavior of MSCs with deep tissue penetration and high precision. This depth-independent and high-resolution stem cell tracking strategy, can be potentially used for monitoring the stem cells in a wide range of regenerative medicine applications.
GW32-e0567
Haoyu Wu1, Chen Wang1, Fenqing Shang2, Zuyi Yuan1
1First Affiliated Hospital of Xi’an Jiaotong University
2Xi’an Chest Hospital
OBJECTIVES Arterial stiffness is considered a complication of hypertension and a comorbidity of various cardiovascular diseases. Clinically, arterial stiffness can be assessed non-invasively by measuring brachial-ankle pulse wave velocity (PWV). Endothelial dysfunction and vascular smooth muscle cell (VSMC) plasticity are critically involved in the pathogenesis of hypertension and arterial stiffness. MicroRNAs (miRNAs) are small non-coding RNAs. By targeting the 3′-untranslated region (3′-UTR) of the targeted mRNA, miRNAs epigenetically regulate gene expression in almost all biological systems. Increasing evidence indicates that extracellular miRNAs can serve as biomarkers for the diagnosis, treatment, and prognosis of cardiovascular diseases. In addition, miRNAs can function as second messengers mediating cellular communication between ECs and neighboring cells within the vascular wall. Here, we investigated the role of endothelial-derived extracellular microRNA-92a (miR-92a) in promoting arterial stiffness by regulating EC-VSMC communication.
METHODS The expression of miR-92a was detected by quantitative real-time PCR (qRT-PCR) in mice and humans. A co-culture system was performed to identify EC–VSMC communication. The relationship between miR-92a and arterial stiffness was verified in Ang II-induced hypertension mice model.
RESULTS Serum miR-92a level was higher in hypertensive patients than controls. Circulating miR-92a level was positively correlated with pulse wave velocity (PWV), systolic blood pressure (SBP), diastolic blood pressure (DBP) and serum endothelin-1 (ET-1) level, but inversely with serum nitric oxide (NO) level in hypertensive individuals. In vitro, angiotensin II (Ang II)-increased miR-92a level in ECs mediated a contractile-to-synthetic phenotype change of co-cultured VSMCs. In Ang II-infused mice, locked nucleic acid-modified antisense miR-92a (LNA-miR-92a) ameliorated PWV, SBP, DBP and impaired vasodilation induced by Ang II. LNA-miR-92a administration also reversed the increased levels of proliferative genes and decreased levels of contractile genes induced by Ang II in mouse aortas. Circulating serum miR-92a level and PWV were correlated in these mice.
CONCLUSIONS EC miR-92a may be transported to VSMCs via extracellular vesicles to regulate phenotype changes of VSMCs, leading to arterial stiffness.
GW32-e0815
Shiran Yu, Hong Chen
Peking University People’s hospital
OBJECTIVES Modulating inflammation is one of major function of lymphatic system. However, the role of lymphatic system in atherosclerosis which is known as a chronic vascular inflammatory disease, is not yet clear. Endothelial microparticles (EMPs) are the major carriers of circulating microRNAs, maybe link lymphatic system and atherosclerosis. Our previous study has shown that microRNA (miR)-19b in EMPs significantly promote atherosclerosis, however, the pathophysiological mechanism still unclear. The aim of the present study was to explore whether miR-19b incorporated in EMPs could affect lymphatic system and further involve in pathological process of atherosclerosis.
METHODS Western-diet-fed apoE−/− mice were injected with phosphate buffered solution (PBS), EMP carrying microRNA control (EMPcontrol) or miR-19b mimic (EMPmiR19b) intravenously. The function of lymphatic system is accessed via confocal microscopy and aortal lymphatic distribution is measured by immunofluorescent staining. We also assessed the pathological changes of atherosclerosis and aortal inflammation.
RESULTS Results show that systemic treatment with EMPmiR19b significantly dampened the transport function and permeability of the lymphatic system, meanwhile, its distribution in aortal is decreased. Further experiments show that lymphatic system reconstruction and dysfunction are companied with the atherosclerosis deterioration manifested as increasing plaque volume, inflammatory cells and inflammatory cytokines infiltration and elastic fibers twist and break in atherosclerotic plaque. Our cell experiments results show that miR19b inhibited lymphatic endothelial cell migration and formatting tube which is the foundation for the function of lymphatic system. As for mechanism, the effects of miR-19b may involve in inhibiting transforming growth factor beta receptor type II (TGF-βRII) expression in lymphatic endothelial cell.
CONCLUSIONS Our findings demonstrate that EMPmiR-19b promotes vascular inflammation and atherosclerosis by dampening the function of lymphatic system in apoE−/− mice, which may rely on the change of TGF-βRII expression.
GW32-e0865
Song Peng, Zhi-yuan Song
Southwest Hospital, Third Military Medical University
OBJECTIVES Psychosocial factors are associated with the development of atherosclerosis, but the mechanism is unclear. Our group previously found a arcuate nucleus (Arc)-Neuropeptide Y (NPY)-regulated neuronal circuit that controls sympathetic output and BAT thermogenesis. This study aimed to utilize Cre-loxp system to specifically regulate Arc NPY expression in transgenic mice, study the role of Arc NPY in atherosclerosis, and explore its central regulatory effect on atherosclerosis.
METHODS Adeno-associated virus carrying the Cre gene was first injected into the arcuate or paraventricular nucleus of transgenic mice via brain stereotactic injection, in order to induce the recovery of NPY expression in the arcuate nucleus of NPY−/− mice and Y1 receptor knockout in the paraventricular nucleus of Y1Rflox/flox mice. Central nervous system (CNS) intervention was followed by the administration of a high-fat, high-cholesterol diet and perivascular carotid collar placement to induce carotid atherosclerosis in mice. Twelve weeks after collar placement, the Left collared carotid arteries were collected for histological analysis and qPCR.
RESULTS Compared with the control group NPY−/− mice without CNS intervention, the NPY−/− mice whose arcuate nucleus NPY expression restored had a smaller carotid artery plaque area and a lower plaque/media ratio. The expression of IL-1β, ICAM-1 and VCAM-1 mRNA in mice with restored NPY expression decreased. Compared with Y1Rflox/flox control mice without CNS injection, Y1Rflox/flox mice with Y1 receptor knockout in the paraventricular nucleus had increased carotid plaque.
CONCLUSIONS CNS intervention in the arcuate nucleus NPY can inhibit carotid atherosclerosis in mice, and this inhibition may also be mediated by the Y1 receptor in the paraventricular nucleus.
GW32-e0964
Linlin Zhu
Nanjing First Hospital
OBJECTIVES Low shear stress (LSS) plays a critical role in the development of atherosclerotic plaques and vascular inflammation. Previous studies have reported Akt phosphorylation induced by LSS. However, the mechanism and role of Akt activation remains unclear in LSS-induced endothelial dysfunction.
METHODS We used LSS (2 dyne/cm2) to stimulate the endothelial cells. The main methods used include western blot, immunofluorescence and PCR. Small interfering RNA and overexpressed plasmid were used to alter the expression of target protein.
RESULTS In this study, our results demonstrated the increased phosphorylation of IKK ε, TBK1 and Akt in HUVECs exposed to LSS. Furthermore, IKK ε silencing using small interfering RNAs significantly reduced LSS-induced Akt phosphorylation. In contrast, silencing of TBK1 or inhibition of PI3K and mTORC2 had no effect on LSS-induced Akt phosphorylation. Notably, Akt inhibition markedly diminished LSS-induced expression of ICAM-1, VCAM-1 and MCP-1, as well as LSS-induced IRF3 phosphorylation and nuclear translocation, without affecting the activation of NF-κB and STAT1. Moreover, endothelial cell specific Akt overexpression mediated by adeno-associated virus markedly increased intimal ICAM-1 and IRF3 expression at LSS area of partially ligated carotid artery in mice.
CONCLUSIONS Our findings suggest that LSS-induced Akt phosphorylation is positively regulated by IKK ε and promotes IRF3 activation, leading to endothelial inflammation.
GW32-e1040
Bo Guan
The First Affiliated Hospital of Dalian Medical University
OBJECTIVES We conducted this systematic review and meta-analysis to evaluate the changes of cardiac function and structural remodeling in pressure-overload mice at different time-point and explore the optimized follow-up time of mice TAC model to best recapitulate the clinical characteristics of heart failure with preserved ejection fraction (HFpEF).
METHODS We systematically searched Pubmed, Embase, and Web of Science for animal studies subjected mice to transverse aortic constriction and reported relevant echocardiographic or hemodynamic parameters. The mean difference (MD) of LVEF, LVEDd and LVEDP under different follow-up time were extracted and pooled using a random-effects model respectively.
RESULTS Seventy-two studies (n=1432 mice) reported at least one predefined parameter of TAC model under either 2 weeks or 4 weeks of follow-up were included in the final meta-analyses. Comparing with the sham group, the pooled results showed that 2-week TAC model showed slightly compromised systolic function (SMD=−1.79; 95% CI: −3.02–0.56; I2=92.8%) and insignificant LV structural remodeling (SMD=−0.20; 95% CI: −1.0–0.62; I2=89.1%) while marked changes in LVEF (SMD=−6.54; 95% CI: −7.74–5.35; I2=91.7%) and LVEDd (SMD=3.81; 95% CI: 2.97–4.65; I2=93.7%) were observe upon TAC model under 4-week of follow up. LVEDP were both elevated in 2-week (SMD=5.13; 95% CI: 2.35–7.90; I2=91.9%) or 4-week (SMD=7.93; 95% CI: 5.45–10.45; I2=90.2%) of TAC comparing with their corresponding sham groups.
CONCLUSIONS In contrast with 4 weeks of aortic constriction, mice TAC model with 2-week of follow up might be a better choice to establish HFpEF, however, direct comparison between the two time point is still warranted.
GW32-e1091
Xu Chen, Yong Wang, Dongqing Guo
北京中医药大学 (Beijing University of Chinese Medicine)
OBJECTIVES In recent years, pyroptosis has been shown to play an important role in post-myocardial infarction and is activated by inflammasomes in the NLRP3 family of oligonucleotide binding oligonucleotide domain-like receptors. However, it is still unclear whether Licochalcone A (LA) can exert myocardial protective effect by inhibiting activation of NLRP3 inflammasomes and thereby inhibiting cardiomyocyte pyroptosis. Therefore, we decided to determine whether LA plays an important role in myocardial protection by inhibiting the activation of inflammasomes.
METHODS In this study, we investigated the myocardial protective effects of LA in vivo and in vitro. Male C57BL/6 mice were treated with LA (20 mg/kg daily, gavage) for 7 days after permanent myocardial infarction induced by coronary artery ligation and performed echocardiography to evaluate cardiac function. The H9C2 were divided into the control group, model group (induced by LPS+ATP), LA treated group (20 μM) and LA +NAC (5 μmol/L ROS inhibitor) group. The CCK8 was used to assay cell viability and Hoechst/PI staining was used to detect cell death. Furthermore, the expression of NLRP3, ASC, caspase-1 and GSDMD were detected with Western blot.
RESULTS Compared with the model group, the area of myocardial infarction was significantly reduced and the cardiac function was significantly improved in the LA treatment group. In addition, we found that myocardial infarct-induced pyroptosis was mainly characterized by cell membrane rupture and increased expression of NLRP3 inflammasome-related proteins and GSDMD. In vitro, we found that LA reduced the elevated levels of Hoechst/PI and pyroptosis-related proteins. All of these changes were prevented by the LA intervention, which was as effective as the ROS inhibitor NAC.
CONCLUSIONS We conclude that LA, at least in part, prevents cardiac damage and dysfunction caused by myocardial infarction by attenuating NLRP3 and subsequent cardiomyocyte pyrolysis, which providing a new approach for the treatment of clinical heart failure.
GW32-e1227
Guanglin Cui
Huazhong University of Science & Technology
OBJECTIVES The purposes of this study were to identify lipid association signals in the promoter region of SCARB1 and then explore the clinical relevance in CHD and potential underlying mechanisms.
METHODS We re-sequenced the SCARB1 promoter region in 168 participants with extremely high plasma HDL-C (>95th percentile, mean HDL-C of 2.19 mmol/L) and 200 healthy control subjects. Putative risk allele were identified with bioinformatics analysis and reporter gene assays. One of the putative functional variant rs144334493 was genotyped in 3605 control subjects and 2423 CAD patients. The molecular mechanism was explored. Furthermore, using capillary electrophoresis method, the association of another 11bp indel variant rs557348251 with plasma lipid levels and coronary artery disease was also investigated.
RESULTS By resequencing, a number of newly and potentially functional variants were identified. Of the 10 common variants with Minor allele frequency (MAF) >0.01, only rs144334493 was confirmed as functional by bioinformatics analysis integrated with the result of luciferase assay. Genotyping data of control subjects and CAD patients demonstrated that rs144334493 was significantly associated with increased CHD risk (odds ratio: 1.28, 95% confidence interval: 1.11–1.48, P=0.001). Functional study revealed that the rs144334493 deletion allele destroyed FOXA1 binding to the promoter of SCARB1, resulting in attenuated luciferase activity. Overexpression of FOXA1 reversely increase the expression of SCARB1. In addition, a more robustly association was found between the previously identified 11 bp indel variant rs557348251 and risk of CHD (odds ratio: 3.31, 95% confidence interval: 2.52–4.33, P=4.65*10–18).
CONCLUSIONS Genetic variants in SCARB1 gene promoter region play an important role in the regulation of plasma lipid levels by regulating SCARB1 gene expression and contribute to the susceptibility of CHD.
GW32-e1288
Jugang Chen1,2, Yang Li3, Xiaojing He4, Meng Gao1, Yimeng Wang1, Jiaxin Wang1, Weifa Wang1, Junpei Zhang1, Bin Li1, Quanwei Pei1, Xiufen Qu1,5, Dechun Yin1,5
1Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
2Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou, China
3Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
4Department of Neonatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
5This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
OBJECTIVES Activated astrocytes in the hypothalamus paraventricular nucleus (PVN) involve in ventricular arrhythmia with sympathoexcitation after acute myocardial infarction (AMI) by central neuro-immune pathway, but it remains unknown how astrocytes were activated. The aim of this study was to investigate the effect of cardiac sympathetic afferent nerves on activated astrocytes in the PVN after AMI.
METHODS The rats were randomly divided into AMI, AMI+BD (baroreceptor denervation), AMI+LCSAA (local cardiac sympathetic afferent ablation) and AMI+BD+ LCSAA groups. Before the generation of AMI, BD and (or) LCSAA were performed. Sympathetic nerve activity (heart rate variability and plasma norepinephrine), activity of glia and neurons as well as expression of inflammatory cytokines (IL-6 and TNF-α) in the PVN were detected during the experiments.
RESULTS At 24 hours after AMI, TRPV1-expressing afferent nerves in AMI+LCSAA and AMI+BD+ LCSAA groups were significantly lower than AMI group. Compared with AMI group, LCSAA significantly reduced the number of Glial fibrillary acidic protein (GFAP) positive cell and its projects as well as the levels of TNF-α and IL-6 in the PVN of AMI+LCSAA and AMI+BD+ LCSAA groups, along with decrease of Fra-LI positive cells and sympathetic nerve activity (P<0.05), but BD had no obvious effect on them in AMI+BD group (P>0.05).
CONCLUSIONS The results of this study demonstrated that activated astrocytes and proinflammatory cytokine in the hypothalamus PVN were inhibited following LCSAA but not BD at the 24 hours after AMI. Our study will provide an intact neural pathway for activated astrocytes and sympathoexcitation after AMI.
GW32-e1380
Qizheng Lu1,2, Hao Zheng1,2, Xiaobo Yao1,2, Chailin Wang1,2, Youming Zhang1,2, *Yunli Shen1,2
1Shanghai East Hospital
2Tongji University School of Medicine
OBJECTIVES Superparamagnetic iron oxide nanoparticles (SPION) is recognized as being a novel MRI contrast agent and targeted carrier, which has attracted much attention over the last two decades. However, the cytotoxicity of SPION limits its clinical transformation in cardiovascular field. Macrophages are the main inflammatory cells, which play an important role in the repair process after acute myocardial infarction. The aim of this study was to explore the effects of SPION on the function and polarization of macrophages, and whether mitochondria targeted antioxidant peptides MTP-131 modification could improve the macrophage toxicity of SPION.
METHODS All the RAW 264.7 mouse macrophages are incubated with SPION and new type SPION loaded with MTP-131 (arginyl-2, ′6′-dimethyltyrosyl-lysyl-phenylalaninamide) at the concentration of 50 μg Fe/mL for 24 h. Scanning electron microscope (SEM) was used to observe morphological change and phagocytosis of macrophages, and transmission electron microscope (TEM) was employed to observe mitochondria damage and flow cytometry was applied to detect cell apoptosis and the markers of macrophage polarization. The inflammation related factors of cell culture supernatant are tested by enzyme linked immunosorbent assay (ELISA). The molecular events were analyzed by real-time quantitative polymerase chain reaction (RT-PCR) and fluorescence imaging. All the experiments were repeated three times.
RESULTS Compared with the control group, SPION significantly induced cell damage, evidenced by the reduction of cell viability and the increase of early cells apoptosis and the reactive oxygen species (ROS), whereas these features occur less in SPION loaded with MTP-131 groups (all P<0.05). Moreover, after 24 h incubation, the pro-inflammatory factor TNFα was significantly upregulated in the SPION group compared to the SPION loaded with MTP-131 group (P<0.05). Correspondingly, the median fluorescence intensity of CD86 and CD80, two classic pro-inflammatory (M1 Like) subtypes maker of macrophage, were expressed higher in the SPION group than those in the SPION loaded with MTP-131 group (P<0.05). Surprisingly, higher levels of anti-inflammatory factors IL-10 and TGFβwere tested in SPION loaded with MTP-131 groups compared with the SPION group (P<0.05). Notably, mitochondrial morphology serious disruption was observed by TEM in the SPION group, but less in the SPION loaded with MTP-131 group. Taken together, SPION can induce macrophage injury and apoptosis by inducing oxidative stress. More than that, SPION can promote macrophages to polarize into M1 like macrophages which secrete pro-inflammatory factors. Mitochondria may be the main target organelle of SPION. However, co-loading mitochondria targeted antioxidant peptides MTP-131 can significantly mitigate the SPION induced macrophage toxicity in vitro study.
CONCLUSIONS SPION has a potential to induce macrophage pro-inflammatory effect, evidenced by promoting macrophages to polarize into M1 like cells secreting more pro-inflammatory factors, whereas co-loading mitochondria targeted antioxidant peptides MTP-131 could significantly mitigate the pro-inflammatory effects of SPION in vitro study.
GW32-e1488
Jianfeng Li, Yanlin Li, Fu Zhang, Bowen Wang, Ping Xie
Gansu Provincial Hospital
OBJECTIVES We sought to assess the efficacy of beta-blockers and angiotensin antagonists in preventing early-onset anthracyclines-induced left ventricular dysfunction and cardiac events.
METHODS We searched relevant articles in PubMed, EMBASE, the Cochrane Library, CNKI, Wanfang Date and Sinomed and supplemented by other search up to July 2017. According to the inclusion criteria and exclusion criteria, the two authors independently sifted the relevant documents, extracted the data and evaluated the methodological quality of the studies, and then analyzed the data by using R software for meta analysis. In meta analysis, the random effect model was used to calculate the mean difference of left ventricular ejection fraction (LVEF), the relative risk (RR) of cardiac events and the corresponding 95% confidence interval.
RESULTS Two thousand eight hundred ninety-two potentially relevant studies were screened. Ten randomised controlled trials evaluating 757 patients treated with any type of anthracycline plus beta-blockers and/or angiotensin antagonists were included. Pooled analysis showed prophylactic treatment with beta-blockers and/or angiotensin antagonists improved post-chemotherapy left ventricular ejection fraction (LVEF) when compared to controls with estimated MD (95% CI) of −5.43 (−9.08; −1.77), P=0.0036. Statistically significant heterogeneity was found in LVEF (I2=93%, P<0.01). Although the cardiac events rate of 9.2% in the experimental group was lower than 25.8% in the control group after chemotherapy with estimated RR 0.45 (95% CI: 0.14, 1.38; P=0.1619), the difference was not statistically significant. In an exploratory subgroup analysis, the benefit of experimental agents on LVEF preservation was prominent in patients treated with higher accumulative dose of anthracyclines, but not in the lower dose group.
CONCLUSIONS Prophylactic treatment with beta-blockers and/or angiotensin antagonists can prevent early-onset anthracyclines-induced cardiotoxicity in adult patients, especially in patients treated with higher dose anthracyclines accumulative dose. More larger and high-quality’s RCT are required to determine the clinical efficacy of beta-blockers and angiotensin antagonists for prevention of early-onset anthracyclines-induced cardiotoxicity.
GW32-e1622
Juan Sun, Refukaiti Abuduhalike, MaheMuti MaheMuti
The First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES To dissect the metabolic remodeling of CHF patients in order to identify novel metabolic biomarkers of heart failure by nuclear magnetic resonance (NMR), and to determine the metabolic changes accompanying heart failure and identify novel diagnostic biomarkers.
METHODS Plasma samples were collected from 100 healthy controls and 200 heart failure patients who were admitted to the First Affiliated Hospital of Xinjiang Medical University from January 2016 to January 2018. The samples were analyzed by proton nuclear magnetic resonance. The study was divided into two groups: healthy control group (n=100) and heart failure group (n=200). Heart group were divided into the following two subgroups (n=100 each). The differential metabolites among the two groups were identified by principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA), and the correlation between metabolite concentration and heart failure was evaluated.
RESULTS Compared to the healthy control group, the serum levels of 3-hydroxybutyrate, alanine, citrulline and acetone were significantly higher in the HFmrEF and HFrEF groups (P<0.05). Furthermore, these metabolites were present in significantly higher concentrations in the HFrEF compared to the HFmrEF group (P<0.05).
CONCLUSIONS The heart failure patients have a distinct metabolome, and 3-hydroxybutyric acid, alanine, citrulline and acetone are potential biomarkers of cardiac dysfunction. Metabolomics can provide a reliable diagnostic method for heart failure.
GW32-e1693
Di Ye, Zhen Wang, Jing Ye, Yongqi Feng, Menglong Wang, Yao Xu, Jishou Zhang, Jianfang Liu, Jun Wan
Renmin Hospital of Wuhan University
OBJECTIVES The kielin/chordin-like protein (KCP) is a secreted protein which was firstly found in 2005, and its main function is to enhance bone morphogenetic protein (BMP) signaling. Recent studies have demonstrated that BMP play important roles in cardiac development and myocardial remodeling. However, there is no report about the role of KCP in the area of cardiac. Doxorubicin (DOX) is known to induce severe cardiac injury and dysfunction. This study aimed to investigate the role of KCP in DOX-induced cardiotoxicity and underlying mechanisms.
METHODS DOX was used to induce cardiac dysfunction and the expression of KCP in the murine cardiac tissues was measured. In addition, to investigate the effect of KCP KO on DOX-induced cardiac injury, KCP KO mice were treated with DOX. The levels of the apoptosis and autophagy were determined by quantitative western blot, immunofluorescence and electron microscopy. Mechanismly, we use KCP recombinant protein to explored the mechanism both in vivo and vitro.
RESULTS KCP levels significantly decreased in the heart following DOX injection. Cardiac injury and dysfunction were induced by DOX, and KCP KO significantly aggravated DOX-induced injury, which is accompanied by impaired autophagy, accumulation of abnormal mitochondria, and excessive apoptosis. Mechanistically, KCP promotes autophagy initiation through mTOR/ULK1 pathway and sustains autophagy via Forkhead box class O (FoxO)-mediated transcriptional reinforcement by targeting phosphoinositide-dependent protein kinase 1 (PDK1).
CONCLUSIONS Our results demonstrated that KCP protest against DOX-induced cardiac injury and dysfunction by promoting autophagy and inhibiting apoptosis. And up-regulation of KCP might contribute to the resolving of DOX-induced cardiotoxicity.
GW32-e1773
Bicheng Li1, Minqiao Lu2, Ye Tian1,2
1The First Affiliated Hospital of Harbin Medical University
2Department of Pathophysiology and Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University
OBJECTIVES Intra-plaque hemorrhage (IPH) is one of the main characteristics of vulnerable plaque, leading to cardiovascular events. Among the deposition of erythrocyte lysate product caused by IPH, hemin could induce ferroptosis and promote matrix metalloproteinase (MMP) secretion. Recently, the role of ferroptosis, a form of cell death catalyzed by iron to produce lethal lipid peroxidation, in atherosclerosis has attracted attention because it aggravates atherosclerosis progression and increases plaque instability. MMPs are also important regulator of atherosclerotic plaque stability. Therefore, we wonder whether ferroptosis is involved in hemin induced hemorrhagic plaque instability, and whether increased MMP expression is accompanied.
METHODS Twenty New Zealand white rabbits were randomly divided into normal saline control group (NS group) and hemorrhagic plaque group (IPH group). According to the experimental requirements, 25 μL normal saline or an equal volume of washed autologous erythrocytes was injected into the established rabbit plaque. After the rabbits were sacrificed, the plaque size, collagen content, iron content, hemin and ferroptosis associated protein expression were analyzed. Mouse peritoneal macrophages were extracted and incubated with different concentrations of hemin and CCK-8 was used to detect cell viability after 24 hours. 150 μmol/L hemin and ferrostatin-1, a ferroptosis inhibitor, were determined to be incubated with macrophages as indicate. Subsequently, the ferroptosis related features, MMP2 and MMP9 expression were detected.
RESULTS In vivo, compared with NS group, the plaque area in IPH group increased by 20% (P<0.01), and the lumen area decreased by 20% (P<0.01). The collagen content in IPH group decreased by 25% (P<0.001). The MMP2 and MMP9 positive area in IPH group significant increased by 25% and 27% (P<0.0001), respectively. As expect the hemin and iron content were increased in IPH group. Moreover, the MMPs expression co-localization with macrophages. In vitro, an increase of macrophage ferroptosis was observed after hemin treatment. Hemin also promotes the synthesis and secretion of MMP2 and MMP9 of macrophage, whereas the ferroptosis inhibitor, ferrostatin-1, reversed this effect.
CONCLUSIONS The results in this study suggest that hemin suspect to increase plaque instability by inducing MMP2/9 expression through macrophage ferroptosis. Targeting macrophage death has become an important therapeutic strategy for atherosclerosis. This study makes a contribute to understand the mechanism of hemorrhagic plaque progression and suggests targeting macrophage ferroptosis may be a new strategy for stabilizing vulnerable plaque.
GW32-e1845
Tianxin Ye1, Jinxiu Yang1, Bo Yang2, Xingxiang Wang1
1Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine
2Department of Cardiology, Renmin Hospital of Wuhan University
OBJECTIVES Atrial fibrillation (AF) is the most common sustained arrhythmia, and inflammation-related fibrosis signals play a crucial role in the pathogenesis of AF. The purinergic receptor P2X7 (P2X7R), activated by ATP, is a ligand-gated cation channel that predominately mediates inflammation and cellular death. Post-operative AF is a common complication in patients undergoing cardiac surgery. Therefore, we evaluated the effects of P2X7R inhibition on atrial arrhythmogenic remodeling in a rat model of sterile pericarditis (SP).
METHODS SP was induced in rats by the epicardial application of sterile talc. An intervention group received daily P2X7R inhibition Brilliant Blue G (BBG) for 4 days, starting 1 day before pericardiotomy. AF susceptibility was assessed in vitro electrophysiology. Atrial histology was determined with Masson staining. The protein expression and gene-expression were analyzed respectively by western blot assays and rt-PCR/gene microarray.
RESULTS In vitro electrophysiology, burst pacing induced atrial tachyarrhythmias in 10% Sham rats vs. 80% SP-only rats, and only 11% BBG-treated SP rats (P<0.01 vs. SP-only). Atrial action potential duration (APD) and activation latency (AL) were significantly prolonged by SP, whereas atrial effective refractory period (ERP)/APD90 ratio were reduced (all P<0.01). The above-mentioned electrophysiological parameters were attenuated by BBG. SP caused atrial fibrosis. BBG strongly attenuated atrial fibrosis. SP increased atrium expression of inflammation- and fibrosis-related gene expression pathways on gene-microarray transcriptomic analysis, which was significantly attenuated by BBG. SP increased protein expression of P2X7R and caused significant increases in mRNA-expression of collagen-1, collagen-3, NLRP3, ASC, CASP1, IL-1β, TGF-β3, and α-SMA vs. Sham. BBG-treatment suppressed all these SP-induced alterations.
CONCLUSIONS The P2X7R inhibition BBG prevents SP-induced atrial remodeling, while suppressing inflammatory changes and fibrotic/electrical remodeling, thus providing new insights into the relationship between P2X7R and atrial arrhythmias.
GW32-e1941
Qianru Yuan, Linaziyesitayi Gu
The First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES Aortic Dissection (AD) is a serious life-threatening cardiovascular emergency, with rapid onset, rapid progress, and high mortality. Among them, lipid metabolism disorder is an important risk factor for aortic dissection. In recent years, with the continuous in-depth research on the Gut Microbiome (GM), it has been revealed that various metabolites of GM such as short-chain fatty acids, secondary bile acids and trimethylamine affect the lipid metabolism in the host. Process, when GM is out of regulation, it will cause the disorder of lipid metabolism in the host. Therefore, this study explored the mechanism of lipid metabolism disorders caused by GM disorders in the pathogenesis of aortic dissection.
METHODS 1. We collected blood samples from 50 healthy controls and 50 AD patients, and detected lipopolysaccharide (LPS), short chain fatty acids (SCFA), and secondary bile acid (SBA), trimethylamine-N-oxide (TMAO), very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL). 2. In order to study the potential role of GM disorders in AD, fecal samples from the above population were collected and used 16S amplicon sequencing to perform flora diversity analysis (including α-diversity, β-diversity), and further screen for different bacteria Group analysis of species composition and abundance comparison, and prediction of flora function. 3. The feces of AD patients will be extracted into bacterial solution and transplanted into sterile C57/BL mice for 4 weeks as the experimental group, and sterile mice as the control group, with β-aminopropionitrile diet for 4 weeks combined with 24 hours Ang II, To induce AD in C57/BL mouse aortic dissection, and compare the formation rate of the two groups of mice. Simultaneously detect the expression levels of LPS, SCFA, SBA, TMAO, VLDL, LDL, HDL in sterile mice before transplantation of fecal bacteria, mice transplanted with fecal bacteria after transplantation, and AD model mice.
RESULTS 1. Compared with the healthy control group, the serum LPS, SCFA, SBA, TMAO, VLDL, LDL expression of AD patients were higher, the difference was statistically significant (P<0.05), the HDL expression was lower, and the difference was statistically significant (P<0.05). 2. The composition of the intestinal microbiome was analyzed, and α-diversity and β-diversity were evaluated respectively. Multivariate linear regression analysis is used to evaluate the relationship between specific bacterial genera identified by LPS, SCFA, SBA, TMAO, VLDL, LDL, and HDL indicator species analysis in different groups. The results show that compared with healthy controls, the intestines of AD patients The tract flora tends to produce LPS, and the difference is statistically significant (P<0.05) 3. Compared with mice that have not undergone fecal bacteria transplantation, fecal bacteria transplanted mice have a higher AD model rate, and Compared with AD mice without fecal bacteria transplantation, serum LPS, SCFA, SBA, TMAO, VLDL, LDL of fecal bacteria transplanted mice increased with fecal bacteria transplantation and model construction, while HDL decreased with fecal bacteria transplantation and model construction.
CONCLUSIONS Lipid metabolism disorder caused by GM imbalance is involved in the occurrence and development of aortic dissection.
GW32-c0336
Wenxiu Liu, Yutong Guo, Yue Liu
The First Affiliated Hospital of Harbin Medical University
OBJECTIVES MI induced myocardial fibrosis is the main mechanism of heart failure. However, the protective role of Calhex231 (231, a specific inhibitor of CaSR) in MI-induced myocardial fibrosis remains unclear. We aimed to investigate whether 231 protects against myocardial fibrosis and its underlying mechanism in MI rat model.
METHODS Wistar rats were divided into sham, MI and MI+231 groups. CaSR expression, infarcted size, myocardial fibrosis, autophagy and pyroptosis were detected.
RESULTS CaSR expression increased over time after MI, however, 231 administration could inhibit the expression of CaSR at the different time points. Meanwhile, the application of 231 could reduce myocardial infarct size and fibrosis. Further studies revealed that this protective effect of 231 was associated with inhibition of autophagy and pyroptosis which were demonstrated by immunohistochemistry, electron microscopy and WB.
CONCLUSIONS The present study indicates that 231 may reduce myocardial infarction size and MI-induced fibrosis, which is probably mediated by suppressing autophagy and pyroptosis. This promotes the potential clinical application of 231 in myocardial fibrotic diseases.
TRANSLATIONAL RESEARCH OF CARDIOVASCULAR DISEASE
GW32-e1658
Siew-Keah Lee1, Kim Wai Parn1, Wei Chih Ling1, Jin Han Chin2
1Universiti Tunku Abdul Rahman
2MAHSA University
OBJECTIVES Epigallocatechin-3-gallate (EGCG) has been frequently recommended as a potential drug candidate in treating hypertension. Our preliminary data had shown that 10 mg/kg body weight of oral EGCG for 2 weeks significantly reduced the raised blood pressure in spontaneously hypertensive rats (SHR), with no clinical signs of toxic effects. Nevertheless, multiple cases of hepatoxicity have been frequently associated with consumption of high doses of EGCG-containing dietary supplements. To date, there is still lack of scientific evidence on the medical efficacy and safety profile of EGCG in any cardiovascular disease model. This is well-known that susceptibility degree of the potential adverse drug effects could be very different in standard healthy model and disease model. Therefore, this study aims to investigate the potential dose-dependent toxicity effect of EGCG supplementation in a cardiovascular disease rodent model, spontaneously hypertensive rats (SHR).
METHODS EGCG at 50, 250, 500 or 1000 mg/kg b.w were given to adult SHR via oral gavage for 28 days. Observation of the behavioural and general toxicity were conducted in accordance with the OECD 407 Guidelines. Changes in skin, fur, eyes, occurrence of secretion, autonomic activity, gait, posture, response to handling, grooming and locomotive patterns were monitored. At the end of the experiment, thoracic and abdominal organs were observed for gross lesion, changes in weight and external appearance. Liver damage biomarkers ALT and AST were determined. Quantitative data were analysed statistically using SPSS software.
RESULTS All the SHR survived, and there were no changes in general behaviours, food and water intake, weight gain, gross anatomy of the abdominal and thoracic organs, and relative organ weights. However, plasma ALT and AST were significantly elevated (P<0.05) in SHR treated with 1000 mg/kg b.w. of EGCG.
CONCLUSIONS Administration of subacute oral EGCG at 1000 mg/kg causes liver damage while EGCG lower than 500 mg/kg is generally considered as safe. This study further recommends that the no observed adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) of EGCG are 500 mg/kg and 1000 mg/kg respectively in SHR. These findings are crucial for better understanding of therapeutic range (toxic dose, effective dose) of EGCG in future cardiovascular research.
GW32-e0253
Bo Liang, Ning Gu
Nanjing University of Chinese Medicine
OBJECTIVES ST-segment elevation myocardial infarction (STEMI) is a serious threat to human health, but the mechanism and clinical biomarker of STEMI developed from stable coronary artery disease (SCAD) are extremely lacking. Here, we conducted a bioinformatics analysis to identify potential mechanism and crucial biomarker in these special populations.
METHODS We obtained GSE59867 to obtain differentially expressed genes (DEGs) were identified and protein-protein interaction network was constructed. Besides, potential function modules were analyzed and hub genes were filtered. After functional enrichment analysis, hub genes were analyzed to detect related miRNAs and transcription factors. Finally, GSE62646 was used to plot receiver operating characteristics to determine the specificity of biomarkers.
RESULTS A total of 133 DEGs between SCAD and STEMI were obtained, then, the protein-protein interaction network was constructed, further analysis has determined hub genes and three molecular complexes. Functional enrichment analysis revealed that immunity, metabolism, and inflammation are involved in the development of STEMI. Besides, 103 related miRNAs and numerous transcription factors were predicted and investigated. Finally, ROC curves indicate MS4A3, KLRC4, KLRD1, AQP9, CD14, and CCR1 owned high sensitivity and specificity in the prediction of STEMI.
CONCLUSIONS This study revealed that immunity, metabolism, and inflammation are involved in the development of STEMI derived from SCAD, and 6 genes including MS4A3, KLRC4, KLRD1, AQP9, CD14, and CCR1 could be employed as candidate biomarkers to STEMI.
GW32-e0948
Bo Liang1, Ning Gu2
1Nanjing University of Chinese Medicine
2Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine
OBJECTIVES Though numerous studies indicated that traditional Chinese medicine has unique and irreplaceable advantages in the treatment of ventricular remodelling, the mechanistic contribution of traditional Chinese medicine in cardiac remodelling remains to be fully elucidated. This study aimed to investigate the anti-ventricular remodelling effect of Guanxin V (GXV) and provide scientific data for its clinical application.
METHODS A ventricular remodelling model after acute myocardial infarction was established by ligating the left anterior descending coronary artery of Syrian hamsters. Four groups, including the control, sham, model, and GXV treatment (6 g/kg/d), groups, were tested. The echocardiography and biochemical indexes of cardiac function and remodelling were determined, and the crucial protein involved in the signalling pathway were subsequently tested by qPCR and/or Western blotting. Moreover, we built remodelling model in cardiomyocytes and further explore the mechanism. Transmission electron microscopy was used to observe the ultrastructure of cardiomyocytes and co-immunoprecipitation was conducted the interaction of transforming growth factor beta 1 (TGF-β1) and vimentin.
RESULTS In hamster cardiac remodelling induced by acute myocardial infarction, GXV alleviated apoptosis, cardiac hypertrophy, cardiac remodelling, and even improved cardiac function. Mechanically, GXV inhibited the remodelling process by directly targeting TGF-β1. Overexpression of TGF-β1 exacerbated the ventricular remodelling, whereas GXV reversed this dysregulation. GXV also increased the down-regulated vimentin level in pathological ventricular remodelling. Moreover, the interaction of vimentin and TGF-β1 was confirmed by co-immunoprecipitation, and GXV impeded this interaction.
CONCLUSIONS The interaction of vimentin and TGF-β1 may be a novel target for ventricular remodelling and GXV might be a new agent to fight against ventricular remodelling by targeting TGF-β1 and impeding its interaction with vimentin.
GW32-e0276
Zhen Meng, Zhe Li, Erli Zhang, Yongjian Wu
State Key Laboratory of Cardiovascular, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Sevelamer hydrochloride is a phosphate binder used for the treatment of hyperphosphatemia in CKD patients which can reduce the valvular and vascular calcification. The aim of the study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs).
METHODS Wister rats were randomly divided into 3 groups according to sevelamer intake and implantation (control-no intervention; normal-implantation and normal diet, sevelamer-implantation and sevelamer diet). Two kinds of BHVs were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to sevelamer group. Animals are executed at 0(immediately after implantation), 7, 14, 28, 56 days. Calcium levels were determined by atomic absorption spectroscopy and von kossa staining. Serum biochemistry analysis, western bloting, real-time qPCR, ALP activity measurement, histopathologic analysis and ELISA were conducted to identify the anti-calcification mechanism of sevelamer.
RESULTS Serum phosphate and calcium were unreacted to sevelamer after 14 days treatment. However, the mean calcium level in the sevelamer group was significantly decreased in 56 days. Inflammatory cell infiltration, system inflammation and expression of BMP2, RUNX2, ALP, IL1b, IL6 and TNF-a were significant reduced in the sevelamer group.
CONCLUSIONS Sevelamer treatment significantly attenuated the calcification of BHVs in and had anti-inflammation effects which are independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful for the longevity of BHVs.
GW32-e1055
Linyi Li, Zhiyong Du, Yunhui Du, Qianwen Lv, Huina Zhang, Xiaolu Jiao, Huahui Yu, Yanwen Qin*
Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Disease, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing 100029, China
OBJECTIVE Chronic intermittent hypoxia (CIH) is the primary pathology of obstructive sleep apnea, which has been shown to exacerbate cardiac remodeling and reduce survival rate following myocardial infarction (MI). However, underlying molecular mechanisms are not fully understood. Iron is critical for sustaining life and maintaining human health. In heart, iron is a recognized double-edged sword as a central player both in cardiac energetics and ferroptosis. Given the links between iron metabolism and oxygen transport, here we integrated metabolomics and transcriptomics to reveal the impact of CIH on the cardiac iron metabolism in post-MI remodeling in mice.
METHODS Adult male mice were subjected to MI (4 weeks) with and without CIH (4 weeks). Cardiac remodeling and infarct size were evaluated by wheat germ agglutinin, Masson and 2, 3, 5-triphenyltetrazolium chloride staining, respectively. RNA-sequencing and LC-MS metabolomics were used to reveal the pathway profiling.
RESULTS CIH significantly exacerbated post-MI pathological hypertrophy and increased infarct size. Metabolomics profiling revealed that CIH+MI group hearts exhibited more severe ferroptosis phenotype (glutathione exhausting and excessive oxylipins) compared to MI group. RNA-sequencing results revealed that iron-sulfur cluster binding, 2 iron, 2 sulfur binding, iron ion binding and transferrin transmembrane transporter activity pathways were significantly downregulated in MI+CIH group hearts compared to MI group. MI increased mRNA expression of transferrin receptor-1 (TFR1), Iron-responsive element-binding protein 2, zinc transporter-14 and PCBP1, decreased ferritin H compared to Sham group. Compared with MI group, MI+CIH significantly increased mRNA expression of HMOX1 and high mobility group protein B1, and decreased TFR1, ACO2, PCBP1, iron-sulfur cluster synthesis-related proteins (FDX1, MIA40, ABCB7, ISCA1) and iron-sulfur proteins (UQCRFS1, NDUFS1).
CONCLUSIONS The findings suggested that both MI and MI+CIH changed iron metabolism of heart, but the mechanisms were different and complex with much remaining to be understood.
GW32-e0436
Zhuqing Li1,2, Chengzhi Lu1
1Tianjin First Central Hospital
2School of Medicine, Nankai University
OBJECTIVES The disruption of mitochondrial redox homeostasis in endothelial cells (ECs) can cause chronic inflammation, a substantial contributor to the development of atherosclerosis. Chronic sympathetic hyperactivity can enhance oxidative stress to induce endothelial dysfunction. We determined if renal denervation (RDN), the strategy reducing sympathetic tone, can protect ECs by ameliorating mitochondrial ROS-induced inflammation to reduce atherosclerosis.
METHODS ApoE deficient mice were conducted RDN or sham operation, and then fed with high-fat diet for 20 weeks. Following sacrificing the mice, the aortic trunk and aortic sinuses were stained by Oil red O to assess the plaque area. Aortic endothelial mitochondrial ultrastructure was characterized by electron microscopy. Oxidative stress was evaluated by examining serum malondialdehyde (MDA) level and superoxide dismutase (SOD) activity, as well as by reactive oxygen species (ROS) levels in aortic sinus plaque sections detected by dihydroethidium (DHE) staining. An enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of inflammatory factors IL-6, IL-1β and TNF-a. Nuclear translocation of NF-kB in aortic endothelium were determined by co-immunofluorescence staining using antibody directed against p65 subunit and endothelial marker CD31. Western blotting was performed to identify the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (Tfam), nuclear factor E2-related factor 2 (Nrf2), mitochondrial antioxidant enzyme SOD2 and Glutathione Peroxidase 4 (GPx4) in the aorta.
RESULTS Compared with the sham-RDN group, RDN conferred an anti-atherosclerotic effect as shown by reduced en face (RDN vs. sham-RDN: 11.8±3.7% vs. 19.8±2.2%, P<0.05) and aortic root sinus (14.7±1.8 vs. 12.3±1.3, P<0.05) lesions size. RDN could significantly improve the mitochondrial ultrastructure of the aortic endothelium. RDN decreased the level of serum MDA (16.9±2.9 vs. 24.7±4.7, P<0.05) and increased SOD activity (10.5±1.2 vs. 8.8±1.3, P<0.05), accompanied by decreased ROS accumulation in plaques. RDN also resulted in a significant reduction of NF-kB nuclear translocation and increased the expression of its downstream inflammatory factors in mice. Additionally, the expression of PGC-1α, Tfam, Nrf2, SOD2 and GPx4 in the RDN group was significantly higher than those in the sham-RDN group.
CONCLUSIONS In conclusion, we demonstrate that RDN improves endothelial function and ameliorates atherosclerosis by inhibiting myocardial oxidative stress and inflammation through PGC-1α-Tfam-Nrf2 pathway and NF-kB mediated signal pathway.
GW32-e1082
Yang Chen
Gannan Medical University
OBJECTIVES Retrospective collection of patients with acute ST-elevation myocardial infarction who were treated with primary PCI in the chest pain center of the First Affiliated Hospital of Gannan Medical College from April 2018 to July 2019. Incomplete data and lost follow-up cases were excluded, a total of 252 cases. Including 212 males and 40 females, aged (27–87 years), average age (62.8±11.7). The Major Adverse Cardiovascular Events from the hospital to the follow-up period were recorded as the endpoint events, a total of 32 cases, 20 in the hospital, and 12 during the follow-up period. The independent risk factors of clinical end-point events were analyzed by comparing the clinical characteristics of event group and normal group. According to the time from onset to reperfusion, 187 cases were divided into early group (t ≤6 hours), 35 cases in middle group (6<T≤12 hours), and 30 cases in extended group (12 hours <T≤48 hours). The differences in characteristics during the same reperfusion period were compared, and independent risk factors affecting the prognosis of patients within 6 months were analyzed in each period.
METHODS Retrospective collection of patients with acute ST-elevation myocardial infarction who were treated with primary PCI in the chest pain center of the First Affiliated Hospital of Gannan Medical College from April 2018 to July 2019. The differences in characteristics during the same reperfusion period were compared, and independent risk factors affecting the prognosis of patients within 6 months were analyzed in each period.
RESULTS The incidence of adverse events was 12.7%, including 19 in the early group, 5 in the middle group, and 8 in the extended group. 1. There were significant differences in age, creatinine, consciousness, cardiac function grade of acute myocardial infarction (Killip) >II, infarct related artery, degree of coronary artery lesions, and reperfusion treatment time in the univariate event group and normal group (P<0.05), and the age, creatinine, cardiac function grade, and degree of disease in the event group were higher than those in the normal group, and the adverse event rate was higher in patients receiving reperfusion more than 12 hours. 2. Binary Logistic regression analysis of differential indicators showed that elderly, coma, three-vessel disease, and reperfusion time over 12 hours were independent risk factors for major adverse cardiovascular adverse events (P<0.05). 3. Grouping patients based on reperfusion treatment time to compare the characteristics of patients with adverse events and no adverse events, in the early group (T≤6 h) showed significant differences in age, creatinine, and myocardial function classification of myocardial infarction. Multivariate analysis of the elderly and creatinine were independent risk factors affecting the prognosis of patients during follow-up.
CONCLUSIONS Patients with STEMI can get a good prognosis by performing primary PCI within the early reperfusion time window (T≤6 h). The angiographic results suggest that older patients with three lesions and preoperative acute heart failure have a higher incidence of adverse events within 6 months.
GW32-e0450
Boda Zhou, Ping Zhang
Beijing Tsinghua Changgung Hospital
OBJECTIVES We aimed to evaluate the safety and feasibility of a novel robotic assisted percutaneous coronary intervention (PCI) remote control system in delivery and manipulation of coronary guidewires in vitro and in vivo.
METHODS The a novel robotic assisted PCI system is composed of three parts: 1) the master actuator, i.e. remote control system, which imitates the traditional torque used by doctor in conventional PCI, 2) the slave actuator includes a guidewire delivery system and a force monitoring equipment, 3) and the communication system connects the master and slave actuators. Following preclinical validation, the system was assessed in experimental pigs. Device description: An overview of the setup of the novel robotic assisted PCI system is shown in Figure 2B. In our robotic PCI system, we sought to overcome limitations for current control systems. We employed a master-slave operation mode, i.e. teleoperation system. During operation, the slave actuator (robotic arm and cassette) is arranged in the operation room under the exposure of X-ray; while doctor stays in the control room away from the X-ray, and operates the master actuator (remote controller) to remotely control the slave actuator (Figure 1E). The communication system in the control room receives operating information from the master actuator and transmits such information to the slave actuator through wireless internet, which could also receive feedback information from the slave actuator and transmit to the slave actuator (Figure 2B). In our system problems such as communication delay and communication uncertainty need to be solved properly. To eliminate communication delay and uncertainty, the transmission mechanism should be greatly simplified by removing the gear and synchronous belt transmission. Or in other words, to let the motor shaft be directly connected to the guidewire clamp in the slave actuator.
RESULTS A total of 3 pigs were enrolled in the study. Both robotic and manual control completed the operation with no device- or procedure-related complications. The first-time user of the novel robotic PCI system used similar time to advance the guidewire into a distal branch of coronary arteries comparing with manual procedure.
CONCLUSIONS Early in vivo experience with the novel robotic assisted angioplasty system demonstrated feasibility, safety, and procedural effectiveness comparable to manual operation, the learning curve may be shorter than current systems. A larger in vivo study and subsequent clinical study is warranted to verify the safety and effectiveness of this system.
GW32-e1235
Luping Du, Qingbo Xu
The First Affiliated Hospital, Zhejiang University School of Medicine
OBJECTIVES CD34+ stem cells have been used to treat the patients with heart failure, but the outcome is variable. It is of great significance to scrutinize the fate and the mechanism of CD34+ stem cell differentiation in vivo during heart failure and explore its intervention strategy.
METHODS We performed single cell RNA sequencing (scRNA-seq) of the total non-cardiomyocytes and enriched CD34-tdTomato+ lineage cells in the murine pressure overload models (transverse aortic constriction, TAC), and total non-cardiomyocytes from human adult hearts. By analyzing the transcriptomes of 59,505 single cells from the mouse and 22,537 single cells from the human heart, in addition, combining genetic lineage tracing, bone marrow transplantation models and partial depletion of CD34+ stem cells in CD34-CreERT2; Rosa26-eGFP-DTA models, we provide cell landscape involved in the pathological process and further to explore the specific role and the origin of CD34+ stem cells in the process of myocardial fibrosis.
RESULTS By analyzing the transcriptomes of 59,505 single cells from the mouse and 22,537 single cells from the human heart, we illustrated the dynamics of cell landscape during the progression of heart hypertrophy (or heart failure), including CD34+ stem cells, fibroblasts, endothelial cells and immune cells. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone marrow derived CD34+ cells give rise to fibroblasts and endothelial cells, while bone marrow derived CD34+ cell turned into immune cells only in response to pressure overload. Interestingly, partial depletion of CD34+ stem cells alleviated the severity of myocardial fibrosis with a significant improvement of cardiac function in CD34-CreERT2; Rosa26-eGFP-DTA models. Similar changes of non-cardiomyocyte composition and cellular heterogeneity were also observed in patients with heart failure. Moreover, immunostaining showed a double labelling of CD34 and fibroblast markers in human heart tissues. Mechanistically, our single cell pseudotime analysis of scRNA-seq data and in vitro cell culture study revealed that Wnt-β-catenin and TGFβ1/Smad pathways are critical in regulating CD34+ cell differentiation towards fibroblasts.
CONCLUSIONS Our study provides a cellular landscape of CD34+ cell-derived cells in the hypertrophy heart of human and animal models, indicating that non-bone marrow derived CD34+ cells differentiate into fibroblasts is largely accounts for cardiac fibrosis. These findings may provide novel insights for the pathogenesis of cardiac fibrosis and have further potential therapeutic implications for the heart failure.
GW32-e0503
Saiyang Xie1,2, Wei Deng1,2, Qizhu Tang1,2
1Department of Cardiology, Renmin Hospital of Wuhan University
2Hubei Key Laboratory of Metabolic and Chronic Diseases
OBJECTIVES Glucagon-like peptide 1 receptor agonists (GLP-1 RA) represent an integral part of the arsenal used in clinical practice to improve cardiovascular outcomes in patients with diabetes. However, beyond these observations, more-detailed understanding of Dulaglutide, a longer-acting GLP-1 RA, is lacking. This study was to elucidate the role and mechanisms of Dulaglutide upon diabetic cardiomyopathy and myocardial energetics in type 2 diabetes.
METHODS In addition to the induction of diabetes by STZ (30 mg/kg; i.p.), a high-fat diet (HFD) provides a commonly used approach to induce insulin resistance in mice with a C57BL/6 background. All mice were subjected to echocardiography and hemodynamics after challenged with Dulaglutide (0.6 mg/kg/week; i.h.) or vehicle. Heart tissues were harvested for transcriptome and metabolome analyses. Moreover, AMPKα2 knockout and PPARα knockout mice with a C57BL/6 background were utilized to explore the mechanism of Dulaglutide upon diabetic cardiomyopathy (DCM) in vivo. Additionally, fenofibrate (100 mg/kg/d, i.g.) was used to investigate whether a combinational treatment with Dulaglutide and a PPARα agonist agent could additively improve therapeutic impacts in DCM. Furthermore, neonatal rat cardiomyocytes (NRCMs) under high-sugar (HG) medium were used to verify the effects of Dulaglutide in vitro.
RESULTS In type 2 diabetes model, Dulaglutide generally attenuated weight loss and insulin resistant, reducing the level of C peptide, ketone bodies, and LDL-c compared with vehicle mice. In addition, echocardiography and hemodynamics revealed that Dulaglutide improved pathological structural features of heart and kidney, increasing the left ventricle acclimation, and attenuated the damage of heart diastolic function restore. Moreover, in vitro assays showed that Dulaglutide significantly ameliorated HG-induced mitochondria damage and mitochondria dysfunction, consistently preserved glucose and lipid metabolism in cardiomyocytes. Mechanically, RNA-Seq screened out AMPKα2-PPARα-Mfn2 axis as the potential molecular pathway upon Dulaglutide in cardioprotection, which was also identified by results of western blot. Further analysis showed that Dulaglutide promoted activation of AMPKα2 in cardiomyocytes, which further led to phosphorylation of serine 12 on PPARα and enhanced the nuclear translocation of PPARα. Subsequently, PPARα located in nuclear was binding to the promoter of Mfn2 and promoted the transcription activation of Mfn2, which maintained the mitochondrial homeostasis in cardiomyocytes. Furthermore, AMPKα2 or PPARα deficiency in vivo effectively abolished Dulaglutide-mediated cardioprotection in type 2 diabetes model. Simultaneously, after administrated with Fenofibrate and Dulaglutide, we observed that compared with monotherapy groups, mice receiving the combinational therapy exhibited optimized heart diastolic function, and their overall weight loss was significantly reduced.
CONCLUSIONS Our study demonstrated that Dulaglutide protected against diabetic cardiomyopathy and preserved myocardial energetics in type 2 diabetes, thereby provided scientific basis for clinical application of Dulaglutide in patients with diabetic cardiomyopathy.
GW32-e1328
Ewnji Yoon1, Wenjing Zhang2, Yunpeng Cai2, Shaohong Dong1, Changnong Peng3
1Shenzhen People’s Hospital
2Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
3Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen
OBJECTIVES The development and progression of atherosclerosis represent a chronic process involving complex molecular interactions. Therefore, identifying the potential hub genes and pathways contributing to coronary artery disease (CAD) development is a key component in understanding the underlying molecular mechanisms.
METHODS To this end, we performed transcriptome analysis of peripheral venous blood collected from 100 patients who were divided into four groups according to disease severity, including 27 patients in the atherosclerosis group, 22 patients in the stable angina group, 35 patients in the acute myocardial infarction group, and 16 controls. Weighted gene co-expression network analysis was performed using R programming. Significant module-trait correlations were identified according to module membership and genetic significance. Metascape was used for functional enrichment of differentially expressed genes between groups, and the hub genes were identified via protein-protein interaction network analysis. The hub genes were further validated by analysis of Gene Expression Omnibus (GSE48060 and GSE141512) datasets.
RESULTS A total of 9633 mRNAs were detected in three modules, among which the blue module was highly correlated with the Gensini score.
CONCLUSIONS The hub genes were significantly enriched in the myeloid leukocyte activation pathway, suggesting its important role in the progression of atherosclerosis. Among the genes, MEFV, TREM2 and E2F3 may play a key role in the progression of atherosclerosis and CAD severity.
GW32-e0530
Huangqiang Li, Yong Liu, Jiyan Chen
Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
OBJECTIVES RNA N6-methyladenosine (m6A) modification is an emerging epigenetic modification associated with many diseases and pathologic progress. The role of RNA m6A modification in acute myocardial infarction (AMI) development, especially in regulating the immune microenvironment, still remains unknown. Thus, we aim to investigate hub genes potentially regulated by m6A modification in AMI and explore the impact of m6A modification on immune regulation.
METHODS Based on the expression of 21 m6A methylase regulators in samples of two AMI datasets downloaded from Gene Expression Omnibus (GEO) database, an unsupervised clustering approach was used to classify AMI samples into different m6A Clusters. Moreover, the probable mechanism and regulatory relationship of m6A in AMI was also explored by Weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis. Hub gens related to AMI were determined by integrating protein interaction network (PPI) analysis and WGCNA analysis. We further demonstrated the differences in expression level of AMI-related hub genes in different m6A clusters and patients with or without AMI. Finally, the impact of m6A modification on AMI immune microenvironment characteristics was discussed.
RESULTS According to the expression of 21 m6A methylase regulators in samples of two GEO datasets, the samples were classified into three m6A clusters. Among 21 m6A, the m6A cluster-B showed the highest expression level, and the m6A cluster-C type the lowest. Five co-expression modules were obtained from 13,540 differentially expressed genes of m6A Clusters by WGCNA. The turquoise modules were the most relevant modules to the m6A Clusters. Genes in this module were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG), and the results showed that these genes enriched in many pathways, including Calcium signaling pathway, vascular smooth muscle construction and other related signaling pathways. Furthermore, five m6A-related hub genes of AMI including ADORA1, EDN2, GLP1R, IGFBP5 and RHOV, were determined. Expression of proinflammatory cytokines showed significant differences among different m6A clusters, except IL-6. T_cells_CD4_naive, T-cells_follicular_helper, NK_cells_resting, and Eosinophils cells showed significant differences in immune infiltration among different m6A clusters.
CONCLUSIONS Our findings demonstrated the m6A modification plays a crucial role in AMI and identified five potential m6A mediated hub genes of AMI. Furthermore, we found that m6A modification is associated with immune microenvironment of AMI.
GW32-e1689
Zhihong Zhao1, Yonggang Chen2, Xinhua Chen3
1New Area Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai
2Hangzhou Ruidi Biotechnology Co. Ltd, Hangzhou 310003, China
3Zhejiang Medical Laboratory of Pulsed Power Technology, Hangzhou 310003, China
OBJECTIVES To investigate the histological damage of rabbit cardiac necroptosis induced by pulsed electric fields (PEF) ablation apparatus and catheter.
METHODS Thirty healthy rabbits with a body weight of 2.5±3.5 kg were selected for left ventricular PEF ablation. The ablation parameters: voltage 800 V, pulse width 50 μs, phase delay 5 μs, and cycle length 1 s. The distance between the electrodes of the ablation catheter was 4 mm, and the pericardium and thoracic cavity were closed after ablation. The histological changes of the ablation area were analyzed immediately after surgery and at different time points until 28 days after surgery.
RESULTS After PEF ablation, myocardial enzyme spectrum level peaked 1 day and returned to normal 1 week later. Immediately after PEF ablation, the boundary of the ablation area was clear, and the ablation area was white and edema. Masson staining analysis, PEF ablation immediate swelling of cardiac myocyte; cardiac myocyte rupture and red blood cells infiltration after 6 h, cardiac myocyte shrinking necrosis, fibrosis, alternative obvious necrosis 1 days later, 3 days to 4 weeks the cardiac myocyte replaced by fibrosis completely, vascular, nerve structure were normal in ablation area, and the area of ablation boundary was clear. TUNEL analysis showed cardiac myocyte apoptosis happened 6 h after ablation and reached to peak at 24 h, the process of apoptosis reduced significantly 3 days later, and disappeared 1 week later.
CONCLUSIONS Our PEF ablation instrument and ablation catheter used in rabbit heart ablation, the cardiomyocytes showed the process of necroptosis, the ablation boundary is clear, and the ablation area was replaced by intact fibrocytes, no island cardiomyocytes were observed, and the blood vessels and nerves in the ablation area not affected too.
GW32-e0235
Hongzheng Li1, Jie Wang1, Zhenpeng Zhang1, Yuchen Guo2, Qiang Du3, Jialiang Gao1, Yan Dong1
1Guang’anmen Hospital, China Academy of Chinese Medical Sciences
2Tsinghua University
3Beijing XiaoBaiShiJi Network Technical Co. Ltd
OBJECTIVES To explore the distribution and combination of syndrome elements in traditional Chinese medicine along the whole course of coronary artery disease.
METHODS The modified Transformer algorithm model was built based on the diagnosis standard of coronary artery disease syndrome and syndrome elements. By comparing 80 groups’ syndrome elements diagnosis between the model and 4 clinicians, the accuracy of model can be acquired. One thousand, two hundred twenty-one inpatients with coronary artery disease in Guang’anmen Hospital, China Academy of Chinese Medical Sciences were diagnosed by the modified Transformer model. Meanwhile, we can acquire the law of syndrome elements distribution and combination in different stage.
RESULTS The accuracy of the model can be 96.46±8.957% comparing with clinicians. The critical coronary disease stage of coronary artery disease mainly consisted of the syndrome elements and combinations of qi stagnation and blood stasis. There were blood stasis, qi deficiency, sputum turbidity, qi stagnation and other syndrome elements in the stage of coronary heart disease angina pectoris without intervention surgery, patients within 12 weeks after coronary artery disease intervention present yin deficiency, qi deficiency, qi stagnation, blood stasis, deficiency-based syndrome elements and combination forms. Patients with concomitant cardiac insufficiency after coronary artery disease intervention more than 1 year are mostly manifested in deficiency syndromes elements such as qi deficiency, phlegm turbidity, and yang deficiency and combinations of them.
CONCLUSIONS There is a certain evolution of the distribution and combination of syndrome elements in the whole course of coronary artery disease, patients would present from excess-based syndrome elements to the combination of excess and deficiency syndromes to deficiency-based syndrome elements. And the syndrome elements differentiation system of CAD based on deep learning algorithm provides a method to diagnose the syndrome elements objectively.
GW32-e0744
Yanfang Yang1, Ke Feng1, Yuxin Liu1, Yuying Zhang2, He Sun2, Yunhui Hu2, Jihong Han1
1College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University
2GeneNet Pharmaceuticals Co. Ltd
OBJECTIVES Heart failure is the leading health killer worldwide. Compound Danshen Dripping Pill (CDDP) is a traditional Chinese medicine and has been used to treat patients with myocardial infarction and other cardiovascular diseases. Herein, we determined the protective effects of CDDP against hypercholesterolemia/atherosclerosis-induced heart failure in mice. We also determined if combined CDDP to simvastatin can synergistically reduce heart failure or side effect of simvastatin.
METHODS We constructed ApoE and LDLR dual deficient (ApoE−/−LDLR−/− or ApoE/LDLR dKO) mice and induced hypercholesterolemia/atherosclerosis by high-fat diet (HFD) feeding. The HFD-fed ApoE/LDLR dKO mice (∼8-week-old) were randomly divided into 5 groups and received the following oral treatment. Group 1 (Control group): HFD containing vehicle; Group 2 (LST group) and 3 (HST group): HFD containing simvastatin (ST) at a low (10 mg⋅kg−1⋅d−1) and high dose (25 mg⋅kg−1⋅d−1), respectively; Group 4 (CDDP group): HFD containing CDDP (660 mg⋅kg−1⋅d−1); Group 5 (CDDP+ST or CST group): HFD containing CDDP (660 mg⋅kg−1⋅d−1) and the low dose ST (10 mg⋅kg−1⋅d−1). The treatment was lasted for 8, 12 and 16 weeks, respectively. Mice in each group were conducted electrocardiograms (ECG) and echocardiographic test at the end of treatment, followed by sacrifice and collection of blood and tissue samples individually.
RESULTS After 12 or 16-week HFD feeding, mice in control group had severe heart injury and myocardial ischemia, hypercholesterolemia and advanced atherosclerotic lesions. Associated with amelioration of hypercholesterolemia, high dose simvastatin (HST), CDDP, CDDP plus LST (CST), but not low dose simvastatin (LST), substantially reduced atherosclerosis by ∼40, 42 and 46%. Meanwhile, HST, CDDP and CST potently reduced the development of heart failure. They attenuated hypercholesterolemia-enlarged heart, serum heart failure parameters and heart fibrogenesis. Reduced left ventricular ejection fraction and fractional shortening were also restored by HST, CDDP and CST. The myocardial protection of HST, CDDP and CST is related to their effect on lipid/glucose metabolism and inflammation. Furthermore, the long-term administration of simvastatin caused muscle dissolution, which was blocked by co-treatment of CDDP.
CONCLUSIONS Our study demonstrates that associated with hypercholesterolemia and atherosclerosis, ApoE/LDLR dKO mice developed severe heart injury. CDDP treatment not only protected mice against heart failure, but also blocked simvastatin-induced rhabdomyolysis. Our study suggests that CDDP alone or its combination with simvastatin at low dose can be a novel therapy for treatment of hypercholesterolemia/atherosclerosis-induced heart failure.
GW32-e1899
Yanbo Wang, Guozhen Hao, Xinshun Gu
The Second Hospital of Hebei Medical University
OBJECTIVES To investigate the effect and mechanism of NBP on angiogenesis in chronic ischemic myocardium of rat model.
METHODS A CMI model was established by subcutaneous injection of isoprinosine hydrochloride (ISO) for 14 days in 40 Wistar rats, which had been randomly divided into, model group (n=10), L-NBP group (n=10), M-NBP group (n=10), and H-NBP group (n=10). An additional 10 Wistar rats received 0.9% sodium chloride via intraperitoneal injection for 14 consecutive days (control group). The heart functions were measured by echocardiography in each group. Staining for factor VIII-related antigen and microvascular density (MVD) determination were performed. The protein and mRNA expressions of VEGF and HIF-1α in the area of chronic ischemic myocardium was measured by Western blotting and RT-PCR, respectively.
RESULTS The echocardiographic parameters of rats in each group were shown in Table 1. After the chronic ischemia model was prepared, the levels of LVEDD and LVESD in the MO group increased significantly, while the levels of LVEF and FS decreased significantly, compared with the CO group. The cardiac functions of rats in the L-NBP group, M-NBP group and H-NBP group were significantly improved compared with those in the MO group. The heart function of rats in H-NBP group was similar to that of CO group. The expression level of factor VIII-related antigen in the L-NBP, M-NBP and H-NBP group was significantly increased, and the expression level in the H-NBP group was the highest, suggesting that high-concentration NBP treatment can promote capillary endothelial cell production and increase capillary density. Compared with the CO group and MO group, the expression of VEGFA in the myocardial tissue of rats in the L-NBP, M-NBP and H-NBP groups increased. As the concentration of NBP increased, the expression of VEGFA in the H-NBP group was the highest. Compared with the CO group and MO group, the expression of VEGFA in the myocardial tissue of rats in the L-NBP, M-NBP and H-NBP groups increased. As the concentration of NBP increased, the expression of VEGFA in the H-NBP group was the highest. Compared with the CO group and MO group, the expression of HIF-α in the myocardial tissue of rats in the L-NBP, M-NBP and H-NBP groups increased. As the concentration of NBP increased, the expression of HIF-α in the H-NBP group was the highest.
CONCLUSIONS NBP treatments promotes protein expression of HIF-1α and VEGF in areas of ischemic myocardium, which may represent useful biomarkers for coronary collateral establishment and offer potential targets for therapeutic angiogenesis in patients with chronic myocardium ischemia.
GW32-e0237
Hongzheng Li, Jie Wang, Jinlei Liu
Guang’anmen Hospital, China Academy of Chinese Medical Sciences
OBJECTIVES Developments in artificial intelligence (AI) has led to new methods to Traditional Chinese medicine (TCM). In this article, we proposed a method to apply artificial intelligence to Traditional Chinese medicine research with small sample data and evidence-based researches.
METHODS The AI+TCM model should have the characteristics of learnability, scalability, practicability, and iteration ability. We have added syndrome elements, syndrome, Chinese herbs, prescriptions, clinical cases, classical medical records and other related content to complete the integration of TCM diagnosis and treatment knowledge systems from different sources. Thus, the corresponding relationship among “symptoms-syndrome elements – syndrome – treatment principles – prescriptions – Chinese herbs” is established. Based on graph convolutional networks, knowledge graph, and improved multilayer perceptron (MLP), we built the models and realize visualization.
RESULTS Constructing a knowledge graph, we use syndrome elements and symptoms as nodes, symptom – syndrome elements correlation as edges, and its weight comes from the symptom scores given by the single disease diagnosis and treatment guidelines. The Laplacian Matrix is calculated by constructing the adjacency matrix and the degree matrix, which represents the weight of different symptoms under the syndrome elements, and then the convolution operation is used to weight and sum the output result. Besides, the improved MLP model was also built. We can divide the symptoms, syndrome elements and herbal medicine were into different grades. Using the dropout layer for regularization, some neurons are randomly inactivated while ensuring the normal flow of information from front to back, preventing the network from learning by rote and improving the information processing ability of single neuron. This model truly simulates the thinking of TCM syndrome differentiation and treatment and expands the knowledge body that the model can learn, making the results of syndrome prediction conform to the guidelines and meeting the needs of clinicians. Taking the prescription system for diagnosis and treatment of coronary artery disease for example. Guideline for Diagnosis and Treatment of Chinese Medicine in Stable Angina Coronary Artery Disease was regarded as a blueprint for this system, TCM application management (about 1900 herbs), syndrome attribute management (about 600 syndromes), symptoms of syndrome management (about 5100 syndrome-symptoms signs), symptoms of disease management (about 600 diseases-symptoms signs), prescription management (about 700 prescriptions signs) and “disease-syndrome-prescription” management (about 600 diseases-syndrome-prescriptions) were established. Five hundred three tagged cases from clinic medical records were needed to train this model in order that the accuracy of weight could be improved. Consequently, it will become a prescription system based on TCM syndrome differentiation, which meets clinical diagnosis and treatment, clinical practice, and realizes prescription and syndrome correspondence. It can also become the working basis of evidence-based standards and guidelines.
CONCLUSIONS TCM+AI system based on syndrome elements makes it possible for TCM physicians to effectively solve the problem of chronic disease with small sample data. The TCM+AI system can effectively reduce the repetitive, high-consumption and low-efficiency work for clinicians and can also solve the problem of different standards among multi-center researches.
GW32-e0814
Xiaodong Peng1, Linling Li2, Mengxia Zhang1, Kui Wu1, Xuesi Wang1, Yukun Li1, Yanfei Ruan1, Nian Liu1
1Anzhen Hospital
2Chuiyangliu Hospital
OBJECTIVES Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have shown improved clinical outcomes in patients with heart failure; so far, the therapeutic mechanisms are still elusive. It has been proposed that improvement of Na+ homeostasis may be underlying the mechanism of SGLT2 treatment in heart failure, while contradictory results in this issue were reported. The study explores whether empagliflozin ameliorates Na+ and Ca2+ handling disorders in a Na+ dependent manner.
METHODS Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model Na+ overload. The effects of empagliflozin on Na+ and Ca2+ handling were evaluated by ionoptix system and confocal microscope.
RESULTS In the absence of ouabain, 1 μmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. 50 μmol/L ouabain significantly enhanced cytosolic Na+ level and dysregulated Ca2+ handling, such as increased Ca2+ transient amplitude and Ca2+ content in sarcoplasmic reticulum, enhanced spontaneous Ca2+ release and spark frequency, which was normalized by the treatment of 1 μmol/L empagliflozin within 10 mins. Intriguingly, pretreatment of Na+/H+ exchanger inhibitor (1 μmol/L cariporide) abolished the above effects of empagliflozin. Next, distinct cytosolic Na+ levels were established by incubation of different ouabain concentrations (10, 50 and 100 μmol/L). All the Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 μmol/L empagliflozin; notably the efficacy of empagliflozin was more potent in the higher cytosolic Na+ level.
CONCLUSIONS Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+ dependent manner by inhibiting Na+/H+ exchanger.
CLINICAL RESEARCH ON CARDIOVASCULAR DISEASES
CORONARY HEART DISEASE
GW32-e0124
Raisa Trigulova, Dilnoza Alimova, Nargiza Tashkenbayeva, Feruza Bekmetova, Lola Ilkhamova
Republican Specialized Scientific Practical Medical Center of Cardiology of the Uzbekistan
OBJECTIVES To analyze the impact of glucagon-like peptide-1 Liraglutide (LG) on the parameters of diastolic function of the left ventricle (LVDF) in patients suffering CHD with diabetes mellitus (DM) type 2.
METHODS The study involved 20 patients, who applied with unstable angina (UA) and diabetes mellitus type 2 (WHO, 1999) in the age of 59.7±3.4 years old to units of RSSPMC of Cardiology. Patients’ BMI was 31.8±1.2 kg/m2; duration of DM type 2 was 9.4±3.6 years. Using standard methods we identified complete lipid spectrum, fasting glycemia (FG), postprandial glycemia (PG), HbA1c, weight, and EchoCG. All EchoCG tests were performed by one and the same cardiologist using «En VisorC» system («PHILIPS», Holland) with 3.5 MHz sensor with patients lying on the left flank with 45° angle in compliance with the standard methods. The basic parameters of LVDF were: E, A, E/A, Ea, E/Ea, PV, cardiac index, and peak ejection rate. Therapy mode: anticoagulants, anti-aggregate agents, nitrates, beta-blockers, RAAS blockers, statins, Liraglutide. Liraglutide efficacy was assessed on the basis of HbA1c decrease from the original level HbA1c ≥0.5%. A group of patients with CHD and DM type 2 receiving Gliclazide (GL) (n-10) was considered to be a control one. The term of follow-up was 6 months.
RESULTS Within the follow-up period there was notable similar positive dynamics of glycemia in both groups: HbA1c −1.2% (−5 mmol/L) vs. comparison group 0.9% (−2 mmol/L), P=0.54. Dynamic alterations in lipid profile, mean SBP and DBP in both groups were similar. In the group of patients receiving LG early diastolic velocity of the mitral annulus on lateral (e-lat) and septal (e-sep) sides increased from 8.9±2.9 to 10.5±5.1 cm/s (P<0.001) and from 7.1±1.4 to 7.9±1.9 cm/s (P<0.003), respectively. Correlation of early and late velocity on lateral and medial sides of the mitral annulus increased from 0.6±0.4 to 0.8±0.3 (P<0.03) and from 0.4±0.1 to 0.5±0.2 (P<0.03), respectively. Ratio of the velocity of early diastolic mitral flow to the velocity of early diastolic myocardial relaxation diminished from 9.5±3.9 to 7.9±2.9 (P<0.04). In the group of comparison receiving GL there was no compatible dynamics.
CONCLUSIONS Our study showed, that regular prescription of Liraglutide for 6 months had positive effect on the diastolic function parameters.
GW32-e0125
Raisa Trigulova, Nargiza Tashkenbayeva, Dilnoza Alimova, Feruza Bekmetova
Republican Specialized Scientific Practical Medical Center of Cardiology of the Uzbekistan
OBJECTIVES Assessment of Sitagliptin and Gliclazide effect on clinical biochemical parameters with the evaluation of diastolic function of the left ventricle in patients with CHD and diabetes mellitus (DM) type 2.
METHODS We studied forty patients with coronary heart disease (CHD), who applied to the second and sixth units of the RSSPMCC within the period of angina destabilization combined with DM type 2 and hypertonic disease aged 59.2±9.5 years old. Using standard methods we determined complete lipid spectrum (TC, LDL C, VLDL C, HDL C, TG), fasting glycemia (FG), postprandial glycemia (PG), HbA1c, and C-reactive protein (CRP). Therapy mode: anticoagulants, anti-aggregate agents, nitrates, RAAS blockers, beta-blockers, statins. Patients with DM type 2 received metformin and sulfonylureas. Exclusion criteria were heart failure (HF) and chronic kidney disease (CKD) 4, any incretin therapy, and insulin therapy. Three-five days after stabilization of the condition with basic therapy 30 patients were randomly chosen to administer Sitagliptin/metformin (SG/M) with a day doze 50/500–50/1000 mg/day, with glycemia control, monitoring of HR, SBP, DBP, lipid profile, CRP level. The rest 10 patients continued receiving Gliclazide (GL). Primary terminal points were changes in the ratio of e’ velocity and E/e’ from the original one within 24 weeks (6 months) of follow-up. Secondary points included HbA1c, lipid profile, CRP. Follow-up duration was 6 months.
RESULTS With the background DPP-4 inhibitors therapy HbA1c decreased more than in the group receiving GL. Corrected mean difference between SBP and DBP in the compared groups was equal to −1.1 mmHg (P=0.514) and 0.3 mmHg (P=0.688), respectively. There was a dynamic decrease in some parameters of lipid spectrum with Sitagliptin: TC to (-) 23±24 mg/dL; P=0.001; LDL C to (-) 13±0.9 mg/dL; P=0.005; TG to 39±40 mg/dL; P=0.001. In the group taking Gliclazide together with similar basic statins therapy there was no notable tendency for decrease. CRP decrease was significant only in Sitagliptin group and as more than in Gliclazide group (−0.82±0.30 vs. −0.30±0.02 mg/L, P=0.017) we registered decrease in E/e’ within the follow-up period (6 months) in the group of patients, who received SG/M (−0.20±0.36) vs. GL (0.75±0.4); P=0.07. Parameters such as e’, E/A did not change in the progress of the therapy (24 weeks).
CONCLUSIONS DPP-4 inhibitor had favorable effect on the parameters of glycemic profile, SBP, and DBP. Administration of Sitagliptin for 6 months was associated with significant decrease in triglycerides and LDL C, improving the general presentation of dyslipidemia in DM type 2. Confirmation of correlation between dyslipidemia and inflammatory markers was similar decrease of CRP. Sitagliptin can be safely used for patients with diabetes mellitus type 2 without LV diastolic function deterioration risk.
GW32-e0078
Yingying Zheng1,2, Xiang Xie2, Tingting Wu2, Ying Gao2, Jin-Ying Zhang1, Yitong Ma2
1Department of Cardiology, First Affiliated Hospital of Zhengzhou University
2Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES There is no generally applied and accepted model to predict long-term mortality in stable coronary heart disease (SCHD) patients who underwent percutaneous coronary intervention (PCI). In the present study, we aimed to develop a novel prediction model in SCHD patients who underwent PCI.
METHODS Four thousand and six SCHD patients from the CORFCHD-PCI cohort were act as the derivation cohort. We analyzed several candidate variables using receiver-operating characteristics (ROC) analysis and area under the curve (AUC) evaluation. A clinical prediction model was developed based on the most important variables using multivariable Cox regression analyses. Both internally bootstrap validation and externally validation were performed to verify the model performance. Eight hundred and sixty-five SCHD patients from CORFCHD-ZZ cohort study acts as the externally validation cohort. The primary outcome was all-cause mortality (ACM). We also explored the model performance for cardiac mortality (CM).
RESULTS There were 221 case of ACM during a median follow-up of 32 months. Initially, eighteen risk factors were selected and ranked according to their AUC value. Finally, we selected age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), rest heart rate, white blood cells, and platelet to develop the final prediction model named “WABHP” model. This model had high discriminatory ability for ACM (c-index 0.740 in derivation cohort, 0.823 in validation cohort), with adequate calibration in both cohorts.
CONCLUSIONS The present study developed and validated a novel model to predict mortality in patients with stable CHD who underwent PCI. This model can be used as a credible tool for risk assessment and management of stable CHD after PCI.
GW32-e0265
Mengjiao Shao1, Jun-Yi Luo1, Xiao-Mei Li1, Yi-Ning Yang1,2
1Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China
2Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
OBJECTIVES Obesity is an independent risk factor for coronary heart disease. The study aimed to investigate the association of Body Roundness Index (BRI) with coronary collateralization (CC) in chronic total occlusion (CTO).
METHODS Coronary collateralization was graded according to Rentrop scoring system in this study involved 926 in patients undergoing PCI for at least one CTO lesion. Data on demographic and clinical characteristics were collected by cardiovascular doctors. Physical examination and fasting blood lipids levels were measured at baseline. Subgroup analysis, mixed model regression analysis, scoring systems and receive operating characteristic (ROC) curve analysis were performed to assess the predictive value of obesity indexes were associated with CC in CTO.
RESULTS Overall, 926 inpatients were assigned to the poor CC group (n=544) and good CC group (n=382). After ROC analysis indicated that the BRI had larger area under ROC curve than Body Mass Index and Waist circumference 0.668 (95% CI: 0.634–0.703) vs. 0.621 (95% CI: 0.586–0.657) and 0.661 (95% CI: 0.627–0.696). After adjustment for covariates, quartiles of BRI remained the risk factors for CC growth in all groups, per 1 increase of BRI was associated with a 1.468-fold higher risk of CC growth (OR=1.468, 95% CI: 1.340–1.609, P<0.001). Those individuals in the top BRI quartile group had the highest risk of CC growth (OR=4.694, 95% CI: 2.991–7.365, P<0.001).
CONCLUSIONS Body Roundness Index was independently associated with coronary collateralization in chronic total occlusion.
GW32-e0595
Bowen Lou, Zuyi Yuan, Jianqing She
Cardiovascular Department, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710048, P.R. China
OBJECTIVES Acute myocardial infarction (AMI), as well as its complications including heart failure, severe arrhythmia, cardiac rupture, are known to present with high morbidity and mortality. Cardiac function deterioration and ventricular remodelling after AMI are known to be correlated to wore long-term outcomes. However, the underlying mechanism remains elusive and there is a shortage of serum prediction markers. This study investigates the relationship between in-hospital Cystatin-C and cardiac function and subsequent prognosis among AMI patients.
METHODS We measured admission Cystatin-C and cardiac function parameters, including ejection fraction (EF) and pro-BNP value in 5956 patients diagnosed with AMI. Simple and multi-regression analysis was performed to investigate the correlation between Cystatin-C and cardiac function in AMI patients. Major adverse cardiovascular events (MACE), cardiovascular and all-cause mortality were documented, and 351 high-Cystatin participants (≥1.09 mg/L) and 714 low-Cystatin (<1.09 mg/L) participants were investigated for survival analysis during a 48-month follow up.
RESULTS Five thousand and nine hundred fifty-six patients with AMI were enrolled in the initial observational analysis and 1065 patients of the whole cohort were included in the follow-up survival analysis. The admission Cystatin-C level was found to be significantly positively correlated to the pro-BNP level (R square=0.2142, 95% CI 4758–5265, P<0.0001) and negatively correlated to the EF value (R square=0.0095, 95% CI −3.503 to −1.605, P<0.0001). Kaplan-Meier survival analysis revealed significantly increased MACE incidence (HR=2.293, 95% CI 1.400–3.755, P<0.0001), cardiovascular mortality (HR=3.016, 95% CI 1.694–5.371, P=0.0002) and all-cause mortality (HR=3.424, 95% CI 2.010–5.835, P<0.0001) in AMI patients with the high-Cystatin level at the end of 4-year follow-up.
CONCLUSIONS Admission Cystatin-C is negatively correlated with cardiac function in AMI patients and acts as a novel predictor for MACE incidence in the whole population. Further studies are needed to investigate the specific mechanism of Cystatin-C in the cardiac function deterioration of AMI patients.
GW32-e0822
Danqing Hu1, Yongchen Hao1, Jun Liu1, Na Yang1, Yong Huo2, Sidney C. Smith Jr3, Junbo Ge4, Gregg C. Fonarow5, Louise Morgan6, Changsheng Ma7, Yaling Han8, Dong Zhao1, Jing Liu1
1Beijing An Zhen Hospital, Capital Medical University
2Department of Cardiology, Peking University First Hospital
3Division of Cardiology, University of North Carolina, Chapel Hill, NC, USA
4Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University
5Division of Cardiology, Geffen School of Medicine at University of California, Los Angeles, CA, USA
6International Quality Improvement Department, American Heart Association, Dallas, TX, USA
7Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University
8Cardiovascular Research Institute and Department of Cardiology, General Hospital of Shenyang Military Region
OBJECTIVES Although percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for AMI, a substantial proportion of patients initially arrive at non-PCI hospitals. The impact of inter-hospital transfer on prognosis of AMI with relatively long ischemia time in real-world practice is still debated. We aimed to evaluate the impact of inter-hospital transfer on treatment delay and in-hospital outcomes of hospitalized patients with AMI in China.
METHODS From November 2014 to December 2019, 94,623 patients with AMI were enrolled from 159 tertiary and 82 secondary hospitals in 30 provinces in China in the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome (CCC-ACS) Project. Patients were divided into those directly admitted or inter-hospital transferred to a PCI hospital. Associations of inter-hospital transfer versus with direct admission in-hospital major adverse cardiovascular events (MACE) were examined by multivariable Cox regression and propensity score matching (PSM) analysis.
RESULTS Among the 94,623 patients, 40,970 (43.3%) were inter-hospital transferred to PCI hospitals. Compared with direct admission, inter-hospital transfer was associated with a longer time from symptom onset to reperfusion (9.8 h vs. 6.0 h for STEMI and 83.3 h vs. 54.4 h for NSTEMI), and lower rates of reperfusion for STEMI (50.7 vs. 63.4%) and timely PCI for NSTEMI (34.7 vs. 41.1%). No associations were found between inter-hospital transfer relative to direct admission and the risk of in-hospital MACE in Cox regression (HRs [95% CIs] were 0.86 [0.70–1.05] for STEMI and 1.24 [0.84–1.82] for NSTEMI), in PSM (0.86 [0.69–1.06] for STEMI and 1.27 [0.79–2.03] for NSTEMI).
CONCLUSIONS There was no significant difference in the risk of in-hospital MACE between directly admitted and transferred patients with AMI in China. Therefore, when direct admission is not feasible, timely transfer to PCI-capable hospitals maybe an alternative in real-world practice.
GW32-e1004
Zefeng Chen, Xing Shui, Bicai Luo, Lin Chen
Department of Cardiovascular Medicine, The Third Affiliated Hospital of Sun Yat-sen University
OBJECTIVES Pulse pressure is a predictor of cardiovascular mortality. This study investigated the relationship between pulse pressure and 30-day and 90-day all-cause mortality among acute myocardial infarction patients.
METHODS Clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database. The MIMIC-III database contains more than 50,000 intensive care patients. Acute myocardial infarction patients from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database with pulse pressure and follow up datas were enrolled. The primary outcome was 30-day all-cause mortality and the secondary outcome was 90-day mortality. Logistic analyses were used to investigate the the relationship between pulse pressure and 30-day and 90-day all-cause mortality. Multivariate analyses were used to control confounders.
RESULTS Two thousand and fourty-one acute myocardial infarction patients were enrolled. The average age of this population is 68 years old and 35.8% of them are female. Thirty-day mortality is 16.4% (336/2041) and 90-day mortality is 20.0% (410/2041). In the model adjusted for multiple confounders, pulse pressure showed significant correlation with 30-day mortality (OR=0.985, 95% CI: 0.976–0.995, P=0.002). The interactions between and age (OR=1.036, 95% CI: 1.020–1.051, P=0.000), blood urea nitrogen (OR=1.027, 95% CI: 1.016–1.039, P=0.000), cardiac troponin T (OR=1.047, 95% CI: 1.017–1.078, P=0.002), ventilator used (OR=5.061, 95% CI: 3.466–7.391, P=0.000) and 30-day mortality were significant. For 90-day mortality, in the model adjusted for multiple confounders, pulse pressure also showed significant correlations (OR=0.982, 95% CI: 0.973–0.990, P=0.000).
CONCLUSIONS Pulse pressure was an independent predictor of 30-day and 90-day mortality for acute myocardial infarction patients.
GW32-e1152
Wei You, Tian Xu, Xiangqi Wu, Zhiming Wu, Fei Ye
Nanjing First Hospital
OBJECTIVES Negative remodelling (NR) often contributes to stenosis of side branch ostium (SBO), which cannot be recognized by angiography only in true coronary bifurcation lesions. We investigated the influence of severe NR of SBO for intrastent neointimal hyperplasia (NIH) after percutaneous coronary intervention (PCI) with a 2-stent strategy for distal left main bifurcation (LMb) lesions.
METHODS From the database of Nanjing First Hospital, only true LMb lesions treated by PCI with a 2-stent strategy with integrated IVUS data pre- and post-PCI and at the one-year follow-up were considered, and a total of forty-eight cases with optimized results guided by IVUS were analysed. The intrastent NIH area measured by IVUS at the 1-year follow-up was the primary endpoint.
RESULTS According to the definition of NR as a vascular cross-sectional area (CSA) at the lesion site smaller than that at the distal reference, which was described as RI<1, NR was frequent at SBO, with a ratio of 82.7% in the left circumflex ostium (LCxO) and 55.8% in the left anterior descending artery ostium (LADO). Multivariate logistic regression analysis of the RI of NR of LCxO (P=0.002) showed that this factor was an independent predictor of the relative intrastent NIH area. Receiver operating characteristic (ROC) curve analysis demonstrated that the predictive cut-off values of the RI of LCxO for relative NIH areas >20%, 30%, 40% and 50% were 0.94 (area under the curve [AUC]: 0.813, 95% CI: 0.692–0.934; sensitivity: 86.4%, specificity: 69.2%; P<0.001), 0.94 (AUC: 0.762, 95% CI: 0.619–0.905; sensitivity: 77.8%, specificity: 71.4%; P=0.002), 0.94 (AUC: 0.846, 95% CI: 0.719–0.973; sensitivity: 74.3%, specificity: 97.3%; P<0.001), and 0.85 (AUC: 0.893, 95% CI: 0.778–1.000; sensitivity: 85.7%, specificity: 83.3%; P=0.002), respectively.
CONCLUSIONS NR of LCxO is associated with more NIH post-PCI for distal LMb lesions with the 2-stent strategy, and severe NR with RI <0.85 is linked to NIH area >50% at the 1-year follow-up.
GW32-e1332
Kwan-Yu Li1,2, Lok-Yee Lam1,2, Calvin Ka-Lam Leung1,2, Mei-Zhen Wu1,2, Qing-Wen Ren1,2, Shuk-Yin Yu1,2, Pui-Fai Wong1,2, Hang-Long Li1,2, Yi-Kei Tse1, Si-Yeung Yu1,2, Nicole Wing-Lam Hon1,2, Lok-Him Tsui1,2, Yun-Di Feng3, Yun-Long Huo3, Hung-Fat Tse1, Kai-Hang Yiu1,2
1The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
2The University of Hong Kong Shenzhen Hospital, China
3PKU-HKUST Shenzhen-Hongkong Institution, China
OBJECTIVES Patients with coronary artery disease (CAD) are at risk of heart failure (HF). Computational pressure-flow dynamics derived fractional flow reserve (caFFR) is a novel index to assess functional significance of stenosis in patients with coronary artery disease, eliminating wire-related complications and hyperaemic induction in conventional fractional flow reserve (FFR). Despite previous validation on its diagnostic performance, the clinical value of caFFR on predicting HF outcomes is undetermined in CAD patients. The aim of the study is to evaluate the prognostic role of caFFR on HF outcomes in stable CAD patients with deferred lesions.
METHODS The study included a total of 558 stable CAD patients (mean age=64.5±11.2, 59.0% male) with ≥1 coronary lesion detected during conventional coronary angiogram in whom revascularization was deferred. Patients were stratified into ischemic group with caFFR≤0.8 (n=68) and non-ischemic group with all known caFFR;0.8 (n=490). The primary endpoint was a composite of HF hospitalization and HF-related mortality at 3 years.
RESULTS A total of 25 composite events occurred, including 20 HF hospitalization and 5 HF-related mortality. The 3-year incidence rate of primary endpoint was 8.82% in patients with caFFR≤0.8 and 3.06% in patients with caFFR>0.8 (P=0.03). Following multivariable adjustment, the risks of primary endpoint (adjusted hazard ratio [HR]=2.85; 95% confidence interval [Cl], 1.10–7.37; P=0.03) and HF-related mortality (adjusted HR, 10.95; 95% Cl, 1.83–65.67; P<0.01) were significantly higher in patients with caFFR≤0.8, compared to those with caFFR;0.8.
The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve for predicting primary endpoint with caFFR is larger than that of syntax score (0.72 vs. 0.66, P<0.01). This reflects the superior predictive ability of caFFR compared to purely angiographic-based syntax score.
CONCLUSIONS In stable CAD patients with deferred lesions, those with more significant myocardial ischemia, defined by caFFR≤0.8, have higher risks of HF hospitalization and HF-related mortality. The finding thus validated the potential clinical use of this non-wire based index to quantify the severity of myocardial ischemia, improve risk-stratification, and predict adverse outcomes after deferral of revascularization.
GW32-e1425
Jing Liang, Zhijian Wang, Yujie Zhou, Xiaoteng Ma, Hongya Han, Qiaoyu Shao, Zhiqiang Yang
Beijing Anzhen Hospital
OBJECTIVES There is limited data on the safety of ticagrelor as part of a triple antithrombotic therapy (TT) in patients underwent drug-eluting stent (DES) implantation post ST-segment elevation myocardial infarction (STEMI) complicated by developed left ventricular thrombus (LVT). The purpose of this study was to investigate the risk of bleeding according to concurrent treatment of warfarin plus dual antiplatelet therapy (DAPT) with aspirin and ticagrelor.
METHODS From 1 January 2014 to 31 December 2019, we retrospectively analyzed post STEMI patients developed with LVT underwent DES using warfarin plus DAPT with aspirin and clopidogrel or ticagrelor before discharge in our hospital. Transthoracic echocardiography (TTE) was performed before discharge and during follow-up period. The primary safety endpoint was 12 months major, minor or minimal bleeding events defined by Thrombolysis in Myocardial Infarction (TIMI). The composite endpoints were 12 months cardiac death, myocardial infarction (MI), stent thrombosis (ST), target lesion revascularization (TLR), ischemic stroke, and systemic embolism (SE).
RESULTS A total of 209 consecutive patients were enrolled. Seventeen received ticagrelor and 192 clopidogrel. Most patients 182 (87.1 %) were male with an average age of 55.6±10.9 years. 171(81.3%) obtained thrombus resolution and warfarin discontinued after disappearance of LVT confirmed by TTE. 16(16/17) and 1(1/17) patients in ticagrelor group and 116(116/192) and 76(76/192) patients discontinued TT 1 month and 3 months after discharge, respectively. There was significant difference in baseline characteristics between ticagrelor and clopidogrel group in three vessel disease (5.9 vs. 0.5%, P=0.030), history of PCI (23.5 vs. 7.8%, P=0.031), prior ST (5.9 vs. 0, P=0.001), lower HAS-BLED score (1.2±0.4 vs. 1.4±0.7, P=0.009) and CYP 2C19 LOF allele carriers (29.4 vs. 12.0%, P=0.043). No intracerebral hemorrhage occurred. There was no significant differences between ticagrelor and clopidogrel group in total bleeding events (17.6 vs. 8.9%, P=0.257), Minor bleeding (upper gastrointestinal hemorrhage) (5.9 and 1.0%) and minimal bleeding (11.8 vs. 7.8%, P=0.622). No cardiac death, stroke and systemic embolism in both groups. No significant differences between ticagrelor and clopidogrel group regarding composite endpoints (0 vs. 4.2%, P=0.396), MI (0 vs. 1.0%, P=0.673), TLR (0 vs. 1.6%, P=0.605), and ST (0 vs. 1.6%, P=0.605)
CONCLUSIONS Ticagrelor as a part of TT maybe a choice for selected LV thrombi post MI patients underwent DES who had a higher risk of ischemia than risk of bleeding. However, the duration of TT should be limited and patients should be treated individualized depending on the risks for clinical complexity factors and combination of clinical and procedural factors.
GW32-e1554
Qiang Li1, Jin Liu1, Weihua Chen2, Shanshan Shi2, Haozhang Huang1, Shiqun Chen1, Yong Liu1
1Guangdong Provincial People’s Hospital, Guangzhou 510080, China
2The School of Clinical Medicine, Fujian Medical University, Fuzhou 364000, China
OBJECTIVES As a common indicator in echocardiogram, left ventricular end-diastolic diameter (LVEDD) was an important indicator of cardiac chamber size and left ventricular (LV) function, and it was also an easily measured non-invasive technique widely used in clinical work. Previous studies had shown that LVEDD was associated with cardiovascular events and all-cause mortality. However, the predictive value of LVEDD is unclear for coronary artery disease (CAD), a heart disease that often leads to LV remodeling. Therefore, we aim to investigate the relationship between LVEDD and long-term all-cause mortality in CAD patients as an association.
METHODS The study enrolled 33,147 patients with CAD who had undergone transthoracic echocardiography between January 2007 and December 2018 in Cardiorenal Improvement (CIN) study (ClinicalTrials.gov NCT04407936). This was a single-center, observational cohort study, which was completed in Guangdong Provincial People’s Hospital in China. These patients were divided into four groups according to the quartile of LVEDD (Quartile 1: LVEDD≤43 mm, Quartile 2: 43 mm<LVEDD≤46 mm, Quartile 3: 46 mm<LVEDD≤51 mm, Quartile 4: LVEDD;51 mm) and were categorized into two groups (Quartile 1–3 vs. Quartile 4). Survival curves were generated with the Kaplan-Meier method, and the differences between groups were assessed by log-rank test. The restricted cubic splines and cox proportional hazards models were used to investigate the association with LVEDD and all-cause mortality.
RESULTS In our study, there were a total of 33,147 patients, whose average age was 63.0±10.6 years and 24.01% of them were female. In the average follow-up period of 5.2 years, a totally of 4288 patients died. The mortality of the larger LVEDD group (Quartile 4) was significantly higher than the lower LVEDD groups (Quartile 1–3) (18.05 vs. 11.15%, P<0.001). After adjusting for age, gender, percutaneous coronary intervention (PCI), hypertension (HT), diabetes (DM), anemia, estimated glomerular filtration rate (eGFR), acute myocardial infarction (AMI), left ventricular ejection fraction (LVEF), patients with the larger LVEDD (Quartile 4) remain had a 1.19-fold risk for all-cause mortality (95% confidence interval: 1.09–1.30) compared with the lower quartile (Quartile 1–3). To assess whether the association between LVEDD and long-term all-cause mortality could be explained by patients’ characteristics and comorbidities, the study conducted multivariable-adjusted hazard ratios for all-cause mortality stratified by age, heart failure (HF), AMI, HT, DM, atrial fibrillation (AF), chronic kidney disease (CKD). There were no significant interactions between the subgroup factors and the effect of the larger LVEDD (Quartile 4) relative to the lower LVEDD (Quartile 1–3) for the long-term all-cause mortality (P for interaction <0.05).
CONCLUSIONS Enlarged LVEDD was an independent predictor of all-cause mortality in patients with CAD. LVEDD is an easily obtained indicator in echocardiogram that can be performed at admission to identity the risk of prognosis in patients with CAD. Patients at high risk of mortality with dilated LVEDD should be paid attention to.
GW32-e1659
Jie Yang
Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Acute hyperglycemia is an established risk factor for adverse cardiovascular events in patients with acute coronary syndrome (ACS). In recent years, some studies have proven that a novel marker described as the stress hyperglycemia ratio (SHR) could reflect the true acute hyperglycemic status and is associated with the short-term poor prognosis in patients with acute myocardial infarction (AMI). Whether the SHR is independently associated with a poor early or late prognosis in ACS patients remains unclear. The present study evaluated the association of the SHR with adverse cardiovascular events in patients with ACS.
METHODS We consecutively enrolled 5538 ACS patients who underwent drug-eluting stent (DES) implantation. All subjects were divided into 5 groups according to the SHR, which was determined by the following formula: ABG/[(28.7×HbA1c %) – 46.7], where ABG represents the admission blood glucose level, and HbA1c represents the glycated hemoglobin level. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs) at the two-year follow-up, and the secondary endpoint was MACCEs at the one-month follow-up.
RESULTS A total of 632 MACCEs were recorded during a median follow-up of 850 days. Kaplan-Meier survival analysis showed the lowest MACCE incidence in quintile 3 (P<0.001). Moreover, the outcomes of restricted cubic spline analysis suggested that there was a J-shaped association between the SHR and early and late MACCEs even after adjusting for other confounding factors.
CONCLUSIONS There is a J-shaped association between the SHR and short-term and long-term MACCEs in ACS patients treated with DES implantation; the SHR corresponding to the lowest risk of adverse cardiovascular events is 0.77–0.78.
GW32-e1789
Huahui Yu, Xiaolu Jiao, Qianwen Lv, Fan Li, Qiuju Sun, Yu Wang, Ming Zhang, Yanwen Qin, Shaoping Nie
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Angiopoietin-2 (Ang-2), a member of the angiopoietin family, secreted by vascular endothelial cells, epithelial cells, plays an irreplaceable role in angiogenesis. Previous study showed that Ang-2 levels are higher in patients with stabile CAD. However, in patients with acute coronary syndrome (ACS) after PCI, whether elevated Ang-2 contributes to an increase in the occurrence rate of MACEs remains unclear.
METHODS In this retrospective study, 954 patients who were referred to PCI for the established ACS were enrolled in the Beijing Anzhen Hospital from October 2016 to February 2018. Follow up time of the study was 2 years. Follow up data with respect to cardiovascular events was available for 913 patients. The primary outcome, major adverse cardiovascular events (MACEs), was a composite of coronary death (fatal myocardial infarction, sudden cardiac death, mortality from congestive heart failure due to CAD), fatal ischemic stroke, non-fatal myocardial infarction, non-fatal ischemic stroke and need for coronary artery bypass grafting, PCI, or revascularization in the carotid or peripheral arterial beds. The second outcome was all-cause deaths. Plasma Ang-2 levels were measured by an enzyme-linked immunosorbent assay kit. Adjusted hazard ratios for the incidence of MACEs were derived from Cox proportional hazards models using z-transformation of continuous variables. Receiver operating characteristic (ROC) analysis was used to examine the potential utility of Ang-2 as a predictive biomarker according to their area under the curve (AUC).
RESULTS During 2-years follow-up, 164 patients suffered MACEs. Circulating Ang-2 levels were significantly higher in ACS patients with MACEs compared with the non-MACEs (1207.78 [774.21–1740.70] vs. 1094.04 [679.12–1500.17] pg/mL, P<0.05). Multivariable Cox regression analysis revealed that Ang-2 levels were independently associated with MACEs in ACS patients (HR=1.289 [95% CI 1.117–1.488], P=0.001). After adjusting for confounding factors including the age, gender, BMI, SBP, DBP, TG, TC, LDL-Cand HDL-C (adj. HR=1.27 [95% CI 1.038–1.555], P<0.05), Ang-2 levels also were significantly associated with cardiovascular events. According to ROC curve analysis, the inclusion of Ang-2 in a default cardiovascular risk model (including age, gender, BMI, SBP, DBP, TG, TC, LDL-Cand HDL-C), Ang-2 significantly improved its predictive performance for MACEs (AUC: 0.606 vs. 0.586) in ACS patients treated with PCI.
CONCLUSIONS Circulating Ang-2 levels were independently associated with MACEs in ACS patients after PCI, and Ang-2 predicts MACEs independently of conventional risk factors.
GW32-e0094
Xianjun Han, Zhenghan Yang, Yi He
Department of Radiology, Beijing Friendship Hospital, Capital Medical University
OBJECTIVES The purpose of this study was to investigate radiologists with different levels of experience and whether the diagnostic performance and time efficiency of coronary computed tomography angiography (CCTA) could be improved by the use of CCTA-artificial intelligence (CCTA-AI) assistance.
METHODS This was a single-centre retrospective analysis that included 200 patients (125 men (62.5%), average age: 63.8±8.8) with complete CCTA and invasive coronary angiography (ICA) data, and ICA results were used as the gold standard. Eighteen radiologists with different levels of experience were divided into three groups (novice, junior and senior), and then the three groups were divided into Group A (without AI-assisted, Group 1 to Group 3) and Group B (with AI-assisted, Group 4 to Group 6) by stratified random sampling, totalling 6 groups (avoided readers’ recall bias). CCTA-AI and each radiologist interpreted the degree of stenosis in 200 CCTA cases. The average sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy, as measured by the area under the receiver operating characteristic curve (AUC), were reported for the 6 groups on patient-based, vessel-based and segment-based. The interpretation time for each radiologist in Group A and Group B was recorded.
RESULTS Compared to without CCTA-AI, the novice group with CCTA-AI had improved sensitivity (75.0 vs. 83.0% on patient-based, P=0.003). AI assistance could identify more segments and vessels in novices. In the seniors, the specificity was better with CCTA-AI assistance than without. There was no significant improvement in CCTA-AI assistance in juniors. The median interpretation times for Group A and Group B were 615 seconds and 413 seconds, respectively, and the difference was statistically significant (P<0.001).
CONCLUSIONS CCTA-AI could assist in and improve the diagnostic performance of radiologists with different levels of experience, with novices exhibiting improved sensitivity while seniors exhibiting improved specificity. Use of CCTA-AI assistance could shorten the training time for radiologists.
GW32-e0269
Yuanhui Liu1, Yining Dai1, Chongyang Duan2, Ning Tan1, Pengcheng He1
1Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences
2Department of Biostatistics, School of Public Health, Southern Medical University
OBJECTIVES Infectious complications are prevalent in patients with acute myocardial infarction, which worsens their outcomes. Proton pump inhibitor (PPI) usage potentially increases infection in several cohorts. However, whether PPI therapy affecting the development of infection in acute myocardial infarction patient is poorly understood.
METHODS In this observational study, we consecutively enrolled ST-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) from January 2010 to June 2018. The patients were then divided into a PPI group and a non-PPI group, according to whether a PPI was given after admission. The primary endpoint was infection during hospitalization.
RESULTS A total of 3027 patients were enrolled with the mean age of 62.2±12.6 years. 310 (10.2%) patients developed infection during hospitalization. After propensity score matching, baseline characteristics were similar in corresponding patients of the PPI and non-PPI groups (n=584 patients per group). PPI utility was significantly associated with infection when using propensity score matching analysis (9.1 vs. 6.0%, OR=1.62, 95% CI=1.02–2.57, P=0.041). Comparing to patients with non-PPI usage, PPI administration was positively associated with higher risk of in-hospital all-cause mortality (2.4 vs. 0.9%, OR=3.25, 95% CI=1.06–9.97, P=0.039) and in-hospital major adverse clinical events (4.6 vs. 1.4%, OR=3.71, 95% CI=1.61–8.56, P=0.002). In subgroup analysis, these findings were consistent.
CONCLUSIONS PPI usage was associated with higher incidence of infection during hospitalization, in-hospital all-cause mortality, and in-hospital MACE in STEMI patients.
GW32-e0596
Bowen Lou, Jianqing She, Zuyi Yuan
Cardiovascular Department, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
OBJECTIVES This study aimed to compare the efficacy of Angiotensin Receptor–Neprilysin Inhibitor (ARNI) therapy with Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker (ACEI/ARB) therapy for cardiovascular outcomes in patients with acute myocardial infarction (AMI).
METHODS Data were collected from the Biobank of the First Affiliated Hospital of Xi’an Jiaotong University between January 2016 and December 2020. Seven thousand and five hundred fifty-six AMI patients were screened for eligibility. Additionally, propensity score matching based on age, sex, blood pressure, kidney function, baseline left ventricular ejection fraction (LVEF) and cardiovascular medication were conducted, resulting in 291 patients with AMI being assigned to ARNI, ACEI and ARB group respectively.
RESULTS Patients receiving ARNI had significantly lower rates of the composite cardiovascular outcome than ACEI [HR 0.51, (95% CI, 0.27–0.95), P=0.02], and ARB users [HR 0.47, (95% CI, 0.24–0.90), P=0.02]. Additionally, patients receiving ARNI showed lower rates of cardiovascular death than ACEI [HR 0.37, (95% CI, 0.18–0.79), P=0.01] and ARB users [HR 0.41, (95% CI, 0.18–0.95), P=0.04]. Subgroup analysis indicated that patients with LVEF no more than 40% tend to benefit more from ARNI as compared to ACEI [HR 0.30, (95% CI, 0.11–0.86), P=0.01] or ARB [HR 0.21, (95% CI, 0.04–1.1), P=0.05]. Patients aged no more than 60 yrd also exhibited reduced composite endpoints [HR for ARNI vs. ARB: 0.11, (95% CI, 0.03–0.46), P=0.002].
CONCLUSIONS In patients with AMI, ARNI was superior to ACEI/ARB in reducing the long-term adverse cardiovascular outcomes. Subgroup analysis further indicate that ARNI are more likely to benefit patients with LVEF less than 40% and aged less than 60 yrd.
GW32-e0824
Han Wu, Han Gong, Xue Xia, Huan Sun, Bo Yu, Ping Yang
China-Japan Union Hospital of Jilin University
OBJECTIVES Myocardial injury after ST-segment elevation myocardial infarction (STEMI) can cause ventricular systolic dysfunction. A large number of previous studies have been conducted on the pathophysiology and functional protection of myocardial infarction area. However, the influencing factors and protective strategies of myocardial function in non-infarct myocardium (NIM) remain unclear. The present study evaluated the changes of left ventricular global longitudinal strain (GLS) and different segmental longitudinal strain (LS) after primary percutaneous coronary intervention (PCI) in STEMI patients. The segmental changes of non-infarct myocardium (NIM) and its influencing factors were further detected, providing new implications for NIM myocardial function protection.
METHODS Seventy-five acute STEMI patients who underwent primary PCI in CHINA-JAPAN Union Hospital of Jilin University between January 2021 and June 2021 were included. Left ventricles were divided into infarct area, adjacent infarct area (ANM) and remote infarct area (RNM) according to the culprit artery. Clinical data, coronary angiography results, global longitudinal strain, regional strain, and left ventricular ejection fraction (LVEF) were collected within 1 week after PCI. Factors of NIM myocardial dysfunction and GLS.
RESULTS Thirty-eight anterior wall myocardial infarction patients and inferior wall myocardial infarction patients were included. The results showed that GLS was significantly negatively correlated with LVEF in STEMI patients (P<0.001 r=−0.802). NIM dysfunction was found in 63 patients (84%) The LS of NIM was significantly correlated with LVEF (P<0.001). GLS was positively correlated with coronary artery stenosis score (Gensini score) (P<0.001 r=0.442). The LS of NIM, including the ANM region and the RNM region, were significantly correlated with the coronary Gensini score (P<0.001 r=0.412; P=0.002 r=0.355; P=0.006 r=0.317). There was no significant correlation between LS of NIM and recanalization time (P=0.298).
CONCLUSIONS NIM dysfunction exists widely in STEMI patients and correlates to global cardiac function in patients with myocardial infarction after primary PCI, which highlighted the NIM protection in STEMI patients. The function of NIM has no clear correlation with recanalization time, but it correlates with the severity of coronary lesion of patients. Therefore, methods on protecting NIM function warrant further investigation.
GW32-e1042
Zhen Ge1, Xiao-Fei Gao1, Jing Kan1, Fei Ye1, Nai-Liang Tian1, Song Lin1, Zhi-Zhong Liu1, Ya-Ling Han2, Feng Chen3, Jun-Jie Zhang1, Shao-Liang Chen1
1Nanjing First hospital
2General Hospital of Northern Theater Command, Shenyang
3School of Public Health, Nanjing Medical University
OBJECTIVES Current guidelines recommend administering dual antiplatelet therapy (DAPT) for 12 months to patients with acute coronary syndromes (ACS) and without contraindications after drug-eluting stent (DES) implantation. A recent study reported that 3 months of DAPT followed by ticagrelor monotherapy is effective and safe in ACS patients undergoing DES implantation compared with the standard duration of DAPT. However, it is unclear whether antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin reduces the incidence of clinically relevant bleeding without increasing the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in ACS patients undergoing percutaneous coronary intervention (PCI) with DES implantation guided by either intravascular ultrasound (IVUS) or angiography who have completed a 1-month course of DAPT with aspirin plus ticagrelor.
METHODS The IVUS-ACS & ULTIMATE-DAPT is a prospective, multicenter, randomized, controlled trial designed to determine 1) whether IVUS-guided versus angiography-guided DES implantation in patients with ACS reduces the risk of target vessel failure (TVF) at 12 months and 2) whether ticagrelor alone versus ticagrelor plus aspirin reduces the risk of clinically relevant bleeding without increasing the risk of MACCE1–12 months after the index PCI in ACS patients undergoing DES implantation guided by either IVUS or angiography. This study will enroll 3486 ACS patients eligible for DES implantation, as confirmed by angiographic studies. The patients who meet the inclusion criteria and none of the exclusion criteria will be randomly assigned in a 1:1 fashion to the IVUS- or angiography-guided group (1st randomization). All enrolled patients will complete a 1-month course of DAPT with aspirin plus ticagrelor after the index PCI. Patients with no MACCEs or major bleeding (≥ Bleeding Academic Research Consortium (BARC) 3b) within 30 days will be randomized in a 1:1 fashion to either the ticagrelor plus matching placebo (SAPT) group or ticagrelor plus aspirin (DAPT) group for an additional 11 months (2nd randomization) (Figure 1). The primary endpoint of the IVUS-ACS trial is TVF at 12 months, including cardiac death, target vessel myocardial infarction (TVMI), or clinically driven target vessel revascularization (CD-TVR). The primary superiority endpoint of the ULTIMATE-DAPT trial is clinically relevant bleeding, defined as BARC Types 2, 3 or 5 bleeding, and the primary non-inferiority endpoint of the ULTIMATE-DAPT trial is MACCE, defined as cardiac death, myocardial infarction, ischemic stroke, CD-TVR, or definite stent thrombosis occurring 1–12 months in the 2nd randomized population.
RESULTS NO.
CONCLUSIONS The IVUS-ACS & ULTIMATE-DAPT trialis designed to test the efficacy and safety of two different antiplatelet strategies in ACS patients undergoing PCI with DES implantationguided by either IVUS or angiography. This study will provide novel insights into the optimal DAPT duration in ACS patients undergoingPCIand provide evidence on the clinical benefits of IVUS-guided PCI in ACS patients.
GW32-e1153
Zhiming Wu1, Lihong Zhang2, Tian Xu1, Wei You1, Xiangqi Wu1, Fei Ye1
1Nanjing First Hospital
2Qinhuai Medical District, Eastern Theater General Hospital of PLA
OBJECTIVES To explore the potential clinical significance of reverberation post rotational atherectomy (RA) by comparison of both IVUS and optical coherence tomography (OCT).
METHODS A total of forty-eight patients with severe calcified coronary lesions who were detected by IVUS and OCT post-RA were enrolled in our retrospective study. If reverberation phenomena were detected by IVUS, intravascular imaging (IVI) data (including distance between IVUS catheter center and surface of reverberation, distance between every reverberation, layers of reverberation, thickness of calcification by OCT) were analyzed at same position and same direction every 1 mm, correlation between reverberation and data of OCT was primary target by statistical analysis.
RESULTS A total of four hundred and twenty-eight reverberation points were analyzed by IVUS and OCT simultaneously, 300 points showed single layer of reverberation, 83 with double layers of reverberation and 42 with multiple layers (≥3 layers) of reverberation by IVUS detection post-RA. Multivariate logistic regression analyzed the layers of reverberation by IVUS was related to thickness of calcification by OCT at same point and direction significantly (P<0.001). Single, double, and multiple layers of reverberation by IVUS corresponds to 0.64±0.24 mm (95% confidence intervals (CI): 0.61–0.66; P<0.001), 0.94±0.15 mm (95% CI: 0.91–0.97; P<0.001) and 1.21±0.18 mm (95% CI: 1.15–1.27; P<0.001) respectively by OCT. No correlation was found between distance between IVI catheter center and surface of reverberation, distance of every reverberation and thickness of calcification.
CONCLUSIONS Layers of reverberation by IVUS is positive associated with thickness of calcification by OCT post-RA.
GW32-e1363
Kwan-Yu Li1,2, Lok-Yee Lam1,2, Calvin Ka-Lam Leung1,2, Mei-Zhen Wu1,2, Qing-Wen Ren1,2, Shuk-Yin Yu1,2, Pui-Fai Wong1,2, Hang-Long Li1,2, Yi-Kei Tse1,2, Si-Yeung Yu1,2, Nicole Wing-Lam Hon1,2, Lok-Him Tsui1,2, Yun-Di Feng3, Yun-Long Huo3, Hung-Fat Tse2, Kai-Hang Yiu2,3
1The University of Hong Kong Shenzhen Hospital, China
2The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
3PKU-HKUST Shenzhen-Hongkong Institution, China
OBJECTIVES Computational pressure-flow dynamics derived fractional flow reserve (caFFR) has emerged for non-invasive assessment of fractional flow reserve (FFR) in patients with stable coronary artery disease (CAD), without the need for hyperaemic induction and guidewire placement in conventional FFR. Despite previous validation on the diagnostic accuracy of caFFR, it was unclear whether its clinical value in diabetic patients, who are at risk of coronary microvascular dysfunction, would decline. The aim of the study is to investigate the use of caFFR in diabetic patients with stable CAD.
METHODS A total of 1253 stable CAD patients (mean age=66.3±10.8, 72.9% male) with ≥1 coronary stenosis detected during coronary angiogram were included. Among them, 212 patients had diabetes. Based on the FFR threshold of 0.8, patients were said to be adherent if all vessels with caFFR≤0.8 were treated with percutaneous coronary intervention (PCI) and all vessels with caFFR;0.8 were not. Otherwise, they were said to be non-adherent. The primary endpoint was 3-year major adverse cardiac events (MACE), defined as a composite of cardiovascular mortality, non-fatal myocardial infarction (MI), unplanned revascularization and stroke.
RESULTS In 212 diabetic patients, there were 111 adherent patients and 101 non-adherent patients. PCI was performed in 62.3% of them. A total of 26 composite events occurred, including 5 cardiovascular mortality, 5 non-fatal MI, 14 unplanned revascularization and 2 strokes. The incidence rate of MACE was significantly lower in adherent patients than in non-adherent patients (5.4 vs. 15.8%; P=0.01). Following multivariable adjustment, adherent patients had a significantly lower risk of MACE than non-adherent patients (adjusted hazard ratio [HR], 0.33; 95% confidence interval [Cl], 0.13–0.83; P=0.02). In 1041 non-diabetic patients, adherence to caFFR significantly reduces the risk of MACE in non-diabetic patients (adjusted HR, 0.49; 95%Cl, 0.32–0.74; P<0.01). The risk of MACE was similar between adherent groups in diabetic and non-diabetic population (adjusted HR, 1.21; 95%Cl, 0.50–2.96; P=0.67).
CONCLUSIONS In stable CAD patients with and without diabetes, caFFR-guided revascularization significantly reduces the risk of MACE at 3 years. This was the first outcome study supporting the potential clinical use of caFFR in guiding revascularization decisions in diabetic patients.
GW32-e1449
Mengge Zhou1,2, Jie Zhang3, Jing Liu1, Changsheng Ma4, Junbo Ge5, Yong Huo6, Jun Liu1, Yongchen Hao1, Feng Gao3, Yamei Sun3, Na Yang1, Guoliang Hu1, Yuhong Zeng1, Yaling Han7, Dong Zhao1
1Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
2Vanke School of Public Health, Tsinghua University, Beijing, China
3Department of Gastroenterology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
4Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
5Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
6Department of Cardiology, Peking University First Hospital, Beijing, China
7Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, Liaoning, China
OBJECTIVES Although guidelines recommend the use of proton pump inhibitors (PPIs) among patients with acute coronary syndrome (ACS) to prevent upper gastrointestinal bleeding, there is a lack of evidence regarding whether PPIs have a protective effect against overall gastrointestinal bleeding for ACS patients in the acute phase, when the risk of bleeding is the highest. This study aims to evaluate the association between PPI use and in-hospital gastrointestinal bleeding among ACS patients taking dual antiplatelet therapy (DAPT).
METHODS This study is based on the Improving Care for Cardiovascular Disease in China-ACS project, an ongoing collaborative registry and quality improvement project of the American Heart Association and Chinese Society of Cardiology. A total of 25,567 ACS patients taking DAPT from 172 hospitals between July 1, 2017 and December 31, 2018 were included. Multivariable Cox regression and propensity score-matching analysis were used to evaluate the association between PPI use and in-hospital gastrointestinal bleeding.
RESULTS Among these ACS patients, 63.9% (n=16,332) were prescribed PPIs within 24 hours of admission. Patients using PPI had a higher rate of gastrointestinal bleeding in comparison with those not using PPI (1.0 vs. 0.5%, P<0.001). In the multivariate Cox regression, early PPI use was associated with a 58% higher risk of gastrointestinal bleeding (HR 1.58, 95% CI 1.15–2.18; P=0.005). Further propensity score-matching analysis attenuated the association, but still showed that patients using PPI had a higher rate of gastrointestinal bleeding (0.8 vs. 0.6%, P=0.04).
CONCLUSIONS In China, PPIs are widely used within 24 hours of admission among ACS patients taking DAPT. An increased risk of gastrointestinal bleeding is observed among inpatients with early PPIs. Randomized trials on early use of PPI in ACS patients receiving DAPT are warranted.
GW32-e1564
Qianwen Lv, Xiaolu Jiao, Huahui Yu, Qiuju Sun, Fan Li, Yu Wang, Ming Zhang, Shaoping Nie, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Angiopoietin-like protein 3 (ANGPTL3) inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) and represent emerging drug targets to lower circulating LDL-C and triglycerides and reduce cardiovascular risk. Obstructive sleep apnea (OSA) has been associated with increased cardiovascular disease (CVD) risk and poor cardiovascular outcomes of CVD in patients. However, the prognostic value of ANGPTL3 for recurrent cardiovascular events after acute coronary syndrome (ACS) is currently undetermined. This study aims to investigate whether the level of ANGPTL3 can be used to predict the cardiovascular outcomes in ACS patients with and without OSA.
METHODS A total of 1174 consecutive eligible patients admitted for ACS were included in this prospective cohort study and underwent polysomnography or portable polygraphy during hospitalization between May 2017 and March 2019. OSA was defined as an apnea-hypopnea index≥15 events/h. The primary point was major adverse cardiovascular events (MACEs), including cardiovascular death, myocardial infarction, stroke. The secondary end point was all-cause death. The association between ANGPTL3 and outcomes was investigated using Kaplan–Meier analysis and multivariable Cox regression.
RESULTS Among 1174 patients with ACS, 630 (53.66%) had OSA. During a median follow-up of 2.17 (1.6) years, MACEs occurred in 205 patients, and 12 patients died. The patients with ACS reporting MACEs had higher plasma ANGPTL3 levels than those without MACEs (37.66 (18.25) vs. 25.52 (20.99) ng/mL, P<0.001), and the ACS patients with OSA had higher ANGPTL3 levels than those without OSA (36.50 (19.47) vs. 23.25 (19.55) ng/mL, P<0.001). Kaplan–Meier analysis revealed that the event-free survival rate was dramatically lower in high ANGPTL3 group (median ANGPTL3 level >29.83 ng/mL) than in the low ANGPTL3 group (log-rank P<0.05). Multiple Cox regression models showed that a higher level of ANGPTL3 was an independent predictor of MACEs development in all ACS patients (HR=1.508, 95% CI 1.078–2.109.186, P<0.001). In subgroup analysis depending on OSA status, the OSA group had a significantly higher level of ANGPTL3, which remained a significant predictor of MACEs in ACS patients with OSA (HR=1.993, 95% CI 1.245–3.189, P<0.001) in multivariable models, but not in ACS patients without OSA (HR=1.074, 95% CI 0.651–1.770, P=0.75). For MACEs, the area under the curve (AUC) of ACS patients with OSA was significantly higher than that of those without OSA (0.644 vs. 0.323). The addition of ANGPTL3 to established risk factors (SMART risk score model) significantly improved risk prediction of the composite outcome of MACEs (C-index, net reclassification index, and integrated discrimination index, all P<0.05) in all ACS patients and ACS patients with OSA.
CONCLUSIONS A higher level of ANGPTL3 predict MACEs in all ACS patients. ANGPTL3 has strong predictive value for cardiovascular adverse events in ACS patients with OSA.
GW32-e1697
Fan Li, Xiaolu Jiao, Huahui Yu, Qianwen Lv, Qiuju Sun, Yu Wang, Ming Zhang, Shaoping Nie, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Angiopoietin-like protein 3 (ANGPTL3) is a multifunctional secretory protein mainly expressed in the liver. It mainly plays an important regulatory role in lipid metabolism and participates in the occurrence and development of coronary artery disease. The elevated fasting ANGPTL3 level in patients with coronary heart disease leads to the occurrence of mace, and the serum ANGPTL3 level is independently associated with the increased risk of mace in patients. A high level of lipoprotein(a)[Lp(a)] is an independent risk factor for incident coronary artery disease (CAD), and elevated Lp(a) values were also proved to be an independent predictor of MACE in patients with established CAD or patients undergone PCI. However, the relationship between ANGPTL3 and high Lp(a) is unclear. This study aims to investigate whether ANGPTL3 levels can be used to predict the future occurrence of major adverse cardiovascular events (MACE) in patients with hyperlipoproteinemia(a) who underwent PCI due to the diagnosis of CAD.
METHODS We included 126 patients with hyperlipoproteinemia(a) who underwent PCI due to the diagnosis of CAD from October 2016 to April 2018. High Lp(a) is defined as Lp(a) in serum greater than 30 mg/dL. During 2-year follow-up, documented the primary outcome, major adverse cardiovascular events (MACE), consisting of myocardial infarction, sudden cardiac death, mortality from congestive heart failure due to CAD, stroke, and need for coronary artery bypass grafting, PCI; The second outcome including all-cause death. ANGPTL3 concentrations were determined in blood samples were measured with an enzyme-linked immunosorbent assay kit. Cox proportional hazard regression was used to calculate the hazard ratio (HR) with 95% confidence interval (CI) for the association between ANGPTL3 and the occurrence of MACE during follow-up in hyperlipoproteinemia(a) patients who underwent PCI due to the diagnosis of CAD.
RESULTS After 2 years of follow-up, 26 cases had occurred MACE in patients with hyperlipoproteinemia(a) who underwent PCI due to the diagnosis of CAD. Patients who reported MACE had a higher serum ANGPTL3 level compared with patients without MACE (29.26[20.94–44.41] ng/mL vs. 24.87[17.78–32.51] ng/mL, P<0.05). Multivariable Cox regression analysis demonstrated that ANGPTL3 levels were independently associated with MACE in patients with hyperlipoproteinemia(a) (HR=1.585/10 ng ANGPTL3; 95% CI: 1.156–2.175; P<0.05) after adjusting for age, gender, body mass index, and classical risk factors.
CONCLUSIONS This study show that serum ANGPTL3 levels could serve as a predictor for future occurrence of MACE in patients with hyperlipoproteinemia(a) who underwent PCI due to the diagnosis of CAD.
GW32-e1808
Linlin Zhao1, Xiaogang Guo1, Bo Yu2
1The First Hospital of Zhejiang Province
2The Second Affiliated Hospital of Harbin Medical University
OBJECTIVES This study sought to investigate: (1) nonculprit plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI) in males versus females, focusing on pancoronary vulnerability; (2) clinical and morphological predictors of pancoronary vulnerability in males versus females.
METHODS Between July 2016 and June 2018, 583 patients (134 females) treated by 3-vessel optical coherence tomography (OCT) at the time of primary percutaneous intervention were included with 103 patients excluded from final analysis. In patients with multiple lesions by OCT imaging, especially within the culprit vessel, the lesion with the most severe stenosis or with evidence of recent plaque disruption, including significant thrombus, was determined as the culprit lesion. Patients with in-stent restenosis (n=16), imaging of the culprit vessel after pre-dilation (n=4), poor image quality (n=29), or incomplete imaging (n=54) were excluded. Plaque features of both culprit and nonculprit lesions (in both culprit and nonculprit arteries) were compared according to sex.
RESULTS A total of 583 culprit lesions and 1419 nonculprit plaques were analyzed. Both patient-based (16.7 vs. 7.5%, P=0.008) and plaque-based (8.1 vs. 3.2%, P=0.002) analyses showed that nonculprit plaque rupture (NC-PR) was more prevalent in males versus females. The total length of analyzed OCT pullbacks was 203.3±32.7 mm: 82.5±21.1 mm in the RCA, 68.5±18.5 mm in the LAD, and 47.9±13.5 mm in the LCX. There was no difference in the length of the analyzed segments between males versus females (206.3±32.4 vs. 194.5±32.7 mm, respectively, P=0.119). Patient-level multivariate analysis showed that male sex and culprit PR were independently predictors of NC-PR (OR: 2.39, 95% CI: 1.18–4.81, P=0.015; OR: 1.96, 95% CI: 1.16–3.30, P=0.012). Culprit PR and age were independently associated with pancoronary vulnerability no matter in males or females, yet HDL-C and TC/HDL-C ratio were independently associated with pancoronary vulnerability in males. Nonculprit plaques in males had a higher prevalence of NC-PR, larger minimal lumen area (MLA) and a wider maximum lipid arc, yet lower prevalence of MLA<3.5 mm2 than those in females. Other nonculprit plaque characteristics were not different between the two groups. In males, nonculprits located in untreated arteries contained more lipid, a thinner fibrous cap, and more microchannels and calcifications than nonculprits located in the treated artery. However, in females, nonculprits located in untreated arteries contained less lipid rich plaque (LRP) and fewer thin-cap fibroatheromas (TCFAs) compared with nonculprits located in the treated artery.
CONCLUSIONS In patients with STEMI, compared to females, males had a higher rate of pancoronary vulnerability, and sex-specific role of risk factors in pancoronary vulnerability should be considered. These findings suggest that sex, as a traditional readily available clinical risk factor, cannot be ignored in predicting the pancoronary vulnerability, and it will be more effective to adjust strategies of lipid-lowering therapy according to sex.
GW32-e0095
Xianjun Han, Zhenghan Yang, Yi He
Department of Radiology, Beijing Friendship Hospital, Capital Medical University
OBJECTIVES To investigate the influence of artificial intelligent (AI) based on deep learning on the diagnostic performance and consistency of inexperienced cardiovascular radiologists.
METHODS We enrolled 196 patents who had undergone both CCTA and invasive coronary angiography (ICA) within 6 months. Four readers with less cardiovascular experience (Reader 1 to Reader 4) and two cardiovascular radiologists (level II, Reader 5 and Reader 6) evaluated all images for ≥50% coronary artery stenosis, with ICA as the gold standard. Reader 3 and Reader 4 interpreted with aid from an AI system, and the other four readers interpreted without the AI system. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy (area under the receiver operating characteristic curve (AUC)) of six readers were calculated at the patient and vessel levels. Additionally, we evaluated interobserver consistency between Reader 1 and Reader 2, Reader 3 and Reader 4, and Reader 5 and Reader 6.
RESULTS The AI system had 94% and 78% sensitivity at the patient and vessel levels, respectively, which were higher than Reader 5 and Reader 6. Reader 3 and Reader 4 aided by AI had a higher sensitivity (range: +7.2∼+16.6% and +5.9∼+16.1%, respectively) and NPV (range: +3.7∼+13.4% and +2.7∼+4.2%, respectively) than Reader 1 and Reader 2 without AI. There was good interobserver consistency between Reader 3 and Reader 4 in interpreting ≥50% stenosis (Kappa value=0.75 and 0.80 at the patient and vessel levels, respectively). Only Reader 1 and Reader 2 had poor consistency (Kappa value=0.25 and 0.37). Reader 5 and Reader 6 had moderate agreement (Kappa value=0.55 and 0.61).
CONCLUSIONS Our study showed that using AI could effectively increase the sensitivity of inexperienced readers and significantly improve consistency in diagnosing coronary stenosis via CCTA.
GW32-e0368
Zeyi Cheng
West China Hospital Sichuan University
OBJECTIVES The purpose of this investigation aimed to the impact of peripheral artery disease (PAD) on the prognosis value of patients with stable coronary artery disease (CAD) underwent percutaneous coronary intervention (PCI).
METHODS A total of 204 patients (median age, 73 years) were enrolled from Shinonoi General Hospital between October 2014 and October 2017 for newly diagnosed stable CAD, received PCI performance, patients with old myocardial infarction (MI) were excluded. We divided patients into two groups with PAD and without PAD. The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke. During a median follow-up of 783 days, 28 experienced MACE. A total of 204 patients (median age, 73 years) were enrolled from Shinonoi General Hospital between October 2014 and October 2017 for newly diagnosed stable CAD, received PCI performance, patients with old myocardial infarction (MI) were excluded. We divided patients into two groups with PAD and without PAD. The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke. During a median follow-up of 783 days, 28 experienced MACE.
RESULTS No statistical difference was found between PAD and non-PAD patients of lesional characteristics. Spearman’s rank correlations indicate Diabetes mellitus (DM) (P=0.019) and HbA1c (P=0.009) are positively correlated with PAD, the lesional characteristics of CAD are not statistically different from whether patients with PAD. In Kaplan-Meier analysis, patients with PAD predicted poor prognosis in MACE (P<0.05) and cardiovascular events (P<0.05), in Multivariable Cox proportional hazards analysis, patients with PAD independently predicted MACE.
CONCLUSIONS CAD patients with PAD independently predicted MACE.
GW32-e0657
Mengping Liu, Rui Hua, Xiang Hao, Zuyi Yuan
First Affiliated Hospital of Medical School, Xi’an Jiaotong University
OBJECTIVES Liver function has relationship with the prognosis of acute coronary syndrome (ACS) but needs further confirmation. The novel liver function grading score, albumin-bilirubin (ALBI) score, plays a decent role in the evaluation of liver function. However, few studies have focused on the correlation between the ALBI score and ACS. We tried to elucidate the influence of liver function on ACS using ALBI score.
METHODS A total of 891 ACS patients were enrolled in this study and divided into four groups (Q1–Q4) according to the quartile of admission baseline ALBI score. The primary endpoint was major adverse cardiac events (MACEs) including all-cause death, revascularization, and acute heart failure. The secondary endpoints were each individual components of the MACEs.
RESULTS ALBI score positively correlated with serum NT-proBNP (β=1.393, 95% CI 1.048–1.738, P<0.001), and negatively correlated with LVEF (β=−7.343, 95% CI −9.911 to −4.776, P<0.001) in ACS patients. Compared to ACS patients in the Q2 group of ALBI score, patients in Q1 (adjusted HR=2.902, 95% CI 1.303–6.456, P=0.009), Q3 (adjusted HR=2.381, 95% CI 1.084–5.230, P=0.031) and Q4 group (adjusted HR=2.614, 95% CI 1.217–5.615, P=0.014) had increased risk of MACEs. No significant differences were found between different quartiles of ALBI score and each individual components of the MACEs, except future acute heart failure.
CONCLUSIONS The novel liver function grading model, ALBI score, was an independent risk factor for MACEs, especially for future acute heart failure in ACS patients.
GW32-e0852
Zizhou Jia, Bao Li
Department of Cardiovascular Medicine, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China
OBJECTIVES To explore the analysis of the relevant factors of fractional flow reserve (FFR) ≥0.80 in coronary borderline lesions.
METHODS From January 2019 to December 2020, 90 patients with stable angina pectoris with FFR examination were confirmed by coronary borderline lesions (50–70% of coronary duct diameter stenosis) and FFR examination in Cardiovascular endovascular angiography. According to the FFR results, it is divided into two groups: group A [FFR≥0.8 (n=52)] and group B [FFR<0.8 (n=38)].
RESULTS The difference between high density lipoprotein cholesterol (HDL-C), platelet and lymphocyte ratio (PLR), blood cells of mononuclear cells to HDL cholesterol (MHR), vascular lesions, smoking and other indicators in both groups were statistically significant (P<0.05). Correlation analysis shows that HDL-C, PLR, MHR, vascular lesions, smoking and FFR values have significant correlations. The analysis of single-factor and multi-factor regression equations shows that MHR (OR 1.067, 95% CI 1.008–1.129, P=0.025), vascular lesions (OR 1.610, 95% CI 1.143–2.266, P=0.006) is an independent risk factor affecting functional ischemia of coronary arteries, and HDL-C (OR 0.304, 95% CI 0.130–0.712, P=0.006) is an independent protective factor for coronary artery functional ischemia. Using the receiver operating characteristic curve (ROC curve), combined with multiple influencing factors has certain predictive value for coronary artery functional ischemia (AUC 0.656, 95% CI 0.597–0.714, P<0.001).
CONCLUSIONS HDL-C, MHR and vascular lesions have an independent predictive effect on functional coronary ischemia and are of certain value in guiding coronary revascularization in patients with stable angina peculiarly lesions.
GW32-e1089
Haoyu Wang1, Kefei Dou1, Bo Xu1, Gregg W. Stone2
1Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
2The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, Clinical Trials Center, Cardiovascular Research Foundation
OBJECTIVES The magnitude of post-procedural biomarker elevation representing a clinically-meaningful PMI after percutaneous coronary intervention (PCI) is controversial. We sought to 1) assess the relationship of different thresholds of creatine kinase-myocardial band (CK-MB) and cardiac troponin (cTn) with subsequent mortality, and 2) evaluate the prognostic significance of periprocedural myocardial infarction (PMI) according to various MI definitions in patients with left main (LM) disease.
METHODS The study enrolled 4013 consecutive patients undergoing LM PCI at a single center from January 2004 to December 2016. CK-MB and cTnI were routinely collected at baseline and at frequent intervals between 8 and 48 hours after PCI, with additional draws required for elevated values or ongoing symptoms until declining values returned. PMI was also adjudicated by the Society for Cardiovascular Angiography and Interventions (SCAI), Academic Research Consortium-2 (ARC-2), and fourth Universal Definition of MI (UDMI) criteria. SCAI-defined PMI was adjudicated: (i) CK-MB ≥10×URL (or cTn≥70×URL) or (ii) CK-MB≥5×URL (or cTn≥35×URL) plus one of the following: new pathological Q-waves in at least two contiguous leads or new persistent non-rate-related left bundle branch block. ARC-2-defined PMI was adjudicated for an absolute increment increase in cTn ≥35×URL (or CK-MB≥5×URL) plus one of the following: (i) New ischemic ECG changes (ST segments) or development of new pathological Q waves; (ii) angiographically documented occlusion of a major epicardial artery or a side branch, major coronary dissection, disruption of collateral flow, distal embolization, or persistent slow flow or no reflow or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Fourth UDMI-defined PMI was adjudicated for cTn >5× URL (or CK-MB >5× URL) plus one of the supporting evidence of myocardial ischemia (electrocardiographic, angiographic, or imaging; same with ARC-2 definition). The primary and secondary outcomes were the covariate-adjusted 3-year rates of cardiovascular (CV) and all-cause mortality, respectively.
RESULTS The 3-year rate of CV mortality progressively increased with higher peak CK-MB values. CV mortality was first independently predicted by a post-procedural CK-MB 3–5× the upper reference limit (URL) (adjusted hazard ratio [aHR]: 2.93; 95% confidence interval [CI]: 1.02–8.40), whereas all-cause death was first independently predicted by CK-MB ≥10× URL (aHR: 3.25; 95% CI: 1.37–7.70). In contrast, no level of peak post-procedural cTnI was associated with CV or all-cause death. PMI by the SCAI, ARC-2 and fourth UDMI definitions was adjudicated in 1.3%, 3.1% and 5.1% of patients respectively. The SCAI definition was significantly associated with 3-year CV mortality (aHR: 4.93; 95% CI: 1.92–12.69) and all-cause mortality (aHR: 3.11; 95% CI: 1.33–7.27), whereas the ARC-2 (CV mortality: aHR: 1.79 [0.70–4.58]; all-cause mortality: aHR: 1.25 [0.54–2.90]) and fourth UDMI definitions (CV mortality: aHR: 1.37 [0.58–3.21]; all-cause mortality [95% CI: 0.44–2.08] were not).
CONCLUSIONS Routine measurements of CK-MB after PCI provide prognostic utility and may be useful for risk stratification and therapeutic decision-making in this high-risk patient population. In this regard clinically relevant outcome measures should be included and actively surveilled, although equally important is not to overweight lesser measures of myonecrosis that are more frequently detectable but less strongly prognostic.
GW32-e1155
Xinyi Chen1, Jiacong Nong2, Wei You2, Xiangqi Wu2, Zhiming Wu2, Delu Yin1, Fei Ye2
1Lianyugang First People’s Hospital
2Nanjing First Hospital
OBJECTIVES Optical flow ratio (OFR) is a novel coronary functional data derived by intravascular imaging of Optical coherence tomography (OCT), which was proved to have a high correlation with fractional flow reserve (FFR) measured by typical pressure wire. Meanwhile, intravascular imaging quantitative index such plaque volume intra-stent, stent volume, minimal luminal area (MLA) et al can be measured precisely. Intra-stent neointimal hyperplasia (NIH) post percutaneous coronary intervention (PCI) could not be avoided completely even using new generation drug-eluting stents, how intra-stent NIH affects focal coronary physiologic index of OFR is not clear. We want to find the correlation between intra-stent NIH and focal coronary physiologic function changes of stent segment at 1-year follow-up.
METHODS A total of one hundred and thirty patients with complete data of OCT images pre-, post-PCI and at 1-year follow-up were enrolled in our retrospective study, who were admitted to Nanjing First Hospital from Jan. 2014 to Dec. 2019. Primary endpoint was OFR-loss which was defined as OFR post-PCI minus OFR at 1-year follow-up. Finally, all the patients were divided into OFR-loss group (OFR-loss >0) and non-OFR-loss group (OFR-loss ≤0). Plaque characteristics of de novo lesion (fibrous, lipid and calcified ratio), stent parameters (average diameter, total length), and the volume and percentage of intra-stent NIH at stent segment were compared between 2 groups. We compared the plaque characteristics of de novo lesion, stent parameters, and the volume and percentage of in-stent hyperplasia with 1 year follow-up between the 2 groups. Meanwhile the correlation between in-stent hyperplasia and OFR-loss was analyzed. Then we evaluated the volume and percentage of in-stent hyperplasia which could predict OFR-loss by receiver operating characteristic (ROC) curve using the area under the curve (AUC), and figured out the cut-off value.
RESULTS Finally, 60 patients (46%) were in OFR-loss group and 70 patients (54%) were in non-OFR-loss group. The volume of intra-stent NIH (8.4 mm3 vs. 26.0 mm3; P<0.01) and the percentage of intra-stent NIH (4.0 vs. 19.0%; P=0.026) were higher in OFR-loss group compared with non-OFR-loss group. OFR-loss was associated with the percentage of intra-stent NIH (r: 0.395; P<0.01) and the volume of intra-stent NIH (r: 0.377; P<0.01). The cut-off value of the volume and percentage of intra-stent NIH were 5.58% (AUC, 0.728 [95% confidence interval (CI): 0.637, 0.819]; sensitivity, 0.812; specificity, 0.603; P<0.001) and 12.56 mm3 (AUC, 0.697 [95% CI: 0.601, 0.793]; sensitivity, 0.800; specificity, 0.644; P<0.001).
CONCLUSIONS Intra-stent NIH is associated with OFR-loss at mid-term follow-up after stent implantation.
GW32-e1364
Kwan-Yu Li1,2, Lok-Yee Lam1,2, Calvin Ka-Lam Leung1,2, Mei-Zhen Wu1,2, Qing-Wen Ren1,2, Shuk-Yin Yu1,2, Pui-Fai Wong1,2, Hang-Long Li1,2, Yi-Kei Tse1,2, Si-Yeung Yu1,2, Lok-Him Tsui1,2, Nicole Wing-Lam Hon1,2, Yun-Di Feng3, Yun Long Huo3, Hung-Fat Tse2, Kai-Hang Yiu1,2
1The University of Hong Kong Shenzhen Hospital, China
2The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
3PKU-HKUST Shenzhen-Hongkong Institution, China
OBJECTIVES Computational pressure-flow dynamics derived fractional flow reserve (caFFR) is a novel index for functional assessment of coronary artery stenosis, without the use of invasive pressure wires and hyperaemic induction in conventional fractional flow reserve (FFR). It has been proved that performing percutaneous coronary intervention (PCI) in stable coronary artery disease (CAD) based on myocardial ischemia assessment could improve clinical outcomes in per-patient level studies. However, the clinical significance of such treatment adherence at per-vessel level remains uncertain.
METHODS A total of 928 stable CAD patents (mean age 66.2±10.5, male 72.7%) who underwent caFFR measurement in the three major epicardial vessels were included. Treatment was defined as adherent when ischemic lesions, indicated by caFFR≤0.8, received PCI, or when functionally insignificant lesions with caFFR;0.8 received optimal medical therapy. Based on the caFFR of each vessel, patients were assigned into Group1: 0 or 1 vessel with treatment adherence; Group2: 2 vessels with treatment adherence and Group3: 3 vessels with treatment adherence. The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause mortality, non-fatal myocardial infarction and any subsequent revascularization.
RESULTS The severity of CAD based on SYNTAX score assessment was 18.6±10.2 in Group 1, 14.6±8.9 in Group 2, and 11.5±9.9 in Group 3 (P<0.001). A total of 109 composite events occurred, including 46 all-cause mortality, 14 non-fatal myocardial infarction and 49 subsequent revascularization. The incidence rates of MACE at 3 years were significantly different across Groups 1, 2 and 3 (17.1 vs. 12.1 vs. 7.4%; P=0.004). Using Group 3 as reference, the risk of MACE was highest in Group 1 patients (adjusted hazard ratio [HR]=1.933; 95% confidence interval [Cl]=1.081–3.457; P=0.026), followed by Group 2 patients (adjusted HR=1.597; 95% CI=1.020–2.501; P=0.041).
CONCLUSIONS In patients with stable CAD, the risk of MACE is incremental when fewer major coronary vessels are treated adhering to caFFR threshold of 0.8. Multivessel treatment adherence to caFFR could improve clinical outcome, demonstrating its clinical value in guiding revascularization decisions.
GW32-e1467
Liang Geng1, Yuan Yuan2, Peizhao Du3, Liming Gao1, Yunkai Wang4, Jiming Li4, Wei Guo4, Ying Huang4, Qi Zhang4
1Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University
2Department of Cardiology, Putuo District People’s Hospital
3Department of Cardiology, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine
4Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University
OBJECTIVES The clinical relevance of moderate coronary stenosis is determined by its morphological characteristics and physiological significance. We investigated the relationship between high-risk plaque characteristics detected by intravascular ultrasound and functional significance assessed with quantitative flow ratio in intermediate coronary lesions.
METHODS Quantitative flow ratio were retrospectively analyzed in 352 intermediate lesions from 330 patients undergoing intravascular ultrasound examination. The functional significance was defined as quantitative flow ratio≤0.8. High-risk plaque morphologies including plaque rupture, echo-lucent, echo-attenuation, and spotty calcification were identified, and attenuation indices including maximum angle, attenuation length, and superficial attenuation were determined. Clinically relevant echo-attenuation was defined as an attenuation length ≥5 mm with a maximum angle ≥ 180°.
RESULTS The prevalence of echo-attenuation was higher (63.0 vs. 37.7%, P=0.001) and attenuation length was longer (12.8±10.3 mm vs. 8.0±5.8 mm, P=0.015) in lesions with quantitative flow ratio ≤0.8 compared to those with quantitative flow ratio >0.8, associated with a higher rate of clinically relevant echo-attenuation (11.1 vs. 4.4%, P=0.044). On multivariable analysis, presence of echo-attenuation was an independent predictor of quantitative flow ratio ≤0.8 (OR 3.162, 95% CI: 1.263–7.917, P=0.014), whereas attenuation length was weakly correlated with quantitative flow ratio value (β=−0.185, B=−0.002, 95% CI: −0.004 to −0.001, P=0.001). Receiver-operating characteristic curve analysis revealed that the best cutoff of quantitative flow ratio in predicting clinically relevant echo-attenuation was 0.88 (AUC=0.695, 95% CI: 0.578–0.812, P=0.004).
CONCLUSIONS Presence of intravascular ultrasound-derived echo-attenuation confers an increased risk of quantitative flow ratio-defined functional significance in intermediate coronary lesions.
GW32-e1583
Liang Hou1, Yanchun Ding2
1General Hospital of the Yangtze River Shipping
2The Second Affiliated Hospital of Dalian Medical University
OBJECTIVES To investigate the association of a LDL 3′-untranslated region (3′ UTR) rs11570892 polymorphism with plasma LDL-C levels and coronary heart disease (CHD).
METHODS The 3′ UTR of LDL were resequenced in 48 randomly selected health controls subjects. Identified common variants were further screened in 200 control subjects and 200 CHD patients. The logistic regression was used to analyze the association of the LPL 3′ UTR polymorphism with plasma LDL-C levels and CHD. Luciferase report assays were used to verify the function of variant.
RESULTS Through re-sequencing, 6 common variant were identified (minor allele; y>0.01). The variant rs11570892 (A>G) in the 3′ UTR of LPL was associated with reduced plasma lipid levels in health controls subjects. The G allele was significantly associated with decreased LDL-C levels [Beta (SE): −0.38 (0.16), P=0.023] in case-control study. Furthermore, the case-control study suggested that the GG genotype resulted in a significant reduction in overall CHD risk [OR, 0.73 (95% confidence interval, 0.43–0.96), P=0.025]. Both in HepG2 and 293T cells, the luciferase reporter activity of the PMIR-G vector (containing G allele of rs11570892) is significantly decreased (P<0.0001) when compared with the PMIR-A construct (containing A allele of rs11570892). And, bioinformatic analysis revealed that the polymorphism rs11570892 occurs in the complementary binding sequence of miR-597 in the LPL 3′ UTR. Studies of potential mechanisms showed that the A allele could facilitate miR-597 binding, and luciferase activity significantly decreased when co-transfected with a LPL 3′ UTR luciferase reporter vector and miR-597 mimics in 293T cells.
CONCLUSIONS A potential functional variant rs11570892 in the 3′UTR of LPL was associated with plasma LDL-C levels and susceptibility to CHD by interfering with miR-597 binding.
GW32-e1721
Ka Lam Calvin Leung1, Lok Yee Lam1, Kwan Yu Li1, Shuk Yin Yu1, Mei Zhen Wu1, Qing Wen Ren1, Pui Fai Wong1, Yi Ki Tse1, Si Yeung Yu1, Hang Long Li1, Yundi Feng2, Yunlong Huo2, Hung Fat Tse1, Kai Hang Yiu1
1Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
2PKU-HKUST Shenzhen-Hongkong Institution, Shenzhen, China
OBJECTIVES A novel index, computational pressure-flow dynamics derived fractional flow reserve (caFFR), was developed to assess the extent of myocardial ischemia in patients with coronary artery stenoses, without the need of pressure wire insertion and hyperemic stimulus. Compared to fractional flow reserve (FFR), caFFR was found to have high accuracy. In patients presenting with acute coronary syndrome (ACS), the non-culprit vessels are often also stenosed, and the degree of ischemia in such vessels may alter clinical outcomes. In this study, we aimed at evaluating the clinical utility of caFFR in non-culprit vessels among ACS patients with multivessel stenoses.
METHODS Patients with at least two vessels having ≥50% diameter stenosis and presented as having acute coronary syndrome (ACS) were included, and the culprit vessels were determined. We performed analyses of caFFR for the two non-culprit vessels of every patient. Based on FFR studies, threshold of 0.8 was used and patients were stratified into ischemic group if any non-culprit vessel had caFFR≤0.8, and into non-ischemic group if all non-culprit vessels had caFFR;0.8. The primary endpoint was major adverse cardiovascular events (MACE), a composite of all-cause mortality, non-fatal myocardial infarction, and repeat revascularization.
RESULTS Our study included 293 patients (mean age 65.3±13.2, male 77.5%), with 133 (45.4%) presented as STEMI, 119 (40.6%) presented as NSTEMI, and 41 (14.0%) presented as unstable angina. Patients in ischemic group (n=176) had more obstructive lesions compared to patients in non-ischemic group (n=117) (3.8±1.5 vs. 3.2±1.1, P<0.001). The 3 years MACE rate was higher in ischemic group compared to non-ischemic group (28.4 vs. 15.4%; adjusted hazard ratio, 1.92; 95% confidence interval, 1.10–3.36; P=0.023).
CONCLUSIONS In multivessel disease patients presenting with ACS, myocardial ischemia in non-culprit vessels assessed by caFFR was associated with adverse clinical outcomes.
GW32-e1827
Shuai Zhao, Jin Li, Chengxiang Li, Kun Lian
Department of Cardiology, Xijing Hospital, The Forth Military Medical University
OBJECTIVES The hybrid algorithm for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) was developed to improve procedural outcomes. However, the domestic application of CTO-PCIs strategy and clinical report are lacking. Meanwhile, the application status and guiding significance of hybrid algorithm and recommended strategy of CTOCC are unclear. Therefore, Our single-center registry study aims to summarize and analyze the experiences of our single-center CTO-PCIs.
METHODS Between January 2018 and December 2020, consecutive patients undergoing hybrid CTO-PCI were prospectively enrolled. Baseline characteristics, procedural techniques, and procedural complications were analyzed.
RESULTS A total of 982 CTO-PCIs were performed in 865 patients, of which 87.1% were men. Mean age was 61.63±11.06 years. The average Japanese CTO score was 2.51±0.52, and was higher in the technical failure group (2.89±0.99 vs. 2.50±0.67; P=0.031). Overall procedure success was 95.4% and major procedural complications occurred in 5.5%. Antegrade wire was the preferred primary strategy in 70.0%, followed by retrograde (22.4%) and antegrade dissection re-entry strategies (7.6%). Primary strategies were successful in 78.3% (AW: 75.1%, ADR: 92.3%, Retrograde: 86.8). Antegrade dissection re-entry tends to be the most common bailout strategy and were successful in 83.5%. Overall procedure and wire crossing time were 115.74±64.33 min and 46.21±44.28 min, contrast volume was 355.96±122.66 mL.
CONCLUSIONS Hybrid algorithm guarantees 95% technical success rate for CTO-PCI and low procedural complications.
GW32-e0096
Peng Han1, Kun Lian2, Chengxiang Li2
1Department of Cardiology, 981 Hospital of Joint Logistics Support Force
2Department of Cardiology, Xijing Hospital, Air Force Medical University
OBJECTIVES To observe the efficacy and safety of PCSK9 inhibitor in the treatment of ultra-high-risk patients with ASCVD.
METHODS A total of 139 patients with ultra-high risk ASCVD who received PCI in the First Affiliated Hospital of Air Force Military Medical University from September 2017 to March 2020 were collected. Among them, 39 patients who received PCSK9 inhibitor lipid-lowering therapy after PCI were in the experimental group, and 100 patients who received statins lipid-lowering therapy after PCI were in the control group. Patients in the PCSK9 inhibitor group were given statin-based lipid-lowering regimen combined with PCSK9 inhibitor (n=38), or PCSK9 inhibitor monotherapy (statin allergy, n=1). Patients in the statin control group were given statin-based lipid-lowering regimen. The serum lipid level was reexamined after 3 months of treatment, and the serum lipid reduction and adverse drug reactions were observed.
RESULTS After lipid-lowering treatment, the LDL-C levels in the statin control group and the PCSK9 inhibitor group were lower than before. The LDL-C levels were 1.79±0.46 mmol/L and 1.52±0.95 mmol/L respectively. The target rate of LDL-C<1.4 mmol/L was 14% and 56.41% respectively. The target rate of LDL-C<1.8 mmol/L was 60% and 79.49% respectively. The average decrease of LDL-C was 0.86±0.29 mmol/L and 1.42±1.09 mmol/L respectively. The level of LDL-C in PCSK9 inhibitor group was lower than that in statin control group, but the difference was not statistically significant (P>0.05). The target rate of LDL-C<1.4 mmol/L, the target rate of LDL-C<1.8 mmol/L and the average decrease of LDL-C in PCSK9 inhibitor group were higher than those in statin control group, and the difference was statistically significant (P<0.05). No liver and kidney function damage and hyperglycemia were observed in all patients, and no adverse reactions were observed in PCSK9 inhibitor group.
CONCLUSIONS PCSK9 inhibitor can effectively reduce the LDL-C level of patients with ultra-high risk ASCVD, and significantly improve the LDL-C compliance rate, which has good efficacy and safety.
GW32-e0458
Yintang Wang1,2, Weihua Song2, Yongjian Wu2, Ping Zhang1
1Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University
2Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, China
OBJECTIVES To investigate risk score systems intended for risk evaluation of Coronary artery ectasia (CAE) patients.
METHODS In a retrospective cohort of 595 patients with CAE, we collected the baseline characteristics (clinical history, biomarkers and quantitative coronary angiography variables). Follow-up were conducted and the end-point event was the composite of all-cause death and non-fatal myocardial infarction. The candidate predictors of end-point event were analyzed using Cox proportional hazards regression models to derive a risk score in the form of nomogram. The predictive performance and discriminative ability of the novel nomogram were determined by concordance index (C-index) and calibration curve, that were validated internally. Risk stratification by nomogram-predicted risk score was further evaluated.
RESULTS During a median follow-up time of 62.3 months, 26 all-cause deaths and 37 non-fatal myocardial infarctions were identified. The final risk-prediction model named ABCD-CAE score included four items: age (A), Brain natriuretic peptide (B), high sensitivity C-reactive protein (C) and maximum Dilated area of ectatic lesions (D). The nomogram yielded a C-index for end-point event of 0.72 (95% confidence interval, 0.64–0.79). The calibration curve demonstrated that there is good agreement between prediction by nomogram and actual observation of end-point events. Compared with the low-risk group (score ≤100), the risk of composite events was significantly increased in the intermediate-risk group (score: 100–130) and high-risk group (score;130) [hazard ratio (95% confidence interval): 2.23(1.23–4.06), P=0.008 and 7.02 (3.81–12.97), P<0.001 respectively].
CONCLUSIONS The ABCD-CAE score is a simple four-item risk score, that provides a clinically useful tool for the risk prediction of all-cause death and myocardial infarction in patients with CAE. This user-friendly tool might support clinical decision making for the management of CAE.
GW32-e0658
Mengping Liu, Zhen Wei, Yuzhi Huang, Zuyi Yuan
First Affiliated Hospital of Medical School, Xi’an Jiaotong University
OBJECTIVES Coronary artery disease (CAD) patients with a controlled low-density lipoprotein cholesterol (LDL-C) level still have a residual risk for adverse clinical outcomes. Inflammation has a significant role in the progression of atherosclerosis. The monocyte to high-density lipoprotein cholesterol ratio (MHR) has been proposed as a novel inflammatory indicator. We aimed to investigate the relationship between the MHR and the occurrence as well as the severity of CAD.
METHODS A total of 2638 consecutive admitted suspected CAD patients with LDL-C<1.8 mmol/L were enrolled in the present study. The patients were divided into quartiles (Q1–Q4) according to the baseline MHR. We evaluated the relationships between the MHR and the occurrence of CAD, as well as the severity of coronary stenosis, indicated as a high Gensini score.
RESULTS CAD patients had a higher level of MHR than non-CAD patients [0.40 (0.29–0.53) vs. 0.33 (0.24–0.44), P<0.001]. Higher MHR quartiles had a higher Gensini score (P<0.001) in all enrolled patients. Suspected CAD patients in the Q3 (adjusted OR=1.452, 95% CI 1.071–1.969, P=0.016) and Q4 (adjusted OR=1.610, 95% CI 1.126–2.303, P=0.009) groups had a stronger association with the occurrence of CAD when compared with patients in the Q1 group. In addition, patients in the Q3 and Q4 groups had 1.345-fold (95% CI 1.035–1.750, P=0.027) and 1.423-fold (95% CI 1.077–1.880, P=0.013) stronger associations with a high Gensini score in reference to those in the Q1 group, even though their LDL-C levels have been<1.8 mmol/L. Subgroup analysis showed that the associations between MHR and the occurrence of CAD, as well as a high Gensini score, persisted in patients with a lower hs-CRP rather than in those with a higher hs-CRP level.
CONCLUSIONS Even though suspected CAD patients have achieved a LDL-C<1.8 mmol/L, there were still associations between the MHR and the occurrence of CAD, as well as a high Gensini score, especially in those patients with both a low level of LDL-C and hs-CRP.
GW32-e0863
Xiaofei Gao, Junjie Zhang, Shaoliang Chen
Nanjing First Hospital, Nanjing Medical University
OBJECTIVES This study aimed to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiography guidance for all-comers undergoing second-generation drug-eluting stent (DES) implantation. The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in “All-Comers” Coronary Lesions) trial showed fewer 1-year TVFs after IVUS-guided DES implantation for all-comers compared with those after angiography guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown.
METHODS A total of 1448 all-comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiography guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk of TVF at 3 years. The safety endpoint was definite/probable stent thrombosis (ST).
RESULTS At 3 years, TVF occurred in 47 (6.6%) patients in the IVUS-guided group and in 76 (10.7%) patients in the angiography-guided group (P=0.01), mainly driven by the decrease in clinically driven target vessel revascularization (4.5 vs. 6.9%, P=0.05). The definite or probable ST rate was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (P=0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure.
CONCLUSIONS IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during a 3-year follow-up in all-comers, particularly for patients who underwent the IVUS-defined optimal procedure, compared with those with angiography guidance.
GW32-e1090
Lixue Xu, Yi He
Capital Medical University Affiliated Beijing Friendship Hospital
OBJECTIVES In this retrospective, multi-centre study, we aimed to estimate the diagnostic accuracy and generalizability of an established deep learning (DL)-based fully automated algorithm in detecting coronary stenosis on coronary computed tomography angiography (CCTA).
METHODS A total of 527 patients (33.0% female, mean age: 62.2±10.2 years) with suspected coronary artery disease (CAD) who underwent CCTA and invasive coronary angiography (ICA) were enrolled from 27 hospitals from January 2016 to August 2019. Using ICA as a standard reference, the diagnostic accuracy of the DL algorithm in the detection of ≥50% stenosis was compared to that of expert readers.
RESULTS In the vessel-based evaluation, the DL algorithm had a higher sensitivity (65.7%) and negative predictive value (NPV) (78.8%) and a significantly higher area under the curve (AUC) (0.83, P<0.001). In the patient-based evaluation, the DL algorithm achieved a higher sensitivity (90.0%), NPV (52.2%) and AUC (0.81). Generalizability analysis of the DL algorithm was conducted by comparing its diagnostic performance in subgroups stratified by sex, age, geographic area and CT scanner type. The AUCs of the DL algorithm in the aforementioned subgroups ranged from 0.79 to 0.86 and from 0.75 to 0.93 in the vessel-based and patient-based evaluations, both without significant group differences (P>0.05).
CONCLUSIONS The DL algorithm that we previously developed performed no inferior to expert readers in CAD diagnosis on CCTA and had good generalizability.
GW32-e1169
Keling Xiao1, Machao Liu2, Jing Li1
1Department of Geriatrics, Xuanwu Hospital, Capital Medical University
2Department of Cardiology, Xuanwu Hospital, Capital Medical University
OBJECTIVES Endothelial dysfunction is associated with adverse events in patients with symptoms and/or signs of ischemia and no obstructive coronary artery disease (INOCA). We aimed to determine the relationship between endothelial function and quality of life (QoL) in INOCA patients.
METHODS This prospective study included 121 INOCA patients in a single center. Endothelial function was assessed by flow-mediated dilatation (FMD). QoL was evaluated by the SF-36 QoL survey. Patients were divided into two groups according to the median of FMD change between the baseline and 1-year follow up (Group A ≥ median of FMD change and Group B<median of FMD change).
RESULTS Baseline characteristics were similar in the two groups except for the proportion of diabetes was greater in Group B (30.0 vs. 14.8%, P=0.04). The median of FMD change was 0.92%. The mean baseline SF-36 scores were comparable between the two groups (53.95±6.46 vs. 53.92±4.29, P=0.98). QoL was better in Group A than in Group B (56.61±5.50 vs. 53.32±5.58, P=0.002) at follow-up. The change in FMD (r=0.34, P<0.01) rather than that in the baseline (r=−0.01, P=0.89) or follow-up (r=0.13, P=0.15) was related to the follow-up SF-36 scores. The FMD improvement was an independent predictor for the increased QoL (OR=3.90, 95% CI: 1.59–9.53, P=0.003).
CONCLUSIONS The change in endothelial function was associated with a corresponding change in QoL. In addition, improvement in FMD enhanced the QoL of patients with INOCA. Although these associations require further investigation to understand the causality between FMD change and QoL, our findings suggest that the change in endothelial function is a useful index in predicting the QoL of patients with INOCA. This indicates that serial tests of endothelial function are needed in clinical practice because endothelial function can be used as a potential therapeutic target for patients with INOCA.
GW32-e1367
Xunxun Feng, Guangyao Zhai, Yuyang Liu, Qianyun Guo, Yujie Zhou
Capital Medical University Beijing Anzhen Hospital
OBJECTIVES As metabolic molecules, bile acids (BAs) can not only promote the absorption of fat-soluble nutrients, but also regulate many metabolic processes, including the homeostasis of glucose and lipids. Although total serum BA (TBA) measurement is a readily available clinical test related to coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM), the relationship between TBA and these pathologies remains unclear, and research on this topic is inconclusive.
METHODS This study enrolled 20,255 menopausal women aged over 50 years, including 6421 T2DM patients. This population was divided in different groups according to median TBA level in order to explore the clinical characteristics of menopausal women with different TBA levels. Spline analyses, GAM model and regression analyses based on TBA level were used to explore the relationship between TBA and different diseases independently.
RESULTS In the general population and the T2DM subgroup, TBA level was significantly lower in the CAD patients than in the non-CAD patients. Spline analyses indicated that within normal clinical range of TBA concentration (0–10 mmol/L), the presence of CAD showed similar trend in total and T2DM population. Similarly, the GAM model indicated that within the 0–10 mmol/L clinical range, the predicted probability for CAD alone and in combination with T2DM was negatively correlated with TBA concentration, and the predicted probability of diseases decreased by about 2–5%. Multivariate regression analysis suggested that low TBA level may be positively related with the occurrence of CAD combined with T2DM (OR: 1.451; 95% CI: 1.141–1.847).
CONCLUSIONS In menopausal women, TBA may represent a valuable clinical serum marker for CAD and T2DM. Low-level TBA could be an independently related with CAD combined with T2DM.
GW32-e1480
Ying Wang, Xiaoxiao Zhao, Peng Zhou, Zhaoxue Sheng, Jiannan Li, Jinying Zhou, Runzhen Chen, Yi Chen, Li Song, Hanjun Zhao, Hongbing Yan
Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences
OBJECTIVES We aimed to investigate the prognostic implication of culprit-plaque morphology and PTX3 for major adverse cardiovascular events (MACE) in patients with ST-segment elevation myocardial infarction (STEMI).
METHODS A total of 236 patients were enrolled and divided into 4 groups: PE/low-PTX3 (n=57), PE/high-PTX3 (n=47), PR/low-PTX3 (n=78) and PR/high-PTX3 (n=54). MACE was defined as the composite of all-cause death, recurrence of myocardial infarction, stroke and unplanned revascularization of any coronary artery.
RESULTS During the follow-up of 1.9 years, a total of 40(16.9%) MACE were observed: 5.3% (3 patients) among patients with PE/low-PTX3, 21.3% (10 patients) among patients with PE/high-PTX3, 17.9% (14 patients) among patients with PR/low-PTX3 and 24.1% (13 patients) among patients with PR/high-PTX3 (log-rank P=0.013). In fully adjusted analyses, patients with high-PTX3 were associated with higher MACE risk (HR: 2.40, 95% CI: 1.26–4.57, P=0.008). Patients with PR/high-PTX3 (HR: 5.63, 95% CI: 1.57–20.16, P=0.008) and PE/high-PTX3 (HR: 5.44, 95% CI: 1.46–20.29, P=0.012) presented higher MACE risk than PE/low-PTX3 group. Adding PTX3 and PR to the risk prediction model increased the area under curves to 76.1% (95% CI: 67.6–84.5%) and the NRI (28.1%, 95% CI: 0.3–48.3%, P=0.040) and IDI (2.4%, 95% CI: 0.1–12.9%, P=0.040).
CONCLUSIONS Patients with PR/high-PTX3 and PE/high-PTX3 presented poor prognosis than PE/low-PTX3 group. Combining the culprit-plaque morphology with PTX3 enhanced the predictive ability for MACE and contributed to better prediction of high-risk patients.
GW32-e1587
Chao Fang1, Yanwei Yin2, Shaotao Zhang2, Jifei Wang2, Yidan Wang2, Lulu Li2, Yini Wang2, Senqing Jiang2, Fangmeng Lei2, Lei Xing2, Jingbo Hou2, Jiannan Dai2, Bo Yu2
1Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University
2Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China
OBJECTIVES Coronary layered plaques are indicative of previous plaque instability. We investigated the prevalence, angiographic, and optical coherence tomography (OCT) characteristics of layered plaques in patients with ST-segment elevated myocardial infarction (STEMI).
METHODS Between January 2017 and August 2018, a total of 318 patients with STEMI who underwent three-vessel OCT imaging were consecutively enrolled. According to the presence of OCT-detected layered plaque phenotype (one or more signal-rich layers of different optical density) at the culprit lesion, all enrolled patients were divided into two groups: Group A (patients with layered culprit plaque, n=152) and Group B (patients without layered culprit plaque, n=166).
RESULTS No significant difference was found in traditional coronary risk factors between patients with and without layered culprit plaque. 47.8% (152/318) of STEMI patients had layered plaque at the culprit lesion. Patients in Group A had severer diameter stenosis (68.7±8.7% vs. 65.6±11.6%, P=0.008) and smaller minimal lumen area (1.8±1.1 mm2 vs. 2.2±1.4 mm2, P=0.006) than those in Group B. The prevalence of lipid-rich plaque (88.8% vs. 83.1%, P=0.146), macrophage accumulation (92.8 vs. 83.7%, P=0.013), microvessels (67.8 vs. 54.8%, P=0.018), and calcification (53.3 vs. 39.2%, P=0.012) at the culprit lesion in Group A was significantly higher as compared with Group B. Patient-based analyses of nonculprit lesions showed that layered nonculprit plaques were detected in 66.4% (211/318) of STEMI patients, with comparable prevalence in two groups (71.1 vs. 62.0%, P=0.090). Of note, as compared with Group B, microvessels at nonculprit lesions (84.9 vs. 75.9%, P=0.045) were more frequent in Group A.
CONCLUSIONS In patients with STEMI, layered plaques were common both at the culprit and nonculprit lesions, with more features of coronary plaque instability and advanced atherosclerosis.
GW32-e1729
Ka Lam Calvin Leung1, Lok Yee Lam1, Kwan Yu Li1, Shuk Yin Yu1, Mei Zhen Wu1, Qing Wen Ren1, Pui Fai Wong1, Yi Kei Tse1, Si Yeung Yu1, Hang Long Li1, Yundi Feng2, Yunlong Huo2, Hung Fat Tse1, Kai Hang Yiu1
1Division of Cardiology, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, China
2PKU-HKUST Shenzhen-Hongkong Institution, Shenzhen, China
OBJECTIVES Computational pressure-flow dynamics derived fractional flow reserve (caFFR) is a novel index to assess the degree of myocardial ischemia in patients having coronary artery disease (CAD), without the need of a pressure wire and hyperaemic stimulus in wire-based fractional flow reserve measurement. The diagnostic performance of caFFR has been validated previously. The clinical value of caFFR on heart failure (HF) outcomes, nonetheless, is uncertain in CAD patients without significant myocardial ischemia. This study aimed at evaluating the impact of PCI on HF hospitalization and HF associated mortality in non-ischemic stable CAD patients as identified by caFFR.
METHODS A total of 420 patients (mean age 66.9±11.0; male 69.0%) with stable CAD but not significant myocardial ischemia, as defined by caFFR;0.80, were included. Patients were subsequently stratified into those underwent PCI (n=307) and did not undergo PCI (n=113). The primary endpoint was a composite of HF hospitalization and HF associated mortality.
RESULTS The number of obstructive lesions was 1.8±1.1 in patients who underwent PCI and 1.4±0.8 in those who did not undergo PCI (P=0.001). The severity of CAD assessed by SYNTAX score was higher in patients who underwent PCI compared to those did not (10.1±5.8 vs. 6.2±3.9, P<0.001). A total of 37 endpoint events occurred at 3 years (28 HF hospitalization and 9 HF associated mortality). The 1-year primary endpoint event rate was 3.3% in patients who underwent PCI and 3.5% in those did not (P=1.000). The primary endpoint rate at 3 years was similar between patients who underwent PCI and patients who did not undergo PCI after multivariable adjustment (8.1 vs. 6.2%; adjusted hazard ratio=1.04; 95% confidence interval=0.44–2.47; P=0.931).
CONCLUSIONS In stable CAD patients without significant myocardial ischemia, as defined by caFFR>0.80, PCI does not prevent HF hospitalization and HF associated mortality at 3 years.
GW32-e1858
Lihuan Zeng1, Hualin Fan2, Pengyuan Chen3, Yuanhui Liu4, Wenfei He3, Ning Tan4, Jiyan Chen4, Pengcheng He4
1The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
2Department of Cardiology, School of Medicine, South China University of Technology, Guangzhou 510006, China
3Department of Cardiology, The Second People’s Hospital of Nanhai District, Guangdong Provincial People’s Hospital’s Nanhai Hospital, Foshan 528200, China
4Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510100, China
OBJECTIVES Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been shown to reduce mortality and are highly recommended in patients with the acute coronary syndrome (ACS), especially in those with left ventricular systolic dysfunction. However, in the era when percutaneous coronary intervention (PCI), antiplatelet therapy, and statin therapy are actively administrated in patients with non-ST-segment elevation ACS (NSTE-ACS), the role of ACEIs/ARBs in such patients without reduced left ventricular ejection fraction (LVEF) remains unclear. Thus, we aimed to evaluate the impact of ACEIs/ARBs on long-term all-cause mortality and major bleeding in patients with NSTE-ACS undergoing PCI.
METHODS A total of 8197 eligible NSTE-ACS patients from January 1, 2010, to December 31, 2014, at 5 hospitals in China were enrolled. Patients with the following conditions were excluded: (1) without the LVEF; (2) LVEF ≤40%; (3) without definite information about PCI. The primary safety outcome was 3-year all-cause mortality and the safety outcome was 3-year major bleeding. Both of them were also evaluated at two follow-up periods: 30 days and 1 year. Survival analyses and multivariable Cox regression analyses were conducted.
RESULTS Six thousand and thirty six patients were finally included. Among them, 4725 were treated with ACEIs/ARBs and 1311 were treated without ACEIs/ARBs. During a median duration of 2.85 years, the 3-year all-cause mortality occurred in 206 patients (4.4%) in ACEIs/ARBs group, and 54 patients (4.1%) in non-ACEIs/ARBs group. Meanwhile, 150(3.2%) patients suffered from the 3-year major bleeding in ACEIs/ARBs group, and 27(2.1%) patients in non-ACEIs/ARBs group. No significant difference was found in 3-year all-cause mortality (adjusted hazards ratio [HR], 0.88; 95% CI, 0.64–1.20; P=0.403) and 3-year major bleeding (HR, 1.35; 95% CI, 0.89–2.06; P=0.161) after adjusting the potential confounders. The similar result was found at 30 days (all-cause mortality: HR, 0.96; 95% CI, 0.33–2.80; P=0.935; major bleeding: HR, 1.14; 95% CI, 0.71–1.83; P=0.594) and 1 year (all-cause mortality: HR, 0.81; 95% CI, 0.50–1.31; P=0.394; major bleeding: HR, 1.25; 95% CI, 0.79–1.98; P=0.341).
CONCLUSIONS In NSTE-ACS patients undergoing PCI and without reduced LVEF, ACEIs/ARBs treatment was not associated with a lower risk of long-term all-cause mortality and higher risk of major bleeding.
GW32-e0147
Ni-Ni Tian1, Guang-Ping Ruan2, Xiang-Qing Zhu2, Juan Ma1, Xiao-Li Zhao3, Hong-Jian Li4, Xing-Hua Pan2
1Department of Cardiovascular Medicine, Kunming First People’s Hospital
2Basic Medical Laboratory of the 920th Hospital of the Chinese People’s Liberation Army
3Department of Laboratory Medicine, Kunming First People’s Hospital
4Department of Surgery, Kunhua Hospital, Kunming University of Science and Technology
OBJECTIVES To investigate the expression of CHOP protein in peripheral venous blood of patients with different cardiac function grades under cardiac ischemia-reperfusion caused by acute myocardial infarction (AMI) within 24 hours.
METHODS 1. Fifty eight patients with normal physical examination were selected as the control group. AMI patients in the 230 case group were divided into the acute cardiac function classification (Killip classification) method after the onset: 122 cases were included in the cardiac function classification 1 group; the cardiac function classification 2 group was included 36 cases; 14 cases were included in the 3-level cardiac function group; 58 cases were included in the 4-level cardiac function group. ELISA method was used to detect the CHOP and BNP content in the patient’s serum within 24 hours.
RESULTS Analysis by non-parametric rank sum test: the CHOP concentration of the control group is 2.41 (1.96–3.14) ng/mL; the heart function level 1 group is: 1.23 (0.97–1.55) ng/mL; the heart function level 2 group is: 1.33 (1.12–1.78) ng/mL; Heart function grade 3 group: 1.42 (1.25–2.7) ng/mL; Cardiac function grade 4 group: 1.62 (1.05–2.14) ng/mL; and P<0.05, there are differences Statistical significance. 2. Serum BNP content is analyzed by non-parametric rank sum test: the BNP concentration of the control group is 49 (32–65) ng/mL; the cardiac function grade 1 group is: 144.6 (130.2–3498) ng/mL; the cardiac function grade 2 The grade group is 611.2 (161.1–1192) ng/mL; the cardiac function grade 3 group is: 1584 (557–14,569) ng/mL; the cardiac function grade 4 group is: 1599 (1019–3212) ng/mL; And P<0.05.
CONCLUSIONS CHOP, as an endoplasmic reticulum stress response protein, has very little expression under normal conditions, but it may be significantly induced in patients with IRI and heart failure caused by AMI.
GW32-e0492
Yu Geng
Beijing Tsinghua Changgung Hospital
OBJECTIVES Gensini score is one of the most widely-used approaches to quantify the severity of angiographic atherosclerosis. However, inconsistent results were reported for the association between Gensini score and cardiac biomarkers.
METHODS A total of 393 consecutive ACS patients with a mean age of 62±11 and an average BP of 131/75 mmHg who received coronary angiography (CAG) from 2016 Aug to 2017 Dec in Beijing Tsinghua Changgung Hospital was enrolled in the study, among whom 129 suffered from ST-elevation myocardial infarction (STEMI), 74 from non ST-elevation myocardial infarction (NSTEMI), 174 from unstable angina pectoris (UAP). Serum cardiac biomarkers including troponin T (TnT), creatine kinase-MB (CK-MB) were measured at admission and every 4-hour in emergency room (ER) for analysis. Participants were divided into five groups as follows according to Gensini score, the indication of the severity of coronary artery disease (CAD): 1. Gensini score ≤22 (n=81); 2. 22<Gensini score ≤31 (n=75); 3. 31<Gensini score ≤43 (n=79); 4. 43<Gensini score ≤65 (n=80); 5. 65<Gensini score ≤243 (n=78). Generalized linear model adjusted for age and gender was used to assess the association between Gensini score groups and cardiac biomarkers at admission or at peak. Subgroup analysis were conducted across different ACS types.
RESULTS Gensini score were right-skewed distributed with a median of 37. Participants with STEMI presented with the highest Gensini score (Median: STEMI vs. NSTEMI vs. UAP: 56 vs. 45 vs. 29, P<0.05). Differences was noticed between each cardiac biomarker and across different subgroup population. Generally, cardiac biomarkers had weak correlation with Gensini score. Peak value of CK-MB had relatively higher positive correlation with Gensini score in overall population (r=0.31, P<0.05). While in AMI (STEMI and NSTEMI) participants, Gensini score correlated relatively better with both TnT at admission (r=0.23, P<0.05) and CK-MB at peak (r=0.23, P<0.05). Peak value of CK-MB increased with elevated Gensini score group (P<0.05). Similar results were observed for TnT at admission and at peak in AMI participants (P<0.05).
CONCLUSIONS Higher Gensini score was associated with higher CK-MB in ACS patients as well as TnT in AMI patients. Further study is warranted for the pathophysiological mechanisms to explain the discrepancy between different cardiac biomarkers.
GW32-e0690
Ling Sun1, Lipeng Mao1, Wenwu Zhu2, Yuan Ji1
1The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University
2XuZhou Central Hospital
OBJECTIVES Contrast induced acute kidney injury (CI-AKI) after intervention therapies was associated with poor outcomes in patients with acute myocardial infarction (AMI). Lower free triiodothyronine (FT3) levels also predicted the poor prognosis of AMI patients. This study evaluated the effect of plasma FT3 level on predicting CI-AKI and short-term prognosis among AMI patients.
METHODS Coronary arteriography (CAG) or percutaneous coronary intervention (PCI) was performed in patients with AMI between January 2010 and January 2018. FT3 levels were measured by using enhanced chemiluminescence. A 1:4 propensity score matched cohort of patients was between CI-AKI and non-CI-AKI group.
RESULTS Of 1480 patients enrolled in the study, 224 (15.1%) patients developed CI-AKI. The concentration of FT3 was lower in CI-AKI patients than non-CI-AKI patients (3.72±0.88 pmol/L vs. 4.01±0.80 pmol/L, P<0.001). Compared with the lowest quartile of FT3, individuals in quartiles 2–4 had multivariable odds ratios, respectively (Ptrend=0.005). The risk of CI-AKI decreased by 19.1% for each unit of FT3 increase after propensity score matching analysis (OR: 0.81; 95% CI: 0.67–0.97, P=0.025). After median follow-up 31 days (interquartile range [IQR]: 30–35 days), 78 died patients including 72 cardiogenic death and 6 non-cardiogenic death. Of them, 53 and 25 patients died in CI-AKI and non-CI-AKI group, respectively, P<0.05.
CONCLUSIONS Lower level of FT3 was associated with an elevated risk of CI-AKI and mortality in AMI patients with intervention therapies by using contrast.
GW32-e0932
Tian Xu, Rajiv Shrestha
Nanjing First Hospital
OBJECTIVES Recanalization of thrombus in coronary artery tree is defined as a honeycomb-like structure. However, the anatomic features and appropriate treatment of honeycomb-like structure still remain largely unclear.
METHODS Between 2014 July and 2017 December, 17 honeycomb-like structure in 16 patients based on optical coherence tomography and intravascular ultrasound were included. Fractional flow reserve was measured for patients who had thrombolysis in myocardial infarction flow grade 3. Angiographic and optical coherence tomography/intravascular ultrasound derived variables were studied. Clinical events (until to 2018 December) were collected.
RESULTS Honeycomb-like structures mostly involved left anterior descending artery (68.8%) and localized at proximal-mid (88.2%) segment of vessels. Eight patients had a side branch ≥2 mm in diameter taking from honeycomb-like structure. Only one patient had a normal fractional flow reserve. Fifteen patients underwent implantation of a stent. Stent implantation was associated with side branch compromise or closure (4 in each). Of 4 patients with side branch closure, all had a creatine kinase myocardial band >5 times increase in hospital, with 3 deaths and 1 target lesion revascularization during follow-up.
CONCLUSIONS Despite the presence of recanalization, most honeycomb-like structure lesion have a positive fractional flow reserve. Further study is required to address how to protect a large side branch taking from honeycomb-like structure.
GW32-e1110
Lei Xiao1, Jiani Liu2, Guo Li2, Yi Zheng2, Ye Zhu2, Sen He2
1Chengdu BOE Hospital
2West China Hospital of Sichuan University
OBJECTIVES Acute myocardial infarction (AMI) is rarely induced by lidocaine injection for local anesthesia; nevertheless, coronary artery spasm is a possible mechanism. The possible serious side effects of lidocaine require the attention and vigilance of clinicians.
METHODS We report a case of AMI secondary to a local injection of lidocaine, the potential mechanism of which may be lidocaine-induced coronary artery spasm.
RESULTS Coronary angiography did not reveal any significant atherosclerotic plaques or stenosis. There was no significant wall motion abnormality or valve abnormalities on echocardiography immediately after angiography, with normal left ventricular ejection fraction. Cardiac contrast-enhanced magnetic resonance imaging did not reveal late gadolinium enhancement. Based on chest distress symptoms of myocardial ischemia, dynamic ST segment changes on electrocardiography, significantly elevated cardiac troponin levels, and normal coronary angiography findings, we suspected AMI caused by coronary artery spasm. We considered that when the blood concentration of lidocaine increased rapidly to a “threshold” level, the transient high concentration of lidocaine inhibited coronary artery relaxation and possible coronary artery spasm effects, leading to coronary artery spasm and AMI.
CONCLUSIONS The possibility of serious side effects (such as causing coronary artery spasm effects, Kounis syndrome, and stress cardiomyopathy) require the attention and vigilance of clinicians. Strict, standardized operating procedures and medical observations are essential for the clinical application of lidocaine.
GW32-e1215
Haili Sun, Qianwen Lv, Xiaolu Jiao, Fan Li, Huahui Yu, Qiuju Sun, Yu Wang, Zhiyong Du, Liny Li, Ming Zhang, Shaoping Nie, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Serum lipoprotein(a)[Lp(a)] has been identified as an independent cardiovascular risk for coronary artery disease (CAD). Current studies have reported the association of Lp(a) with adverse cardiovascular risk in patients with obstructive sleep apnea (OSA). However, the prognostic importance of Lp(a) for recurrent major adverse cardiovascular events (MACEs) is currently undetermined in patients with OSA.
METHODS From May 2017 to December 2019, 645 patients who were treated with percutaneous coronary intervention (PCI) and polysomnography in our hospital were enrolled. OSA was defined as apnea–hypopnea index (AHI)≥15/h. Patients were categorized into CAD with OSA and without OSA, followed up for recurrent MACEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Serum Lp(a) was detected by immunoturbidimetry, Kaplan–Meier and Cox regression analyses were performed.
RESULTS During 22.6 months followup, 73 MACEs occurred, including 4 cardiac death. Lp(a) levels were significantly higher in CAD with OSA patients than without OSA patients [15.2 (6.5, 37.3) vs. 11.4 (5.4, 24.7) mg/dL, P=0.023]; Lp(a) levels were significantly higher with MACEs than counterparts [13.3 (5.5, 34.8) vs. 22.7 (9.3, 44.5) mg/dL, P=0.044] in CAD with OSA patients. Kaplan–Meier analysis revealed that the eventfree survival rate was dramatically lower in high Lp(a) (≥30 mg/dL) group than that in low Lp(a) (<30 mg/dL) group in CAD with OSA patients. Furthermore, multivariate Cox regression models indicated that Lp(a) was independently associated with MACEs in OSA patients [HR (95% CI): 1.584, 95% CI: 1.101–2.252, P=0.013].
CONCLUSIONS Lp(a) was an independent predictor for MACEs in OSA patients after PCI, suggesting that Lp(a) measurement may help to further cardiovascular risk stratification for OSA patients.
GW32-e1368
Liming Gao
Shanghai East Hospital
OBJECTIVES We aimed to investigate the predictors and prognosis of LVA in patients with acute anterior myocardial infarction treated with primary PCI in the contemporary era.
METHODS A total of 942 consecutive patients with acute anterior myocardial infarction undergoing primary PCI were prospectively enrolled, among which 15.92% were in the LVA group and the rest were in the non-LVA group. The primary endpoint of major adverse cardio-cerebral events (MACCEs) was defined as a composite of cardiac death, target vessel revascularization, and ischemic stroke. Baseline characteristics and 1-year clinical outcomes were compared by Chi-square test, t-test, or Kaplan-Meier survival analysis as appropriate. Multiple logistic regression was applied to predict LVA formation.
RESULTS At 1-year clinical follow-up, the primary endpoint of MACCEs was significantly increased in the LVA group than in the non-LVA group (15.33 vs. 6.44%, P<0.01), which was mainly driven by higher incidence of cardiac death (8.00 vs. 2.78%, P<0.01), target vessel revascularization (5.33 vs. 2.27%, P=0.03), and ischemic stroke (4.00 vs. 1.39%, P=0.03). Longer symptom-to-balloon time [odds ratio (OR): 1.16, 95% confidence interval (CI): 1.11–1.21, P<0.01], increased initial SYNTAX Score (OR: 1.19, 95% CI: 1.14–1.24, P<0.01) and residual SYNTAX Score (OR: 1.33, 95% CI: 1.22–1.45, P<0.01), impaired left ventricular ejection fraction within 3 days (OR: 0.87, 95% CI: 0.85–0.90, P<0.01), and persistent ST segment elevation (OR: 1.89, 95% CI: 1.06–3.38, P=0.03) were independent predictors of LVA formation in patients with acute anterior myocardial infarction undergoing primary PCI by multivariate analysis.
CONCLUSIONS In the contemporary era, patients with LVA still had worse clinical outcomes. Promote reperfusion with less symptom-to-balloon time and complete revascularization may help to prevent LVA and improve the prognosis of patients with acute anterior myocardial infarction treated by primary PCI.
GW32-e1497
Qi Zhao, Ziwei Zhao, Yujing Cheng, Yingkai Xu, Tienan Sun, Yujie Zhou
Beijing Anzhen Hospital
OBJECTIVES The visceral adiposity index (VAI) is proposed as a surrogate marker of insulin resistance (IR) and, when increased, is related to elevated cardiovascular risks. However, the prognostic value of VAI in patients diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing elective percutaneous coronary intervention (PCI) remains unclear.
METHODS The current study ultimately enrolled 2308 subjects diagnosed with NSTE-ACS who received elective PCI. All participants received a routine follow-up after discharge. The VAI was obtained from the equation described by former studies. Adverse cardiovascular events included all-cause death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and ischemia-driven revascularization, composite of which was defined as the primary endpoint.
RESULTS Overall, 547 (23.7%) primary endpoints were documented during a 48-month follow-up. Despite adjusting for confounding variates, the VAI remains to be a significant risk predictor for the primary endpoint, with a hazard ratio (HR) [95% confidence interval (CI)] of 2.257 (1.765–2.843) (P<0.001). A significant incremental effect on the predictive performance for the primary endpoint was found when adding the VAI into a baseline model including traditional cardiovascular risk factors [area under the receiver-operating characteristic (ROC) curve (AUC), 0.828 for baseline model vs. 0.851 for baseline model + VAI, P<0.001; net reclassification improvement (NRI), 0.185, P<0.001; integrated discrimination improvement (IDI), 0.026, P=0.002].
CONCLUSIONS The VAI is an independent risk predictor for adverse cardiovascular events in subjects diagnosed with NSTE-ACS undergoing elective PCI. Further prospective studies are needed to verify the present results.
GW32-e1597
Wei Wei, Qi Zhang
Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine
OBJECTIVES Coronary artery ectasia (CAE) is not an uncommon clinical condition, which could be associated with adverse outcome. CAE may be coronary artery dilatation with unknown etiology. When CAE mixed with stenosis in 1 or 2 arteries, the outcomes may differ from pure CAE, This study aimed to compare the differences between pure CAE, mixed CAE and CAE to investigate their pathogenesis.
METHODS Two hundred and thirty five patients with confirmed CAE from September 2017 to October 2019 were included when we examined 16,484 patients who had angiograms at this 2 years. The CAE patients divided into two groups, pure CAE (n=82) and mixed CAE (n=153). Clinical and angiographic variables of patients with CAE were later compared with 242 age-matched controls with confirmed normal coronary artery (NCA) and 283 age-matched patients with confirmed CAD. All patients completed examinations of the ankle-brachial index (ABI), pulse wave rate, and carotid ultrasonography; were tested for routine blood, lipid, and immune parameters; and given a routine oral loading dose of antiplatelet drugs before coronary angiography. Blood samples were collected 1 week after the withdrawal of antiplatelet drugs, and vascular inflammatory indexes (hsCRP, ESR, IL-6, c-ANCA, p-ANCA, ds-DNA, E-selectin, L-selectin, ET-1, MMP-9, GDF-15, MPO, TNF-α), thromboelastography were measured. Analysis of variance and the chi-square or Fisher exact test was used in statistical analysis.
RESULTS The prevalence rate of hypertension was significantly higher in CAE than in NCA (P<0.05). The mean age and smoking rate were significantly higher in pure CAE than in NCA and in mixed CAE (P<0.05). The CAD group had the highest prevalence rate of hyperlipidemia. The right coronary artery was most frequently involved in pure CAE compared with left circumflex artery and left anterior descending artery. The endothelial-1(ET-1), matrix metallopeptidase-9 (MMP-9), and tumor necrosis factor-α (TNF-α) were significantly higher in pure CAE than in other 3 groups, while cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibody (c-ANCA and p-ANCA) was appreciably higher in pure CAE than in mixed CAE and NCA (P<0.05). GDF-15 were significantly higher in CAE than in NCA (P<0.05). But the levels of E-selectin, L-selectin and dsDNA were not different in different groups. The atherosclerosis index showed that, ABI was significantly lower in pure CAE than in NCA and CAD groups (P<0.05), LDL/HDL ratio was significantly higher in mixed CAE than in pure CAE and NCA (P<0.05), and the detection rate of carotid artery thickening was significantly higher in CAD and mixed CAE than in pure CAE (P<0.05). The Gensini and SYNTAX scores were significantly higher in CAD and in mixed CAE (P<0.05).
CONCLUSIONS Pure CAE was closely related to inflammation, whereas mixed CAE was closely related to atherosclerosis and related with CAD.
GW32-e1758
Jun Qian, Fei Chen, Xuebo Liu
Shanghai Tongji Hospital
OBJECTIVES Plaque rupture (PR) followed by thrombosis is considered the main mechanism of acute coronary syndromes (ACS), accounting for approximately two-thirds of acute myocardial infarction. In recent years, the proportion of plaque erosion (PE) increased with the intensity of lipid-lower therapy, and the pathological difference with PR is unclear. Here, we used single cell RNA sequencing to identify subsets of immune cells and genes mediating inflammation and to dissect the immunological network of ACS.
METHODS Transcriptomic profiles of peripheral blood mononuclear cells were analysed in 5 patients diagnosed with PR and 5 patients with PE by single cell RNA sequencing. By focusing our analysis on immune cells, we obtained a higher resolution identification of the monocyte and T cell subsets in patients experiencing with PR and PE.
RESULTS Compared with patients with PE, the classical monocytes of PR showed an significantly increased expression of leukocyte-endothelial cell adhesion genes as ICAM1, ITGAL, RUNX3 and pro-inflammatory genes as CCL5, TLR7, and CX3CR1 with similar cell numbers. Non-classical monocytes were predominated in patients with PR, and its gene ontology (GO) term were mainly enriched in cellular response to lipopolysaccharide, positive regulation of NF-kB transcription factor activity and cellular response to interferon-gamma. Among the upregulated genes in PR with non-classical monocytes were CCL5, TLR7, and CX3CR1, which augments inflammatory response. While up-regulated genes in PE mainly induced a neutrophil degranulation and regulation of neutrophil apoptotic process. Conversely, the number of intermediate monocytes in patients with PE was significantly increased, and plays an important role in activating neutrophils and leading to neutrophils degranulation. T cells were observed at the highest percentage of all immune cells. The GO analysis of regulatory T cells (Tregs) in patients with PE was mainly enriched in autophagy, process utilizing autophagic mechanism and macroautophagy, with NAMPT was significantly associated with these biological process. Moreover, the NAMPT expression level was significantly increased in PE. CD4+ effector T cells, in which the expression of CCL5, CXCR3 and NKG7 were upregulated in PR, mainly enriched in the cell activation, chemokine and cytokine production. While CD8+ effector T cells expressed more effector molecule in patients with PE as GZMB, GNLY and PRF1, which may promote the apoptosis and shedding of endothelial cells.
CONCLUSIONS This study demonstrates that circulating monocytes of patients with PR exhibit a highly pro-inflammatory characteristic compared to PE, while CD8+ effector T cells releasing a series of effector molecules caused endothelial cell death, which may contribute to the progress of PE.
GW32-e1906
Liang Geng, Yuan Yuan, Peizhao Du, Liming Gao, Yunkai Wang, Jiming Li, Wei Guo, Ying Huang, Qi Zhang
Department of Cardiology, East Hospital, Tongji University, Shanghai 200120, China
OBJECTIVES Currently there is lack of data regarding the coronary physiological evaluation in diabetes mellitus (DM) patients, especially for the new emerging angiography-based fractional flow reserve. We sought to explore the impacts of DM and glucose control on the quantitative flow ratio (QFR) and its association with intravascular ultrasound (IVUS) derived anatomical severity.
METHODS IVUS and QFR were retrospectively analyzed in 352 de novo intermediate coronary lesions of 330 patients. The lesions were divided into the non-DM group (93 patients with 102 lesions), DM with adequate glucose control group (47 patients with 53 lesions, HbA1C<7.0%) and DM with poor glucose control group (46 patients with 49 lesions, HbA1C≥7.0%). Lesions with QFR≤0.8 were considered hemodynamically significant. Anatomical significance of the lesions was defined as the minimum lumen area (MLA) ≤4.0 mm2 and plaque burden (PB, %) ≥70.
RESULTS IVUS-derived PB (65.0±9.1 vs. 67.6±7.7 vs. 69.6±8.5, P=0.002) increased, and MLA decreased (4.4±1.8 mm2 vs. 4.1±1.2 mm2 vs. 3.8±1.5 mm2, P=0.074) stepwise across non-DM, DM with adequate glucose control and DM with poor glucose control. However, QFR was consistent among the three groups. PB was correlated significantly with QFR in lesions with non-DM (r=−0.356, P<0.001), but not in lesions with DM (r=−0.150, P=0.134). The DM (OR 1.962, 95% CI: 1.047–3.678, P=0.036) and higher HbA1C (OR 1.317, 95% CI: 1.059–1.636, P=0.013) are independent predictors of QFR-defined non-significant lesions (QFR;0.8) with high-risk IVUS features (MLA≤4.0 mm2 and PB≥70%).
CONCLUSIONS DM and poor glucose control affect the IVUS-derived anatomical severity but not the QFR-derived functional severity. DM and HbA1C are the independent predictors of discrepancy between IVUS and QFR.
GW32-e0175
Yipin Zhao, Qingwei Chen, Bin Lin
The Second Affiliated Hospital of Chongqing Medical University
OBJECTIVES Previous studies have shown that both serum creatinine and D-dimer levels were associated with atherosclerotic coronary artery disease (CAD). We aimed to determine whether DCR is associated with coronary Gensini score in patients with ST-elevation myocardial infarction (STEMI).
METHODS Three hundred and thirty seven STEMI patients with complete D-dimer and creatinine and other necessary information were included in the analysis. According to the values of the DCR, patients were divided into the lower DCR group (DCR ≤1.42, n=173) and the higher DCR group (DFR >1.42, n=174), and the differences between the two groups were compared. Multivariate linear and multivariate logistic regression analyses were performed to determine independent predictors of Gensini score.
RESULTS High DCR group had higher Gensini score compared with low DCR group (P<0.05). DCR was positively correlated with Gensini score (r=0.493, P<0.001). Multiple linear regression analysis showed that Previous MI (r=11.312, P=0.035) and DCR (r=5.129, P<0.001) were independent risk factors associated with Gensini score. Multivariate logistic regression analysis showed that, compared to the group 1, DCR is independent risk factor for Group 2, Group 3, Group 4 (P<0.001). DCR is positively correlated with coronary Gensini score in STEMI patients and can be used as an independent predictor of higher Gensini score.
CONCLUSIONS As a new and useful clinical marker, DCR is positively correlated with coronary Gensini score in STEMI patients and can be used as an independent predictor of higher Gensini score.
GW32-e0570
Zhihua Huang1,2, Ling Wang2, Jiyan Chen2, Pingyan Chen3, Yanpeng Wu3, Guang Li2
1Department of Cardiology, Fuwai Hospital, National Clinical Research Center for Cardiovascular Diseases, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
3Department of Biostatistics, School of Public Health, Southern Medical University, Guangzhou, China
OBJECTIVES Little is known regarding the quantification of hypoxemia-elicited heart rate (HR) response and its prognostic significance of the cardiovascular risk. We sought to explore the impact of HR response to obstructive sleep apnea (OSA)-induced minimal oxygen saturation (minSaO2) on the occurrence of a common cardiovascular event – acute myocardial infarction (AMI).
METHODS Consecutive patients with suspected OSA were enrolled and underwent nocturnal respiratory study and electrocardiography monitoring. The minSaO2 was determined from the oxygen saturation curve under a subject-specific search window. Primary HR metrics such as maximal HR in response to minSaO2 were computed from the synchronized recordings. Multivariate analyses were conducted to analyze the associations of minSaO2-associated HR parameters and the occurrence of AMI.
RESULTS Of 2748 patients recruited, 39% (n=1071) had moderate-to-severe OSA (respiratory event index, REI≥15), and 11.4% (n=313) patients had AMI. Patients with AMI experienced severer OSA, severer minSaO2 and greater HR reactions. Patients with minSaO2 <90% had an adjusted odds ratio of 1.48 (95% confidence interval [CI] 1.09–2.00, P=0.012) for AMI. Notably, minSaO2-induced elevated mean HR response (HR mean;73 bpm) was significantly associated with AMI (odds ratio: 1.72 (95% CI 1.32–2.23), P<0.001). Patients with severe minO2 (<90%) and elevated HR mean carried an additive odds ratio of 2.65 (95% CI 1.74–4.05, P<0.001) for the risk of AMI after adjustment for potential confounders.
CONCLUSIONS Patients with substantial HR reactions to OSA-induced oxygen nadir were at increased risk of developing AMI. Detection of nocturnal autonomic response to hypoxemia may help improve cardiovascular risk stratification.
GW32-e0705
Chenbo Xu1, Mengya Dong2, Lizhe Sun1, Lisha Zhang3, Shan Shu1, Chang He1, Yangyang Deng1, Juan Zhou1,4, Zuyi Yuan1,5
1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University
2Department of Cardiovascular Medicine, Shaanxi Provincial People’s Hospital
3Department of Cardiology, The Second Affiliated Hospital of Xi’an Jiaotong University
4Key Laboratory of Molecular Cardiology of Shaanxi Province
5Key Laboratory of Environment and Genes Related to Diseases
OBJECTIVES Circadian system plays an important role in cardiovascular health. Experimental studies have identified sex disparities in circadian system which are less studied in clinical investigation. Therefore, we aim to explore sex differences in the relationship between STEMI onset time and in-hospital adverse outcomes.
METHODS Data were used from the Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome Project. The outcomes included all-cause mortality and a composite of major adverse cardiovascular and cerebrovascular events (MACCE) during hospitalization.
RESULTS Eighteen thousand and two hundred seventy-one STEMI patients undergoing primary percutaneous coronary intervention (PCI) entered the current study, including 14,785 (80.9%) men and 3486 (19.1%) women. Most participants experienced STEMI onset during 6:00 to noon, and there was no difference in onset pattern between men and women (P=0.582). Logistic regression showed that, after adjustment of cardiovascular risk factors, symptom onset time was significantly associated with in-hospital mortality in men not women. The odds ratios (ORs) for male patients were 1.88 (95% CI 1.07–3.30) for midnight to 6:00, 1.58 (95% CI 0.95–2.64) for 6:00 to noon, and 0.93 (95% CI 0.50–1.74) for 18:00 to midnight as compared with STEMI presenting during noon to 18:00.
CONCLUSIONS Our data shows that STEMI onset time was a prognostic factor for in-hospital mortality in men, firstly indicating that sex-related differences exist in the association between onset time of STEMI and mortality during hospitalization.
GW32-e0949
Ke Gao
The First Affiliated Hospital of Xi’an Jiaotong University
OBJECTIVES Sarcopenia correlates with accelerated aging and adverse outcomes, including mortality. However, chronological age (CA) is not a perfect proxy for the true biological aging state of the body. Phenotypic Age, a novel aging measure, representing the expected age within the population that corresponds to a person’s estimated mortality risk. Phenotypic Age Acceleration (PhenoAgeAccel) reflects whether a person’s biological age is older [positive value] or younger [negative value] than expected based on his/her CA. To date, there is a paucity of research on the joint association of sarcopenia index (SI), a practical screening marker for sarcopenia, and PhenoAgeAccel with mortality among patients with coronary artery disease. This study aimed to evaluate the combined association of SI and PhenoAgeAccel with mortality in coronary chronic total occlusion (CTO) patients after percutaneous coronary intervention (PCI).
METHODS A total of 671 CTO patients who underwent PCI attempt and with follow-up were retrospectively enrolled. SI was calculated as (serum creatinine/cystatin C) ×100. Phenotypic Age was calculated using an equation constructed from CA and 9 clinical biomarkers. PhenoAgeAccel was calculated according to the residual resulting from a linear model when regressing Phenotypic Age on CA. The cut-off point for SI (SI<85.7 or SI;85.7) was calculated based on the receiver operating characteristic curve (ROC). Combined classifications of SI and PhenoAgeAccel were generated with the following four subgroups derived: i) High SI alone, ii) Low SI alone, iii) Positive PhenoAgeAccel, and iv) Low SI with Positive PhenoAgeAccel. The clinical outcomes were all-cause mortality and cardiovascular mortality on follow-up. Cox proportional hazards regression models were performed to evaluate the joint association of SI and PhenoAgeAccel with mortality with the report of hazards ratio (HR) and 95% confidence interval (CI).
RESULTS After a median follow-up of 33.7 months, the incidence of all-cause mortality in high SI alone, low SI alone, positive PhenoAgeAccel, and low SI with positive PhenoAgeAccel subgroups were 1.7% (3/175), 10.2% (23/225), 9.9% (14/142), 18.6% (24/129), respectively (P for trend <0.001). Those with low SI and positive PhenoAgeAccel also had a significantly higher incidence of cardiovascular mortality than high SI subgroup (P<0.05). After adjusting for confounding factors, patients with both low SI and positive PhenoAgeAccel had higher risks for all-cause mortality (HR: 7.98, 95% CI: 1.85–34.34, P=0.005) and cardiovascular mortality (HR: 8.96, 95% CI: 1.12–72.01, P=0.039) compared with controls with high SI alone. ROC curves revealed that the addition of both low SI and positive PhenoAgeAccel to the baseline risk model including traditional risk factors significantly promoted the ability of risk prediction for all-cause mortality (AUC: baseline risk model, 0.778 vs. baseline risk model+low SI and positive PhenoAgeAccel, 0.817, P=0.015).
CONCLUSIONS In conclusion, the SI and PhenoAgeAccel were significantly associated with an increased risk of mortality in patients with CTO. The present study provided compelling evidence that a novel index based on combination of preoperative SI and PhenoAgeAccel may be complementary in predicting mortality risk for CTO patients.
GW32-e1122
Yiqian Yang1, Yongchen Hao1, Jun Liu1, Na Yang1, Yong Huo2, Sidney C. Smith3, Junbo Ge4, Gregg C. Fonarow5, Louise Morgan6, Chang-Sheng Ma7, Yaling Han8, Dong Zhao1, Jing Liu1
1Department of Epidemiology, Beijing An Zhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases
2Department of Cardiology, Peking University First Hospital
3Division of Cardiology, University of North Carolina, Chapel Hill
4Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai
5Division of Cardiology, Geffen School of Medicine at University of California
6International Quality Improvement Department, American Heart Association
7Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University
8Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command
OBJECTIVES Revascularization therapies are key treatments of ST-segment elevation myocardial infarction (STEMI). However, little is known about the contemporary practice among Chinese patients with STEMI. We aimed to explore the recent patterns of revascularization among hospitalized patients with STEMI in China.
METHODS A total of 59,442 STEMI patients admitted to 159 tertiary hospitals from 30 provinces in China were included in the Improving Care for Cardiovascular Disease in China (CCC)-ACS project from November 2014 to December 2019. The patterns of revascularization (including primary percutaneous coronary intervention [pPCI], fibrinolysis alone, pharmaco-invasive strategy, and elective PCI) were assessed. Associations between therapies and in-hospital MACE after 1 day of admission were examined with multivariate Cox regression.
RESULTS Among the 59,442 patients, 48,897 (82.3%) underwent revascularization, including 28,280 (47.6%) received pPCI within 12 hours from symptom onset, 4649 (7.8%) received pPCI between 12 and 24 hours from symptom onset, 1314 (2.2%) received fibrinolysis alone, and 1751 (2.9%) received pharmaco-invasive strategy. A total of 12,903 patients (21.7%) received elective PCI, among which 1486 (11.5%) initially received fibrinolysis. Overall, 37,480 patients (63.1%) received reperfusion therapy, including 32,929 (55.4%) received pPCI, which was 7.2-fold higher than that of fibrinolysis (4551, 7.7%). Among patients receiving fibrinolysis, only 38.4% (1751/4551) received pharmaco-invasive strategy, including 25.2% for pharmaco-invasive PCI and 13.3% for rescue PCI. As for procedural characteristics, the usage rates of DES (98.7%) and transradial approach (93.8%) was markedly high, which are recommended by guidelines. However, another higher-performing metric was thrombus aspiration (19.2%), which is not recommended in the ESC guideline. All PCI strategies, but not fibrinolysis alone, were associated with decreased risk of in-hospital MACE compared with no reperfusion/revascularization, with the adjusted HR (95% CI) of 0.46(0.38, 0.56) for pPCI<12 h, 0.38(0.27, 0.55) for pPCI 12–24 h, 0.38(0.16, 0.95) for rescue PCI, 0.27(0.13, 0.59) for pharmaco-invasive PCI, 0.28(0.21, 0.37) for elective PCI, and 0.86(0.57, 1.29) for fibrinolysis alone.
CONCLUSIONS Revascularization therapies are widely used in patients with STEMI in China. However, there are notable gaps between guideline recommendations and the clinical practice in terms of timely reperfusion, especially pharmaco-invasive strategy. Early reperfusion therapies should be further strengthened.
GW32-e1220
Yitian Zheng1, Yu Qi2, Wenyao Wang1, Jie Yang1, Chen Li1, Qing Zhou1, Xiangbin Meng1, Kuo Zhang1, Samuel Seery3,4, Chunli Shao1, Yi-Da Tang5
1Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, CAMS & PUMC
2Department of Cardiology, Peking University Third Hospital, Beijing, China
3School of Humanities and Social Sciences, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
4Faculty of Health and Medicine, Division of Health Research, Lancaster University, Lancaster, United Kingdom
5Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
OBJECTIVES To investigate the long-term outcomes of those with coronary artery disease (CAD) who undergo percutaneous coronary intervention (PCI) with or without COPD based on propensity-score matching.
METHODS Ten thousand seven hundred and twenty-four consecutive CAD cases who underwent percutaneous coronary intervention in our clinic were enrolled. Participant characteristics, comorbid disorders, and procedural details were collected by two physicians, independently. Participants were then divided into two cohorts, i.e., a COPD and non-COPD group. After percutaneous coronary intervention, participants were follow-up at 30 days, six months, and two years. The primary endpoints were major adverse cardiac events (MACEs) including cardiac death, revascularization, and myocardial infarction. Propensity score matching was performed to control confounding factors, using a nearest neighbor matching method within a caliper of 0.01 on the propensity score scale. COPD participants were matched to non-COPD participants at a 1:4 ratio.
RESULTS After propensity-score matching (PSM), the COPD group (n=245) and the non-COPD group (n=965) were comparable. Those with COPD were generally older than non-COPD group (65.4±9.2 vs. 58.2±10.3, P<0.001, Standardized Difference=78.4%). The COPD also encountered more renal dysfunction (6.0 vs. 3.4%, P=0.023, Standardized Difference=11.2%), cerebrovascular diseases (16.5 vs. 10.6%, P=0.003, Standardized Difference=16%), and peripheral vascular diseases (12.5 vs. 7.5%, P=0.003, Standardized Difference=19%). After PSM, there was no significant age difference between the two groups (65.3±9.1 vs. 64.6±9.9, P=0.257, Standardized Difference=7.2%). CAD classification was also similar between the two, after PSM (CCS: 9.8 vs. 9.9, ACS: 90.2 vs. 90.1%, P=0.943, Standardized Difference=0.6%). Follow-up was completed for 99.8% (n=1207) of our sample. The average follow-up was 794.2 days. There is no significant difference between groups in terms of endpoints, before or after adjustments (All P>0.05). Subgroup analysis indicated that among participants over 75 years old, hazard ratio (HR) of COPD was 2.37, with 95% CI: 1.01–5.79, P=0.05). For those with peripheral vascular diseases, the HR in the COPD group was 3.26 (95% CI: 0.84–12.68, P=0.08), which was considered of borderline significance. For MACEs and all-cause death, adjusted HR were significantly different in COPD group versus non-COPD group in participants over 75 years old (MACEs: 1.26, 95% CI: 1.10–1.51, P=0.009; death: 1.26, 95% CI: 1.01–1.58, P=0.04). An adjusted P value for interactions highlighted a significant interaction between age (75+ years) and COPD (MACEs: adjusted P=0.016; death: adjusted P=0.003).
CONCLUSIONS COPD was not seen to have a worse impact on CAD patients at two-years after PCI. Those with COPD had a similar incidence of MACEs when compared to the non-COPD group although age appears to be a significant factor for those with COPD. COPD patients older than 75 years, who receive PCI, are at a three-fold increased risk of encountering MACEs.
GW32-e1372
Ju Huang, Juan Zhao
Department of Cardiology, First Affiliated Hospital of Harbin Medical University
OBJECTIVES This study is to investigate the role of brain-derived neurothrophic factor (BDNF) in the middle-aged patients with acute myocardial infarction (AMI).
METHODS Based on clinical examination and coronary angiography, the 150 middle-aged patients were divided into three groups: the control group (Con, n=50); the group with angina pectoris [AP, coronary stenosis (CS) 50∼75%, n=50); the group with AMI (AMI or coronary occlusion, n=50), with the demographic and laboratory data collected at admission. All patients were evaluated by Hamilton anxiety scale (HAS) at admission and the 1st month after enrollment. At the same time, serum levels of BDNF, tropomyosin receptor kinase B (TrkB), endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule-1 (ICAM-1) were determined by enzyme linked immunosorbent assay (ELISA).
RESULTS Serum BDNF, TrkB and eNOS levels were gradually decreasing, by contrast, the ICAM-1 level was slowly increasing (P<0.05) from the controls to the AMI group. Moreover, serum BDNF level in the AMI group was positively correlated with the TrkB and eNOS level (r=0.594, P=0.009; r=0.548, P=0.019) and negatively correlated with the ICAM-1 levels (r=−0.555, P=0.017). The result of RT-qPCR assay also shows that the BDNF and TrkB mRNA expression in the AMI group was significantly decreased as compared with the Con and AP groups (all P<0.05).
CONCLUSIONS Taken together, these findings demonstrate that the down-regulated BDNF expression may be involved in the AMI formation of the middle-aged patients, which is closely associated with TrkB signaling pathways, subsequently by decreased eNOS and upregulated iNOS, VE-cad, VEGF-A and ICAM-1 expression.
GW32-e1500
Siqi Lv, Yanmin Yang, Jun Zhu
Fuwai Hospital
OBJECTIVES This study aims to evaluate the predictive performance of the REACH, PARIS, BleeMACS, and PRECISE-DAPT scores in Chinese patients undergoing coronary drug-eluting stent (DES) implantation.
METHODS A total of 1911 patients undergoing coronary DES implantation were consecutively recruited and followed up for 1 year. The primary endpoint was defined according to the bleeding academic research consortium (BARC) criteria as major (BARC 3a, 3b, 3c, and 5) and any bleeding (BARC 2, 3a, 3b, 3c, and 5). The secondary endpoint was major adverse cardiovascular events (MACE), referring to a composite of all-cause death, myocardial infarction, stroke, definite or probable stent thrombosis, and target vessel revascularization. The associations between the risk scores and outcomes were evaluated by univariable Cox regressions. Analysis of the receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were utilized to assess and compared the predictive performance of different bleeding risk scores.
RESULTS BARC class ≥3 bleeding occurred in 28 patients (1.5%), while BARC class ≥2 bleeding was seen in 90 patients (4.7%). The BleeMACS score and the PRECISE-DAPT score were significantly associated with 1-year risk of BARC class ≥3 bleeding, but not BARC class ≥2 bleeding. Neither the REACH score nor the PARIS score was significantly associated with BARC class ≥3 bleeding and BARC class ≥2 bleeding. The discriminative capacity of the PRECISE-DAPT score for BARC class ≥3 bleeding was moderate with a c-statistic of 0.633, while those of the REACH (c-statistic: 0.533), PARIS (c-statistic: 0.553), and BleeMACS scores (c-statistic: 0.613) were relatively low. However, the analysis of c-statistic, NRI, and IDI detected no significant discrimination improvement of the PRECISE-DAPT score for BARC class ≥3 bleeding compared to the other three scores (all P>0.05). The calibrations of the PRECISE-DAPT and BleeMACS scores were good according to the Hosmer-Lemeshow test (all P>0.05).
CONCLUSIONS In patients undergoing coronary DES implantation, the PRECISE-DAPT score performed moderately for predicting BARC class ≥3 bleeding, while the discrimination of the REACH, PARIS, BleeMACS scores were relatively low. But no significant discrimination improvement of the PRECISE-DAPT score compared to the other scores could be detected. Further studies are required to develop standardized bleeding risk scores for this population.
GW32-e1603
Haiping Cao, Kangyin Chen
The Second Hospital of Tianjin Medical University
OBJECTIVES The sex differences in outcomes of patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains disputed. Our aim was to investigate the effect of gender on prognosis in patients with NSTEMI.
METHODS A total of 3258 patients with NSTEMI were screened from the Korea Acute Myocardial Infarction Registry (KAMIR) database and stratified by gender (2214 males and 1044 females). Baseline characteristics, in hospital all-cause death, and all-cause death at 12 months were compared between the two groups. Logistic regression models were used to examine the association of sex with all-cause death during hospitalization, and cox proportional hazards models were performed to evaluate the relationship between sex and all-cause death at 12 months.
RESULTS Female patients were older (70.6 vs. 62.0 years, P<0.001), more likely to have hypertension and diabetes mellitus and more likely to die during hospitalization or at 12 months than male patients. Before considering relevant confounders, females displayed a trend to a higher risk of all-cause death during hospitalization compared with males (odds ratio [OR]: 1.372, 95% confidence interval [CI]: 0.991–1.899, P=0.056) after NSTEMI and were at higher risk of all-cause death at 12 months (hazard ratio [HR]: 1.319, 95% CI: 1.034–1.681, P=0.026). After adjustment for baseline differences, risks for all-cause death during hospitalization (OR: 0.596, 95% CI: 0.373–0.950, P=0.030) and at 12 months (HR: 0.630, 95% CI: 0.466–0.852, P=0.003) were all lower among females compared with males.
CONCLUSIONS The present study suggested that Asian female patients with NSTEMI had higher crude mortality than male patients. Females, however, were at lower risk of mortality than males after NSTEMI after adjusting for relevant confounders.
GW32-e1771
Guanqi Zhao1, Ge Wang1, Changsheng Ma2, Junbo Ge3, Yong Huo4, Yongchen Hao5, Jun Liu5, Jing Liu5, Dong Zhao5, Yaling Han6, Shaoping Nie1
1Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
2Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
3Zhongshan Hospital, Fudan University, Shanghai, China
4Department of Cardiology, Peking University First Hospital, Beijing, China
5Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
6Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China
OBJECTIVES The use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) initiated early after acute myocardial infarction (AMI) has been widely established. However, the proportion of patients receiving ACEI/ARB was consistently low in clinical practices, much lower than other therapies, such as dual antiplatelet therapy (DAPT) and statins that are considered evidence-based medications for patients with AMI. An important explanation for the low usage rate of ACEI/ARB is the clinician’s consideration of low blood pressure. However, there is no research to evaluate whether systolic blood pressure (SBP) level is an important indicator of ACEI/ARB prescription in acute phase. Therefore, this study will evaluate the effects of ACEI/ARB using within 24 hours of admission on the in-hospital outcomes according to SBP levels.
METHODS This study is based on the Improving Care for Cardiovascular Disease in China-ACS project, an ongoing collaborative registry and quality improvement project of the American Heart Association and Chinese Society of Cardiology. After excluding those with renal failure, and those with cardiac shock at admission, 90,639 AMI patients from 240 hospitals between November 2014 and December 2019 were included. Multivariable logistic regression was used to evaluate the association between ACEI/ARB use and in-hospital all-cause death.
RESULTS Of 90,639 patients with AMI, 48.93% (n=44,354) used ACEI/ARB within 24 hours of admission, with 20.41% using ACEI and 28.52% using ARB. The use rate of ACEI/ARB significantly increased with the increase of SBP, from 19.15% among patients with SBP<90 mmHg to 61.55% among those with SBP≥140 mmHg (P for trend<0.001). Patients with ACEI/ARB use had a consistent lower incidence of all-cause death, compared with those without ACEI/ARB use, no matter their SBP levels (SBP<90 mmHg: 3.40 vs. 4.11%, P=0.576; 90–99 mmHg: 1.27 vs. 2.65%, P=0.006; 100–109 mmHg: 1.19 vs. 2.54%, P<0.001; 110–119 mmHg: 1.03 vs. 1.80%, P<0.001; 120–129 mmHg: 0.96 vs. 1.57%, P=0.001; 130–139 mmHg: 0.72 vs. 1.52%, P<0.001; ≥140 mmHg: 0.83 vs. 1.57%, P<0.001), although without statistical significance among those with SBP<90 mmHg. It showed that ACEI/ARB use was significantly associated with lower risk of in-hospital all-cause death among those with SBP levels ≥100 mmHg after multivariate adjustment (SBP 100–109 mmHg: OR 0.56, 95% CI 0.39–0.81; 110–119 mmHg: OR 0.70, 95% CI 0.5–0.96; 120–129 mmHg: OR 0.72, 95% CI 0.53–0.97; 130–139 mmHg: OR 0.51, 95% CI 0.36–0.71; ≥140 mmHg: OR 0.66, 95% CI 0.52–0.82).
CONCLUSIONS In China, there was a gap between the guideline recommendation and clinical practice in the use of ACEI/ARB in AMI patients. Among patients with admission SBP≥100 mmHg, the early use of ACEI/ARB was significantly associated with the reduced risk of all-cause the death during hospitalization. This finding highlight the urgent need for improving the early use of ACEI/ARB among AMI patients in clinical practice.
GW32-e1946
Qianwen Lv, Zhiyong Du, Xiaolu Jiao, Huahui Yu, Qiuju Sun, Fan Li, Yu Wang, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES To investigate whether a metabolic signature consisting of multiple plasma metabolites can be used to characterize the metabolic response to obstructive sleep apnea (OSA) in the acute coronary syndrome (ACS) cohort and whether such a metabolic signature is associated with the cardiovascular disease (CVD) risk for patients with ACS.
METHODS Post-hoc analysis of the OSA-CVD project, including 1296 patients admitted for ACS (ChiCTR-ROC-17011027). The presence of OSA (apnea-hypopnea index ≥15 events/h) was assessed using a polysomnography (PSG) or portable polygraphy and the plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. Patients were followed up for a minimum period of one year.
RESULTS The median (IQR) follow-up was 3.17 (1.6) years. For patients with ACS, the effect of OSA showed an adjusted hazard ratio of 1.364 (95% CI, 1.021–1.816, P=0.035). We observed substantial metabolomic changes with respect to OSA, with nearly one eighth of the assayed metabolites significantly associated with OSA (false discovery rate <0.05). Using elastic net regularized regressions, we identified a metabolic signature comprised of 44 metabolites, which was robustly correlated with OSA (r=0.38 between the signature and OSA, P=0.001). In multivariable Cox regressions, the metabolic signature showed a significant coincident association with CVD incidence after adjusting for known risk factors (hazard ratio) [HR] per standard deviation increment in the signature=1.71, P<0.001, which remained after further adjustment for Gensini scores (HR=1.73, P=0.004). Further association and pathway analysis revealed that the metabolic signature was significantly associated with the parameters of OSA involved in amino acids, fatty acids metabolism and the oxidation of them.
CONCLUSIONS For ACS patients, OSA is associated with an increased risk of recurrent cardiovascular events. We identified a metabolic signature that robustly reflects metabolic response to OSA, and the presence of OSA and the associated metabolic response predict future CVD risk independent of traditional risk factors in the ACS cohort.
GW32-e0054
Duo Xu, Li Li
Department of Cardiology, CHC International Hospital, Cixi, Zhejiang 315310, China
OBJECTIVES To evaluate the impact of opportunistic use of glucocorticoid on short-term mortality in patients of acute myocardial infarction (AMI) with coronary stent implantation.
METHODS A retrospective study was performed using the MIMIC-III database derived from a large teaching hospital in Boston. According to usage of glucocorticoids (GC), the included patients were divided into two groups: GC group and no GC group. Propensity score matching was used to keep the balance of baseline between two groups before statistical processing. After matching, logistic binary regression was used to assess the association between glucocorticoid use and in-hospital mortality. Survival analysis was used to assess the association between glucocorticoid use and 30-day mortality.
RESULTS A total of 2046 inpatients were included in this study. Of these patients, 169 patients had received glucocorticoids during hospitalization. After propensity score matching, 165 patients in GC group and no GC group respectively were matched as one by one pairs. In-hospital mortality in GC group was 18.2% (30/165), and 17.6% (29/165) in no GC group. The univariate analysis showed that Wald χ2 was 0.021, OR 0.960, 95% CI 0.546–1.685, P value 0.886. Within 30 days, the survival of GC group was 84.8% (25/165), no GC group 83.6% (27/175). The log-rank χ2 was 0.011, hazard ratio 0.972, 95% CI 0.570–1.657, P value 0.916.
CONCLUSIONS The opportunistic use of glucocorticoid during hospitalization in patients of acute myocardial infarction with coronary stent implantation didn’t increase in-hospital and 30-day mortality.
GW32-e0229
Mengjiao Shao1, Jun-Yi Luo1, Xiao-Mei Li1, Yi-Ning Yang1,2
1The Frist Affiliated Hospital of Xinjiang Medical University
2Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
OBJECTIVES Obesity is an independent risk factor for coronary heart disease. We investigated that evaluate the predicting value of new obesity measures including waist-to-height ratio (WHtR), cardiometabolic index (CMI), Lipid accumulation product (LAP), Body adiposity index (BAI), visceral adiposity index (VAI) and Chinese visceral adiposity index (CVAI) were associated with coronary collateralization (CC) in chronic total occlusion (CTO).
METHODS Coronary collateralization was graded according to Rentrop scoring system in this study involved 876 consecutives in patients undergoing PCI for at least one CTO lesion. Data on demographic and clinical characteristics were collected by cardiovascular doctors. Physical examination and fasting blood lipids levels were measured at baseline. Nine obesity indexes were determined. Subgroup analysis, mixed model regression analysis, scoring systems and receive operating characteristic (ROC) curve analysis were performed to assess the predictive value of obesity indexes were associated with CC in CTO.
RESULTS Overall, 876 inpatients were assigned to the poor CC group (n=520) and good CC group (n=356). After ROC analysis and Delong test indicated that the WC, LAP, WHtR and CVAI had larger area under ROC curve than BMI, VAI and BAI in male and female, then the potential predictive value of CVAI with a best area under the ROC of 0.667 (95% CI: 0.632–0.703), followed by other obesity index. After adjustment for covariates, quartiles of CVAI remained the risk factors for CC growth in all groups, per 1 increase of CVAI was associated with a 1.010-fold higher risk of CC growth (OR=1.010, 95% CI: 1.007–1.013, P<0.001). Those individuals in the top CVAI quartile group had the highest risk of CC growth (OR=4.057, 95% CI: 2.583–6.372, P<0.001). Subgroup analyses showed similar results quartiles of CVAI remained the risk factors for CC growth.
CONCLUSIONS Our results demonstrate that CVAI was independently associated with coronary collateralization in chronic total occlusion.
GW32-e0572
Wenyuan Li, Juan Zhou, Zuyi Yuan
First Affiliated Hospital of Xi’an Jiaotong University
OBJECTIVES Too high or too low thyroid-stimulating hormone (TSH) have been associated with the progress and prognosis of coronary artery disease (CAD). However, whether TSH within their normal reference ranges play a role in the severity of CAD remains unclear. Thyroid hormones also have multiple interactions with diabetes. In the present study, we mainly explored the potential relationship of hypersensitive TSH (hs-TSH) with the severity of CAD in euthyroid patients with or without diabetes.
METHODS A total of 7357 CAD patients with euthyroidism were enrolled in this study. Of those, 1997 had diabetes and 5360 did not. The severity of CAD was evaluated through the risk of myocardial infarction (MI) and the severity of coronary lesions, which was calculated using the Gensini score (GS). Logistic regression models treating hs-TSH as a categorical variable grouped by quartiles and restricted cubic spline analyses treating it as a continuous variables were used to evaluate the associations of hs-TSH with the severity of CAD. The propensity score matching method was used to further validate the differences between diabetic and nondiabetic patients.
RESULTS CAD patients with diabetes had lower levels of hs-TSH (1.6(0.97, 2.53) vs. 1.67(1.00–2.64)) in serum compared with CAD patients without diabetes. Meanwhile, hs-TSH was independently related to the severity of CAD. In CAD patients with vs. without diabetes, the associations of hs-TSH with the severity of CAD were different. The U-shaped relationship between hs-TSH and MI was more prominent in CAD patients without diabetes, and the significant U-shaped association between higher GS and hs-TSH remained only in nondiabetes.
CONCLUSIONS hs-TSH within the normal reference range has a U-shaped association with the severity of CAD in nondiabetic patients, which is markedly diluted in diabetic patients.
GW32-e0708
Yanqiu Chen, Heyu Meng, Jianjun Ruan, Zhaohan Yan, Fanbo Meng
China-Japan Union Hospital of Jilin University
OBJECTIVES Thrombospondin-1 (THBS1) is a glycoprotein that is mainly released by activated platelets. The protein has been shown to play a role in platelet aggregation. The aim of this study is to assess whether the expression level of THBS1 in peripheral plasma can be used as a biomarker for acute myocardial infarction.
METHODS In this study, we selected 188 patients with acute myocardial infarction (AMI) as the experimental group and 163 patients with stable coronary artery disease (SCAD) as the control group. The peripheral blood was collected and then the plasma was isolated. THBS1 protein expression levels in the peripheral blood were determined by the Enzyme linked immunosorbent assay (ELISA). The two groups of clinical data were also analyzed and compared.
RESULTS The expression levels of the THBS1 protein in AMI patients was 0.87 times that in SCAD patients (P<0.05), and the level of the THBS1 protein showed low expression in AMI. The results of clinical basic data analysis demonstrated significant differences between the two groups in the risk factors of coronary heart disease (CHD) including CREA, GLU, TC, LDL-C, ApoA1, ApoB (P<0.05). Binary logistic regression analysis documented that the low expression of THBS1 protein was an independent risk factor for AMI.
CONCLUSIONS THBS1 protein is obviously lower-expressed in peripheral blood of patients with AMI. Low expression of THBS1 is an independent risk factor for the occurrence of AMI. THBS1 protein can be served as a biomarker to assess the risk of AMI.
GW32-e0995
Shiqi Yan, Yi-Tong Ma
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES Despite Drug-eluting stent (DES) have considerably reduced the rates of in-stent restenosis (ISR). ISR is still the most common limitation of percutaneous coronary intervention (PCI). The aim of this study was to investigate potential predictors on ISR in patients with DES implantation for Coronary heart disease (CAD).
METHODS A retrospective case-control study was conducted. A total of 916 patients who underwented DESs implantations and angiography follow-up within one year at the First Affiliated hospital of Xinjiang medical University, between September, 2013, and September, 2016, were included. The subjects were divided into 2 groups, ISR (n=315) and non-ISR (n=601), ISR was defined as a diameter stenosis of ≥50% located within a coronary stent or up to 5 mm beyond the stent edges. Clinical data and angiographic characteristics were collected. CAD severity was evaluated by calculating the Gensini score. The logistic regression and ROC analysis were performed to screen out efficient predictors.
RESULTS Comparation between the ISR group and the non-ISR group, Gensini Score, diastolic pressure, waist, blood glucose, left ventricular end diastolic diameter (LVED), left ventricular end systolic diameter (LVES) levels were higher in ISR group, and ApoA1, ejection fraction (EF%), and accidence of myocardial infarction (MI) were lower in the ISR group. Comparation of angiographic characteristics between the groups, the results showed the occurrence of stenosis in vessels of left main coronary artery (LM), left anterior descending artery (LAD), or right coronary artery (RCA) have more vulnerability to ISR. Patients in the ISR group have been implanted more stents. In univariate regression analysis, diastolic pressure, waist, history of MI, ApoA1, number of implanted stents, and Gensini Score were associated with ISR. After multiple logistic regression analysis, Gensini score was screen out to be an independent risk factor of ISR. Receiver operating characteristic curve analysis identified that the Gensini score was a reliable predictor for ISR, area under curve (AUC): 0.80 (0.78–0.83), Sensitivity and specificity were 73.33% and 72.33%, respectively.
CONCLUSIONS Gensini score was independently associated with ISR, and was a good predictor for ISR in patients with DES implantation.
GW32-e1134
Xiaolu Jiao, Qiuju Sun, Huahui Yu, Qianwen Lv, Fan Li, Yu Wang, Yanwen Qin
Beijing Anzhen Hospital, Capital Medical University
OBJECTIVES Angiopoietin-like protein8 (ANGPTL8), a hormone produced in liver and adipose tissue, plays important roles in lipid metabolism and atherosclerosis. Previous study showed that levels of circulating ANGPTL8 were positively associated with the severity of coronary artery disease. However, there are no clear data exploring ANGPTL8’s potential to predict cardiovascular events in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI).
METHODS We enrolled 967 consecutive patients who were referred to PCI for the established or suspected ACS from October 2016 through April 2018. Follow up time of the study was up to 2 years. Follow up data with respect to cardiovascular events was available for 897 patients. The primary outcome, major adverse cardiovascular events (MACE), was a composite of coronary death (fatal myocardial infarction, sudden cardiac death, mortality from congestive heart failure due to CAD), fatal ischemic stroke, non-fatal myocardial infarction, non-fatal ischemic stroke and need for coronary artery bypass grafting, PCI, or revascularization in the carotid or peripheral arterial beds. The second outcome was all-cause deaths. Circulating full-length ANGPTL8 levels were measured by an enzyme-linked immunosorbent assay kit. Adjusted hazard ratios for the incidence of MACE were derived from Cox proportional hazards models using z-transformation of continuous variables. Receiver operating characteristic (ROC) analysis was used to examine the potential utility of ANGPTL8 as a predictive biomarker according to their area under the curve (AUC).
RESULTS During follow-up, 152 patients suffered a MACE. Circulating ANGPTL8 levels were significantly higher in ACS patients with MACE compared with the controls (1247.26±655.17 vs. 882.66±492.95 pg/mL, P<0.001). The Kaplan-Meier plot clearly indicates that event-free survival of patients with low ANGPTL8 (<567.93 pg/mL) in serum was significantly more common than in patients with medium (567.93–814.67 pg/mL) or high (>1201.85 pg/mL) ANGPTL8. High ANGPTL8 was significantly and positively associated with MACE both univariately (HR=1113 [95% CI 1.080–1.146], P<0.001) and after adjusting for confounding factors including the age, gender, BMI, smoking habit, SBP, DBP, TG, TC, LDLC, HDL-C, ALT, and creatinine (adj. HR=1.118 [1.1078–1.159], P<0.001). According to ROC curve analysis, the inclusion of ANGPTL8 in a default cardiovascular risk model (including age, sex, BMI, LDL, HDL, triglycerides, and hypertension status, the current smoking status and the diabetes mellitus type 2 status) significantly improved its predictive performance for MACE (AUC: 0.702 vs. 0.589) in ASC patients treated with PCI.
CONCLUSIONS This study shows that circulating ANGPTL8 levels are an independent risk factor for MACE and ANGPTL8 predicts MACE independently of conventional risk factors.
GW32-e1238
Zefeng Chen, Xing Shui, Shunxiang Li, Lin Chen
Department of Cardiovascular Medicine, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
OBJECTIVES Depression and cardiovascular diseases are associated with each other. This study investigated risk and predictors of depression following acute myocardial infarction.
METHODS Clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database. The MIMIC-III database contains more than 50,000 intensive care patients. Acute myocardial infarction patients from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database with depression related data were enrolled. Logistic analyses were used to investigate predictors of depression following acute myocardial infarction patients. Multivariate analyses were used to control confounders.
RESULTS Two thousand and ninety-seven acute myocardial infarction patients were enrolled. The average age of this population is 68 years old and 36.1% of them are female. 9.6% (201/2097) of them have hypertension and 22.1% (465/2097) of them have diabetes. 3.3% (69/2097) of them have stroke history. 3.1% (65/2097) of them have alcohol abuse and 2.0% (42/2097) of them have drug abuse. 4.8% (101/2097) of them were diagnosed with depression before discharge. Thirty-day mortality of this population was 16.7% (352/2097). In the model adjusted for multiple confounders, gender (male) (OR=0.413, 95% CI: 0.218–0.783, P=0.007) and partial pressure of arterial carbon dioxide (OR=1.033, 95% CI: 1.006–1.060, P=0.016) showed significant correlation with the incidence of depression.
CONCLUSIONS Female sex and partial pressure of arterial carbon dioxide are risk factors of depression following acute myocardial infarction.
GW32-e1375
Haoyu Wang
Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Diabetes mellitus (DM) is frequently encountered in patients who underwent PCI and contributes to a prothrombotic state and residual cardiovascular risk, posing unique challenges in the antiplatelet management of such patients due to a higher risk for ischemic events and mortality than patients without DM. Diabetic patients often have many other concomitant co-morbidities that predispose them at high ischemic risk, which suggests that this high-risk population may derive particular benefit from prolonged use of DAPT. The efficacy and safety of prolonged (>1-year) dual antiplatelet therapy (DAPT) duration in high-risk patients with DM undergoing PCI remain unknown.
METHODS All patients undergoing PCI at our hospital between January 2013 and December 2013 were prospectively enrolled into our hospital PCI registry. Three thousand six hundred and ninety-six high-risk diabetics patients with at least one additional atherothrombotic risk factor (age ≥65 years, current smoking, chronic renal dysfunction with estimated glomerular filtration rate <60 mL/min, heart failure, peripheral artery disease [PAD], history of ischemic stroke, history of myocardial infarction [MI], multivessel coronary artery disease [CAD]) were screened for inclusion. The primary efficacy outcome was the composite of all-cause mortality, myocardial infarction, or stroke.
RESULTS The median follow-up duration was 887 days. 69.8% of DM patients were on DAPT at 1 year without discontinuation. Based on multivariate Cox regression model and inverse probability of treatment weighting (IPTW) analysis, long-term (>1-year) DAPT reduced the risk of primary efficacy outcome (1.7 vs. 4.1%; adjusted hazard ratio [adjHR]: 0.382, 95% confidence interval [CI]: 0.252–0.577; IPTW-HR: 0.362 [0.241–0.542]), as well as cardiovascular death and definite/probable stent thrombosis, compared with short-course (≤1-year) DAPT. Risk of the safety endpoint of clinically relevant bleeding (adjHR: 0.920 [0.467–1.816]; IPTW-HR: 0.969 [0.486–1.932]) was comparable between longer DAPT and shorter DAPT. A lower number of net clinical benefit adverse outcomes was observed with >1-year DAPT versus ≤1-year DAPT (adjHR: 0.471 [0.331–0.671]; IPTW-HR: 0.462 [0.327–0.652]), which appeared increasingly favorable in those with multiple atherothrombotic risk characteristics.
CONCLUSIONS In high-risk patients with DM receiving PCI who were event free at 1 year, DAPT prolongation resulted in significant reduction in the risk of ischemic events not offset by increase of clinically meaningful bleeding events, thereby achieving a net clinical benefit. Extending DAPT beyond the period mandated by guidelines seems reasonable in high-risk DM patients not deemed at high bleeding risk.
GW32-e1539
Xiaoqun Wang1, Weifeng Shen2
1Department of Cardiology, Rui Jin Hospital, Shanghai Jiao-Tong University School of Medicine
2Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China
OBJECTIVES Coronary collaterals provide salvaging effect on the ischemic myocardium subtended by occluded coronary artery. We investigated the relation of chromogranin B (CgB) and collateral conditions to left ventricular (LV) functional improvement after successful recanalization of chronic total occlusion (CTO).
METHODS Serum level of CgB was assayed in 237 patients with stable angina and CTO of at least one major coronary artery. The degree of coronary collaterals supplying the distal aspect of a total occlusion was graded according to Rentrop classification. Two-dimensional echocardiography was performed before and 12 months after successful recanalization of CTO.
RESULTS Serum levels of CgB were comparable between patients with poor and good collaterals (934 [IQR 315∼2422] pg/mL vs. 1124 [IQR 436∼2674] pg/mL, P=0.530). CgB correlated positively with NT-proBNP level (Pearson’s r=0.42, P<0.001) both in patients with poor and good collaterals, and was inversely related to LV ejection fraction (Pearson’s r=−0.23, P=0.007) only in good collateral condition. At 12 months, the increase in LV ejection fraction was reduced stepwise across tertiles of serum CgB in patients with poor collaterals (P=0.031) but not in those with good collaterals (P=0.124). After multivariate adjustment, elevated serum CgB remained an independent determinant of impaired LV functional improvement after recanalization of CTO lesions with low collateralization.
CONCLUSIONS LV function and its recovery potential in CTO patients are associated with CgB level and collateral conditions. Elevated circulating CgB level may serve as a surrogate biomarker of impaired LV functional improvement after successful CTO recanalization in patients with poor coronary collaterals.
GW32-e1607
Yuexi Wang, Yingjun Zhang
1st Affiliated Hospital of Inner Moglia Medical University
OBJECTIVES The purpose of this study is to explore the effect of the combination of Chinese and western medicine on coronary stent restenosis effect and endothelial function after stent intervention.
METHODS This study included 84 cases of in-stent restenosis, 40 cases in the experimental group of drug balloon combined with Guanxin Qiwei tablet, and 44 cases in the control group of dilation with drug balloon alone. This study collected the general information of patients before and after operation and the results of angiography before and after operation, and then followed up for 6 months, and evaluated the levels of nitric oxide (NO) and endothelin (ET) before and after treatment. And then this study evaluated the efficacy of the drug balloon dilatation control group and its effect on endothelial cell function.
RESULTS (1) According to the postoperative data, there was no significant difference in the length, diameter, degree of stenosis, minimum diameter, NO and ET (P>0.05). (2) After a follow-up of 6 months, the experimental group and the control group were compared in terms of the degree of stenosis (19.53±4.59% vs. 20.94±4.70%), the rate of late vessel loss (0.12±0.28 mm vs. 0.12±0.35 mm), the number of restenosis cases (2 vs. 4), MACE events (all cause death, non lethal myocardial infarction or target lesion TLR or TVR) are 4 vs. 6. There were no significant statistical differences between the two groups (P>0.05). (3) In terms of recurrent angina, there were statistical differences between the experimental group and the control group (P=0.04<0.05). (4) The measured value of NO group after treatment was significantly higher than that before treatment (42.43±4.17 μmol/L vs. 33.17±3.14 μmol/L), compared with the control group (37.12±3.37 μmol/L vs. 33.04±3.12 μmol/L), there were no significant statistical differences between the two groups before treatment (P=0.85, >0.05), and there were significant statistical differences after treatment (P=0.00<0.05).
CONCLUSIONS (1) The combination of drug balloon and Guanxin Qiwei tablet can improve the ISR lesions. (2) Drug balloon expansion is safe and effective in treating ISR patients, and it is still the main treatment method. (3) The drug balloon combined with Guanxin Qiwei tablet has a significant therapeutic effect on recurrent angina pectoris in ISR patients.
GW32-e1782
Pengfei Gong, Pengyi He, Muhuyati Wulasihan
The First Affiliated Hospital of Xinjiang Medical University
OBJECTIVES To evaluate the efficacy and safety of bivalirudin on percutaneous coronary intervention (PCI) in patients with ST-segment Elevation Myocardial Infarction (STEMI).
METHODS A retrospective study was performed on 400 patients with ST-segment Elevation Myocardial Infarction (STEMI) who received PCI in the emergency Center of the First Affiliated Hospital of Xinjiang Medical University in recent three years. Patients were divided into the Bivalirudin-treated group (n=203) and heparin + Tirofiban-treated group (n=197). In heparin + Tirofiban group, patients were preoperatively treated with common heparin sodium 100 U/kg and tirofiban 10 μg/kg intravenously as loading dose, and tirofiban was maintained at 0.15 μg/(kg⋅min) for 18–36 h. In bivalirudin-treated group: the preoperative intravenous loading dose was 0.75 mg/kg, intraoperatively maintained at 1.75 mg/(kg⋅h) until the end of operations, and the postoperatively maintained at 1.75 mg/(kg⋅h) (the average duration was 190 min). In heparin+Tirofiban group: the preoperative intravenous injection loading dose: common heparin sodium 100 U/kg and tirofiban 10 μg/kg, tirofiban was maintained at 0.15 μg/(kg⋅min) for 18–36 h. Postoperative bleeding events were recorded at two time points, namely, 30 days, and one year after operations. The rate of postoperative bleeding events and the occurrence rate of major adverse cardiac and cerebrovascular events (MACCE) were then compared between two groups.
RESULTS A total of 397 patients (99.3%) completed the 30-day, and 1-year follow-up. There was no significant difference in basic clinical conditions and data of interventional surgery between the two groups. Overall, 30-day bleeding events occurred in 10 patients (4.9%) in the bivalirudin group and in 22 patients (11.2%) in the heparin + tirofiban group (RR, 0.44; 95% CI, 0.21–0.91; P=0.003). The rates of MACCE were 3.4% in bivalirudin group, and 10.1% in heparin + tirofiban group during the first 30 days after operation, respectively (P=0.009), and were 5.9% and 16.2% (P=0.001) within one postoperative year, respectively. There were 19 bleeding events in the bivalirudin group (9.4%) and 26 bleeding events in the heparin + tirofiban group (13.2%) during 1-year-follow up (RR, 0.71; 95% CI, 0.41–1.24; P=0.27).
CONCLUSIONS The application of bivalirudin in STEMI patients with perioperative of PCI is safe and effective, It is beneficial to reduce bleeding and MACCE.
GW32-e0060
Yue Ma
Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Percutaneous coronary intervention (PCI) is the treatment of myocardial ischemia perfusion by using cardiac catheter technique to dredge the stenosis or occlusion of the coronary artery. There is a certain proportion of in-stent restenosis (ISR) after stent implantation that causes problems clinically. ISR involves many pathologic mechanisms, including intraplaque inflammation, lipid deposition, proliferation of vascular smooth muscle cells, endoluminal thrombus formation, and intraplaqu angiogenesis. Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelin 1 (ET-1) is a potent vasoconstrictor that in patients with coronary artery disease is related with the occurrence of cardiovascular events. However, the low circulating concentration and the short half-life of ET-1 make it difficult to measure, big endothelin-1 (Big ET-1) is the precursor of ET-1 and has the same measurement value. The aim of this study is to investigate the relationship between big endothelin-1 and the risk of in-stent restenosis in patients with coronary artery disease undergoing PCI.
METHODS After retrieving the patient database, 3098 patients who diagnosed with coronary artery disease and underwent percutaneous coronary intervention (PCI) at Fuwai hospital from October 2014 to March 2015 were enrolled. All patients received standard dual therapy with aspirin 100 mg/day and clopidogrel 75 mg/day for 12 months following PCI. The patient’s level of plasma big endothelin-1 (Big ET-1), general condition, related risk factors of admission, other laboratory examination, coronary lesion characteristics, interventional therapy and other baseline data was recorded. All patients were followed up for the occurrence of in-stent restenosis (ISR) and other cardiovascular events. ISR was defined as the presence of >50% diameter stenosis in the stented segment. Statistical software SPSS22.0 was used for data analysis of the clinical epidemiological characteristics and prognosis. The study followed the principles outlined in the Declaration of Helsinki and it was approved by the ethics committee.
RESULTS In all participants, the level of plasma big endothelin-1 (Big ET-1) is associated with the risk of in-stent restenosis (ISR). Patients with a higher level of plasma Big ET-1 (>0.25 pmol/L) had a significantly higher incidence of ISR (2.89 vs. 0.44%, P=0.011) and incidence of angina after stent implantation (13.2 vs. 2.8%, P=0.007) during the follow-up. In logistic multivariable analysis, high level of plasma Big ET-1 (HR 1.968, 95% CI 1.083–5.022, P=0.031) was significantly associated with incidence of ISR.
CONCLUSIONS Elevated level of plasma big endothelin-1 is associated with the risk of in-stent restenosis in patients undergoing percutaneous coronary intervention.
GW32-e0264
Xinghui Li1, Zhi-He Da2, Cun-Wen Deng3, Ping Xie1, Jun-Xian Han4, Yong-Fen Hua5
1Department of Cardiology, Gansu Provincial Hospital, Lanzhou
2Department of Cardiology, Wuwei Hospital of Traditional Chinese Medicineu of Gansu Province
3Department of Cardiology, Jiuquan People’s Hospital of Gansu Province
4College of Clinical Medicine, Lanzhou University
5College of Clinical Medicine, Ningxia Medical University
OBJECTIVES To observe and analyze the influence of sandstorm weather on the incidence of coronary heart disease (CHD) in Gansu Hexi corridor.
METHODS The sandstorm weather data in Hexi Corridor of Gansu Province from January 1, 2016 to December 31, 2020 were obtained from Gansu Meteorological Bureau. A total of 1500 residents were selected as the exposure group. The same number of residents in the less sandstorm area of Southeast Gansu Province were selected as the control group, and the relevant factors were matched. The subjects were followed up and examined regularly, including outpatient, emergency and inpatient registration of CHD, inflammatory factors testing included C-reactive protein (CRP), Interleukin-1 (IL-1), Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2), and routine ECG and echocardio-graphy examination.
RESULTS The frequency of sandstorm in Hexi corridor was higher than that in Southeast of Gansu province (P<0.05). The number of outpatients, inpatients of CHD and unstable angina pectoris in exposure group were higher than those in control group (P<0.05). CRP, IL-1, TNF-αand MIP-2 in exposure group were higher than that in control group (P<0.05). The proportion of ECG with myocardial ischemia or infarction and arrhythmia in exposure group was higher than that of control group (P<0.05), and the proportion of echocardiography with cardiac cavity enlargement and LVEF<50% in exposure group was higher than that of control group (P<0.05).
CONCLUSIONS Sandstorm weather can induce the incidence and progress of CHD in Hexi Corridor, Gansu Province. Local people need to minimize personal exposure and strengthen sandstorm control.
GW32-e0581
You Zhang1,2,3, Shan Wang1,2,3, Chuanyu Gao1,2,3
1Central China Fuwai Hospital of Zhengzhou University, Henan Provincial People’s Hospital Heart Center
2Henan Institute of Cardiovascular Epidemiology
3Henan Key Laboratory for Prevention and Control of Coronary Heart Disease
OBJECTIVES To assess differences in reperfusion treatment and outcomes between secondary and tertiary hospitals in predominantly rural central China.
METHODS The prospective Henan STEMI registry has consecutively enrolled patients with STEMI within 30 days of symptom onset in 50 secondary and 16 tertiary hospitals in Henan from 2016 to 2018. The primary outcomes were in-hospital mortality, and in-hospital death or treatment withdrawal.
RESULTS Among 5063 patients of STEMI, 2553 were treated at secondary hospitals. Reperfusion (82.0 vs. 73.0%, P<0.001) including fibrinolytic therapy (70.3 vs. 4.4%, P<0.001) were more preformed, whereas primary PCIs (11.7 vs. 68.6%, P<0.001) were less frequent at secondary hospitals. In secondary hospitals, 53% received fibrinolytic therapy 3 hours after onset, and 5.8% underwent coronary angiography 2–24 hours after fibrinolysis. Secondary hospitals had a shorter onset-to-first-medical-contact time (176 min vs. 270 min, P<0.001). Adjusted in-hospital mortality (4.6 vs. 3.2%, adjusted OR 1.23, 95% CI 0.89–1.70) and in-hospital death or treatment withdrawal were similar (8.6 vs. 6.9%, adjusted OR 1.18, 95% CI 0.82–1.70) between secondary and tertiary hospitals.
CONCLUSIONS With fibrinolytic therapy as the main reperfusion strategy, the reperfusion rate was higher in secondary hospitals, whereas in-hospital outcomes were similar compared with tertiary hospitals. Public awareness, establishment of integrated regional network, and the medical care capacity of secondary hospitals need to further improve.
GW32-e0806
Suining Xu, Kun Lian, Chengxiang Li
Department of Cardiology, Xijing Hospital, Fourth Military Medical University
OBJECTIVES This study was scheduled to explore the efficacy and safety of ticagrelor in comparison with clopidogrel on a background of aspirin for elderly Chinese CAD patients during 12 months follow-up after PCI.
METHODS We assigned CAD patients aged ≥75 years from January 2010 to July 2019, and 908 patients complied with DAPT after PCI for up to 12 months were enrolled in the study. The included patients received ticagrelor in combination with aspirin (n=264) or clopidogrel in combination with aspirin (n=644). Efficacy endpoints were evaluated by the major adverse cardiac events (MACE), encompassing all-cause death, nonfatal myocardial infarction and clinically driven revascularization. The safety endpoints were recorded as the incidence of BARC bleeding.
RESULTS The patients who took ticagrelor were younger than those who took clopidogrel (79.13±3.70 vs. 80.69±4.54, P<0.01). Males accounted for 69.70% in the ticagrelor group and 70.81% in the clopidogrel group. Compared with the clopidogrel cohort, a higher percentage of patients had prior PCI (37.88 vs. 24.53%, P<0.01), whereas a lower percentage of patients were smokers (19.32 vs. 27.17%, P<0.05) in the ticagrelor cohort. The level of Glucose, TG and LDL-C in the ticagrelor group were higher than those in the clopidogrel group, yet the level of TC and HDL-C were lower (P<0.05). Left main (LM) PCI was performed more frequently among the ticagrelor patients (23.48 vs. 9.32%, P<0.0001), while patients in the clopidogrel group suffered more from left circumflex (LCX) PCI (34.32 vs. 23.11%, P<0.01). The two groups were well balanced in terms of clinical and angiographic characteristics. We found that ticagrelor had more benefits than clopidogrel did in the reduction of the incidence of MACE with IPTWs model (IPTW-OR, 0.493; 95% CI: 0.356–0.684). There was no significant difference in terms of the risk of BARC bleeding between the patients who took ticagrelor and clopidogrel (P>0.05).
CONCLUSIONS During 12 months after PCI, ticagrelor outperformed clopidogrel in elderly Chinese CAD patients in reducing MACE without increasing the incidence of BARC bleeding events.
GW32-e1003
Aibibaimu Aizezi, Dilare Adi, Yi-Tong Ma
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES The purpose of this study was to investigate the predictive value of SYNTAX score II combined with TyG index for adverse cardiovascular events after percutaneous coronary intervention (PCI) in patients with acute ST segment elevation myocardial infarction and multivessel disease.
METHODS From January 2014 to January 2020, 946 patients with ST segment elevation myocardial infarction complicated with multivessel disease were enrolled in this retrospective cohort study. The general clinical data, laboratory examination results, coronary angiography results and medication were collected. According to the prognosis, they were divided into good prognosis group (n=659) and poor prognosis group (n=287). According to the area under the ROC curve of TyG index, the patients were divided into low TyG index group (TyG<10.04, n=558) and high TyG index group (TyG≥10.04, n=388). According to the SYNTAX score II International score standard, the patients were divided into low SSII group (0–22, n=490), medium SSII group (23–32, n=371) and high SSII group (≥33, n=85). Multivariate Cox regression model was used to analyze the influencing factors of adverse cardiovascular events. The diagnostic value of SYNTAX score II combined with TyG index for adverse cardiovascular events was evaluated by likelihood ratio test, Akaike information criterion (AIC), receiver operating characteristic (ROC) curve, net weight classification improvement (NRI) and comprehensive differentiation improvement (IDI).
RESULTS During the follow-up period of 24 months, with the increase of SYNTAX score II and TyG index, the incidence of adverse cardiovascular events increased significantly (P<0.05). The survival time of low TyG index group was longer than that of high TyG index group (P<0.05). Multivariate COX regression analysis showed that SYNTAX score II and TyG index were independent risk factors for adverse cardiovascular events in STEMI patients with multivessel disease after PCI (HR=1.616 and 1.165, 95% CI: 1.201–2.176 and 0.988–1.046, P<0.05). ROC curve analysis showed that SYNTAX score II and TyG index had diagnostic value in predicting adverse cardiovascular events in STEMI patients with multivessel disease after PCI. When SYNTAX score II and TyG index were combined, the diagnostic efficiency increased: [AUC: (SSII: 0.612 vs. SSII + TyG index: 0.729, P<0.05)]. The maximum likelihood estimation method was used to estimate the parameters, and AIC analysis was performed to select the best prediction model. It was concluded that syntax II score combined with TyG index had better fitting, and AIC value was lower (all P<0.001). With the inclusion of TyG index, the net weight classification index and overall differentiation index of SYNTAX score II model for diagnosing the risk of adverse cardiovascular events in STEMI patients with multivessel disease were significantly increased (NRI=0.319, P<0.001, P<0.001; IDI=0.034, P<0.001).
CONCLUSIONS The combination of TyG index and SYNTAX score II can better predict long-term adverse cardiovascular events in patients with acute STEMI and multivessel disease, which is expected to be applied to clinical prognosis evaluation.
GW32-e1150
Tian Xu, Xiangqi Wu, Wei You, Zhiming Wu, Fei Ye
Nanjing First Hospital
OBJECTIVES In this retrospective study, we used optical coherence tomography (OCT) to analyze the “half-moon” like phenomenon of myocardial bridge (MB) in left anterior descending (LAD) coronary artery by intravascular ultrasound (IVUS) detection, and its characteristics and explored its clinical role in guiding the drug-eluting sent (DES) implantation.
METHODS From Jan 2013 to Dec 2019, the first forty-five patients who received both IVUS and OCT detection for LAD were divided into non-MB group (n=25), mild-MB group (n=16), and moderate to severe MB group (n=4) based on angiography and IVUS data. Characteristics and definition of MB in OCT were specified. Then, among the next 2676 patients with OCT detection, 626 patients with high quality OCT imaging of LAD MB were divided into non-MB (n=326), mild MB (n=204), moderate MB (n=75), and severe MB (n=21) groups based on angiography findings. Finally, the incidence of in-stent restenosis (ISR) was compared between 4 groups at 1-year follow-up.
RESULTS In the first 45 patients, compared with IVUS findings, we found a visible muscular layer with the same density as the media smooth muscle layer around the same segment vessel adventitia, which was only found in cases where MB was found in IVUS and located at the comparable position of the “half-moon” layer. Maximal thickness, arch, and total length of the “half-moon” layer were significantly positively related with those of the muscular layer, respectively (r=0.962, 0.985, 0.742, P<0.01). Besides, the larger the thickness and arch of a muscular layer around the vessel adventitia, the more severe the myocardial bridge (P<0.05). At 1-year follow-up, there was no significant difference in ISR in MB not covered by DES(s) among the 4 groups (P>0.05). However, ISR in MB covered by DES(s) showed a notable difference among 4 groups (P<0.05), and ISR in DES(s) aggravated with the MB severity.
CONCLUSIONS OCT could also evaluate the characteristics of a visible muscular layer around the vessel adventitia in patients with MB accurately compared to IVUS. OCT had a higher rate of detecting MB than CAG. Finally, it is safe and effective to guide DES covering the mild MB segment in patients with severe coronary lesions detected by the OCT.
GW32-e1293
Haoyu Wang
Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES The present study sought to examine the prevalence, clinical characteristics and long-term outcomes of patients undergoing percutaneous coronary intervention (PCI) to complex lesions (3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, treatment of chronic total occlusion, unprotected left main PCI, in-stent restenosis target lesion, and severely calcified lesion) in a prospective registry.
METHODS Ten thousand and one hundred sixty-seven consecutive patients undergoing PCI were prospectively enrolled in Fuwai PCI Registry. Clinical outcomes were stratified by procedure complexity, and further by number and type of complex features. The primary ischemic endpoint was 30-month major adverse cardiovascular events (MACE) (composite of cardiac death, myocardial infarction, definite/probable stent thrombosis, and target lesion revascularization), and primary bleeding endpoint was 30-month Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding.
RESULTS Of 10,167 patients (mean age: 58.3±10.3 years) with available angiographic characteristics, 3651 (35.9%) underwent complex PCI. Patients who underwent complex PCI were more likely to be elderly and male with a high prevalence of diabetes mellitus and hypertension. Subjects with complex PCI were more likely to display involvement of thrombotic lesion, type B2/C lesion, and higher SYNTAX scores. In adjusted Cox regression analysis, patients having complex PCI procedures experienced higher risks of MACE (hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.38–1.92; P<0.001), MI (adjusted HR: 2.16 (1.62–2.87); P<0.001), definite/probable ST (adjusted HR: 2.71 (1.66–4.41); P<0.001), and TLR (adjusted HR: 1.59 (1.29–1.95); P<0.001), compared with noncomplex PCI. In contrast, the risk of clinically relevant bleeding was statistically similar between the 2 groups (HR: 0.86 [0.66–1.11]; P=0.238). By including complex PCI as a continuous variable within the same multivariable models, the risk of MACE tended to be greater as the number of high-risk procedural characteristics increased (per number of complex PCI variables increase, adjusted HR: 1.16, 95% CI: 1.09–1.23; P<0.001). Individual high-risk features, such as ≥3 stents implanted, bifurcation with 2 stents, >60 mm total stent length, in-stent restenosis target lesion, and severely calcified lesion, are independent predictors for MACE but not for clinically relevant bleeding.
CONCLUSIONS Compared with noncomplex PCI, PCI complexity was associated with a considerably higher risk of adverse ischemic events. The findings provide operators with novel insights regarding clinical outcomes of individual complex features and emphasize that the number and types of complex features both have an impact on procedural outcomes.
GW32-e1396
Jingyi Li, Qian Chen, Xueqing Zhu, Lihong Xu, Wei Wu, Zhenyu Liu
Peking Union Medical College Hospital
OBJECTIVES Although enoxaparin 0.5 mg/kg is a recommended anticoagulation regimen for percutaneous coronary intervention (PCI), a randomized study demonstrated that more patients receiving enoxaparin 0.75 mg/kg compared to those receiving 0.5 mg/kg achieved therapeutic anticoagulation without increase of major bleeding. However, no detailed data regarding the anticoagulation profile of enoxaparin 0.75 mg/kg was reported in the study. Therefore, we prospectively assessed the anticoagulation profile of enoxaparin 0.75 mg/kg vs. 0.5 mg/kg in troponin-negative patients undergoing elective trans-radial coronary angiography (CAG).
METHODS Eligible patients were randomly assigned to receive enoxaparin 0.75 mg/kg (High-dose group) or 0.5 mg/kg (Standard-dose group) before CAG. Patients underwent subsequent PCI in each group were excluded. Anti-Xa levels were assessed at 0 min (immediately before), 10 min, and 90 min after enoxaparin administration. Therapeutic anticoagulation was defined as anti-Xa level of 0.5–1.8 IU/mL. Bleeding was according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.
RESULTS The baseline characteristics were well balanced between the two groups. The anti-Xa levels were higher in the High-dose group (n=48) vs. the Standard-dose group (n=47) both at 10 min (1.354±0.228 IU/mL vs. 0.976±0.213 IU/mL, P<0.001) and 90 min (0.827±0.195 IU/mL vs. 0.583±0.169 IU/mL, P<0.001). The percentages of patients with therapeutic anticoagulation were similar at 10 min (100% [46/46] vs. 100% [46/46], P=1.000) but higher at 90 min (100% [41/41] vs. 75% [33/44], P=0.001) in the High-dose group vs. the Standard-dose group. No TIMI major or minor bleeding occurred within 24 h of randomization in both groups.
CONCLUSIONS Enoxaparin 0.75 mg/kg compared to 0.5 mg/kg provided higher anticoagulation which was adequate for up to 90 min of administration. Enoxaparin 0.75 mg/kg would be a superior anticoagulation regimen for PCI, especially when the procedure duration is long.
GW32-e1549
Hengdao Liu, Heping Gu, Hailong Tao
The First Affiliated Hospital of Zhengzhou University
OBJECTIVES Drug eluting stent (DES) plus Drug coated balloon (DCB) is a safe and effective treatment strategy for coronary artery bifurcation lesions, but there is no report about this strategy used for left main (LM) bifurcation lesions. We aim to explore the efficacy and safety of DES plus DCB in the treatment of LM bifurcation lesions.
METHODS Total 100 patients diagnosed with LM bifurcation lesions by coronary angiography were enrolled. They received either two-stent strategy or main branch (MB) stenting plus side branch (SB) DCB strategy, and accordingly divided into the 2-DES group and DES+DCB group. Clinical data was collected and quantitative coronary analysis was performed.
RESULTS For immediate postoperative angiography, though two groups had no differences in the minimal luminal diameter (MLD) and luminal stenosis of MB, the DES+DCB group had significantly lower SB ostial MLD and higher degree of residual lumen stenosis than the 2-DES group (P<0.05). At the time of follow-up, the SB ostial MLD of the DES+DCB group was higher than that of the 2-DES group, but lumen stenosis, late lumen loss (LLL), and LLL at the distal end of the left MB were all smaller than those of the 2-DES group (Ps< 0.05). Furthermore, the incidence of lumen restenosis and MACE between the two groups had no significance.
CONCLUSIONS The combination of DES and DCB is relatively safe and effective for the treatment of LM bifurcation lesions, and this strategy seems to have advantages in reducing LLL at the SB ostium.
GW32-e1609
Yuexi Wang, Rong A
1st Affiliated Hospital of Inn Mogolia Medical University
OBJECTIVES To investigate the effect of oral allopurinol alone, pure hydration and allopurinol combined with hydration on coronary heart disease (CHD) and hyperuricemia patients with percutaneous coronary intervention (PCI). There is no significant difference in the preventive effect of CIN.
METHODS The hydration group (n=40), the allopurinol group (n=40), the allopurinol+hydration group (n=40) and the control group (n=40). The hydration group was given 1 mL/(kg×h) of water before operation to 6 h after operation the speed and total amount of intravenous infusion can be adjusted individually according to the heart function, renal function, urine volume and weight of the selected subjects. The patients in the allopurinol group took allopurinol tablets of 300 mg (100 mg once, 3 times a day) within 24 hours before PCI, and the allopurinol+hydration group was given with the hydration and allopurinol before operation.
RESULTS There was no statistical significance in the comparison of baseline data between the four groups, which was comparable; the data of the comparison group of SCr and eGFR were statistically significant before and after operation. There was no statistical significance between the allopurinol group, the allopurinol+hydration group and the postoperative 24 h and 48 h after operation. There was no statistical difference between the two groups before and after operation. There was a statistical difference between the two groups. The results showed that there was no statistical significance in the comparison of the other data. The data between the comparison groups were as follows: the data of the hydration group, allopurinol group, the hydration+allopurinol group were compared with the control group, and the differences between the three groups were not statistically significant, which was comparable. The results showed that the results showed that there was no significant difference between the three groups, and there was no statistical significance between the three groups. The results showed that the results showed that the results showed that the results showed that there was no significant difference between the three groups. The results showed that the difference was statistically significant. No adverse drug reactions occurred in the patients who were selected in the study, and no adverse events occurred in the follow-up within half a year after operation.
CONCLUSIONS 1. The treatment of preoperative hydration, allopurinol and allopurinol can effectively reduce the incidence of CIN in patients with coronary heart disease and hyperuricemia after PCI; 2. There is no significant difference between allopurinol treatment and hydration combined with allopurinol treatment in the prevention of CIN after PCI in patients with coronary heart disease and hyperuricemia. The effect of pure hydration may be slightly inferior to that of pure allopurinol treatment and combination of allopurinol treatment and hydration.
GW32-e1788
Zejia Wu1, Liwen Li2,3
1Affiliated Dongguan People’s Hospital, Southern Medical University (Dongguan People’s Hospital)
2Guangdong Cardiovascular Institute
3Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences
OBJECTIVES The purpose of the current study was to investigate the effect of chronic kidney disease (CKD) on the prognosis in patients with ischemic heart failure (IHF).
METHODS This is a prospective cohort study and participants with IHF were consecutively enrolled from the Department of Cardiology, Guangdong Provincial People’s Hospital from December of 2015 to June of 2019. Participants were followed through October 15th, 2020 using phone call interview. Participants were followed until the occurrence of clinical endpoint, which was defined as all-cause mortality. Length of follow-up was calculated using the date of the last follow-up or the date of death minus the date of discharge from index hospitalization.
RESULTS One thousand and five hundred sixty-eight patients with IHF were included (mean age of 63.5±11.0 years, 85.8% men) from December 2015 to June 2019. Patients were divided into the CKD (n=434) and non-CKD (n=1134) groups based on the estimated glomerular filtration rate of 60 mL/min/1.73 m2. The incidence rate of all-cause mortality in CKD and non-CKD patients was 13.7 per 100 person-years and 6.1 per 100 person-years, respectively, with an incidence rate ratio of 2.44 (95% confidence interval: 1.89–3.15; P-value <0.001). After a median follow-up of 2.1 years, the cumulative incidence rate of all-cause mortality in CKD and non-CKD patients was 40.7% and 19.4% (P-value=0.05). Adjusted for multiple covariates, CKD were still associated with all-cause mortality (hazard ratio: 1.35, 95% confidence interval: 1.03–1.76, P-value=0.029). In patients with IHF, all-cause mortality was consistently increased with CKD as compared with non-CKD in 8 subgroups. With the decrease of eGFR, the risk of all-cause mortality in patients with IHF gradually increased.
CONCLUSIONS CKD is an important risk factor for poor prognosis in patients with IHF. Management of CKD is essential to reduce all-cause mortality in IHF patients.
HYPERTENSION
GW32-e1754
Nina Shurkevich1, Alexander Vetoshkin1,2, Lyudmila Gapon1, Sergey Dyachkov1, Ani Simonyan1
1Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
2Medical Unit “Gazprom dobycha Yamburg” LLC
OBJECTIVES To study gender differences in potential risk factors for cardiovascular diseases in rotational shift workers in the Arctic.
METHODS Within 6 days of September 2019, in the polar settlement of Yamburg (68 N), on the basis of Yamburggazdobycha LLC medical unit, out of 213 registered and examined patients, 183 individuals were enrolled in groups, comparable by age: 99 were males (M) with mean age of 48 years (41.5; 58.5) and 81 were females (F) with mean age of 49 years (43.6; 58.1) (P=0.441); by number of years of rotational shift work: 16.5 (9.0; 26.4) years in M and 16.3 (8.5; 26.9) years in F (P=0.635); by number of individuals with arterial hypertension (AH): 49.5% were M, 43.9% were F (P=0.344) and normotensive individuals (P=0.544). Office BP was 149.4 (119.1; 180.2) mmHg in M group, 149.6 (128.5; 178.5) mmHg in F group (P=0.250). Ultrasound examination of carotid arteries (CA) was performed with detection of atherosclerotic plaque (ASP) presence/absence, calculation of local stiffness parameters of CA and femoral arteries (FA); cardio-ankle vascular index (CAVI), pulse wave velocity (PWV) were investigated. According to the standard method ABPM, EchoCG with calculation of HFpEF probability using H2FPEF score (Heavy; Hypertensive; Atrial Fibrillation; Pulmonary Hypertension; Elder; Filling Pressure) were carried out; biochemical blood test was conducted to determine lipid spectrum, concentration of high-sensitivity C-reactive protein (hs-CRP), homocysteine, C-peptide, insulin, level of brain natriuretic peptide precursor (NT-pro-BNP). Risk factors (RF) were studied: smoking, physical activity (PA), perceived stress level.
RESULTS Assessment of gender differences of traditional RF frequency showed that overweight (P=0.039), smoking (P=0.014) were significantly more often common in M than in F. Low self-esteem level of psychosocial stress was significantly more often registered in F: 93 vs. 54% (P<0.0001), while mean level was more often found in M: 46 vs. 7% (P<0.0001). In M group, there was significant increase homocysteine (P<0.001), which was associated with growth of stiffness index β in CA (P=0.004), FA (P=0.004), Peterson’s elastic modulus Ep CA (P=0.009), higher detection rate of ASP in CA (P=0.021). F group showed significant increase in hs-CRP (P=0.03), NT-pro-BNP, (P<0.001). Odds ratio of gender-related indicators determined association of male sex with predictor of arterial lesion, arterial stiffness, formation of ASP in CA, and female sex with markers of systemic inflammation and neurohumoral activation. According to HFpEF probability, assessed by H2FPEF score, M and F did not differ significantly (P=0.303), however, not excepting gender distinctiveness in formation of structural and functional changes in the left ventricle.
CONCLUSIONS Data obtained will allow for identifying the most significant factors with high gender-specific risk of CVD development among individuals working rotating shifts in the Arctic in order to prevent and make early diagnosis focusing on economic efficiency.
GW32-e0844
Yang Hua1, Hengli Liu2, Xiangqing Kong1, Wei Sun1, Yaqing Xiong2
1The First Affiliated Hospital of Nanjing Medical University
2Geriatric Hospital of Nanjing Medical University
OBJECTIVES Hypertension is a significant risk factor of cardiovascular diseases, posing a serious threat to global health. Calcium is a basic element of human body and plays an important role in regulating body homeostasis. Less is known about the association between serum calcium and the prevalence of hypertension.
METHODS Cross-sectional data from the 2007–2018 National Health and Nutrition Examination Survey were analyzed. Total calcium was categorized into quartiles, and the lowest quartile was set as the reference group. We performed the Spearman correlation coefficient to assess the association of total calcium and systolic/diastolic blood pressure. Adjusted multivariable logistic regression analysis and restricted cubic spline were used to investigate the association of serum calcium with the prevalence of hypertension.
RESULTS A total of 26,778 participants were included. The increase in calcium levels showed a positive association with the prevalence of hypertension in all three models with ORs of 1.347 (1.249–1.454), 1.522(1.401∼1.654), and 1.438 (1.306∼1.583). Subgroup analysis was subsequently performed based on categories of sex, age, race, BMI, eGFR. For total calcium, a robust trend was observed across all subgroup analyses. The restricted cubic spline plot exhibited an S-curve relationship between calcium and hypertension.
CONCLUSIONS Our studies demonstrated a robust and significant association between higher serum calcium levels and the prevalence of hypertension. Our findings highlighted serum calcium levels in hypertensive patients.
GW32-e1669
Ken Chen1,2, Dachun Yang3
1Chongqing Renji Hospital, University of Chinese Academy of Sciences (The Fifth People’s Hospital of Chongqing)
2Cardiovascular Research Center of Chongqing Institute, Chinese Academy of Sciences
3The General Hospital of Western Theater Command
OBJECTIVES Bone formation and metabolism disorders have been identified as risk factors leading to cardiovascular disease. Whether the bone endocrine factors regulate the blood pressure and is associated with the risk of hypertension are unclear.
METHODS In the present study, 109 hypertension patients and 30 normotensive subjects were recruited. The circulating bone-derived factors including Dickkopf-related protein 1 (DKK1), osteoprotegerin (OPG), osteocalcin (OC), osteopontin (OPN), osteonectin and osteocrin were measured by a protein liquid-chip assay.
RESULTS The serum DKK1, osteonectin and osteocrin concentrations derived from hypertensive participants were considerably lower than those of controls (Figure 1). On average, the serum of controls contained 1770±88.96 pg/mL DKK1, 537.7±34.94 pg/mL osteonectin and 100.2±13.49 pg/mL osteocrin; while the serum of patients with hypertension contained 1475±52.25 pg/mL DKK1, 416.2±14.46 pg/mL osteonectin and 78.9±5.35 pg/mL osteocrin. The logistic regression analysis was performed to test the association of DKK1, osteonectin and osteocrin concentrations with hypertension. The data showed that the osteonectin is significantly associated with hypertension (OR=0.997, 95% CI: 0.994–0.999; P<0.05) after adjustment for age and gender. Therefore, second model that including BMI, FBG, HbA1c, HDL-C and eGFR showed both DKK1 and osteonectin were independent predictors for hypertension after adjustment for BMI, FBG, HbA1c, HDL-C and eGFR (DKK1: OR=0.999, 95% CI: 0.998–1.00; osteonectin: OR=0.996, 95% CI: 0.993–1.00; P<0.05). Additionally, a full model that including all the covariates was performed and showed lower DKK1 is one of the risk factors for hypertension (OR=0.998, 95% CI: 0.997–1.00; P<0.05).
CONCLUSIONS In conclusion, our present study found that the decreased DKK1 and osteocrin in circulation are associated with risk of hypertension. These findings indicate that the bone-derived factors such as DKK1 and osteocrin may be involved in the pathophysiology of hypertension and call for further basic and clinical investigation.
GW32-e0902
Jin-Yu Sun, Yang Hua, Hua-Yi-Yang Zou, Wei Sun, Xiang-Qing Kong
The First Affiliated Hospital of Nanjing Medical University
OBJECTIVES Waist circumference has shown a significant positive correlation with cardiovascular-specific and all-cause mortality. This study aimed to investigate the association of general and abdominal adiposity with the prevalence of hypertension.
METHODS Cross-sectional data from the 2007–2018 National Health and Nutrition Examination Survey were analyzed. Distributions of waist circumference were illustrated by gender groups using kernel density estimation with Gaussian kernels, whereas the historical trend of abdominal obesity was assessed by the Cochran-Armitage trend test. After preprocessed by the multiple imputation strategy, we used generalized additive models to assess the association of waist circumference with systolic/diastolic blood pressure and performed correlation analysis by the Spearman correlation coefficient. Moreover, we used multivariable logistic regression (crude, minimally-adjusted, and fully-adjusted models), subgroup analysis, and restricted cubic spline to investigate the association of waist circumference with the prevalence of hypertension.
RESULTS A total of 27,927 participants were included, with a median waist circumference of 97.7 cm and a median body mass index (BMI) of 28.2 kg/m2. Hypertension was observed in 13,318 (47.7%) individuals among the overall population. The heatmap and smooth trajectories showed that both BMI and waist circumference were positively and significantly correlated with systolic/diastolic blood pressure. Further, a significant growth trend for the prevalence of obesity and abdominal obesity from 2007 to 2018. In the minimally-adjusted model (including sex, race/ethnicity, education levels, height, diabetes history, smoking status, alcohol consumption, sodium intake, triglycerides, and total cholesterol levels), increased BMI alone was significantly associated with hypertension in young [odd ratio (OR), 2.27; 95% CI, 2.13–2.41] and old individuals (OR, 1.89; 95% CI, 1.77–2.02). However, when introducing waist circumference as a continuous variable in the fully-adjusted model (additionally including waist circumference), we observed no significant positive association between BMI and hypertension. Differently, the increase in waist circumference showed a robust positive correlation with the prevalence of hypertension in all three models with ORs of 1.51 (1.48–1.55), 1.45 (1.41–1.49), and 1.42 (1.32–1.54) in young individuals, and ORs of 1.42 (1.39–1.46), 1.38 (1.34–1.42), and 1.55 (1.44–1.66) in old individuals, respectively. When fully adjusting for BMI, sex, race/ethnicity, education levels, diabetes history, smoking status, alcohol consumption, height, sodium intake, triglycerides, and total cholesterol levels, participants in the second to fourth quartile displayed a higher risk of hypertension compared with the lowest quartile of waist circumference. Subgroup analysis demonstrated a robust hypertension trend across all BMI categories with ORs of 8.40 (3.89–18.90), 3.22 (2.86–3.64), 2.73 (2.49–3.00), 1.91 (1.73–2.12), 1.40 (1.22–1.60), and 1.27 (1.11–1.45) in underweight, normal weight, overweight, class I obese, class II obese, and class III obese individuals, respectively. However, in the fully-adjusted model, a protective effect of BMI was observed in underweight, normal weight, overweight, class I obese with ORs of 0.01 (0–0.20), 0.14 (0.09–0.21), 0.26 (0.18–0.38), 0.44 (0.28–0.69), respectively.
CONCLUSIONS This study highlighted the importance of fat distribution in the adverse effect of obesity on obesity-related cardiometabolic risk and supported the use of waist circumference in addition to BMI when evaluating hypertension risk. Further studies are warranted to validate these findings and elucidate the underlying mechanisms.
GW32-e1804
Jianshu Chen1, jing yu2
1Second Hospital of Lanzhou University
2Lanzhou University Second Hospital
OBJECTIVES The present study was to investigate the effects of free androgen index (FAI) on ambulatory blood pressure (ABP) and target organ function in postmenopausal hypertensive women.
METHODS Two hundred and eighty-five number postmenopausal hypertensive women (mean age 54.06±3.61) were admitted to the Department of Hypertension of Lanzhou University Second Hospital between December 2018 and December 2020. According to the serum FAI level, the participants were divided into a low-FAI (≤0.15) group, a medium-FAI (0.15–0.2) group and a high-FAI (≥0.2) group. The relationship of FAI with 24-h ABP, left ventricular mass index (LVMI) and cardio-ankle vascular index (CAVI) was analyzed.
RESULTS The LVMI, CAVI, 24-h mean systolic blood pressure (SBP), 24-h SBP coefficient of variation and 24-h SBP standard deviation, 24-h SBP average real variation (ARV) and 24-h diastolic blood pressure (DBP) ARV in high-FAI group were significantly higher than those in low- and medium-FAI groups (P<0.05). After adjusting for confounding factors, partial correlation analysis showed that FAI was positively correlated with LVMI (r=0.728, P<0.001), CAVI (left: r=0.718, P<0.001; right: r=0.742, P<0.001), 24-h SBP ARV (r=0.817, P<0.001) and 24-h DBP ARV (r=0.747, P<0.001). After adjusting for confounding factors, it was found that LVMI increased by 17.64 g/m2 for every 1 unit increase in FAI. In addition, the results also showed that LVMI decreased by 0.198 g/m2 and 0.009 for every 1 unit increase in SHBG. Multivariable linear regression showed that FAI was an independent risk factor for 24-h SBP ARV (OR: 20.416, 95% CI 8.143–32.688, P=0.001) and 24-h DBP ARV (OR: 16.539, 95% CI 0.472–32.607, P=0.044). The results also showed that SHBG was an independent factor of 24-h SBP ARV (OR: −0.022, 95% CI −0.044 to 0.000, P=0.048) and 24-h DBP-ARV (OR: −0.018, 95% CI −0.029 to −0.008, P=0.001).
CONCLUSIONS Higher serum FAI levels in postmenopausal hypertensive women indicate abnormal BP regulation and more serious target organ damage. FAI is closely related to 24-h SBP ARV and 24-h DBP ARV in postmenopausal hypertensive women.
GW32-e0903
Jin-Yu Sun, Qiang Qu, Yue Yuan, Wei Sun, Xiang-Qing Kong
The First Affiliated Hospital of Nanjing Medical University
OBJECTIVES Waist circumference has shown a pronounced correlation with multiple cardiovascular diseases and mortality. This study aimed to examine the association of waist circumference with hypertension and cardiometabolic dysregulation among normal-weight adults.
METHODS In this cross-sectional study, 8795 participants aged 20–79 years were included from the 2009–2018 National Health and Nutrition Examination Survey. To maximize statistical power and minimize the selection bias, we performed multiple imputation strategies based on five replications. Then, we used boxplots to illustrate the distribution of waist circumference across body mass index (ten categories) by gender, and the waist circumference distributions were also shown based on kernel density estimation with Gaussian kernels. Moreover, we conducted adjusted multivariable logistic regression, subgroup analysis, and restricted cubic spline to analyze the association between waist circumference and the prevalence of hypertension. The random forest supervised machine learning method, together with the least absolute shrinkage and selection operator (LASSO), was implemented to select hypertension-related features and created a predictive model based on regression analysis to identify hypertension in normal-weight individuals.
RESULTS Waist circumference ranged from 61.3 to 117.6 cm with a median of 82.5 cm (namely 85.0 cm in males and 80.8 cm in females). Hypertension was observed in 2963 (33.7%) individuals among the overall population, and the prevalence as well as blood pressure increased with the increase of waist circumference. When analyzed as a continuous variable, waist circumference was positively and significantly associated with hypertension in crude, minimally-adjusted (including age categories in decade, gender, race/ethnicity, diabetes, weight, height, smoking status, alcohol consumption, education levels, poverty-income ratio levels, total-to-HDL cholesterol, triglycerides, energy intake, sodium intake, and physical activity), and fully-adjusted (additionally including body mass index) models with ORs of 2.28 (2.14–2.44), 1.27 (1.12–1.44), and 1.27 (1.12–1.44), respectively. In the fully-adjusted model, individuals in the fourth quartile showed a 3.87-fold risk of hypertension compared with those in the lowest quartile of waist circumference. Sensitivity analysis demonstrated that the positive association between waist circumference and increased prevalence of hypertension remained robust across gender, age, total-to-HDL cholesterol ratio, and physical activity categories. Among the demography, body measure, comorbidities, and health behavior variables, waist circumference was identified as the most critical feature only second to age, with a mean decrease accuracy of 41 and a mean decrease Gini index of 437. Additionally, these features with the top 12 mean decrease accuracy or Gini values were assessed by the LASSO method with an optimal value for penalization coefficient lambda, and a total of 13 variables were finally selected to create the predictive model. The visualized nomogram can be easily accessed in https://data15651725761.shinyapps.io/Predict-hypertension-in-normal-weight-individuals/. In the testing set, the predictive model showed a reliable performance with an area under the curve of 0.803, sensitivity of 0.72, specificity of 0.76, and negative predictive value of 0.84.
CONCLUSIONS Waist circumference could provide an additional opportunity to evaluate the risk of hypertension better and manage cardiometabolic risk in normal-weight individuals. Nevertheless, further studies are warranted to extend these findings, which if corroborated, may indicate a routine measure for waist circumference in clinical practice.
GW32-e1928
Jun Qian, Yun Du, Gang Yang, Qi Zhou, Bo Xiong, Shunkang Rong, Yuanqing Yao, Yonghong Jiang, Que Zhu, Changming Deng, Dichuan Liu, Jing Huang
The Second Affilated Hospital of Chongqing Medical University
OBJECTIVES Adrenal venous sampling (AVS) is the gold standard for the for the classification and diagnosis of primary aldosteronism (PA). However, variable location of the orifice of the right adrenal vein (RAV) induced a poor success rate of sampling. This study intends to explore the relationship between RAV orifice and the right renal contour, sought to evaluate the value of using the renal contour as a reference for RAV orifice location.
METHODS We retrospectively reviewed the imaging data in a sample of 96 PA patients with technically successful AVS. All patients were divided into three groups based on the body mass index (Normal, Overweight, and Obese group). On the basis of the anterior view of the RAV, the cranio-caudal level of the RAV orifice was determined relative to vertebral bodies and disks. The vertical distance from RAV orifice to the right renal upper contour was measured manually in all patients.
RESULTS In 87.7% of the patients, the RAV orifice were mainly distributed from the upper 1/3 segment of T11 to the middle 1/3 segment of the T12. High BMI was associated with a higher level of the RAV orifice location (r=0.413, P<0.05). The right renal contour could be clearly visible in all patients directly or after a small amount of contrast medium injection. The average distance between RAV orifice to the right renal upper contour was 10.1±6.2 mm, and had no significant difference among different BMI groups.
CONCLUSIONS Under X-ray, the right renal contour under might provide a reference for the location of RAV orifice, that could help increase the RAV catheterization success rate for less experienced AVS operators.
GW32-e1048
Bo Zhuang, Ting Shen, Yuqin Shen
Department of Cardiology, Tongji Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, China
OBJECTIVES Previous studies have revealed that triglyceride-glucose (TyG) index is one of major risk factors of cardiovascular diseases, insulin resistance and metabolism syndrome. However, research about the correlation between TyG index and arterial stiffness is limited. The purpose of this study was to assess the association between the TyG index and arterial stiffness in participants at medical check-up.
METHODS The TyG index was calculated using the formula ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. Arterial stiffness was measured through brachial-ankle pulse wave velocity (baPWV). The association between the TyG index and arterial stiffness was assessed by liner regression analysis. Subgroup analyses were conducted according to sex, age, BMI, et al.
RESULTS A total of 912 participants were enrolled. After adjusting potential confounders (age, sex, BMI, SBP, DBP, AST, ALT, GGT, uric acid, TC, HDL-C LDL-C, eGFR, smoking and exercise status, fatty liver, alcohol consumption and ABI), multivariate linear regression analyses showed that TyG index was independently and positively associated with baPWV (β=42.75; 95% CI: 10.48∼75.02). For the purpose of sensitivity analysis, we handled TyG index as a categorical variable (quartile), and found P for the trend <0.01. Analyses using restricted cubic spline confirmed that the associations of TyG index with baPWV was linear. Subgroup analyses in participants with younger age (less than 60 years old) showed that TyG index had a positive correlation with baPWV (β=46.00, 95% CI: 14.45∼77.55), and the P for the interaction was less than 0.01.
CONCLUSIONS The TyG index is independently associated with arterial stiffnes in participants at medical check-up.
GW32-e1403
Feng Hu, Zeying Tao
The Second Affiliated Hospital of Nanchang University
OBJECTIVES Hyperhomocysteinemia (HHcy) and metabolic syndrome (MS) are established cardiovascular risk factors of stroke and are frequently associated with hypertension. However, studies about the combined effect between HHcy and MS on stroke risk in hypertensive patients were absent. In this study, we investigated the combined effect between HHcy and MS on the prevalence of stroke in Chinese adults with elevated blood pressure.
METHODS In selected 14,059 participants with elevated blood pressure who underwent systematic assessment of demographics and anthropometric characteristics, lifestyle, past medical history and blood biochemical tests including plasma total Hcy, we assessed the prevalence of the MS defined by CDS criterion and stroke. Multivariate analysis was used to examine the association between Hcy or (and) MS and stroke in different models. We also did the subgroup analyses that were performed using stratified multivariate regression and interaction analyses and presented in tabulated form or forest plot.
RESULTS The prevalence of HHcy and MS were 49.96% and 42.21%, respectively. Patients with stroke had significantly higher plasma Hcy levels and prevalence of MS (P<0.001). The multivariate analyses indicated that HHcy and MS are independently associated with greater prevalence of stroke after adjusting for all confounders (adjusted-OR: 1.36, 95% CI 1.17–.58; adjusted-OR: 1.68, 95% CI 1.44–1.96, respectively). The multivariate analyses indicated that there are a statistically significant higher prevalence for stroke in isolated HHcy group, isolated MS group and HHcy+MS group (adjusted-OR: 1.32, 95% CI 1.07–1.62, P=0.008; adjusted-OR: 1.78, 95% CI 1.41–2.23, P<0.001; adjusted-OR: 2.46, 95% CI 1.97–3.08, P<0.001, respectively; P for trend <0.001) compared to control group (P for trend <0.001). Moreover, subgroup analyses found that the combined effect between HHcy and MS on the prevalence of stroke was still stable in different subgroups.
CONCLUSIONS HHcy and MS had a combined effect on the increased prevalence of stroke in Chinese adults with elevated blood pressure.
GW32-e1404
Feng Hu, Zeying Tao
The Second Affiliated Hospital of Nanchang University
OBJECTIVES The previous results concerning the role of hyperuricemia (HUA) as an independent risk factor for stroke in hypertensive patients were still controversial. We investigate the association between serum uric acid (SUA) levels and the risk of first stroke in Chinese adults with hypertension.
METHODS This prospective study enrolled 14,268 participants and was conducted in 2018 in Wuyuan, Jiangxi province of China. Computed tomography or magnetic resonance as well as imaging medical records were conducted to confirm first stroke events. The Cox proportional hazards models were used to examine the associations between the SUA levels and the risk of first strokes. The effects of whether or not hyperuricemia on first strokes were evaluated by Kaplan-Meier survival curves.
RESULTS A total of 99 (0.84%) first stroke events (51 ischemic events, 15 hemorrhagic events and 33 unspecified stroke events) occurred. There were no statistically significant differences in various stroke events between groups by the quartiles of baseline SUA levels (P>0.05). Then Cox proportional hazards models indicated that in comparison without HUA group, there were not a statistically significant higher risk of total first stroke events (adjusted-HR: 1.22, 95% CI 0.79–1.90, P=0.373), ischemic stroke events (adjusted-HR: 1.28, 95% CI 0.69–2.39, P=0.440) and hemorrhagic stroke events (adjusted-HR: 1.48, 95% CI 0.45–4.85, P=0.516) in population with HUA. Subgroup analyses found that this association between SUA levels and total first stroke events was modified by aging (age ≥60 years): in group with age less than 60 years, subjects with HUA had an statistically significant higher risk of total first stroke events compared to population without HUA (adjusted-HR: 4.89, 95% CI 1.36–17.63, P=0.015). However, this positive association was disappeared in aging population (adjusted-HR: 0.97, 95% CI 0.60–1.56, P=0.886; P-value for interaction=0.043). Survival analysis further confirmed this discrepancy (Kaplan–Meier, log-rank P=0.013 for non-aging group, P=0.899 for aging group, respectively).
CONCLUSIONS No significant evidence in present study indicates that increased SUA levels were associated with the risk of first stroke in Chinese adults with hypertension. Nonetheless, subgroup analyses found that this association was modified by aging.
GW32-e0493
Ningjing Qian, Xiaohong Pan, Yaping Wang
The Second Affiliated Hospital of Zhejiang University School of Medicine
OBJECTIVES Hypertension, one of the most common cardiovascular diseases, is considered as a critic risk factor leading to death. Ambulatory blood pressure monitoring (ABPM) has been an important method for diagnosis and evaluation of hypertension. However, sleep disturbances during ABPM considerably matter. The risk for sleep disturbances during ABPM may vary widely among populations. The objective of this study is to assess sleep disturbances during ABPM in multiple dimensions and to screen for the characteristics of people who are more susceptible to sleep disturbances during ABPM.
METHODS Five hundred sixty-four consecutive participants who underwent ABPM in the Second Affiliated Hospital of Zhejiang University School of Medicine, were recruited between March and November 2019. Physical and psychological characteristics including anxiety, depression, sleep reactivity and daily sleep status were assessed by Generalized Anxiety Disorder scale-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Ford Insomnia Response to Stress Test (FIRST) and Pittsburgh Sleep Quality Index (PSQI) before ABPM. Sleep status of each single night before and during ABPM were obtained by St. Mary’s Hospital Sleep Questionnaire twice, separately. And a tolerance visual scale was applied to assess ABPM tolerance before and after ABPM twice. All eligible individuals were recruited after signing written informed consent.
RESULTS 41.7% of participants complained about dissatisfying sleep during the night on ABPM. For the whole study population, sleep depth, sleep quality and sleep efficiency were decreased during the night on ABPM (all Ps<0.001). Correspondingly, the number of awakening, sleep latency and bed time were significantly increased (all Ps<0.001). The tolerance of ABPM became poorer at the end of ABPM compared to that at the beginning (9.0 vs. 8.0, P=0.001). PSQI score was the factor that generally associated with sleep disturbances of multiple dimensions during ABPM. Each 1-point increase in PSQI score was associated with a decreased incidence of sleep disturbances, including decreased sleep depth (OR 0.89, 95% CI 0.82–0.96, P=0.001), decreased sleep efficiency (OR 0.89, 95% CI 0.83–0.96, P=0.002), decreased sleep quality (OR 0.87, 95% CI 0.81–0.94, P<0.001), reduced sleep duration (OR 0.93, 95% CI 0.86–0.99, P=0.041) and prolonged sleep latency (OR 0.88, 95% CI 0.81–0.95, P=0.001). Furthermore, Participants with PSQI score of 0–2 were observed with higher risks of disturbances in sleep depth (OR 2.48, 95% CI 1.32–4.66, P=0.005), sleep efficiency (OR 2.81, 95% CI 1.48–5.31, P=0.002), number of awakenings (OR 2.27, 95% CI 1.03–5.00, P=0.042), sleep quality (OR 3.17, 95% CI 1.67–6.04, P<0.001), sleep duration (OR 1.93, 95% CI 1.03–3.61, P=0.041) and sleep latency (OR 2.39, 95% CI 1.23–4.63, P=0.010), comparing to those with PSQI score ≥9.
CONCLUSIONS ABPM induces sleep disturbances in multiple dimensions, including sleep depth, quality, efficiency, nocturnal awakenings, sleep latency and bed time. Good daily sleep quality is the specific characteristic of population at high-risk for sleep disturbances during ABPM and individuals with better sleep in usual have higher risks of these sleep disturbances.
GW32-e1592
Wei Zhou, Lingjuan Zhu, Huihui Bao, Xiaoshu Cheng
The Second Affiliated Hospital of Nanchang University
OBJECTIVES Physical activity (PA) and sedentary behavior (SB) have been associated with mortality, while the joint association with mortality is rarely reported among Chinese population. We aimed to examine the independent and joint association of PA and SB with all-cause mortality in southern China.
METHODS A cohort of 12,608 China Hypertension Survey participants aged ≥35 years were enrolled in 2013–2014, with a follow-up period of 5.4 years. Baseline self-reported PA and SB were collected via the questionnaire. Kaplan-Meier curves (log-rank test) and Cox proportional hazards regression were performed to evaluate the associations of PA and SB on all-cause mortality.
RESULTS A total of 11,744 eligible participants were included in the analysis. Over an average of 5.4 years of follow-up, 796 deaths occurred. The risk of all-cause mortality was lower among participants with high PA than those with low to moderate level (5.2 vs. 8.9%; hazards ratio [HR]: 0.75, 95% confidence interval [CI]: 0.61–0.87). Participants with SB ≥ 6 h had a higher risk of all-cause mortality than those with <6 h (7.8 vs. 6.0%; HR: 1.37, 95% CI: 1.17–1.61). Participants with prolonged SB (≥6 h) and inadequate PA (low to moderate) had a higher risk of all-cause mortality compared to those with SB<6 h and high PA (11.2 vs. 4.9%; HR: 1.67, 95% CI: 1.35–2.06). Even in the participants with high PA, prolonged SB (≥6 h) was still associated with the higher risk of all-cause mortality comparing with SB<6 h (7.0 vs. 4.9%; HR: 1.33, 95% CI: 1.12–1.56).
CONCLUSIONS Among Chinese population, PA and SB have a joint association with the risk of all-cause mortality. Participants with inadequate PA and prolonged SB had the highest risk of all-cause mortality compared with others.
GW32-e0652
Zhiyuan Wu1,2, Yue Liu1, Xiangtong Liu1, Jingbo Zhang3, Wei Wang2, Xiuhua Guo1,2, Lixin Tao1
1Capital Medical University
2Edith Cowan University
3Beijing Physical Examination Center
OBJECTIVES The relationship of triglyceride-glucose (TyG) index and cardiovascular diseases may be mediated by arterial stiffness. However, the effect of TyG index on arterial stiffness progression remains unclear yet. This study aims to evaluate the association of TyG index and arterial stiffness progression in a non-normotensive population.
METHODS A total of 1895 prehypertensive or hypertensive participants were enrolled from the Beijing Health Management Cohort in 2013 and 2014 as baseline. The arterial stiffness status was measured by brachial-ankle pulse wave velocity (baPWV) during the annual examination until December 31 of 2019. The adjusted linear regression model was used to analyze the association of TyG index with baPWV change [absolute difference between baseline and last follow-up], baPWV change rate [change divided by following years], and baPWV slope [regression slope between examination year and baPWV measures].
RESULTS During a median follow-up of 4.71 years, we observed an increasing trend of baPWV measures in the population. There showed linear and positive associations of TyG index with three baPWV parameters. The differences (95% CI) in baPWV change (cm/s), baPWV change rate (cm/s/year) and baPWV slope, comparing participants in the highest quartile versus the lowest of TyG index, were 129.5 (58.7–200.0), 37.6 (15.3–60.0) and 30.6 (9.3–51.8), respectively. The observed associations were stronger in the hypertensive population (P for interaction <0.05).
CONCLUSIONS Our study indicates that TyG index, reflecting the insulin resistance severity, is significantly associated with the arterial stiffness progression, especially in hypertensive population. Monitoring TyG index deserves more attention in clinical practice for preventing the arterial stiffness progression and other vascular complications in hypertensive population.
GW32-e1639
Ken Chen1,2, Junxiu Yao3, Yongjian Yang3
1Chongqing Renji Hospital, University of Chinese Academy of Sciences (The Fifth People’s Hospital of Chongqing)
2Cardiovascular Research Center of Chongqing Institute, Chinese Academy of Sciences
3The General Hospital of Western Theater Command
OBJECTIVES Metabolism have been identified to play a key role in the development of hypertension. Liver is the key organ in glucose production and lipoprotein metabolism. The role of the liver endocrine factors, hepatokines, in hypertension remains unclear.
METHODS In this present study, 196 hypertensive patients, including 112 non-controlled hypertensive patients and 82 well-controlled hypertensive subjects, and 108 normotensive controls were recruited, and additional subgroup analyses of non-obese population were also performed. The concentration of circulating liver-derived factors α-fetoprotein (AFP), Angiopoietin-like Protein (ANGPTL) 3, ANGPTL4, ANGPTL6, fatty acid-binding protein (FABP) 1, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, and hematopoietic growth factor (HGF) were measured by a protein liquid chip assay.
RESULTS The data showed the circulating levels of ANGPTL4 and FGF21 were increased in hypertensive patients, compared with those in the control individuals and well-controlled hypertensive subjects. Further correlation and regression logistic analyses indicated that the ANGPTL4 level was positively correlated with blood pressure (BP) and an independent predictor for hypertension and anti-hypertension treatment after adjustment. In non-obese subjects, the concentrations of ANGPTL4 and FGF21 levels were higher, in hypertensive patients than the normotensive subjects in the non-obese population, and antihypertension treatment significantly decreased the ANGPTL4 and FGF21 levels. ANGPTL4 was also significantly associated with hypertension and blood pressure control in non-obese subjects.
CONCLUSIONS In conclusion, we found that ANGPTL4 levels are associated with hypertension and blood pressure control. These findings indicate that ANGPTL4 may be involved in the pathophysiology of hypertension and may be a new target for anti-hypertension treatment.
GW32-c1496
Zixu Zhao1, Tao Feng2, Yang Zhao2, Anqin Dong2, Jiayue Fei2, Wenli Zhang2, Liming Li2
1Department of cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing
2Department of Cardiopulmonary Rehabilitation, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan
OBJECTIVES Short-term and long-term comparative outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for multivessel coronary artery (MVCA) or left main coronary artery (LMCA) disease are highly debated.
METHODS Literatures were searched from January 1, 2000 to January 1, 2021, including randomized clinical trials (RCTs) and observational studies (OSs) which compared PCI with CABG for patients with MVCA or LMCA in 10-year follow-up.
RESULTS There was no significant difference between PCI and CABG in all-cause mortality in either RCTs or OSs, in cardiac mortality in RCTs, whereas PCI was associated with higher cardiac mortality in OSs. The difference between PCI and CABG in repeated revascularization in either RCTs or OSs, in myocardial infarction in either RCTs or OSs were not significant. In OSs, stroke rate in PCI group was lower than those in CABG, but not in RCTs.
CONCLUSIONS Evidences from RCTs and OSs show that PCI had a higher rate in cardiac mortality, lower rate of stroke than CABG among patients with MVCA or LMCA, while no significant differences in other outcomes. More long-term trials are needed to better define differences of outcome between two techniques.
GW32-c1900
Pan Liu, Lina Ma
Department of Geriatrics, Xuanwu Hospital, Capital Medical University, China National Clinical Research Center for Geriatric Disorders
OBJECTIVES To explore the relationship between frailty and the prognosis of older hypertensive people and the epidemiological characteristics of frail Chinese older adults with hypertension.
METHODS Data were from Beijing Longitudinal Study of Aging (BLSA) with 8-year follow-up (n=1111) and China Comprehensive Geriatric Assessment Study (CCGAS, 2011–2012, n=5844). Frailty was defined by 68-item frailty index.
RESULTS In the BLSA cohort, the prevalence of frailty was 19.6% in community-dwelling older adults in Beijing, and frailty was associated with higher 8-year mortality. Moreover, hypertension was independently associated with frailty. In the CCGAS study, the prevalence of frailty in older hypertensive adults was 13.8% in China. The prevalence of frailty was significantly higher in hypertensive patients than in normal controls. The awareness and treatment of hypertension were higher in frail individuals. The control rate of hypertension did not differ significantly between the two groups.
CONCLUSIONS Frail older hypertensive adults had higher mortality, older age, poor marital status, chronic diseases, worse lifestyle and psychological status were factors related to frailty in Chinese older adults with hypertension.
ARRHYTHMIAS
GW32-e0817
Franco Francesco Naccarella1, Alessandro Nobili2, Massimo Galli3, Lei Sun4, Marina Marini5, Lucio Pardo6, Enrico Drago7, Zheming Zhu8
1University of Bologna
2Sorident, Sorimed Clinic, Cardiology Home Care, Preventive and Social Medicine Unit
3State University Milan, Sacco Hospital Chair of Communicable Diseases
4NGO Quale Medicina 2000 of Italy MIUR, Euro China Society for Health Research Srl. Home Care, Preventive and Social Medicine Unit
5University of Bologna Biology Department
6NGO Sanita’ e Conoscenza, Bologna The BSC, Bologna Health and Knowledge Committee
7Sport Medicine Department Bologna
8Genertec Italia SOE, Import, Export & Solutions from China, Milan
OBJECTIVES Premise. Lungs and Cardiac involvement in COVID 19 patients, have been shown to severely affect short and long term outcomes (S/LTO), but relevant variables for treatment and prognosis, have not been deeply understood. Patients selection and research methodology. Thus, 150 Consecutive patients have been enrolled in a Clinical Cardiology/ Internal Medicine Outpatients Clinic (OC), in the Emilia Romagna Region, including Caucasian, Jewish and Chinese patients, referred to Our OC, since early December 2019.
METHODS Methodology and preliminary results. Of the 150 patients, mean age 68±11, 100 had mild associated comorbidities (MCO) and 50 were fragile patients (FP), for sever cardiovascular conditions, heart failure (HF), Diabetes (DM), autoimmune disease or reduced immunologic competence (AD) and chronic associated comorbidities (CCM). Eighty male (53%) and 70 female (47%). They all received serial blood O2 saturation (%S) and body temperature (BT) evaluations, serum antibodies levels and Nasopharyngeal test (NFT) and appropriate blood test (ABT), chest/cardiac echo (CE) at control 30/45 and 250/360 days after vaccination, if required. Forty patients (27% GROUP A) were COVID 19 affected or contacts and 110 (73% GROUP B) a consecutive cohort, part of Our CCM patients.
RESULTS GROUP A) 32 out 40 (80%) had a positive NPT and 8 (20%) negative. CE was positive for lungs involvement in 56 and 62% respectively (NS) GROUP B) Out of 110 of 150 Non Covid Patients (73%), 20 out of 110 (18%) and 90 of 110 (82%) were positive at NFT. CE was positive in 55% of Positive NFT, but also in 22/90 (25%) of negative NFT, who showed different degree of lung involvement, confirmed by TAC or NMR imaging or clinical follow up outcomes evaluation. Furthermore Cardiac Covid 19 localizations were found in 5/150 subjects and non Covid 19 Pericardial Myocardial Involvement in 7/159, diagnosed by specific antibodies serum tests.
CONCLUSIONS Preliminary conclusions. Non invasive appropriated, even out of hospital or at home cardio/chest/lung evaluation, integrated by NST and appropriate (APT), documenting clear lung involvement or negative imaging, have been shown. 1) to be critical value in early diagnosis and staging of COVID 19 patients and in a high risk fragile population, 2) to decide for further imaging evaluation when necessary 3) for hospital admission versus home and out patients clinic care and 4) to start a tracking, adequate monitoring and less costly and more accepted by patients follow up. These results are clinically relevant for a more appropriate, diffuse, high benefit/cost ratio management of larger patients population, to day or after vaccination, or in case of relapses of new waves of the Covid 19 Pandemia. An appropriate and results oriented screening tracking and monitoring approach have been proposed and made operative, for patients screening, early risk stratification and follow up and outcomes researches, in different countries, during the second year of the Pandemia and in case of recurrences of the disease. Implications for sport activity fitness and follow up of workers for the disease consequences and ability of returning to active work will be discussed and further commented upon.
GW32-e0227
Songwen Chen, Xiaoyu Wu, Xiaofeng Lu, Genqing Zhou, Yong Wei, Shaowen Liu
Shanghai General Hospital
OBJECTIVES This study was performed to investigate the incidence and clinical practice of rate-dependent conduction block of mitral isthmus (MI).
METHODS A total of 66 consecutive patients in whom bidirectional conduction block of MI was achieved were prospectively enrolled. The rate-dependent conduction block of MI was evaluated during stimulation via the mapping catheter placed within left atrial appendage. The conduction breakthrough sites was mapped and eliminated by reinforcement ablation.
RESULTS During the 30-min observation period, acute conduction recurrence of MI developed 14.2±11.5 min after the confirmation of bidirectional conduction block in 12 (18.2%) patients. Among the 12 patients with acute conduction recurrence, 4 (33.3%) had the pitfall of rate-dependent conduction block. The conduction breakthrough sites that presented with rate-dependent conduction block were all distributed along the course of Ligament of Marshall (LOM), which was identified based on its location by both the venography and electroanatomic mapping system. After the confirmation of bidirectional conduction block, the time to rate-dependent conduction block was 23.3±5.7 min, which was similar to that for CBS without rate-dependent conduction block (10.2±11.2 min, P=0.054). All 4 patients (100%) with rate-dependent conduction block were free from AF recurrence without antiarrhythmics during a mean follow-up period of 15.5±2.9 months.
CONCLUSIONS In conclusion, rate-dependent conduction block, predominantly due to recurrent LOM connection, was an uncommon phenomenon during MI ablation. To improve efficacy and durability of MI ablation, more attention should be paid to the evaluation of rate-dependent conduction block. It is important to use a longer pacing CL, not a constant pacing CL, for all patients to avoid the pitfall of rate-dependent conduction block, especially in patients undergoing ablation for LOM-LA/CS connections.
GW32-e0908
Qiang Qu1,2, Jin-Yu Sun1,2, Zhen-Ye Zhang2, Yue Su1,2, Ru-Xing Wang2
1The First Affiliated Hospital of Nanjing Medical University
2Wuxi People’s Hospital Affiliated to Nanjing Medical University
OBJECTIVES Atrial fibrillation (AF) is the most common sustained cardiac arrhythmias, posing substantial health and financial burden worldwide. This study aimed to identify significant microRNAs (miRNAs) and genes associated with the occurrence and progression of AF.
METHODS Microarray-based miRNA and mRNA expression data were obtained from the Gene Expression Omnibus database. We screened differentially expressed miRNAs using the linear models for microarray data (limma) algorithm, and identified key modules (each containing certain miRNAs) by weighted gene co-expression network analysis (WGCNA). Then, we predicted the targeted genes via experimentally verified databases (ENOCRI, miRTarBase, and Tarbase), and the overlapped genes with differentially expressed genes (DEGs) from external datasets were identified as key genes. We also constructed an integrated analysis of the association between hub miRNAs and key genes to predict cellular organization and protein functions. Moreover, we conducted gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis based on DEGs from external datasets.
RESULTS A total of 3 differentially expressed miRNAs (hsa-miR-146b-5p, hsa-miR-378a-5p, and hsa-miR-490-3p) and 320 DEGs were identified according to the cut-off criterion of false discovery rate <0.05 and |log2 FC|>0.5. Functional enrichment analysis and protein-protein interaction network revealed that DEGs were mainly involved in cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, viral protein interaction with cytokine and cytokine receptor, and chemokine signaling pathway. Furthermore, five representative enrichment terms of the top 20 clusters displayed a close association with inflammation, highlighting the crucial role of inflammation in the development of AF. Hierarchical cluster analysis indicated a distinct expression pattern between AF and non-AF groups, and seven modules were identified, of which none were merged due to the paucity of similarity (module eigengene below the height of 0.25). The red (r=−0.46; P=0.02) and blue modules (r=0.36; P=0.06) were most strongly related to AF, and showed the highest values of module significance among all modules, with 39 and 106 miRNAs separately included. After overlapping differentially expressed miRNAs with those in key modules, hsa-miR-146b-5p and hsa-miR-378a-5p were identified as the hub miRNAs. After miRNA-target gene mapping in electronic databases, 38 overlapped genes with DEGs were validated as the key genes. Moreover, a miRNA-gene interaction network demonstrated hsa-miR-146b-5p as the top hub node with a degree of 36, comprising 40 nodes (2 miRNAs and 38 genes) and 57 pairs of interaction relationship. Accordingly, a highly connected core region was detected by the cytoHubba algorithm, containing nine nodes considered as the hub genes (ATP13A3, BMP2, CXCL1, GABPA, LIF, MAP3K8, NPY1R, S100A12, SLC16A2).
CONCLUSIONS In combination with WGCNA and a miRNA-gene interaction network, we identified two hub miRNAs and nine hub genes in the occurrence and progression of AF. This study could provide an additional opportunity to better understand underlying molecular mechanisms and reveal potential therapeutic targets against AF. Further confirmatory experiments are warranted to validate these findings and elucidate the underlying mechanisms.
GW32-e1688
Zhihong Zhao, Qiang Huan, Saihua Wang, Zhongping Ning, Xiang Song
New Area Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai
OBJECTIVES Cardiac tamponade (CT) is the most serious complication of atrial fibrillation (AF) patients during and after left atrial appendage occlusion (LAAO). The anatomical structure of the left atrial appendage-pulmonary artery, left superior pulmonary vein and acute or delayed CT in LAAO patients have not been systematically studied.
METHODS Acute or delayed CT after LAAO, emergency pericardiocentesis and drainage were enrolled in Zhoupu Hospital from August 2016 to June 2021, the mean follow-up time was 16±12 months. The clinical data of the patients were retrospectively analyzed, to analyze the relationship between the left atrial appendage and pulmonary artery, vein anatomy by cardiac CTA before and after LAAO.
RESULTS Thirteen LAAO patients with pericardiocentesis and drainage were enrolled, including 7 males (age 72.1±8.3 years), 6 of whom cryo-ablation was performed at the same time, left auricle including cauliflower and chicken wing types. The incidence of CT were LACbes 6.6% (6/91 cases), Watchman 0.71% (4/562 cases), LAmbre 0.93% (2/216 cases) and Laager 6.25% (1/16 cases) respectively. The average diameter of the seal plate was 29.5±2.8 mm; 10 patients have cardiac CTA reviewed, 8 of whom the occlude were attached to pulmonary artery, 1 patient attached to pulmonary artery and left superior pulmonary vein, and 1 patient attached to left superior pulmonary vein only, except 1 patient death 2 days after LAAO, the prognosis of the other patients was good.
CONCLUSIONS Anatomic relationship of the left atrial appendage, pulmonary artery and left superior pulmonary vein related to acute and delayed CT after LAAO, and more closely related to large occlude and anchor hook.
GW32-e0231
Mengjiao Shao, Luxiang Shang, Jia Shi, Xianhui Zhou, Baopeng Tang
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
OBJECTIVES Second-generation cryoballoon (2G-CB) ablation is widely used to achieve pulmonary vein isolation (PVI) in patients with persistent atrial fibrillation (PersAF). In this study, we analyzed the midterm clinical outcome of a single procedure with a 2G-CB for PersAF in a Chinese single-center and performed a systematic review of the literature.
METHODS The 1-year success rate, complication rate, and predictors of recurrence were evaluated in patients with PersAF undergoing their first 2G-CB ablation for PVI at our center from November 2016 to January 2018. We further searched PubMed, Web of Science, ScienceDirect, and the Cochrane Library for studies on PVI using 2G-CB for PersAF up to August 2020. Studies showing clinical success rates and total complication rates at the mid-term follow-up were included in the systematic review. Quantitative analysis of 1-year success rate without recurrence and total complication rate were performed using random-effects model.
RESULTS Our single-center study included 118 patients with PersAF. Procedure-related complications occurred in 5 (4.2%) patients. At the 1-year follow-up, 75.4% of patients remained in sinus rhythm. The Cox regression showed that early recurrence, left atrial diameter and CHA2DS2-VASc score independently predicted late recurrence. Thirty-four studies were included in the systematic review; of which thirty and our single-center results were included in the quantitative analysis. The success rates ranged from 33 to 77% at 12 months follow-up, 47–62% at 18 months follow-up, and 36.8–57% at 24 months follow-up. The quantitative 1-year success rate was 67% [95% confidence interval (CI): 64–70%], and the total complication rate was 5% (95% CI: 4–6%). Early recurrence and diagnosis-to-ablation time were predictors of late recurrence.
CONCLUSIONS Overall, our study describes promising midterm efficacy and safety results of a single procedure with a 2G-CB in PersAF. However, outcome measures are heterogeneous, and results vary widely. More research is required to define the optimal ablation strategy for PersAF.
GW32-e1026
Zefeng Chen, Xing Shui, Yongxia Wu, Binghan Zheng, Wenyu Tang, Lin Chen
Department of Cardiovascular Medicine, the Third Affiliated Hospital of Sun Yat-sen University
OBJECTIVES The red blood cell distribution width (RDW) is an index of the heterogeneity of red blood cell size. This study investigated the relationship between red blood cell distribution width and the incidence of atrial fibrillation among acute myocardial infarction patients.
METHODS Clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database. The MIMIC-III database contains more than 50,000 intensive care patients. Acute myocardial infarction patients from the Multiparameter Intelligent Monitoring in Intensive care III (MIMIC-III) database with red blood cell distribution width and atrial fibrillation datas were enrolled. Logistic analyses were used to investigate the the relationship between red blood cell distribution width and the incidence of atrial fibrillation among acute myocardial infarction patients. Multivariate analyses were used to control confounders.
RESULTS Two thousand ninety-seven acute myocardial infarction patients were enrolled. The average age of this population is 68 years old and 36.1% of them are female. 25.3% (530/2097) of them have atrial fibrillation. In the model adjusted for multiple confounders, red blood cell distribution width showed significant correlation with the incidence of atrial fibrillation (OR=1.418, 95% CI: 1.075–1.871, P=0.013). The interactions between age (OR=1.057, 95% CI: 1.019–1.097, P=0.003), partial pressures of arterial oxygen (OR=1.004, 95% CI: 1.001–1.007, P=0.004) and the incidence of atrial fibrillation were significant.
CONCLUSIONS Red blood cell distribution width is an independent risk factor for the incidence of atrial fibrillation among acute myocardial infarction patients.
GW32-e1737
Cheng Cai1, Gang Yang1, Nan Wu1, Shu Yang1, Minglong Chen1, Sunny Po2
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University
2Section of Cardiovascular Diseases and Heart Rhythm Institute, University of Oklahoma Health Sciences Center
OBJECTIVES The autonomic nervous system regulates the heart rate and rhythm and can be responsible for arrhythmia initiation and perpetuation. Autonomic neuromodulation serves as a potential therapy to control ventricular arrhythmia. Low-level tragus stimulation (LLTS) has been shown to be effective in treating human diseases including tinnitus, epilepsy and atrial fibrillation. This study was a pilot study to explore the effect of LLTSs in patients with frequent premature ventricular contractions (PVCs).
METHODS Patients with PVC burden >10% were screened and consented. Once enrolled, LLTS (frequency: 20 Hz, pulse width: 0.2 ms) was delivered using an ear clip attached to the tragus for 1 hour twice per day over 1 month. The stimulating electric current was determined as the level above the perception threshold and below the discomfort level. PVC burden and heart rate variability (HRV) over 1-week periods were assessed by noninvasive continuous electrocardiogram monitoring at baseline and after 1-month treatment.
RESULTS A total of 11 patients were enrolled and completed 1-month follow-up. The median PVC burden decreased from 21.7 (12.7, 23.0)% at baseline to 16.0 (4.0, 20.9)% after treatment (P=0.0830). The HRV data suggested that LLTS led to higher parasympathetic activity based on increased SDNN (baseline vs. post-LLTS: 127.1±42.3 vs. 161.1±66.4, P=0.0477) and LF/HF ratio (baseline vs. post-LLTS: 0.54±0.16 vs. 0.63±0.12, P=0.2385).
CONCLUSIONS LLTS reduces PVC burden in patients with frequent PVCs though no significance has been reached, likely due to small sample size and short duration. Future larger and longer term clinical trials are warranted.
GW32-e0476
Ying Yang, Tingting Lv, Siyuan Li, Ping Zhang
School of Clinical Medicine, Tsinghua University
OBJECTIVES β-blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the effect of sodium channel blockers in all LQT patients remains unknown.
METHODS We conducted a systematic electronic search of PubMed, Embase and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc≥500 ms and QTc≤460 ms in LQTS patients.
RESULTS Pooled analysis of 14 studies with 213 LQTS patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (MD −49.43, 95% CI −57.80 to −41.05, P<0.001), reduced the incidence of CEs (OR 0.12, 95% CI 0.04–0.32, P<0.001) and the proportion of QTc≥500 ms (OR 0.15, 95% CI 0.09–0.26, P<0.001), and increased the proportion of QTc≤460 ms (OR 18.00, 95% CI 7.49–43.26, P<0.001). Sodium channel blockers significantly shortened QTc both in LQT3 and non-LQT3 patients, while the QTc shortening effect in LQT3 was superior to that in non-LQT3 (57.39 ms vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 ms vs. 49.08 ms vs. 50.10 ms).
CONCLUSIONS Sodium channel blockers can be useful both in LQT3 and non-LQT3 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.
GW32-e1065
Jia-Qing Yu, Yi-Tong Ma
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) could prevent the recurrence of atrial fibrillation (AF).
METHODS A systemic literature search of PubMed, EMBASE, and Cochrane controlled Trials Register till 2020 was performed to identify randomized controlled trials (RCTs) involving the prevention of recurrence of AF with statin therapy. Search terms included ‘3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, statins’ and individual statin agents combined with ‘atrial fibrillation, sinus rhythm’. Effect size was expressed as odds ratio (OR) with 95% confidence interval (CI). Subgroup analysis was performed to explore the reasons for heterogeneity. Publication bias was checked through funnel plot and Egger’s test.
RESULTS Fourteen RCTs including 2004 patients with AF were identified. Overall, the recurrence of AF was significantly reduced in patients using statins [OR 0.51, 95% CI 0.36–0.73, P=0.0002]. A significant benefit was observed in atorvastatin [OR 0.45, 95% CI 0.27–0.74, P=0.002], with a dose-dependent relationship, high-dose atorvastatin was more effective [OR 0.61, 95% CI 0.44–0.84]. However, no protective effect was founded in rosuvastatin subgroup [OR 0.59, 95% CI 0.29–1.18]. Statins could still decrease the recurrence of AF beyond the effect of catheter ablation [OR 0.46, 95% CI 0.26–0.81] and electrical cardioversion treatment [OR 0.60, 95% CI 0.44–0.83] and heterogeneity did not exist in these two subgroups.
CONCLUSIONS Statin therapy is effective for the secondary prevention of AF, especially in patients undergone electrical cardioversion. High-dose atorvastatin was significantly associated with a decreased risk of recurrent AF whereas rosuvastatin was not. Thus, further prospective studies are warranted.
GW32-e0477
Ying Yang
School of Clinical Medicine, Tsinghua University
OBJECTIVES Cardiac arrhythmias are the most threatening complications of digoxin toxicity, but typical ECG manifestation can be concealed by pacemaker, the ECG manifestation in patients with pacemaker is rare reported. This case report typical ECG manifestations in a 82-year-old man with a dual-chamber pacemaker (Medtronic A3DR01), including the pacing mode ranged from atrial pacing to ventricular pacing, ST-T changed like a fishhook in V6 and aVF leads, U wave appeared in precordial lead.
METHODS Cardiac arrhythmias are the most threatening complications of digoxin toxicity, but typical ECG manifestation can be concealed by pacemaker, the ECG manifestation in patients with pacemaker is rare reported. This case report typical ECG manifestations in a 82-year-old man with a dual-chamber pacemaker (Medtronic A3DR01), including the pacing mode ranged from atrial pacing to ventricular pacing, ST-T changed like a fishhook in V6 and aVF leads, U wave appeared in precordial lead.
RESULTS Cardiac arrhythmias are the most threatening complications of digoxin toxicity, but typical ECG manifestation can be concealed by pacemaker, the ECG manifestation in patients with pacemaker is rare reported. This case report typical ECG manifestations in a 82-year-old man with a dual-chamber pacemaker (Medtronic A3DR01), including the pacing mode ranged from atrial pacing to ventricular pacing, ST-T changed like a fishhook in V6 and aVF leads, U wave appeared in precordial lead.
CONCLUSIONS Cardiac arrhythmias are the most threatening complications of digoxin toxicity, but typical ECG manifestation can be concealed by pacemaker, the ECG manifestation in patients with pacemaker is rare reported. This case report typical ECG manifestations in a 82-year-old man with a dual-chamber pacemaker (Medtronic A3DR01), including the pacing mode ranged from atrial pacing to ventricular pacing, ST-T changed like a fishhook in V6 and aVF leads, U wave appeared in precordial lead.
GW32-e1201
Dongchen Zhou1, Jian Yang1, Liangrong Zheng1, Xingxiang Wang1, Xiaogang Guo1, Jianwei Xuan2
1The First Affiliated Hospital, Zhejiang University School of Medicine
2Institute of Health Economic Research, Sun Yat-Sen University
OBJECTIVES Radiofrequency catheter ablation is a therapy of choice for atrial fibrillation (AF). It traditionally requires access to the left atrium (LA) via transseptal puncture (TP) under the guidance of fluoroscopy. During this procedure, both patients and operators are exposed to scattered radiation. Performing TP with the use of intracardiac echocardiography (ICE) could achieve zero fluoroscopy. This study aims to investigate the procedural effectiveness and safety of ICE-guided radiofrequency catheter ablation of AF without fluoroscopy in China.
METHODS The retrospective single-center real-world study included 37 consecutive patients between June 2019 and June 2020 who underwent radiofrequency catheter ablation of AF with SOUNDSTAR® catheter. The effectiveness endpoint included acute pulmonary vein isolation (PVI) rate, immediate success rate, total procedure time, transseptal duration time and total ablation time. The primary safety endpoint was the incidence of major adverse events.
RESULTS Acute PVI was achieved in all patients (n=37, mean age: 62.5±11.2 years. male: 70.3%, left ventricular ejection fraction: 63.0±5.8%, paroxysmal AF [PAF]: 48.6%, persistent AF [PsAF]: 51.4%) and immediate success rate was 100%. No punctures required fluoroscopy. Mean total procedure time was 135.7±33.2 min (143.0±42.7 min in the PsAF subgroup vs. 128.0±16.8 min in the PAF subgroup; P=0.174). Mean transseptal duration time was 7.6±5.5 min (7.4±4.6 min for PsAF subgroup vs. 7.8±6.5 min for PAF subgroup; P=0.803) and mean total ablation time was 30.3±8.6 min (32.4±9.6 min for PsAF subgroup vs. 28.1±7.0 min for PAF subgroup; P=0.133). There was no major complication during the overall ablation procedure such as death, cardiac tamponade, stroke or atrial-esophageal fistula occurred. In the subgroup analysis, all of the above-mentioned effectiveness outcomes were similar between PAF and PsAF patients. During six-month hospital follow up, no major complications occurred and there was one patient readmitted to hospital as recurrence.
CONCLUSIONS This study demonstrates that zero fluoroscopy procedure with ICE-guided radiofrequency catheter ablation can safely and effectively treat AF in a “real world” experience of a single center in China.
GW32-e1915
Shanshan Liu1, Hongyang Guo2, Suyan Bian1, Jian Zhu1
1The Second Medical Center, Chinese PLA General Hospital
2The First Medical Center, Chinese PLA General Hospital
OBJECTIVES To systematically study the differential expression profile of circulating circular RNAs (circRNAs) in Chinese paroxysmal atrial fibrillation (PAF) patients with late recurrence (>3 months) after transcatheter radiofrequency ablation, and analyze their function and targeted regulatory network, so as to provide bioinformation for exploring circRNAs’ regulatory mechanism in late recurrence of PAF after radiofrequency ablation.
METHODS Based on standard 12-lead ECG or 24-hour ambulatory ECG, 6 patients with PAF who received radiofrequency catheter ablation in our hospital from October 2020 to February 2021 were enrolled in this study (clinical trial registration number: ChiCTR2100049230). Among them, 3 were with recurrent PAF within 3–12 months after operation (i.e. late recurrence), while 3 were with non-recurrence PAF at least longer than 12 months after operation. Whole blood from these patients were collected for circRNAs differential expression analyses by high-throughput sequencing. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the top five up-regulated and down-regulated circRNAs were performed to predict the potential functions of the differentially expressed genes and PAF recurrence-related pathways.
RESULTS A total of 12,834 differentially expressed circRNAs were found to be differentially expressed in PAF recurrence. Among them, 5491 were down-regulated, and 7343 were up-regulated. The top five up-regulated circRNAs were hsa_circ_0003831, hsa_circ_0040533, hsa_circ_0001081, hsa_circ_ 0060816 and hsa_circ_0008825; the top five down-regulated circRNAs were hsa_circ_0046464, hsa_circ_0002615, hsa_circ_0083756, hsa_circ_0022739 and hsa_circ_0062022. The most enriched GO terms in molecular function, bioengineering and cellular component aspects were catalytic activity, cellular metabolic process and intracellular part, respectively. KEGG enrichment analysis indicated that endocytosis was the most important metabolic pathway regulated by differential circRNAs.
CONCLUSIONS The differential expression of circRNAs in circulation after radiofrequency ablation of PAF may participate in the regulatory mechanism of postoperative recurrence, which might be selected as new biomarkers or intervention targets for PAF postoperative recurrence.
GW32-e0593
Jing Yang, Ping Zhang
Beijing Tsinghua Changgung Hospital
OBJECTIVES To evaluate the efficiency of left cardiac sympathetic denervation (LCSD) in inherited arrhythmia patients with adrenergic activity-induced malignant ventricular arrhythmia, and observe exercise-stress test electrocardiograms features before and after LCSD.
METHODS This study included catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndromes (LQTS) patients who underwent video-assisted LCSD at Beijing Tsinghua Changgung Hospital and Peking University People’s Hospital during September 2006 and May 2020. The indications for LCSD surgery were intolerant or refractory to beta-blocker medication. Clinical and exercise-stress tests data of the patients who met the inclusion criteria were collected before and 1 month after LCSD. Heart rate, exercise tolerance, atrial and ventricular arrhythmia, QTc interval and sudden cardiac death predictors were analyzed.
RESULTS Five patients (2 CPVT, 1 LQT1, and 2 LQT2) were included in the study. All patients experienced syncope as first symptom at the median age of 12(10.16) years, and underwent LCSD at the median age of 21(16.26) years, Baseline heart rate was similar before and after LCSD ((65.6±6.5) beats/min vs. (68.0±11.1) beats/min, P=0.57); while maximum workload tended to be lower after LCSD ((12.1±2.8) metabolic equivalents (METS) before surgery vs. (10.5±2.4) METS after surgery, P=0.07). Incidence of atrial and ventricular arrhythmia were significantly reduced post LCSD, and the ventricular arrhythmia score was decreased after LCSD in CPVT patients (4 points before LCSD vs. 3 points after LCSD in case 1; 5 points before LCSD vs. 4 points after LCSD in case 2). QTc interval was shortened significantly in three LQTs patients (QTc interval at baseline heart rate: (546.6±72.3) ms before surgery vs. (493±61.1) ms after LCSD, P=0.047; QTc interval at maximal exercise heart rate: (516.3±73.7) ms before surgery vs.(486.7±64.2) ms after LCSD, P=0.035). Additionally, sudden cardiac death risk indicator ΔHRR1 (heart rate decreasing value within the first 1 min during recovery phase) decreased from (51.5±21.1) beats/min before surgery to (32.0±13.9) beats/min after surgery (P=0.035).
CONCLUSIONS LCSD surgery can be safely and effectively performed in most hereditary arrhythmia patients with adrenergic activity-induced life-threatening cardiac events. Exercise stress tests showed that LCSD could reduce malignant arrhythmias and cardiac events as well as improve sudden cardiac death risk indicators without decreasing heart rate.
GW32-e1445
Zhuoxian Zhao, Mu Guo, Yunqiang Zhang, Haiqing Liang, Zhao Wang, Yu Song
TEDA International Cardiovascular Hospital
OBJECTIVES Patients with electrical storm (ES) have repetitive ventricular tachycardia (VT) or ventricular fibrillation (VF), which is refractory to conventional antiarrhythmic medications, resulting in poor outcomes and high mortality rate. Except for conventional antiarrhythmic treatment, ES patients could benefit from sedation and anesthetic drugs that reduce over-activated sympathetic nerve and contribute to the termination of ES. Dexmedetomidine has been mainly used in ICU or anesthetic-related issues. However, it is unknown whether the administration of dexmedetomidine is associated with reduced mortality in patients who developed ES after acute myocardial infarction or with cardiomyopathy. We aimed to evaluate whether dexmedetomidine in combination with antiarrhythmic medications could improve the survival of patients with ES.
METHODS This was a retrospective and cohort study enrolling patients who were diagnosed with ES and treated in TEDA International Cardiovascular Hospital in Tianjin, China. All the subjects who received cardioversion or defibrillation were initially screened in the hospital electrical database between January 2012 and June 2021. ES was defined as ≥3 episodes of sustained VT or VF within a 24-hour period, each of which required emergent electrical or medical cardioversion. Patients who met the diagnostic criteria of ES were included into the study. Patients whose refractory ventricular arrhythmias were irrecoverable due to end-stage disease status were excluded from the study. According to whether ES patients received dexmedetomidine, they were divided into Non-DEX Group (standard antiarrhythmic treatment) and DEX Group (standard antiarrhythmic treatment plus dexmedetomidine). All the ES patients were treated with the standard protocol recommended by guidelines. Baseline characteristics were collected and outcomes (whether ES persisted after treatment, in-hospital mortality and all-cause mortality at 12 month after discharge) were analyzed between Non-DEX Group and DEX Group. Multivariate stepwise logistic regression was further performed to determine whether dexmedetomidine was independently associated with the study outcomes.
RESULTS A total of 74 patients with ES were included into analysis. Among them, 38 patients were classified into Non-DEX Group, 25 (66%) survived at discharge and 11 (29%) survived at 12 month after discharge, compared with 36 patients in DEX Group, 33 (92%) survived at discharge and 24 (67%) survived at 12 month after discharge. ES patients who received dexmedetomidine had significant higher rates of terminated ES (89 vs. 39%), survival at discharge (92 vs. 66%) and survival at 12 month after discharge (67 vs. 29%) compared with patients who did not receive dexmedetomidine. Multivariate regression analysis suggested that dexmedetomidine use was independently associated with reduced rates of persisted ES (adjusted odds ratio [OR] 0.046, 95% confidence interval [CI] 0.010–0.214, P<0.001), reduced in-hospital mortality (adjusted OR 0.097, 95% CI 0.016–0.579, P=0.011) and reduced all-cause mortality at 12 month after discharge (adjusted OR 0.097, 95% CI 0.021–0.437, P=0.002).
CONCLUSIONS In this retrospective cohort study, dexmedetomidine use was significantly associated with reduced rates of persisted ES, reduced in-hospital mortality and reduced all-cause mortality at 12 month after discharge. Future study of randomized control trial was needed to provide solid evidence to prove the clinical benefits of dexmedetomidine for patients with ES.
GW32-e1542
Yan Dong1, Wen Yang1, Xiujuan Zhou1, Xiaorong Li2, Bing Yang2, Kejiang Cao1
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University
2Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine
OBJECTIVES Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM). This study aimed to investigate the basic clinical characteristics of HCM patients with or without AF, and to analyze the risk factors of AF in HCM patients and the prognosis of the two groups.
METHODS This study retrospectively enrolled HCM patients without AF who were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2013 to December 2018. The follow-up was conducted by telephone or outpatient visits. The patients were divided into two groups (AF group or non-AF group) based on the new-onset atrial fibrillation. The risk factors of AF in HCM patients were analyzed by using Logistic regression method; the Kaplan-Meier survival curves were drawn and the all-cause mortality, HCM-related mortality and the incidence of ischemic stroke were compared between the two groups.
RESULTS A total of 412 patients with HCM were enrolled in this study. During a follow-up of 4.8±1.6 years, AF was documented in 44 patients. All patients were divided into two groups: 44 patients in the AF group and 368 patients in the non-AF group. Multivariate logistic regression analysis showed that advanced age (OR 1.032, 95% CI 1.002–1.062, P=0.034), enlarged LAD (OR 1.086, 95% CI 1.027–1.149, P=0.004) and higher log NT-proBNP level (OR 4.471, 95% CI 1.590–12.572, P=0.005) were independent risk factors for AF in patients with HCM. A total of 38 patients (9.2%) died, and HCM-related deaths occurred in 21 patients (5.1%). There were no significant difference in the all-cause mortality and HCM-related mortality between the two groups (9.8 vs. 4.5%, P=0.406; 5.2 vs. 4.5%, P=1.000). New ischemic stroke occurred in 20 patients (4.9%). The incidence of new ischemic stroke in the AF group was significantly higher than that in the non-AF group (13.6 vs. 3.8%, P=0.013).
CONCLUSIONS Advanced age, increased LAD and higher NT-proBNP level are independent risk factors for AF in HCM patients. Atrial fibrillation increases the incidence of ischemic stroke in patients with HCM.
GW32-e0191
Ran Mo, Yan-Min Yang, Jun Zhu
Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Atrial fibrillation (AF) and heart failure (HF) often coexist. The impact of rate-control regimens in AF and HF patients has not been well understood.
METHODS In this multicenter, prospective registry with one-year follow-up, 1359 persistent or permanent AF patients got enrolled. A 1:1 HF to non-HF propensity score matching was applied to adjust for confounding variables. The primary endpoint was all-cause mortality while the secondary endpoint was defined as cardiovascular death and stroke. Multivariate Cox analysis was performed to evaluate the association between different rate-control treatment and incidence of adverse events.
RESULTS Before matching, HF patients were much younger and more likely to be female. They had a much higher prevalence of previous myocardial infarction, chronic obstructive pulmonary disease and valvular heart disease. Among 1359 participants, we identified 1016 matched patients. The number of drugs did not affect the risk of all-cause mortality in both cohorts. For non-HF patients, using calcium channel blockers (CCBs) plus digoxin had a significant higher risk of all-cause death (HR=5.703, 95% CI 1.334–24.604, P=0.019) and cardiovascular death (HR=9.558, 95% CI 2.127–42.935, P=0.003) compared with patients not receiving rate-control treatment. The use of beta-blockers, CCBs, digoxin alone, other dual or triple combinations was not related to risk of adverse events in both groups.
CONCLUSIONS The combined use of CCBs and digoxin was related to increase all-cause and cardiovascular mortality in AF patients without HF but not for those with HF. However, the ideal rate-control regimen for AF and HF patients has not been established and well-designed clinical trials are needed.
GW32-e0748
Bin Tu
Fuwai
OBJECTIVES To determine the associations of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with disease progression and with the recurrence of life-threatening ventricular arrhythmia in a large cohort of patients with arrhythmogenic right ventricular cardiomyopathy.
METHODS This retrospective observational cohort study included patients with a definite diagnosis of ARVC as determined by 2010 task force diagnostic criteria. Disease progression was evaluated according to imaging data with linear mixed model. Cox proportional hazard regression models were used to evaluate the association between life-threatening ventricular tachycardia events and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers usage.
RESULTS Among the total 311 patients [age, 39.1±14.4 years; male, 233 (74.9%)] included, 113 (36.3%) received ACEI/ARB after the first-time discharge from our hospital. During a median follow-up of 5.9 (interquartile range 3.7–8.6) years, 203 patients experienced life-threatening ventricular arrhythmia events. Compare to patients without ACEI/ARB, patients under treatment were associated with slower decrease in tricuspid annular plane systolic excursion (0.61 mm vs. 0.37 mm per year decrease, P<.001), slower increase in right ventricular late gadolinium enhancement (1.2 vs. 0.9% per year increase, P=0.032), and reduced risk of life-threatening ventricular arrhythmia (adjusted HR: 0.71, 95% CI: 0.52–0.96, P=0.031).
CONCLUSIONS ACEI/ARB usage was associated with slower disease progression and reduced risk of life-threatening ventricular arrhythmia in patients with ARVC. Delaying disease progression might pave a new way for the treatment of ARVC.
GW32-e1567
Wen Zhuo1, Hualong Liu2, Kui Hong2
1南昌大学第二附属医院 (The Second Affiliated Hospital of Nanchang University)
2The Second Affiliated Hospital of Nanchang University
OBJECTIVES We conducted this systematic review and meta-analysis to evaluate whether digitalis is associated with an increased rate of appropriate shocks or mortality in patients who received ICDs or CRT-Ds implantation.
METHODS We systematically retrieved relevant studies using the Cochrane Library, PubMed, and Embase database. A random-effect model was used to pool the effect estimates (hazard ratios [HRs] and 95% confidence intervals [CIs]) when the studies were of high heterogeneity, otherwise, a fixed-effect model was used. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the included studies. The meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Review Manager 5.3 (Cochrane Collaboration, Copenhagen, Denmark) was used to perform the meta-analysis.
RESULTS The meta-analysis initially identified 1108 articles through electronic retrieval strategies, after duplicates and off topic articles were removed, twenty articles containing 41 412 ICDs or CRT-Ds recipients were included. The quality of all selected studies was assessed using the Newcastle-Ottawa Scale, and the average score was 7.8. Digitalis was associated with an increased rate of appropriate shocks (HR=1.59, 95% CI: 1.40–1.81, P<0.01) and a shorten time to first appropriate shock (HR=1.76, 95% CI: 1.17–2.65, P=0.007) in ICDs or CRT-Ds recipients. Besides, the all-cause mortality increased in ICDs recipients with digitalis therapy (HR=1.56, 95% CI: 1.27–1.91, P<0.01), but the all-cause mortality was unchanged in CRT-Ds recipients (HR=1.26, 95% CI: 0.88–1.81, P=0.20). The sensitivity analyses confirmed the robustness of the results. The meta-analysis was performed according to the PRISMA guidelines.
CONCLUSIONS Our study suggests that digitalis confers a detrimental effect in ICDs recipients. Digitalis is associated with an increase in appropriate shocks, a reduced time to first appropriate shock in ICDs or CRT-Ds recipients, and an increase in all-cause mortality in ICDs recipients. However, digitalis did not increase the all-cause mortality of CRT-Ds recipients, underscoring the significance of reassessing the effect of digitalis in the contemporary management of HF patients who received ICDs or CRT-Ds treatment.
GW32-e0222
Genqing Zhou, Xiaoyu Wu, Xiaofeng Lu, Yong Wei, Songwen Chen, Juan Xu, Yu Ding, Shaowen Liu
Shanghai General Hospital
OBJECTIVES The purpose of this study was to investigate the procedural safety and efficacy of modified box ablation in patients with persistent atrial fibrillation (AF) who underwent radiofrequency catheter ablation.
METHODS A total of 156 consecutive patients (105 male, mean age 61.1±9.9 years, mean left atrial diameter 44.6±3.5 mm) with persistent/long-standing persistent AF were enrolled in this study, all of whom underwent radiofrequency catheter ablation navigated by CARTO system for the first time in Shanghai General Hospital. The individualized ablation strategy, was composed by circumferential pulmonary veins isolation (PVI) and modified box ablation, additional complex fractionated atrial electrograms (CFAEs) and linear ablation was performed if necessary. Patients were followed up for at least 12 months. Recurrence was defined as episode(s) of AF/atrial tachycardia (AT) lasting over 30 seconds during follow-up after the 3-month blanking period.
RESULTS PVI was achieved in all of the 156 patients. The left atrial posterior wall isolation (PWI) rate was 32.7%, with bidirectional conduction block achieved in 95.5% of the roof line and 35.9% of the modified posterior-inferior line. Logistic multivariate stepwise regression analysis showed that right pulmonary vein first-pass isolation (β=1.350, OR=3.857, 95% CI 1.676–8.876, P=0.001) and area of the posterior wall (β=−0.263, OR=0.769, 95% CI 0.654–0.905, P=0.002) were both multivariate predictors of PWI. During modified box ablation, rhythm conversion occurred in 17 (10.9%) patients. Additional ablation was performed in 126 (80.8%) patients, including mitral isthmus line in 52 (33.3%) patients, tricuspid isthmus line in 40 (25.6%), and CFAEs in 103 (66.0%). Sinus rhythm was restored by direct current cardioversion in 107 (68.6%) patients. Periprocedural complications occurred in 3 (1.9%) patients, and no atrioesophageal fistula encountered. During a median follow-up of 30.0 (22.0–36.0) months, the 12-month single-procedural success rate was 80.1%, with an overall success rate of 70.5%. Among the 46 recurrent patients, 29 (63.0%) recurrenced with AT, and 17 with AF. Logistic multivariate stepwise regression analysis showed that left pulmonary vein first-pass isolation (β=-1.201, OR=0.301, 95% CI 0.131–0.691, P=0.005) and CFAEs ablation (β=1.208, OR=3.346, 95% CI 1.279–8.751, P=0.014) were predictors of single-procedural recurrence.
CONCLUSIONS PVI and modified box ablation based individualized ablation strategy is associated with a high long-term success rate and very low procedure-related complication rate.
GW32-e0834
Zhuxin Zhang1, Chao Jiang1, Liu He1, Yu Bai2, Jiahui Wu1, Rong Hu1, Qiang Lv1, Man Ning1, Li Feng1, Ribo Tang1, Caihua Sang1, Deyong Long1, Jianzeng Dong1, Xin Du1,2,3, Changsheng Ma1
1Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University; National Clinical Research Centre for Cardiovascular Diseases, Beijing, China
2The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia
3Heart Health Research Center, Beijing, China
OBJECTIVES Anemia is found to be a common comorbidity in patients with atrial fibrillation (AF) in recent studies. However, reports on the association of anemia and adverse events in patients with AF are limited.
METHODS Based on data from the China atrial fibrillation registration study (China-AF), a total of 18,106 AF patients enrolled between August 2011 and December 2018 with baseline results of hemoglobin (Hb) value were included in this study. Patients were classified into three groups according to Hb levels: 15,606 patients in no anemia group (male Hb≥130 g/L; female Hb≥120 g/L), 1800 patients in mild anemia group (male 110≤Hb<129 g/L; female 110≤Hb<119 g/L) and 700 patients in moderate to severe anemia group (Hb≤109 g/L). Multivariable Cox regression models were used to determine if anemia was independently associated with all-cause death, cardiovascular death or major bleeding, after adjusting for confounders.
RESULTS Anemia was present in 13.8% of the population at baseline. During a median follow-up of 4.01 years, the incidences of all-cause death (1.8, 4.9 and 8.9 per 100 person-years), cardiovascular death (1.0, 2.9 and 4.5 per 100 person-years) and major bleeding (0.5, 0.6 and 0.7 per 100 person-years) were gradually accentuated in patients with no anemia, mild anemia and moderate to severe anemia, respectively. Compared to patients with no anemia, those with anemia had higher risks for all-cause death (mild anemia; adjusted HR: 1.22, 95% CI: 1.08–1.38; moderate to severe anemia; adjusted HR: 1.53, 95% CI: 1.31–1.77), as well as for cardiovascular death (mild anemia; adjusted HR: 1.29, 95% CI: 1.10–1.52; moderate to severe anemia; adjusted HR: 1.27, 95% CI: 1.03–1.57), but not for major bleeding (mild anemia; adjusted HR: 0.91, 95% CI: 0.67–1.25; moderate to severe anemia; adjusted HR: 1.07, 95% CI: 0.66–1.73) in AF patients. The association between anemia and all-cause death was similar among subgroups stratified by of sex, kidney function, anticoagulant or ablation therapy.
CONCLUSIONS Anemia was associated with increased risks of all-cause death, cardiovascular death, but not for major bleeding in AF patients. The effect of anemia correction on the prognosis of patients with AF needs further clinical trials to confirm.
GW32-e1635
Qiuzhen Lin, Qiming Liu
The Second Xiangya Hospital, Central South University
OBJECTIVES Malnutrition is a common medical comorbidity and is associated with adverse outcomes, particularly in patients >65 years of age. The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool and is a significant prognostic factor in various diseases. However, there is limited evidence regarding the association between GNRI and elderly patients (>75 years of age) with atrial fibrillation. The aim of the present study was to examine the association between the GNRI and elderly patients with atrial fibrillation.
METHODS This study was a retrospective observational analysis. There was 976 patients (including 610 male and 366 female) with atrial fibrillation at department of cardiovascular medicine, the Second Xiangya Hospital, Central South University from June 2014 to January 2020 were recruited in this study. All subjects were divided into two groups, i.e., patients <75 years of age as group 1 and ≥75 years of age as group 2. The most often used conventional nutritional index, GNRI=1.489×serum Alb (g/L)+41.7×(measured BW (kg)/ideal BW (kg)). Ideal BW was calculated using the Lorentz-formula. Ideal BW=(height (cm) − 100) − (height (cm) − 150)/4 for men and (height (cm) − 100) − (height (cm) − 150)/2 for women. The scores of GNRI were divided into three risk groups, including high (GNRI<82), intermediate (GNRI 82–98) and normal (GNRI>98) nutritional risk.
RESULTS There were 820 patients (aged from 22 to 74 years) in group 1 and 156 patients (aged from 75 to 90 years) in group 2. Diastolic blood pressure, levels of haemoglobin, triglycerides, total cholesterol, serum albumin and score of GNRI were significant lower in group 2 (mean score of GNRI was 104 in group 1 and 97 in group 2, respectively) (P<0.05). However, the systolic blood pressure and N-terminal brain natriuretic peptide were significant higher in group 2 (P<0.05). There was no significant difference in body mass index, diastolic blood pressure, systolic blood pressure, levels of serum albumin, serum creatinine, N-terminal brain natriuretic peptide, total cholesterol and GNRI, except for levels of haemoglobin and triglycerides between male and female in group 2. In the whole sample (N=976), the prevalence of severe/moderate (GNRI<98) nutritional risk was 28.07%. The prevalence of severe/moderate (GNRI<98) nutritional risk was 24.2% (197/820) in group 1 and was 49.36% (77/156) in group 2, respectively. There was significant higher percent of severe/moderate (GNRI<98) nutritional risk in group 2 than group 1 (P<0.05).
CONCLUSIONS Levels of haemoglobin, total cholesterol, serum albumin and score of GNRI were significant lower in in atrial fibrillation patients ≥75 years of age. The prevalence of severe/moderate (GNRI<98) nutritional risk was about 50%. Thus, Geriatric Nutritional Risk Index should be taken seriously in elderly patients with atrial fibrillation.
HEART FAILURE
GW32-e1192
Noor Muhammad Azlan Shah Atan, Firdaus Hadi, Alexander Loch
University Malaya Medical Centre
INTRODUCTIONS Cardiac remodeling is a detrimental consequence of heart failure. The angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan has been shown to reverse cardiac remodeling and to improve systolic function in observational studies. There is a lack of local data regarding the effects of ARNI on cardiac remodeling in Asian populations. There are few studies comparing the remodeling effect of ARNIs with conventional heart failure medications.
OBJECTIVES 1. To determine the impact of ARNI on reverse cardiac remodeling. 2. To compare the effects of ARNI on reverse cardiac remodeling with those of Perindopril.
METHODS The study was conducted at University Malaya Medical Centre as a retrospective cohort study. Data was collected for the period from January 2017 until December 2020. Patients were included if they fulfilled the following criteria: i) age >18 years, ii) recent diagnosis of HFrEF (EF<40%), iii) baseline Echocardiography was performed not more than 18 months prior to initiation of ARNI or Perindopril, iv) Echocardiography reassessment was performed not earlier than 6 months and not later than 18 months post initiation of ARNI or Perindopril, v) the HFrEF must have been diagnosed not more than 1 year prior to initiation of therapy. Echocardiographic parameters analyzed included Left Ventricular Ejection Fraction (LVEF), Left Ventricular End Diastolic Volume (LVEDV), and Left Ventricular End Systolic Volume (LVESV). Epidemiological, laboratory, and clinical variables were recorded as well. Paired sample t-test and one-way repeated measures ANOVA were used to analyze normally distributed data. An equal number of HFrEF patients with similar clinical characteristics and treated with Perindopril was identified and analyzed in the same manner.
RESULTS From the hospitals electronic medical record system, 40 patients with complete echocardiographic sets treated with ARNI were identified. Another 40 patients treated with Perindopril and matching clinical characteristics were identified accordingly. Patients receiving ARNI recorded an increase in the LVEF from 24.9±8.0% (mean±standard deviation) to 36.4±12.3% (P<0.001) and improvement in LVESV by 17% from the baseline (P=0.003). Patients treated with Perindopril demonstrated a similar improvement in the LVEF from 28.7±7.4% to 40.5±15.9% (P<0.001) with improvement in LVESV by 12.7% from the baseline (P=0.093). The changes in LVEDV were less significant in both group (5.8% volume reduction in ARNI group and 2.6% in Perindopril group; P value 0.224 and 0.584, respectively).
CONCLUSIONS Treatment of recently diagnosed HFrEF patients with both ARNI and Perindopril resulted in significant improvement in the LVEF within 18 months after initiation of therapy. Cardiac volume reductions were largest for the end-systolic volumes. The results of the study must be interpreted with caution as for the small sample size, the retrospective character of the study, and the relatively short follow-up period.
GW32-e0190
Ran Mo, Yan-min Yang, Li-tian Yu, Hui-qiong Tan, Jun Zhu
Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
OBJECTIVES Systolic blood pressure (SBP) on admission is a well-established predictor for short-term outcomes in acute decompensated heart failure (ADHF). The present study aimed to evaluate sex-specific association between SBP and in-hospital prognosis in ADHF.
METHODS In this single-center, observational study, a total of 1268 critically-ill ADHF patients were enrolled and divided into two groups according to the gender. The primary endpoint was either all-cause mortality, cardiac arrest or utilization of mechanical support devices during hospitalization while the second endpoint was in-hospital death and the length of hospital stay. Uni- and multi-variate logistic regression analysis was performed to assess the predictive power of SBP on short-term outcomes based on gender.
RESULTS Female patients were more likely to be older (P<0.001) and have a lower rate of ischemic heart disease, cardiomyopathy (P=0.027) and reduced ejection fractions (P<0.001). The baseline prevalence of diabetes (P=0.971) and hypertension (P=0.258) were similar between genders. Multivariate analysis demonstrated that low SBP (OR=2.286, 95% CI 1.116–4.682, P=0.001) was associated with significant worse prognosis compared with normal SBP in the entire population. In male patients, the inverse correlation between SBP strata and prognosis still existed (low SBP vs. normal SBP: OR=3.320, 95% CI 1.512–7.289, P=0.002; high SBP vs. normal SBP: OR=0.215, 95% CI 0.049–0.954, P=0.036). However, such association was not identified in female patients with ADHF.
CONCLUSIONS Low admission SBP was related with increased in-hospital incidence of adverse events in ADHF patients. The correlation between decreased SBP and worse prognosis was dependent on gender, which was only identified in male. These data provide novel insights into gender differences in early decision-making systems for critically-ill ADHF patients.
GW32-e1066
Min Han, Yi-Tong Ma
Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
OBJECTIVES Heart failure (HF) remains a rising global health burden across different racial regions, of which heart failure with reduced ejection fraction (HFrEF) is the worst phenotype. However, the HF phenotypes are not distinguished in most epidemiological studies, and there is limited epidemic data on HFrEF in the Chinese general population.
METHODS A four-stage stratified cluster random sampling scheme was adopted to recruit represented participants among Han, Uygur, and Kazak population in northwest China. HFrEF was diagnosed by meeting the signs or symptoms of heart failure and EF≤40%. Multiple logistic regression was applied to identify associated factors of HFrEF.
RESULTS A total of 14,618 participants aged 35–101 years were included and 170 (1.2%) of them had HFrEF. The prevalence rate of HFrEF increased strikingly with age (all P<0.05) and was higher in males than that in females (1.5 vs. 0.8%, P=0.001). There exist significantly racial differences in HFrEF prevalence across Han, Uygur, and Kazak population (0.9%, 1.4%, and 1.3%, P<0.05). After multiple regression, age, hypertension, hyperuricemia, atrial fibrillation, valvular heart disease, and low HDL-C were identified as risk factors, while female sex was identified as a protective factor for HFrEF.
CONCLUSIONS HFrEF differed significantly by age, sex, and ethnicity in the natural population from Xinjiang. The exploration of prevalence and risk factors of HFrEF helps determine subjects ‘at risk’ of developing HFrEF and make ethnicity-specific strategies for the prevention of HFrEF.
GW32-e1440
Kuo Liu, Haijuan Hu, Demin Liu, Qian Wang, Lihui Zhang, Wei Cui
The Second Hospital of Hebei Medical University
OBJECTIVES At present, N-terminal pro-brain natriuretic peptide (NT-proBNP) has been widely used in the diagnosis and prognosis evaluation of patients with heart failure. An increasing number of studies have proved that the assessment of NT-proBNP on cardiac function is affected by the body’s long-term blood glucose concentration, and patients with cardiac dysfunction often have comorbid conditions with elevated blood glucose, such as diabetes and stress hyperglycemia. This study was designed to investigate the effect of fluctuation in blood glucose concentration over a short period of time on NT-proBNP level.
METHODS Thirty-two inpatients who underwent the OGTT test in the Department of Endocrinology of the Second Hospital of Hebei Medical University from September to October 2019 were randomly selected. Plasma NT-proBNP, blood glucose, insulin and C-peptide levels were measured at fasting, 30 minutes, 60 minutes, 120 minutes and 180 minutes after the start of OGTT test. Correlation between individual NT-proBNP level and blood glucose concentration was explored by Pearson and Spearman correlation analysis, and one-way repeated measures analysis of variance followed by generalized linear mixed model were applied to further analyse the effects of time, blood glucose, insulin and C-peptide on NT-proBNP level.
RESULTS Correlation analysis showed that there was a significant correlation between NT-proBNP level and blood glucose concentration in only 5 of 32 patients (P<0.05). However, the correlation trends and best fit curves between NT-proBNP level and blood glucose concentration were different in each patient. One-way repeated measures analysis of variance showed that there was no significant difference in NT-proBNP level at different time and different blood glucose concentration (F (1.36, 40.87)=1.23, P=0.29, η2=0.04). Generalized linear mixed model showed that NT-proBNP level was not affected by measurement time, blood glucose, insulin or C-peptide concentration (P>0.05).
CONCLUSIONS Acute fluctuation in blood glucose concentration does not affect the level of NT-proBNP, so it does not affect the evaluation of cardiac function by NT-proBNP.
GW32-e1723
Shanshan Liu1, Suyan Bian1*, Yifei Wang2, Binhua Wang2, Jian Zhu1
1Department of Cardiology, the Second Medical Center, Chinese PLA General Hospital
2Chinese PLA General Hosipal
OBJECTIVES To investigate overall as well as sex-specific underlying cardiac etiology and comorbidity among elderly patients hospitalized with heart failure in our hospital.
METHODS Through the hospital information system and inpatient electronic medical case information system, the gender, age, past medical history, and discharge diagnosis of elderly patients (≥60 years old) hospitalized with heart failure in our hospital from 2008 to 2020 were collected, and the underlying cardiac etiology and concurrent diseases were analyzed and compared between genders.
RESULTS A total of 10,874 eligible cases were enrolled, with an average age of 72.00±7.60 years, and a male predominance of 6146 cases (56.52%). The hospitalization age of men was much younger than that of women (71.36±7.47 years vs. 72.84±7.68 years, P<0.05). The top five cardiac causes for elderly heart failure admission were consistent across genders, though with some differences in the constituent ratio. Among them, ischemic heart disease ranked first (8044 cases, accounting for 73.97%), more in men than in women (76.67 vs. 70.47%, P<0.05); followed by essential hypertension (6802, 62.55%), arrhythmia (4216, 38.77%), valvular heart disease (1759, 16.18%), and primary cardiomyopathy (729, 6.70%), all of which were more in women than in men (P<0.05). The top four comorbidities in elderly heart failure inpatients were in a consistent order in both genders; they were dyslipidemia (9768, 89.83%), diabetes mellitus (3649, 33.56%), anemia (212, 29.54%), and chronic kidney disease (2708, 24.90%); the fifth was ischemic cerebrovascular disease in males (1162, 18.91%), but obesity in females (909, 19.23%). Diabetes and obesity were more common in females, while dyslipidemia and chronic kidney disease more common in males (P<0.05). No gender difference was noted in anemia and ischemic cerebrovascular disease.
CONCLUSIONS The underlying etiology and comorbidity for heart failure in elderly hospitalization are roughly the same in both genders, though with little differences, among which ischemic heart disease and dyslipidemia are the most common ones, respectively.
GW32-e0247
Zhaodong Guo1, Ming Ying2, Bo Wang2, Yong Liu2, Shaohong Dong1
1Shenzhen People’s Hospital
2Guangdong Cardiovascular Institute
OBJECTIVES Undefined adequate hydration may increase the risk of post-percutaneous coronary intervention (PCI) acute heart failure (AHF) while reducing the risk of contrast-associated acute kidney injury (CA-AKI) in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study is to evaluate the association of post-PCI AHF and long-term cardiovascular (CV) prognosis and establish a simple nomogram model for predicting post-PCI AHF in this patient group.
METHODS In this prospective observational study, 13,120 NSTEMI patients undergoing coronary angiography (CAG) were included in the final analysis. Patients were assigned into the non post-PCI AHF group (n=12,350) or the post-PCI AHF group (n=770).
RESULTS The overall incidence of post-PCI AHF was 770/13,120 (5.9%). The incidence of long-term CV death was significantly higher in the post-PCI AHF group than in the non post-PCI AHF group (50.6 vs. 17.0%, P<0.01). After adjusting for female, LVEF, eGFR, anemia, hypertension, diabetes mellitus, and PCI, post-PCI AHF was the strongest predictor of long-term CV death (hazard ratio: 3.11; 95% CI: 1.83–5.30; P<0.01). A nomogram developed based on the four variables was with the AUC 0.83 on internal validation. Decision curve analysis (DCA) indicated that our model was clinically useful.
CONCLUSIONS In patients with NSTEMI undergoing CAG, post-PCI AHF is the strongest predictor of long-term CV death. The simple nomogram showed an effective value of predicting post-PCI AHF using pre-PCI predictions.
GW32-e1076
Wang Qi1,2, Yan Ji1, Su Guohai2
1The First Affiliated Hospital of USTC, University of Science and Technology of China
2Jinan Central Hospital Affiliated to Shandong University
OBJECTIVES Predicting the risk of malignant arrhythmias (persistent ventricular tachycardia, ventricular fibrillation) in hospitalized patients with heart failure (HF) is challenging. Machine learning (ML) can handle a large volume of complex data more effectively than traditional statistical methods. Therefore, we explored the feasibility of ML methods for predicting the risk of malignant arrhythmias in hospitalized patients with HF.
METHODS We evaluated the baseline data and malignant arrhythmia events of 2794 hospitalized HF patients in an HF cohort in Anhui Province and randomized the subjects into a training set and a validation set at a 7:3 ratio. The risk prediction models were constructed in the training set using Lasso logistic regression, multivariate adaptive regression splines (MARS), classification and regression tree (CART), Random Forest (RF) and the eXtreme gradient boosting (XGBoost) algorithm, and the model performance was validated with the validation set. Model discrimination and calibration were estimated using the areas under the receiver operating characteristic curves (AUCs) and Brier scores, respectively. An evaluation of the clinical utility of the Lasso logistic regression model was performed using decision curve analysis (DCA).
RESULTS In the training set, the AUC of the XGBoost model was 0.998, which was higher than that of the other models (all P<0.001). In the validation set, the AUCs of the Lasso logistic model 1, Lasso logistic model 2, MARS model, RF model, and XGBoost model were similar (0.867, 0.828, 0.852, 0.804, 0.864, respectively, all P>0.05) and higher than those of the CART model (0.743, all P<0.05). Brier scores for all predictive models were less than 0.05. DCA results showed that the Lasso logistic model had a net clinical benefit. When the threshold probability was ≤40%, Lasso logistic model 1 was superior to model 2.
CONCLUSIONS The application of ML techniques may help to effectively predict the risk of malignant arrhythmias in hospitalized patients with HF. Meanwhile, the combination of new and traditional statistical analysis methods can improve the overall performance of the prediction model.
GW32-e1509
Chendie Yang1, Xiaoqun Wang1
1Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China
OBJECTIVES Left ventricular (LV) diastolic dysfunction (LVDD) is the defining feature of heart failure with preserved ejection fraction (HFpEF), and predicts subsequent incident heart failure (HF) and all-cause mortality. Mounting evidence reveals that cardiometabolic risk factors play critical roles in the development of LVDD. In this study, we sought to investigate the relation between serum uric acid (SUA) level and the progression of LVDD in apparently healthy patients.
METHODS A total of 1082 apparently healthy subjects without diagnosed cardiovascular disease and with relative normal LVDD (grade 0∼1) were consecutively enrolled. SUA levels were measured and repeat echocardiography and tissue Doppler imaging (TDI) were performed at baseline and during 1-year follow-up.
RESULTS By dividing the study population based on quartiles of SUA, we found subjects in higher quartiles had greater increases in TDI-derived early diastolic velocity (e´) and E (peak LV filling velocity) /e´ ratios during 1-year follow-up. After multivariate adjustment, high SUA persisted to be an independent predictor for the subsequent worsening of LVDD (odds ratio: 1.351 [95% CI 1.125∼1.625], per 100 μmol/L SUA). Subgroup analysis suggested that the association between SUA and LVDD development was more pronounced in subjects without other cardiometabolic risk factors involved. Factor analysis demonstrated that high SUA was the major cardiometabolic attribute in patients with LVDD progression.
CONCLUSIONS Our findings suggest that high SUA is an independent cardiometabolic risk factor for the progression of LVDD in apparently healthy subjects.
GW32-e1809
Guangda He, Lihua Zhang, Jing Li
National Clinical Research Center for Cardiovascular Diseases, NHC Key Laboratory of Clinical Research for Cardiovascular Medications, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases
OBJECTIVES To assess and compare the prognostic value of high-sensitivity C-reactive protein (hsCRP) levels at acute and stable phases among patients hospitalized heart failure (HF).
METHODS We included patients hospitalized for HF from 52 hospitals in China between 2016 and 2018, who had their hsCRP levels at admission and 1-month after discharge measured at central laboratory. Multivariable Cox models were developed to evaluate the relationship between hsCRP and all-cause death within 2-year follow-up. The candidate covariates were chosen based on literature review. The hazard ratios (HRs) were scaled per 1 unit increase of logarithms of hsCRP levels. In order to determine which hsCRP level was more prognostically important in predicting the risk long-term death, we put hsCRP levels at admission and 1-month into one Cox model. Furthermore, we also performed subgroup analyses among patients with left ventricular ejection fraction (LVEF) <40 and LVEF ≥40 to assess the interaction between hsCRP levels and LVEF.
RESULTS In total, we included 2463 patients hospitalized for HF. The median (interquartile range, IQR) age was 66 (55, 74) years old and 36.3% were female. The median (IQR) levels of hsCRP were 4.0 (1.6, 11.5) mg/L at admission and 1.7 (0.7, 3.9) mg/L at 1-month of discharge. The adjusted HRs of 2-year all-cause death were 1.02 (95% confidential interval [CI], 0.95–1.10) for admission hsCRP and 1.26 (95% CI, 1.17–1.36) for 1-month hsCRP. There was no significant interaction between LVEF and either admission hsCRP level (P=0.0683) or 1-month hsCRP level (P=0.4329). Among patients with LVEF <40, the HRs were 1.08 (95% CI, 0.96–1.21) and 1.29 (95% CI, 1.15–1.45) for admission hsCRP and 1-month hsCRP, respectively. Similarly, in the subgroup of LVEF ≥40, the HRs were 0.99 (95% CI, 0.89–1.09) and 1.26 (95% CI, 1.14–1.39), respectively.
CONCLUSIONS Among patients hospitalized for heart failure, hsCRP level at 1-month of discharge is significantly associated with increased risk of long-term all-cause death, rather than the admission hsCRP level. It implies the hsCRP level at stable phase was more prognostic than that at acute phase in heart failure.
GW32-e0393
Yi Zhou, He Li, Mingxing Xie
WuHan Union Hospital
OBJECTIVES In patients with heart failure (HF), interventions to reduce elevated left atrium pressure (LAP) can improve symptoms and reduce the risk of hospital admission. D-Shant device (D-Shant device; WeiKe Medical Inc., WuHan, CN) is the first domestic therapeutic left-to-right interatrial shunting device. We aimed to assess the safety and potential efficacy of D-shant device in HF patients with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), and further to assess whether this shunt function confer benefits in cardiac remodeling.
METHODS Patients (age ≥50 years) with New York Heart Association (NYHA) class III chronic HFpEF and HFrEF patients were enrolled in the pilot trial. Device implantations were done after transseptal catheterization with transesophageal echocardiographic guidance under general anesthesia. Patients had clinical, invasive hemodynamics and echocardiography evaluations at baseline and months 1 after shunt implantation.
RESULTS Ten HFpEF and 10 HFrEF patients were enrolled. The device was successfully implanted in all patients; no device-related or procedural adverse events occurred during follow-up. Transesophageal echocardiography at 1 month showed that all shunts were patent, with no thrombosis or migration. Invasive hemodynamic studies confirmed a sustained reduction in the LAP (P<0.01), without an increase in pulmonary pressure or pulmonary vascular resistance. No patient was admitted to hospital for worsening HF. Conventional echocardiogram showed a significant reduction in LA (P<0.05) both in two groups, with slightly stable increase in the right atrium size (P<0.05) in HFpEF group. Although no change of LVEF has been noted in both groups, biventricular global longitudinal strains (P<0.05) substantially increased in both groups from baseline to 1-month follow-up. Furthermore, both two groups showed the reduction of the severity of functional mitral regurgitation.
CONCLUSIONS This first-in-man experience with an implanted left-to-right interatrial shunt demonstrates initial safety and early beneficial clinical, hemodynamic outcomes, and cardiac reverse remodeling in patients with HFpEF and HFrEF.
GW32-e1099
Cheng Zhao, Xing Hao, Chao Xue, Yichen Zhao, Jiangang Wang
Beijing Anzhen Hospital
OBJECTIVES Acute right ventricular failure remains a difficult and common clinical syndrome in heart transplant recipients, while ECMO is a proven strategy for this situation. Outcomes after weaning and during follow-up are not well studied. We evaluated the right-sided heart function in these ECMO survivors.
METHODS From September 2005 to December 2019, 205 patients with end-stage heart failure underwent standard orthotopic heart transplantation were enrolled. 68 (33.2%) in ECMO group and 137 (66.8%) in non-ECMO group. Echocardiography was performed to evaluate right-sided heart characteristics.
RESULTS Of the 68 patients in the ECMO group, 42 (61.8%) were successfully weaned from ECMO (median duration 4.7 days [IQR 3–6]). Doner age (OR 3.10, 95% CI 1.40–6.86, P=0.005), CPB time (OR 2.91, 95% CI 1.40–6.04, P=0.004), SPAP (OR 3.67, 95% CI 1.79–7.53, P<0.001), right atrial diameter (OR 4.20, 95% CI 1.97–8.95, P<0.001) and RVOT diameter (OR 2.14, 95% CI 1.01–4.54, P<0.049) were risk factors for ECMO use. After a median follow-up time of 53 months [IQR 24–105], there were 25 (59.5%) and 27 (23.7%) deaths in the ECMO and non-ECMO groups, respectively (OR 2.30, 95% CI 1.20–4.39, P value=0.01). Patients in the ECMO group had a larger RV diameter than the non-ECMO group in both the discharge (P=0.002) and follow-up (P=0.004) evaluations. Meanwhile, the ECMO group had a higher right ventricle Tei index than the non-ECMO group (P=0.02) in the follow-up.
CONCLUSIONS Right-sided heart characteristics were strong predictors of ECMO after HTx. ECMO patients had high mortality in the perioperative period and follow-up. Although RV function in these ECMO survivors after HTx was poor during follow-up, ECMO was still performed as a life-saving method for critically ill patients following HTx.
GW32-e1538
Chendie Yang, Xiaoqun Wang
Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P.R. China
OBJECTIVES Heart failure (HF) with improved or recovered ejection fraction (EF, HFrecEF) has been recognized as a new type of HF with different underlying clinical phenotype, pathophysiology and prognosis. However, few studies have analyzed the relationship between type 2 diabetes and HFrecEF, and the impact of glycemic level on myocardial function recovery. In the present study, we sought to investigate the relation between HbA1c level and HFrecEF in patients with type 2 diabetes.
METHODS A total of 796 HF patients with reduced left-ventricular ejection fraction (LVEF, <40%) and type 2 diabetes were consecutively enrolled from August 2012 to July 2020. During follow-up for up to 24 months, patients were classified into HFrecEF for whom developed recovered LVEF (≥40% and absolute increase ≥5%) and HFrEF for whose LVEF was persistently reduced (<40%). The relation between HbA1c and the recovery of LV function was analyzed.
RESULTS HF patients with type 2 diabetes had significantly lower rates of LVEF recovery when having higher versus lower HbA1c levels in the baseline (the lowest tertile: 62.4%, intermediate tertile: 50.4%, the highest tertile: 46.8%; P<0.001). There were stepwise decreases in changes of LVEF (P<0.001) and increases in changes of LV end-systolic diameter (LVESD; P=0.093) with increasing tertiles of LVEF during follow-up. In the subgroup analysis, the impact of HbA1c on LVEF recovery was more prominent in patients with ischemic heart disease (P<0.001) than those with dilated cardiomyopathy (P=0.536). A significant interaction term was present between HbA1c and etiology of heart failure with regard to LVEF recovery (P=0.012). After multivariate adjustment of conventional confounding factors, high HbA1c level remained to be an independent risk factor lower incidence of HFrecEF in patients type 2 diabetes.
CONCLUSIONS Our study suggests that optimal glycemic control is an independent predictor for incidence of HFrecEF in patients with type 2 diabetes.
GW32-e1866
Lingyu Zhang1, Shiqun Chen2, Zhidong Huang2, Xiaoli Zhao3, Xiemuxikaimaier Aobuliksimu4, Jin Liu2, Yan Liang1, Yong Liu2
1Maoming People’s Hospital
2Guangdong Provincial People’s Hospital
3The Third Affiliated Hospital of Sun Yat-Sen University
4The First People’s Hospital of Kashgar
OBJECTIVES Available evidence is incomplete and heterogeneous on the outcome of heart failure (HF) patients with preserved ejection fraction (HFpEF), mild reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). And there are limited data on the proportions and long-term prognosis among 3 HF phenotypes in China. We aimed to characterize the 5-year prognosis in 3 HF phenotypes according to EF in a cohort of hospitalized HF patients in southern China.
METHODS Hospitalized patients who complicated with HF were enrolled in the Cardiorenal ImprovemeNt cohort study (CIN, ClinicalTrials.gov NCT04407936) between January 2007 to December 2014. HF types were defined as HFpEF (EF ≥50%), HFmrEF (EF 40% to 49%) and HFrEF (EF <40%). Kaplan-Meier and Cox proportional hazards models were constructed to examine differences in 5-year outcomes in HF patients with different phenotypes.
RESULTS A total of 4880 HF patients (mean age: 61.8±10.3, male: 3156 [64.7%]) were included: 2768 (57%) had HFpEF, 1015 (21%) had HFmrEF, and 1097 (22%) had HFrEF. Patients with HFrEF were older and more likely to be male than those with HFpEF. With 5 years of follow-up through the end of December 2019, 1624 (27.6%) patients died. Controlling confounding variables, declined EF category was independently associated with increased 5-year mortality. (HFrEF 25.2 vs. HFpEF 13.4%, adjusted hazard ratio (aHR): 1.85 [95% confidence interval (CI): 1.45–2.35]; HFmrEF 18.1 vs. HFpEF 13.4%, aHR: 1.40 [95% CI: 1.08–1.81]; in addition, HFrEF 25.2 vs. HFmrEF 18.1%, aHR: 1.32 [95% CI: 1.02–1.71]).
CONCLUSIONS In this Chinese cohort, patients with HFrEF account for less than a fourth of HF patients. One to two out of eight individuals with 3 HF types dead in 5 years. HFrEF was associated with nearly 2-fold increased risk of 5-year mortality than HFpEF. Further studies are needed to prospectively evaluate the efficacy of improving treatment on outcomes in all of 3 HF phenotypes.
GW32-e0445
Yizhou Feng1, Xiaojing Chen1, Maria Schaufelberger2, Qing Zhang1, Michael Fu2
1Department of Cardiology, West China Hospital, Sichuan University
2Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg
OBJECTIVES Clinical phenotype and prognosis of heart failure (HF) maybe variable among different racial populations. Therefore, a patient-level comparison of admitted HF patients in two university hospitals from China and Sweden were performed.
METHODS We made secondary analysis of patients with heart failure prospectively enrolled in the Swedish Heart Failure Registry from Sahlgrenska University Hospital/Östra Hospital, Sweden and West China Hospital, China from 2011 to 2015. Clinical characteristics and 6-month mortality were compared between the populations.
RESULTS Nine hundred and forty-nine Chinese and 1639 Swedish patients were included in our analysis. Higher systolic blood pressure (126.1±20.3 vs. 114.2±15.4 mmHg, P<0.001) and NT-proBNP level (4540 vs. 3251 pg/mL, P=0.013) were found in Swedish cohort, also more patients with ischemic heart disease (32.0 vs. 19.2%), hypertension (64.2 vs. 36.8%), valvular heart disease (40.9 vs.31.6%) and atrial fibrillation (55.3 vs. 39.6%) (all P<0.001). The use of ACEIs/ARBs (48.8 vs. 80.8%) or beta-blockers (58.8 vs. 86.5%) (both P<0.001) was lower in Chinese cohort. Given younger age in Chinese cohort (61.6 vs. 76.4 years, P<0.001), age-stratified analyses were conducted, as there were similar patient numbers in 50–74 years in Chinese (n=550) and Swedish (n=554) cohorts, therefore baseline characteristics and prognosis were further compared. The age- and sex-adjusted outcome (HR 0.80 [95% CI 0.55–1.19], P=0.273) were comparable between the two populations. The NT-proBNP and eGFR independently predict 6-month mortality in both Chinese (HR [95% CI] 1.006 [1.003–1.008], 0.986 [0.976–0.999]) and Swedish cohort (1.003 [1.000–1.007], 0.988 [0.976–0.999]).
CONCLUSIONS Patient-level comparison of real-world HF populations from China and Sweden demonstrated different clinical phenotypes and therapy but similar prognosis and their predictors.
GW32-e1181
Ayiguli Abudukeremu, Xiao Liu, Yuling Zhang, Jingfeng Wang
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
OBJECTIVES Although B-type natriuretic peptide (BNP) was reported being a promising predictor of stroke in patients with or without atrial fibrillation (AF), the clinical predictive ability of BNP for risk of stroke in heart failure patients with preserved ejection fraction (HFpEF) has not been assessed. We aim to assessed the predictive value of BNP for stroke risk in patients with HFpEF.
METHODS Seven hundred and ninety-nine heart failure patients with preserved ejection fraction participants from The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) was included. We evaluated the association of baseline BNP with stroke using the Cox proportional hazard model. Results were reported with adjusted hazard ratios (HRs) and confidence intervals (CIs). The discriminatory ability of the BNP was expressed using the C-index which calculated by the area under the receiver operating characteristic curve. What’s more, net reclassification improvement (NRI), the integrated discrimination improvement (IDI) was used to compare the predictive power for stroke between BNP-added traditional clinical models and traditional clinical models (CHADS2/CHA2DS2-VASc/R2CHADS2 score).
RESULTS A total of 34 (4.3%) patients among 799 patients with HFpEF experienced stroke events after a median of 2.85 years of follow-up. The stroke group showed a higher BNP level (375 pg/mL vs. 241 pg/mL, P=0.006). Echocardiographic parameters showed stroke group had higher left ventricle relative wall thickness (P=0.015), higher posterior wall thickness (P=0.048) and higher right ventricular outflow tract velocity time integral (P=0.05). The survival classification and regression tree analysis revealed that the accurate cut-off point of BNP in predicting post-discharge stroke was 278 pg/mL. Cox regression model showed higher BNP level was associated with an increased risk of stroke after adjustments (HR 3.11,95% CI=1.41–6.85) and have a moderate performance for stroke prediction (C-index=0.67). Adding the BNP to the CHADS2/CHA2DS2-VASc/R2CHADS2 scores improved its predictive value for stroke (CHADS2: C-index=0.67, BNP+CHADS2: C-index=0.77, NRI=40.9%, IDI=3.0%; CHA2DS2-VASc: C-index=0.64, BNP+CHA2DS2-VASc: C-index=0.74, NRI=41.4%, IDI=2.2%; R2CHADS2: C-index=0.70, BNP+R2CHADS2: C-index=0.78, NRI=40.9%, IDI=3.2%).
CONCLUSIONS BNP could predict the occurrence of stroke alone and improved predictive ability in combination with established CHADS2/CHA2DS2-VASc/R2CHADS2 score in patients with HFpEF.
GW32-e1555
Qiang Li1, Jin Liu1, Shanshan Shi2, Weihua Chen2, Haozhang Huang1, Shiqun Chen1, Yong Liu1
1Guangdong Provincial People’s Hospital, Guangzhou 510080, China
2The School of Clinical Medicine, Fujian Medical University, Fuzhou 364000, China
OBJECTIVES Contrast-associated acute kidney injury (CA-AKI) is a common complication after coronary angiography (CAG) and interventional procedures, with an estimated prevalence of up to 12%. Previous studies have shown that acute kidney injury (AKI) is strongly associated with the development of heart failure (HF). Cardiac remodeling (CR) is a vital process in the progression of HF. Recent studies found that the patient with AKI have higher levels of oxidative stress, inflammation, calcium transport abnormalities, and other pathophysiological mechanisms through activation of the renin-angiotensin system. Meanwhile, oxidative stress, inflammatory responses, calcium transport abnormalities and especially the renin-angiotensin system also play an essential part in the pathophysiology of CR. However, it remains unclear whether AKI is independently associated with CR. The study aims to investigate the association between AKI and CR in a large Chinese population underwent CAG. Moreover, this study contributes to guide clinicians to identify and intervene early in CR and reduce the incidence of HF after AKI.
METHODS We included consecutive patients undergoing CAG from January 2007 to December 2018 at Guangdong Provincial People’s Hospital (ClinicalTrials.gov NCT04407936). CA-AKI was defined as a serum creatinine (Scr) increase ≥50% or 0.3 mg/dL from baseline within the first 48–72 hours after the procedure. CR was defined as: 1) a ≥10 points decline from baseline left ventricular ejection fraction (LVEF), 2) or a follow-up measurement of LVEF <40%. Univariable and multivariable logistic regressions were used to assess the association AKI and CR.
RESULTS Of the 1573 patients (mean age 62.2±9.7 years, female 36.7%) included in the study, 253 (17.2%) had AKI. The prevalence of CR was higher in patients with AKI than in those non-AKI (24.7 vs. 14.5%). Univariate logistic regression analysis indicated that the CR (odds ratio [OR], 1.93; 95% CI, 1.37–2.68; P<0.001) was significantly associated with AKI. After adjusting for age, gender, acute myocardial infarction (AMI), percutaneous coronary intervention (PCI), diabetes (DM), hypertension (HT), chronic kidney disease (CKD) and congestive heart failure (CHF), multivariate logistic regression showed that AKI is associated with a significantly higher risk of CR (adjusted odds ratio [aOR] 1.89; 95% CI, 1.33–2.67; P<0.001). In addition, Kaplan-Meier curves showed that CR patients had higher all-cause long-term mortality compared to non-CR patients (9.7 vs. 19.05%, log-rank test, P<0.001).
CONCLUSIONS Our study suggested that nearly a quarter of AKI patients suffered CR and the patient with AKI has a 2-fold risk of CR than the patient without AKI. Our findings notice that more active measures should be taken to prevent the patient with AKI developing into CR.
GW32-e1868
Lingyu Zhang1, Qingbo Xu1, Shiqun Chen2, Zhidong Huang2, Xiaoli Zhao3, Jin Liu2, Yan Liang1, Yong Liu2
1Maoming People’s Hospital
2Guangdong Provincial People’s Hospital
3The Third Affiliated Hospital of Sun Yat-Sen University
OBJECTIVES The relationship between early ejection fraction (EF) deterioration and mortality in heart failure with preserved ejection fraction (HFpEF) has been not well addressed. Our study aimed to assess effect of early decline in EF values on the prognosis of HFpEF patients.
METHODS Twenty-one thousand and nine hundred fifty-eight consecutive HF patients undergoing coronary angiograph were included from January 2007 to December 2018 at Guangdong Provincial People’s Hospital. Three hundred and fifty-seven patients with EF ≥50% were included in analysis. After 3–12 months, HFpEF patients were further classified as early worsening EF and non-worsening EF. Early worsening HF was defined by the following criteria: a ≥5 points decline from baseline EF within 3–12 months.
RESULTS Finally, 1418 patients with EF ≥50% met study criteria during a follow-up of 4 years, the rate of early worsening EF and non-worsening EF all-cause mortality was 9.2% and 5.2%, respectively. Declining EF indicated worse prognosis in HFpEF patients. (aHR 2.11, 95% CI: 1.32–3.37; P=0.002). In logistical models, LVEDD and HDL-C emerged as predict factors of early worsening EF.
CONCLUSIONS Early worsening EF is common among patients with HFpEF and is strongly associated with increased all-cause mortality. Clinical trials are need to prospectively assess the efficacy of heart structure and function related management on outcomes in HFpEF.