[GW28-e0048]
Cordyceps Sinensis prevents contrast-induced nephropathy in diabetic rats by inhibiting p38 MAPK and Akt/mTOR/P70S6K signaling pathways
Kai Zhao1 Qiaoying Gao2 Kai Zhao1
1. Department of Cardiology, Tianjin Nankai Hospital
2. Department of Pharmacology, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital
Objectives: Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). Cordyceps sinensis (CS), a time-honored tonic food and herbal medicine in China, can improve the microcirculation, increase the tolerance to ischemia in patients with microcirculatory disorders. As CS has been found to be renoprotective and anti-apoptotic in multiple kidney injuries, we hypothesized that CS would prevent CIN. The objective of this research is to study the mechanism of CS on tubular epithelial cell apoptosis in diabetic CIN rats.
Methods: Eighty SD rats were randomly divided into four groups of twenty rats each: control group, rats treated with low-dose CS group (CS 2.0g/kg, per day), rats treated with middle-dose CS group (CS 2.5g/kg, per day), and rats treated with high-dose CS group (CS 3.0g/kg, per day). We used a rat model of Iodixanol-induced CIN. Serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1 (KIM-1), interleukin (IL)-18 and neutrophil gelatinase associated lipocalin (NGAL) were measured to evaluate kidney function. Nitric oxide (NO), malonaldehyde (MDA), and superoxide dismutase (SOD) level in renal tissue homogenate were assessed to discuss the effect of CS on oxidative stress in CIN. The pathological changes of kidney were observed by hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) analysis. Apoptosis was assessed by transmission electron microscopy and transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Fork-head box O1 transcriptional factor (FoxO1) mRNA expression was evaluated by quantitative real-time PCR. Phospho-p38 mitoge-activated protein kinase (MAPK) and Akt/mTOR/P70S6K protein expression was assessed by immunohistochemistry and Western blotting.
Results: Pretreatment with CS attenuated the effect of induction of CIN, and the absolute increase of Scr, BUN, KIM-1, IL-18, NGAL, NO, MDA and SOD levels were significantly lower than in the control group (p<0.05).
Histological evaluation of kidney sections in the CIN group revealed severe vacuolization of the renal cortex, intratubular cast formation, and medullary congestion. Pretreatment with CS markedly attenuated the development of these lesions. In addition to CS, renal tubular apoptosis was assessed by TUNEL staining in kidney sections. When compared to the control group, TUNEL-positive tubular cells were markedly decreased in the pretreatment with CS groups. To further confirm the presence of apoptosis in CIN rats, we investigated the cleavage of caspase-3, caspase-9 substrate, using Western blotting. Pretreatment with CS significantly decreased the apoptotic cell numbers. Rats treated with high-dose CS group were even lower than those in the control group (p<0.01).
We examined whether the increased tubular epithelial cell apoptosis was associated with Bax, Bcl-2 in vivo. Mechanistically, CS inhibited inducible Bax protein expression while it upregulated Bcl-2. In addition, CS decreased the expression of p38 MAPK, Akt/mTOR/P70S6K and FoxO1 signal pathways.
Conclusions: In summary, CS can effectively reduce kidney damage caused by contrast medium. The underlying mechanism may be that CS accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress and inhibiting p38 MAPK, Akt/mTOR/P70S6K and FoxO1signal pathways. Thus, CS may be a new potential therapeutic agent to prevent CIN, and high-dose CS might be more effectively.
[GW28-e0075]
Exercise training modulation of inward rectifier potassium channels and control blood pressure in hypertensive rats
Chun Zi Jin Wenbo Liu Lan Cui
Yan Bian University Hospital, Yanji, Ji Lin Province
Objectives: This study aimed to explore the mechanisms underlying high blood pressure control by physical exercise through modulation of inward rectifier potassium channels.
Methods: Hypertension animal models with or without physical exercise were established. The blood pressure in the rat models was monitored by a tail-cuff method using a multi-channel multi-animal Coda Non-Invasive Blood Pressure System (Kent Scientific Corporation, USA). After 4 weeks of preparation of animal models, the deep femoral arteries were removed from the rats under inhalational anesthesia. The luminal diameter of vessels was measured using a vessel diameter image analysis system. The patch-clamp technique was used to measure the Kir current, and Western blotting assay was used to determine the expression level of the Kir 2.1 protein.
Results: 1. No statistically significant difference in the body weight, heart weight, ventricular+Septum weight, Right ventricular weight and (ventricular+Septum) weight/Right ventricular weight were found between the hypertension group and the hypertension-exercise group. 2. The systolic blood pressures and diastolic pressure two weeks after the angiotensin II injection (no other treatments) did not show significant differences between the hypertension group (systolic blood pressures: Week 0: 125±2.9 mmHg, Week 1: 148±2.8 mmHg, Week 2: 145±3.1 mmHg; diastolic pressure :Week 0: 93.5±2.9 mmHg, Week 1: 95±3 mmHg, Week 2: 110±2.9 mmHg) and the hypertension-exercise group(systolic blood pressures: Week 0: 125±2.9 mmHg, Week 1: 148.5±3 mmHg, Week 2: 144±2.9 mmHg; diastolic pressure: Week 0:93.5±2.9 mmHg, Week 1: 94.5±2.8 mmHg, Week 2: 110.5±3.1 mmHg) (both P>0.05). At Week 4 post-angiotensin II injection (i.e., two weeks of exercise treatment for the hypertension-exercise group), the systolic blood pressure showed statistically significant difference between the hypertension group (Week 4: 170±2.9 mmHg) and the hypertension-exercise group (Week 4: 148±2.8 mmHg), so did the diastolic blood pressure(Week 4: 125±2.8 mmHg v.s. 105±2.9 mmHg) (P<0.05).Compared to the hypertension group, the hypertension-exercise group exhibited remarkably effective control of blood pressure. 3. As indicated by the vessel diameter image analysis, the vasodilation response in the hypertension-exercise group was more significant, which could be suppressed by the blocker (50mM BaCl2) of the inward rectifier potassium channels. 4. The patch-clamp recording of the Kir current revealed that the Kir current in the hypertension-exercise group was larger than that of the hypertension group (P<0.05). In addition, the expression of the Kir 2.1 protein in the hypertension-exercise group was higher than that of the hypertension group, as indicated by Western blotting assay.
Conclusions: The present study investigated the effects of long-term exercise on cells, in particular its effect on blood-pressure control through increasing membrane Kir current. This study revealed that, long-term exercise can enhance the vasodilation capacity of vessels while such improvement is critical for improving the quality of life and reducing the risk of hypertension and related cardio-cerebral vascular complications in hypertension patients.
[GW28-e0645]
Surgical treatments for giant left atrium in patients with valvular diseases
Siyi He Hui Ouyang Jinbao Zhang
Department of cardiovascular surgery, Chengdu Military General Hospital
Objectives: Once associated with giant left atrium (GLA), poor prognosis will easily occur in patients with valvular diseases. GLA could cause postoperative respiratory and circulatory dysfunction by compression of left ventricle and pulmonary, leading to increased mortality. Various surgical procedures have been employed to GLA, but the efficacy remains unclear. The present study concludes several left atrial reduction operations in single cardiovascular center, intending to give a comprehensive description of surgical treatments for GLA.
Methods: All consecutive patients with left atrial diameter greater than 60mm were enrolled in the present research. We conducted a retrospective study from 2009.02 to 2014.12 and a prospective RCT study in comparison of modified left atrial circuit plication procedure (circuit-LAP group) with other left atrial reduction operations (control group) from 2012.06 to 2014.01. Modified left atrial circuit plication was proceeded as follows: from initiation of left atrial roof, left atrial appendage is firstly closed, the suture line is subsequently alongside mitral valve ring and central section of pulmonary veins, and finally ends in the first stitching. All patients were followed up for 12 months.
Results: 166 left atrial appendage closing, 205 partial left atrial plication, 2 cut-and-sew procedure, 311 modified left atrial circuit plication were used. Once patients received surgical treatments, CPB time and aortic clamping time was significantly increased, but there was no obvious difference in incidence of postoperative complications and mortality. In the perspective study, 75 patients were enrolled in control group while 69 patients were enrolled in circuit-LAP group. These two groups had almost the same CPB time, aortic clamping time and ratio of auto-rebeating. The volume of left atrium was reduced more in circuit-LAP group respectively in the follow-up time of 0, 3, 6, 12 months. Compared with control group, circuit-LAP could significantly increase LVEDD, LVEF as well as E/A value measured by ultrasound, implying that this procedure was beneficial for improvement of cardiac function. As for clinical outcomes, reduced incidence of Low Cardiac Output Syndrome, IABP implantation, and decreased mechanical ventilation time, ICU stay time, hospitalization time could be observed in circuit-LAP group. However, there was no significant difference in ratio of acute kidney injury, ventilator-associated pneumonia, infectious endocarditis, ventricular arrhythmias as well as mortality. In addition, the ratio of sinus rhythm recovery was significantly higher in circuit-LAP group compared with control group in the follow-up time of 3, 6, 12 months.
Conclusions: Surgical left atrial reduction operations are safe and effective for treatment of giant left atrium, of which modified left atrial circuit plication is associated with better prognosis.
[GW28-e0429]
Protective Effect of Physcion on Homocysteine-induced Endothelial Dysfunction via Activation of PI3-kinase/Akt- and Ca2+-eNOS-NO Pathway
Hangji Lyu2 Xiaowei Ji3 Ziqi Zhou3 Mei Zhuang3 Qingqing Yang3 Songnan Jin3 Kyungwoo Cho1 Jinfu Wen1
1. Institute of Atherosclerosis, Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, Shandong, 271000, China
2. College of Basic Medical Sciences, Taishan Medical University, Taian, Shandong, 271000, China
3. School of Pharmacy, Taishan Medical University, Taian, Shandong, 271000, China
Objectives: Homocysteine (Hcy) plays important roles in the occurrence and development of cardiovascular disease. Chronic cardiovascular complications induced by hyperhomocysteinemia (HHcy) have been most relatively associated with endothelial cell injury. Recently, Natural products have attracted increasing interests in the prevention and treatment of cardiovascular diseases. Physcion, an anthraquinone derivative, has been widely used as mild laxatives. It has also been reported that physcion has a variety of pharmacological properties including hepatoprotective, anti-inflammatory, and anti-microbial activities. However, the effect of physcion on Hcy-induced endothelial dysfunction has not yet been defined. The purpose of the present study was to define the protective effect of physcion on homocysteine-induced endothelial dysfunction and its mechanisms involved.
Methods: Sprague-Dawley rats were assigned randomly to four groups: control, physcion, HHcy and physcion + HHcy groups. HHcy was induced in rats by feeding a high-methionine diet, which consisted of a regular diet plus 3% methionine. Physcion (50 mg/kg/d) was administrated by intragastrical gavage for 8 weeks. The isometric tension of isolated phenylephrine-precontracted rat thoracic aorta rings in response to different concentrations of acetylcholine (ACh), SNAP and CNP were measured respectively. Human umbilical vein endothelial cells (HUVECs) were cultured in vitro. Hematoxylin-eosin (HE) staining, methyl thiazolyl tetrazolium assay (MTT), enzyme linked immunosorbent assay (ELISA), fluorescent staining, confocal fluorescence detection, flow cytometry, and western blot were used.
Results: In the aortic sections, intimal endothelial layers of HHcy rats were rougher than those of control rats. Both plasma Hcy and ANP levels were elevated in HHcy rats. Treatment with physcion significantly reversed the endothelial cell morphological changes and decreased the elevated plasma levels of Hcy and ANP in HHcy rats. ACh, SNAP and CNP induced vasorelaxation in a concentration-dependent manner in aortic rings from control and HHcy rats, respectively. The responses were significantly attenuated in aortic rings from HHcy rats compared to those from control rats and treatment with physcion significantly reversed the attenuated responses. Physcion reversed the impaired viability and apoptosis of HUVECs induced by Hcy in a dose-dependent manner. Moreover, physcion enhanced the protein ratio of p-Akt/Akt, increased the expression and phosphoylation of endothelial nitric oxide synthetase (eNOS) and nitric oxide (NO) formation in HUVECs injured by Hcy. These effects were blocked by wortmanin, a PI3-kinase/Akt inhibitor. In HUVECs, physcion increased Hcy-induced decrease in the levels of intracellular calcium, which was inhibited by 2-Aminoethyl diphenyl borate (2-APB), a novel inhibitor of store-operated Ca2+ channels. Furthermore, physcion suppressed Hcy-induced increase in reactive oxygen species (ROS) and and malondialdehyde (MDA) levels, and increased Hcy-induced decrease in superoxide dismutase (SOD) in HUVECs.
Conclusions: Physcion prevents Hcy-induced endothelial dysfunction via modulation of PI3-kinase/Akt- and Ca2+-eNOS-NO pathways, attenuating oxidative damage and apoptotic signaling.
This work was supported by a research grant from the National Natural Science Foundation of China (Nos. 31571175, 81270920), the Natural Science Foundation of Shandong Province (No. ZR2015HM037).
[GW28-e0586]
Study on the pathological mechanisms of heart failure by integrative analysis of transcriptomics and proteomics
Jian Zhang1 Yong Wang1 2 Weili Lin3 Ruixin Zhu4 Wei Wang1
1. Basic Medical College, Beijing University of Chinese Medicine, Beijing, China
2. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
3. Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences Shanghai, China
4. Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China
Objectives: Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Elucidating the mechanisms of HF remains a significant challenge due to multidimensional alterations at molecular, cellular, tissue, and organ levels. Integrative analysis of multiple layers (transcriptome and proteome) of genetics information provides new insights into pathogenesis of HF for better understanding the molecular pathological mechanisms of HF.
Methods: Rat model of HF was induced by left anterior descending (LAD) artery ligation operations. At 28 days after surgery, cardiac functions were assessed by echocardiography. The pathological damage of myocardial tissues was assessed by HE and Masson’s trichrome staining. The expression profiles of mRNAs and proteins were detected by high-throughput digital gene expression (DGE) sequencing and two-dimensional electrophoresis coupled mass spectrometric (MS) proteomic analysis in the border zone of infarct myocardial tissue. Multiple co-inertia analysis (MCIA) were performed to integrate transcriptome and proteome data and detect key genes of HF on both mRNA and protein levels. Subsequently, quantitative real-time PCR (qRT-PCR) and western blot (WB) were applied to validate the expression of key genes and proteins.
Results: Echocardiography showed that ejection fraction (EF) decreased obviously and left ventricular end-diastolic dimension (LVEDd) and left ventricular end-systolic dimension (LVEDs) increased significantly in HF. Furthermore, HE and Masson’s trichrome stain also demonstrated pathological changes of myocardial injury. Transcriptomic analysis indicated that pattern of gene expression was substantially altered in HF, yielding 1925 differentially expressed genes (FDR<0.05), including 202 key genes. Proteomic analysis revealed differentially expressed 32 proteins (FDR<0.05), including 7 key proteins. Total 17 pathways were significantly enriched included the differential genes and proteins. Interestingly, the key genes Acca2, Ndufa10, Nnt, Ckmt2, and the key protein Acot1, considered as the key factors related to energy metabolism disorder especially the lipid utilization disorder in HF, were remarkably down-regulated. These changes were further confirmed by both qRT-PCR and WB. Moreover, both omics result and qRT-PCR validation result also demonstrated that the key genes Mmp17, Sfrp2 and Mant4 which were related to extracellular matrix (ECM) in HF, were significantly up-regulated. Interestingly, the key protein Tubb4, a cytoskeletal protein which was previously considered as a conserved gene, was decreased in HF.
Conclusions: The combined analysis of transcriptomics and proteomics provides new strategy about screening key potential target genes and proteins for heart failure. The results suggested that the disorders of energy metabolism, ECM and cytoskeletal protein played critical roles during the development of HF. The identified key genes and proteins can provide better understanding of pathological mechanism as well as novel therapeutic targets for HF.
[GW28-e0956]
The relationship between the contralateral collateral supply and myocardial viability of 18F-FDG PET/CT subtended by chronic total occluded coronary arteries
Wei Dong Jianan Li Xiantao Song Xiaofen Xie Jian Jiao Quan Li Yehong Zhang Hongzhi Mi
Beijing Anzhen Hospital, Capital Medical University
Objectives: Coronary angiography(CAG) often showed collateral flow supply for the coronary artery of chronic total occluded(CTO) in asynergic myocardial regions. However, little is reported on the relationship between collateral circulation and positron emission tomographic (PET) patterns of viable myocardium subtended by CTO. The aim of this study is to analyze of the relationship between the collateral flow of CTO and myocardial viability detected by 18F-FDG PET /CT imaging.
Methods: A prospective analysis of 80 patients with 93 CTO coronary arteries diagnosed by CAG from September 2015 to January 2017 in department of Cardiology of our hospital. All patients performed 99mTc-MIBI rest myocardial perfusion imaging(MPI) in one week. 18F-FDG PET/CT was further examined in abnormal myocardial perfusion and wall motion regions. The collateral circulation of CTO was graded with rentrop classification as absent (grade 0 and 1) in 12 CTO vessels, partial collateral (grade 2) in 28 CTO vessels and well collateral (grade 3) in 53 CTO vessels. Myocardial viability was determined with 99mTc-MIBI MPI and 18F-FDG PET imaging results. The patterns were interpreted as mismatch (perfusion defect with enhanced 18F-FDG uptake); transmural match (severe concordant decreased or absence of both perfusion and 18F-FDG uptake) or nontransmural match (mild to moderate concordant decreased of both perfusion and 18F-FDG uptake) and normal perfusion and 18F-FDG uptake.
Results: There was no significant correlation (P= 0.726) between the severity extent of perfusion defect and collateral circulation grade. The extent of viability myocardium was unrelated to the present or the grade of collateral vessel. The myocardial viability was common present in mild and moderate hypokinetic regions (42/42,100%)and decreased in severe (25/26,96%)or akinetic-dyskinetic regions (18/25,72%). The presence of collateral circulation was a sensitive(93%)but not a specific (17%)sign of myocardial viability.
Conclusions: In CTO patients, the presence and increased grade of collateral circulation in CAG does not seem to be an effective way for predicting myocardial viability. Further analysis of PET patterns of viable myocardium is needed to guide further revascularization and predict functional improvement and survival benefit.
[GW28-e0063]
Predictors of TAVI-associated bleeding and its impact on short-term mortality
Jiayang Wang1 2 Yujie Zhou3
1. Department of Cardiac Surgery Beijing An Zhen Hospital Capital Medical University, Beijing 100029, China
2. Center for Cardiac Intensive Care Beijing An Zhen Hospital Capital Medical University, Beijing 100029, China
3. Department of Cardiology Beijing An Zhen Hospital Capital Medical University, Beijing 100029, China
Objectives: Background: This study aimed to investigate the impact of post-Transcatheter Aortic Valve Implantation (TAVI) bleeding according to the bleeding definition from the Valve Academic Research Consortium-2 (VARC-2) criteria on 30-day postoperative mortality and to examine the correlation between pre- or intra-operative variables and the bleeding.
Methods: This systematic review and meta-analysis were conducted and reported in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Multiple electronic literature databases were searched using predefined criteria, with bleeding defined per VARC-2 criteria. A total of 10 eligible articles with 3,602 patients were included in the meta-analysis. Differences are expressed as odds risk (OR) with 95% confidential interval (CI). Study heterogeneity was tested using the I2 statistic. Study heterogeneity was considered significant when P values < 0.10 or I2 > 50%. A fixed-effects model was used when study heterogeneity was not significant; a random effects model was used when study heterogeneity was significant. Egger’s linear regression test was used to estimate publication bias. Meta-regression analysis was performed to examine whether covariates, which could be potential modifiers, can affect the end results of the meta-analysis.
Results: The meta-analysis revealed that post-TAVI bleeding was associated with a 323% increase in 30-day postoperative mortality (OR: 4.23, 95%CI: 2.80-6.40, P<0.0001) without significant study heterogeneity and publication bias. Subgroup analysis found that the patients with major bleeding/life-threatening bleeding showed 410% increase in the mortality compared with the patients without bleeding (OR:5.10, 95%CI: 3.17-8.19, P<0.0001). Transapical access was associated with a significant 83% increase in the incidence of bleeding compared with transfermoral access (OR: 1.83, 95%CI: 1.43-2.33, P<0.0001). Multiple logistic regression analysis revealed that atrial fibrillation (AF) independently correlated with TAVI-associated bleeding (OR: 2.63, 95% CI: 1.33-5.21, P=0.005). The potential modifiers, such as STS Score, mortality, the logistic EuroSCORE, aortic valve area, mean pressure gradient, LVEF, preoperative hemoglobin and platelet levels, and study design had no effects on the end results of the meta-analysis.
Conclusions: To the best of our knowledge, this is the first meta-analysis to use the VARC-2 definitions to investigate the effect of TAVI-associated bleeding on 30-day postoperative mortality and to comprehensively examine the association between prior intraprocedural variables and post-TAVI bleeding. Our key findings are: (1) post-TAVI bleeding, in particular major bleeding or LTB, was associated with a significant increase in 30-day postoperative mortality; (2) TA access significantly increased the incidence of post-TAVI bleeding; and (3) preexisting AF independently correlated with post-TAVI bleeding. Recognition of the importance and determinants of post-TAVI bleeding should lead to strategies to improve outcomes
[GW28-e0161]
Association of CHADS2 and CHA2DS2-VASc Scores with acute myocardial infarction with Nonvalvular Atrial Fibrillation
Hui Pang Bing Han Hui Pang
Xuzhou Central Hospital
Objectives: Coronary artery disease (CAD) and Atrial fibrillation (AF) have close relationship and interact with each other. The coexistence of the two diseases increases the risk of future cardiovascular events and stroke dramatically. The CHADS2 and CHA2DS2-VASc scoring systems have been proved efficacy to stratify stroke and thromboembolism risk in patients with non-valvular AF (NVAF). The objective of our study was to investigate the predictive value of CHADS2 and CHA2DS2-VASc scores for acute myocardial infarction (AMI) risk in AF, and subsequently compare the accuracy of the CHADS2 score with CHA2DS2-VASc score in predicting the AMI incidence.
Methods: This study enrolled 5140 consecutive patients with NVAF who presented to our department of cardiology from November 2013 to October 2016. The following information was collected from the database: age, gender, history of CAD, congestive heart failure (HF), hypertension, diabetes mellitus (DM), stroke or transient ischemic attack (TIA), thromboembolism, vascular disease, hyperlipidaemia, hyperuricemia, hyperthyroidism, hypothyroidism and obstructive sleep apnea (OSA). We identified the optimal cut-off values of the CHADS2 and CHA2DS2-VASc scores each based on receiver operating characteristic (ROC) curves to predict the risk of AMI. The differences between the areas under the two ROC curves were assessed by a univariate z-score test.
Results: Both CHADS2 score and CHA2DS2-VASc score were associated with an increased odds ratio of the prevalence of AMI in patients with AF, after adjustment for hyperlipidaemia, hyperuricemia, hyperthyroidism, hypothyroidism and obstructive sleep apnea. The present results showed that the area under the curve (AUC) for CHADS2 score was 0.787 with a similar accuracy of the CHA2DS2-VASc score (AUC 0.750) in predicting “high-risk” AF patients who developed AMI. However, the predictive accuracy of the two clinical-based risk scores was fair. The CHA2DS2-VASc score has fair predictive value for identifying high-risk patients with AF and is not significantly superior to CHADS2 in predicting patients who develop AMI.
Conclusions: Focusing specifically on risk stratification of AMI by the CHADS2 and CHA2DS2-VASc scores as well as means for optimizing outcomes in the treatment of AF is the significance of our study. Even if the accumulated evidence has shown that CHA2DS2-VASc is better at identifying ‘truly low-risk’ patients with AF who develop stroke and thromboembolism, our data demonstrate that CHA2DS2-VASc is not significantly superior to CHADS2 for predicting AMI in AF patients.
[GW28-e0388]
A novel machine-learning model for identification of significant coronary artery disease
Gang Wang1 Ya Gao1 Feng Xu2 Jiali Wang2 Benteng Ma3 Genshan Ma4 Yong Xia3 5 Yuguo Chen2
1. Department of Emergency Medicine, the Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
2. Department of Emergency Medicine, Qilu Hospital, Shandong University, Jinan, China
3. Shaanxi Key Lab of Speech & Image Information Processing (SAIIP), School of Computer Science, Northwestern Polytechnical University, Xi’an, China
4. Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, China
5. Centre for Multidisciplinary Convergence Computing (CMCC), School of Computer Science, Northwestern Polytechnical University, Xi’an, China
Objectives: Significant coronary artery disease (sCAD) was defined as the presence of ≥50% luminal narrowing in any major epicardial coronary artery. Previous studies showed that patients with sCAD had higher all-cause mortality than patients without sCAD. In addition, coronary angiography (CAG) revealed up to half of patients with suspected CAD to have no significant stenosis in coronary arteries. Therefore, it is important to identify the patients with suspected CAD who are like to have sCAD prior to cardiac catheterizations are carried out. The goal of our study was to establish a bedside prediction model for the early distinction of sCAD using common laboratory test results only in machine learning models.
Methods: Patients with suspected CAD were recruited from the Second Affiliated Hospital, Xi’an Jiaotong University from 2010 to 2014 and undergoing CAG in the cardiac catheterization lab based on international guidelines. Those with disqualified CAG reports were excluded. Then laboratory results and CAG reports were collected for database setup, feature selection, model training and statistical assessment. The size and predictive power of the different lab marker combinations were tested in four classical classifiers including k-Nearest Neighbor, Decision Tree, Random Forest and Support Vector Machine (SVM) using Genetic algorithms. The area under the receiver operating characteristic (AUROC) was used for measuring the performance of the models.
Results: Based on whether major epicardial coronary artery had ≥50% stenosis, 1957 patients were divided into sCAD group (n=1442) and non-sCAD group (n=515). A total of 87 laboratory markers were input into the prediction model. Six types of optimal combinations (T1, T2,…, T6) were obtained, in which the number of selected lab markers ranged from one to six. From T1 to T6, the highest accuracy in each subset was 77.47%, 85.21%, 85.63%, 85.21%, 85.21% and 84.65%, respectively. Eventually, two combinations of three clinical laboratory markers in SVM model reached the highest accuracy (85.63%). Then ROC test revealed that the combination of platelet large cell ratio, prealbumin and cholinesterase presented the better performance in the prediction of sCAD patients with a higher AUROC (0.76).
Conclusions: This is the first study to report that the combination of platelet large cell ratio, prealbumin and cholinesterase in SVM model could distinguish sCAD patients in clinics. It may serve as an early screening approach for evaluating the value of CAG in the future. The machine learning model and our results should be tested in a prospective observational study in the future.
[GW28-e0612]
Liver X receptor agonist T0901317 ameliorates sepsis-induced myocardial injury and dysfunction: the role of SIRT1 signaling
Han Dong1 2 Chen Jiangwei1 2 Cao Feng1 2
1. Department of Cardiology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, China 100853
2. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
Objectives: Sepsis patients suffering from cardiac dysfunction experience a 70–90 % mortality rate, which is overwhelmingly higher than those without cardiac dysfunction of only 20 %. In this regard, it is pertinent to develop novel therapeutic strategy dealing with sepsis-induced myocardial injury and dysfunction in order to improve the outcome of sepsis patients. Liver X receptor (LXR) was recently reported to protect liver and lung against septic injury. However, studies addressing the effects of LXR activation on septic heart injury are still lacking.
Methods: Male cardiac-specific SIRT1 knockout mice (SIRT1-/- ) mice and their wild-type littermates were subjected to sepsis by cecal ligation and puncture (CLP). LXR agonist T0901317 was administrated intraperitoneally (30 mg/kg). The survival rate of mice was recorded in the 7-day period post CLP. Left ventricular functional analysis with non-invasive echocardiography and invasive hemodynamic assessment were performed on post-operational day 2(POD2) to evaluate cardiac function. Morphological changes of myocardial tissues were observed by H&E staining under a light microscopy. Myocardial apoptosis was evaluated by a TUNEL assay kit. Biochemical indices of heart injury including serum AST, LDH, CK and CK-MB using commercially available assay kits following the manufacturer’s instructions. Myocardial endoplasmic-reticulum(ER) stress (protein level of CHOP, GRP78, GRP94, IRE1α, and ATF6) were assessed by both Western Blot and immunohistochemical staining. SIRT1 signal and its substrates were also detected by Western Blot
Results: Our data showed that LXR agonist protected against CLP-induced myocardial injury and dysfunction, as evidenced by improved myocardial morphological changes, improved hypotension, reduced serum concentration of biochemical indices of heart injury (AST, LDH, CK and CK-MB), and elevation of cardiac functional parameters(LVEF 55.6±2.2% vs. 64.1±3.4%, respectively, N=11-14, p=0.0005). Furthermore, we found that LXR agonist reduced the level of inflammatory cytokines, such as TNF-α, IL-1β, IL-6 and HMGB1, the overproduction of ROS and MDA, and the accumulation of endoplasmic-reticulum stress. Additionally, LXR agonist increases the activity of antioxidant enzymes, such as SOD, GPx, and CAT. However, these aforementioned beneficial actions of LXR agonist administration following CLP was abolished in cardiac specific SIRT1 KO mice, suggesting the protective effects of LXR agonist is associated with SIRT1 signaling activation. Western Blot analysis of SIRT1 signal and its substrates further revealed that T0901317 enhanced SIRT1 signaling and subsequent deacetylation and activation of anti-oxidative FoxO1 and anti-ER stress HSF1, deacetylation and inhibition of pro-inflammatory NF-kB and pro-apoptotic P53, thereby alleviating sepsis-induced myocardial injury and dysfunction.
Conclusions: In conclusion, our current work demonstrated a beneficial role of LXR agonist in septic murine heart mainly through attenuating oxidative stress, endoplasmic-reticulum stress, inflammation, and apoptosis. Furthermore, by employing SIRT1-/- mice, we demonstrated that the beneficial actions of LXR agonist in septic heart were possibly associated with activation of SIRT1 signaling and subsequent deacetylation and activation of FoxO1 and HSF1, as well as deacetylation and inhibition of NF-kB and P53. Those findings may guide the prospective clinical trial to evaluate the latent therapeutic effect of LXR agonist for patients with sepsis.
[GW28-e0668]
Angiotensin-(1-7) Inhibits Angiotensin II-Induced Matrix Metalloproteinase-8 in Vascular Smooth Muscle Cells
Feng Zhang Sufang Li Juxian Song Hong Chen Feng Zhang
Department of Cardiology, Peking University People’s Hospital, Beijing, China
Objectives: Angiotensin II (Ang II) is a bioactive peptide involved in the development of cardiovascular disease, such as atherosclerosis, while Angiotensin-(1-7) (Ang-(1-7)) shows cardiovascular protection in contrast to Ang II. Matrix metalloproteinase-8 (MMP-8) is thought to participate in plaque destabilization though degradation of extracellular matrix, improving the development of atherosclerosis. We studied whether Ang-(1-7) can protect against atherosclerosis through regulating Ang II-induced MMP-8.
Methods: Ang-(1-7), Ang II and their antagonists was used to treat smooth muscle cells, and MMP-8 and p38 MAPK were analyzed by RT-PCR and Western blotting. ApoE-/- knockout mice were fed with a high fat diet and subjected to Ang II, Ang-(1-7), Ang II+Ang-(1-7) (± A779), and atherosclerotic plaques in aortic root were analyzed using immunohistochemistry. MMP-8 in blood serum was measured by ELISA.
Results: Treatment with Ang II resulted in an increase of MMP-8 mRNA and protein expression in vascular smooth muscle cells, whereas Ang-(1-7) alone had no effect. However, preincubation with Ang-(1-7) inhibited Ang II-induced MMP-8 expression, and this effect was abolished by the competitive antagonist of Ang-(1-7) at the MAS receptor. Furthermore, Ang II induced p38 MAPK activation, and this was inhibited by the presence of Ang-(1-7). P38 MAPK inhibitor SB203580 inhibited Ang II-induced MMP-8 expression, and also augmented the inhibitory effect of Ang-(1-7) on Ang II-induced MMP-8 expression. In ApoE-/- mice that developed atherosclerotic lesions, treatment with Ang-(1-7) significantly inhibited Ang II-induced MMP-8 both in atherosclerotic plaques and in blood serum, and this effect was abolished by Ang-(1-7) receptor antagonist A779. The atherosclerotic plaques in mice treated with Ang-(1-7) and Ang II appeared to be more stable with more type I collagen contents than those in mice treated Ang II.
Conclusions: Our results suggest that Ang-(1-7) plays an important role in protecting against atherosclerosis via counter-regulating Ang II-induced MMP-8.
[GW28-e1195]
The prognostic analysis of elderly high-risk severe aortic stenosis treated by different therapy procedure
Yunqing Ye
National Center for Cardiovascular Diseases Cardiovascular Institute & Fuwai Hospital
Objectives: To provide China’s early experience of TAVI technology, verify the validity of the TAVI treatment.
Methods: We retrospectively analyzed elderly high-risk patients with SAS hospitalized between September 2012 and June 2015. According to the treatment method, patients were divided into TAVI group, SAVR group and the drug therapy group. Patients were followed-up, and the primary end point was death from any cause at 1 year, and secondary end point included cardiac function class(NYHA), vascular complication, valvular function, non-fatal myocardial infarction, new atrial fibrillation, stroke, bleeding, pacemaker implantation, acute renal failure, and readmission. The survival curves were performed with the use of Kaplan-Meier estimates and were compared between groups with the use of the log-rank test.
Results: There were 242 patients conform to the enrolled criteria, 81 patients undergo TAVI (including 57 cases of transfemoral approach, 12 cases of tansaortic approach, 12 cases of transapical approach), 59 patients undergo SAVR, and 102 patients treated by drug. The rates of combined diabetes were 27.2% in the TAVI group and 11.9% in the SAVR group(P=0.027), and combined chronic obstructive pulmonary disease were 18.5% and 6.8% respectively (P=0.045). The rates of renal failure were higher in the SAVR group than the TAVI group, 13.6% vs. 4.9% respectively (P=0.072). More patients combined with complex valve dysfunction in the SAVR group. The average risk score of the Society of Thoracic Surgeons(STS) was 7.28 in the TAVI group, and 5.67 in the SAVR group(P=0.036), indicating higher operating risk in the TAVI group than in the SAVR group. The rates of perioperative vascular complications were 6.3% in the TAVI group and 0% in the SAVR group (P=0.057). The new pacemaker implantation and mild paravalvular regurgitation were more frequent with TAVI group, 11.3% vs. 0% (P=0.025) and 29.6% vs. 1.7% (P<0.001) respectively. Adverse events that were more frequent after SAVR at 1 year included new onset atrial fibrillation (2.3% vs. 0% P=0.674) and rehospitalization (21.3% vs. 3.0% P=0.005). At 1 year, the rates of stroke were 3.0% in the TAVI group and 6.8% in the SAVR group(P=0.628). The rates of death from any cause were 3.8% in the TAVI group and 5.2% in the SAVR group at 1 month (P=1.000), and 5.8% and 9.8% respectively at 1 year(P=0.636)). The mortality at 1 year was 54.9% in the drug therapy group. The New York Heart Association (NYHA) functional status were improved significantly in both groups at 1 year.
Conclusions: In elderly high-risk patients with SAS, the prognosis were very poor when treated only by drug; transcatheter and surgical procedures for aortic-valve replacement were associated with similar short-term and long-term prognosis, although there were important differences in periprocedural risks.
[GW28-e0486]
3D Echocardiographic evaluation of the association between pulmonary hypertension and right ventricle function in patients with severe rheumatic mitral stenosis
Jingjing Liu Lingyun Fang
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan
Objectives: Post-capillary Pulmonary hypertension (PH) is a significant contributor to right ventricle (RV) dysfunction and morbidity. The two hemodynamic profiles in left heart disease with PH, passive PH with increased pulmonary venous pressure and reactive PH with increased pulmonary vascular resistance (PVR>3 Wood units, WU), are difficult to distinguish non-invasively. The clinical significance of PVR on right ventricle function remains to be elucidated in patients with rheumatic mitral valve stenosis (RMS).
Methods: Between 2014-2016 thirty-nine patients referred to our hospital for the management of pure severe RMS (mitral valve area ≤1.5 cm2, stage D) were included in this study. Two groups were formed based on PVR (calculated based on the ratio of TRV/TVIRVOT), 18 patients have PVR≤3 WU (group II), and 21 patients have PVR>3 WU (group III). Twenty age-matched healthy subjects with normal echocardiograms served as controls (group I). RV function was assessed using 3D echocardiography according to the recommendations of the American Society of Echocardiography. 3D longitudinal global strain of the RV freewall (RV GLS-freewall) and interventricular septum (RV GLS-septum) were measured using commercially available hardware and software (Philip IE33, Tomtec 4D-RV-analysis software).
Results: All indices of RV function were significantly lower in patients with reactive PH (Group III) including RV EF, FAC (fractional area change), TAPSE (Tricuspid annular plane systolic excursion, mm) and increase in Tei index (myocardial performance index) compared to group I and II. Patient with passive PH (Group II) have moderate reduced EF and elevation in Tei index as compared to normal controls (Group I). There are no significant difference in FAC and TAPSE between group I and II. RV GLS-freewall and GLS-septum were significant lower in group II compared to group I (p<0.01). Group III patients had further decrease in RV GLSfreewall and GLS-septum compared to group I or II (p1<0.01, p2<0.05, respectively). Multiple linear regression analysis revealed a significantly correlations between GLS (freewall) systolic strain and PVR (r=0.825,p <0.001), as well as between GLS(septum) systolic strain and PVR (r=0.756, p<0.001).
Conclusions: Incremental impairments of RV dysfunction were observed in severe rheumatic MS patients from passive to reactive PH. Our study identified a significant correction between global RV longitudinal systolic strain and PVR, suggesting that RVGLS may serve as good index for assessing PH subtypes and RV dysfunction.
[GW28-e0806]
Pyr1-Apelin 13 is a negative modulator of angiotensin II-mediated adverse myocardial hypertrophy, remodeling and fibrosis
Jiuchang ZHONG1 Zhenzhou Zhang1 Haiyan Jin1 Wang Wang2 Yuwen Cheng1 Xueyi Chen2 Yingle Xu1 Bei Song1 Josef M Penninger3 Gavin Y Oudit2 Jiuchang Zhong1
1. State Key Laboratory of Medical Genomics, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension
2. Division of Cardiology, Department of Medicine, University of Alberta, Mazankowski Alberta Heart Institute
3. Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Objectives: The apelin (APLN)/APJ receptor system and angiotensin (Ang) II-Ang II type 1 receptor (AT1) pathways have emerged as potent regulators of blood pressure and cardiovascular function. The beneficial effects of the APLN/APJ receptor system are well-established in diverse conditions such as hypertension, atherosclerosis, and heart failure. However, little was elucidated upon the interaction between the APLN/APJ receptor and Ang II-AT1 signaling in heart disease. Here, we examined the regulatory role of pyr1-apelin-13 in the atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice in response to Ang II.
Methods: The male 10-week aged male WT, APLN-/y and ApoEKO mice were randomized to deliver either Ang II (1.5 mg.kg-1.d-1) or saline with an osmotic minipump for 4-weeks. To evaluate myocardial fibrosis, Masson’s Trichrome and Picrosirius Red staining was performed. Transmission electron microscope analysis of left ventricular samples was carried out using a conventional scanning transmission electron microscope.
Results: Gross histology data demonstrated normal morphology between young WT and APLN-/y mice. Intriguingly, loss of APLN resulted in greater myocardial hypertrophy and remodeling in Ang II-treated APLN-/y mice. Loss of apelin potentiated Ang II-induced perivascular and interstitial myocardial fibrosis and transcriptional activation of pro-fibrotic mediators resulting in great accumulation of collagen I and collagen III in APLN-/y hearts. In ApoEKO mice, myocardial hypertrophy was increased based on morphological characterization with equivalent pressor response compared with WT mice in response to Ang II. These changes resulted in increased myocardial fibrosis in the Ang II-infused ApoEKO mice. Pyr1-apelin-13 treatment prevented Ang II-mediated hypertrophy and fibrosis in both WT and ApoEKO mice, along with decreased myocardial mRNA expression of ANF, BNP, b-MHC, collagen I and collagen III. Ang II-induced altered myocardial ultrastructure characterized by disruption or dissolution of myocardial myofilaments, vacuolar degeneration and swollen mitochondria were aggravated in the ApoEKO mice which were prevented by pyr1-apelin-13.
Conclusions: Loss of APLN exacerbates Ang II-mediated cardiac hypertrophy and fibrosis. The APLN/APJ pathway has a protective role against Ang II-mediated heart disease and pyr1-apelin-13 mediates therapeutic effects in ApoE-mutant mice. These findings highlight the importance of enhancing APLN/APJ action as a novel therapeutic target for heart disease. This work was supported by the National Natural Science Foundation of China (81370362), the National Basic Research Program of China (2014CB542300) and the National Major Research Plan (91339108).
[GW28-e0651]
Association between homocysteine levels and calcific aortic valve disease: a meta-analysis
Qingchun Zeng Guandi Wu Jiayi Xian Jun Li Die Zhu Ruxia Liang Xi Yang Jiaying Li Ying Huang Yan Tu Dingli Xu
Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Objectives: Previous studies have reported inconsistent results regarding the association between homocysteine (Hcy) levels and calcific aortic valve disease (CAVD). This study aims to investigate the association between Hcy levels in patients with CAVD by conducting a meta-analysis.
Methods: We conducted a systematic search in the database of PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials and Chinese Biomedical Literature Database (CBM) up to March 2017. Eligible studies evaluating plasma Hcy levels in CAVD patients and controls were identified by two independent investigators. Pooled results were reported as weighted mean difference (WMD) and the corresponding 95% confidence intervals (95% CI).
Results: Ten studies involving 6349 participants were included. Pooled analysis demonstrated that Hcy levels were significantly elevated in patients with CAVD compared wih controls (pooled WMD: 2.98, 95%CI: 1.59 to 4.38). Significantly higher Hcy levels were found both in mild-to-moderate CAVD patients (WMD: 0.62, 95% CI: 0.11 to 1.13) and severe CAVD patients (WMD: 3.15, 95% CI: 2.44 to 3.86) than in controls. In addition, Hcy levels were significantly higher in severe CAVD patients than in mild-to-moderate CAVD patients (WMD: 3.23, 95% CI: 1.14 to 5.32).
Conclusions: The present meta-analysis revealed that Hcy levels significantly increased in CAVD patients with the progression of the disease.
[GW28-e0509]
Reference value measurements of tracheal cross-sectional area in fetuses between 22 and 32 weeks
Hui Zhang Yanling Zhan Aohua Zhang Junlin Zhong Rongqin Zheng
The 3rd Affiliated Hospital of Sun Yat-sen University
Objectives: Measuring reference value of tracheal cross-sectional area in fetuses between 22 and 32 weeks with ultrasound to study changes of fetal tracheal cross-sectional area with gestational age.
Methods: From October 2016 to April 2017 three hundred and thirty pregnant women were enrolled in the Third Affiliated Hospital of Sun Yat-sen University. The pregnant women aged 19-45 years old, average age 27±5 years. The fetuses were between 22 and 32 weeks. These fetuses were divided into 11 groups. Inclusion criteria: (1)pregnant women have no drinking and smoking history, (2)pregnant women have no hypertension, diabetes, severe arrhythmia, autoimmune disease, hyperthyroidism or congenital heart disease,(3)The fetus checked by 3D ultrasound of prenatal examination to exclude structural abnormalities and arrhythmias, (4)checked the early and Mid Down’s screening and noninvasive detection of DNA or amniocentesis to exclude related abnormal chromosome. GE Voluson 730 color Doppler ultrasonic diagnostic apparatus were used, convex array probe, frequency 4-8MHz, HITACHI-ALOKA F75 color Doppler ultrasonic diagnostic apparatus were used, convex array probe, frequency 3-6MHz. According to the 2011 fetal echocardiography guidelines of American Society of Echocardiography, showed the three vascular plane, obtained the cross section of the trachea, measured cross-sectional area of the trachea in ventricular systole. Data were analyzed by SPSS17.0 statistical software, all data were expressed as mean±standard deviation.
Results: All the fetal tracheal cross-sectional area as follows: 22-22+6: 3±1mm2, 23-23+6: 3±1mm2, 24-24+6: 4±1mm2, 25-25+6: 5±1mm2, 26-26+6: 5±2mm2, 27-27+6: 5±2mm2, 28-28+6: 6±2mm2, 29-29+6: 6±3mm2, 30-30+6: 7±3mm2, 31-31+6: 8±2mm2, 32-32+6: 8±2mm2.
Conclusions: This study found that fetal tracheal cross-sectional area increased linearly correlated with gestational age. The results of this study can help for further studies of tracheal compression in fetus with congenital isolated vascular ring. It also can provide literature base to judge prognosis of fetuses with congenital isolated vascular ring after birth.
[GW28-e0456]
Value of Three Dimensional Strain Imaging on Assessing Left Ventricular Systolic Function and Predicting Short-term Outcome in Chronic Aortic Regurgitation undergoing Valve Replacement Surgery
LI Yuan Mingxing Xie
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
Objectives: This study aimed to evaluate the subtle left ventricular function change in chronic aortic regurgitation (AR) patients using three dimensional strain imaging (3D STI) and to investigate the 3D STI value in predicting short-term outcome after aortic valve replacement surgery (AVR).
Methods: Conventional LV volume and function indexes, Global longitudinal strain (GLS), Global circumferential strain(GCS), Global radial strain(GRS), torsion, basal rotation (RoB), apical rotation (RoA) as well as all segmental strains by 3D STI were analyzed in 30 controls (age, 49.8±14.3 yrs, male 16), 31 chronic AR patients with preserved LV function (AR+PEF group, LVEF≥55%, age 50.4±14.2 yrs, male 18), and 36 chronic AR patients with LV dysfunction (AR+REF group, LVEF<55% , aged 48.0±14.1 yrs, male 23). Among them, 32 patients underwent AVR, with perioperative cardiac adverse events, pre and post operation echo recorded.
Results: 1. As compared to normal group, GLS (-19.93±1.82% vs. -17.87±2.43%), GRS (43.63±3.28% vs. 39.80±4.51%), torsion(2.31±0.60°/cm vs. 1.65±0.41°/cm) were significantly reduced in AR+PEF but GCS (-32.47±3.53%vs. -30.87±3.58%)was preserved. GLS (-19.93±1.82% vs. -12.56±2.62 %), GCS(-32.47±3.53%vs. -20.74±4.82%), GRS(43.63±3.28% vs. 27.13±5.90 %), torsion (2.31±0.60 °/cm vs. 1.17±0.46°/cm) were all significantly reduced in AR+REF.
2. Strains from three directions were all decreased in middle segments (LS -18.44±3.34%vs. -15.21±3.50% , CS -37.03±5.51%vs-33.67±4.09%, RS 46.02±5.82% vs. 40.22±4.34%, respectively)and apical segments(LS -21.73±5.27 % vs. -19.18±7.85% , CS -39.07±5.32 %vs. -35.08±4.64 %, RS 50.73±6.74 % vs. 45.20±9.24 %, respectively) in AR+PEF. However, strains in basal segments LS (-17.96±3.27 %vs. -17.69±3.89%), CS(-29.80±5.30 %vs. -29.55±3.74%) and RS(38.48±5.00%vs.38.54±5.07%) were all preserved. RoA(10.42±2.92°vs.8.47±3.07°) was significantly reduced in AR+PEF, while RoB(-7.28±2.30°vs. -6.45±3.16°) was preserved.
3. In our study, preoperative GLS was the only independent predictor of cardiovascular adverse events during and after the operation. The receiver operating characteristic curves showed that optimal cut-off point was -15.65% with the area under the curve 0.765 (sensitivity and specificity was 0.733 and 0.875, respectively).
Conclusions: 3D STI can accurately evaluate subclinical left ventricular dysfunction in patients with chronic aortic regurgitation. For patients with preserved LVEF, GCS, basal ventricle strains and rotation played an important role to maintain normal LEVF. GLS can predict occurrence of adverse cardiovascular events during and after AVR, providing a critical role in selecting the appropriate timing of surgery.
[GW28-e0871]
Rationale and design of the randomized controlled trial of intensive versus usual ECG screening for atrial fibrillation in elderly Chinese by an automated ECG system in the community health centre in Shanghai (AF-CATCH)
Yi Chen Jiguang Wang
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Objectives: The randomized controlled trial will investigate whether more frequent electrocardiographic (ECG) recordings and analyses with an automated ECG system would improve detection of atrial fibrillation compared to a single annual ECG screen in elderly Chinese in the community health centre.
Methods: Men and women (≥65 years) will be randomized into intensive (n=3500) and usual screening groups (n=3500), and within the intensive screening group into intensive (n=2625) and more intensive subgroups (n=875). ECG recordings will be performed with an automated ECG analysis system AliveCor® Heart Monitor at 1 year in the usual screening group, at 3, 6, 9 and 12 months in the intensive screening subgroup, and at 1, 2, 3 and 4 weeks and 3, 6, 9 and 12 months in the more intensive screening subgroup. The primary outcome is the detection rate of atrial fibrillation between the usual and intensive screening groups. Sample size estimation was based on a projected detection rate of atrial fibrillation of 2.0% by a single ECG recording at 12 months, an improvement of 50% with more frequent ECG recordings, a=0.05, power=80% and one-sided test.
Results: The outcome measure is the detection rate of atrial fibrillation in the usual and intensive screening groups. The primary comparison is between the usual and intensive screening groups. The hypothesis is that the detection rate of atrial fibrillation would be 50% higher in the intensive than usual screening groups. An exploratory comparison is between the intensive (ECG recordings quarterly) and more intensive (quarterly plus weekly in the first month after randomization) screening subgroups within the intensive group.
Conclusions: The trial will provide evidence on the clinical effectiveness of more frequent ECG recordings by a handheld automated analysis system in the detection of atrial fibrillation. If proved effective, intensive screening by more frequent ECG recordings might have to be considered in people at high risk of atrial fibrillation. If not, for instance, for inadequate power of the trial, an extended follow-up with an even more intensive screening approach may be considered to increase the detection rate of atrial fibrillation.
[GW28-e0905]
Plasma HDL-C Responses to Endurance Exercise Training: Is It a “wonder” Drug? A Meta-analysis of Randomized Controlled Trials
Runlu Sun1 Canxia Huang1 Jieyu Jiang2 Jinlan Bao1 Yuling Zhang1
1. Sun Yat-sen Memorial Hospital, Sun Yat-sen University
2. The Sixth Affiliated Hospital, Sun Yat-sen University
Objectives: Evidence is lacking for the exercise characteristics in increasing HDL-C level regardless of endurance exercise elevating HDL-C level. The aim of this study is to clarify the effect and characteristics of exercise in increasing HDL-C in randomized control trials (RCTs).
Methods: The potential RCTs were identified by using electronic and manual searches between 1999 and 2012. The original articles selected for all prospective studies that assessed potential associations between endurance exercise training and changing level of HDL in adults (≥18 years of age at baseline) but excluded subjects having specific medical problems in which treatments such as with drugs would influence the effect of exercise (history of cancer, hemodialysis treatment and coronary heart disease). The methodological quality of each included trial was assessed by means of the instrument described by Jadad et.al. Results were expressed as WMD (weighed mean difference) and 95% confidence intervals (CIs). A univariate regression and a multivariate regression were performed to evaluate the exercise characteristics in HDL-C level. Subgroup analysis was used to explore sources of heterogeneity. Meta regression was used to examine the association between net change in HDL-C and lipid profiles of pre-exercise. Data were analyzed using Stata SE (12.0).
Results: 14 RCTs with total 777 subjects were included in this meta-analysis. Net change in HDL-C level was increased significantly (WMD: 4.41 mg/dl; 95% CI: 2.16- 6.66 mg/dl; P<0.001) in exercise intervention group. Univariate and multivariate analysis indicated that exercise length may be a good predictor of net change in HDL-C level (r=0.56, p=0.01 and r=0.43, p=0.006). By subgroup analysis, we found exercise length; subject’s charactersitics, continent, BMI and quality assessment effected the net change in HDL-C. Meta-regression showed that subjects with a lower TC level responded better to exercise training, leading to a higher net change of HDL-C level (p=0.012).
Conclusions: Our study suggests that regular endurance exercise increases HDL-C level with longer exercise length and lower TC level. Higher HDL-C level by endurance exercise results in limiting risk for atherosclerosis and prevent cardiovascular disease in healthy as well as in metabolic syndrome.
[GW28-e1043]
Cardiac Hemodynamics and Mechanical Function of Left Atrial in Swine with Interatrial Conduction Delay
Jieling Cai Yumin Sun
Shanghai jing’an district central hospital, Fudan University, Shanghai, 200040, China
Objectives: To explore the correlation between P wave prolongation and the mechanical function of left atrial (LA), cardiac hemodynamics in swine with interatrial conduction delay (IACD), and consequently to provide a new insight into the knowledge of heart failure with preserved ejection fraction (HFpEF) at the level of the atrium in an experimental model, which might result from atrial dyssynchrony syndrome.
Methods: In eight male mini-swines, IACD was induced by radiofrequency catheter ablation (RFCA) in Bachmann bundle (BB). Echocardiographic LA volumes/functions, mitral E/A and E/e’ ratios were studied before, instantly after and three months after the ablation. Standard invasive Swan-Ganz was performed to measure right atrial pressure (RAP), right ventricular pressure (RVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and cardiac output (CO) before, instantly after the ablation and three months later respectively. These echocardiographic and hemodynamic measurements of studied swines were compared with themselves before and after the intervention in both acute and chronic phases.
Results: P-wave duration (PD) elongated after the intervention instantly and three months later (95.63±24.00 vs. 67.88±3.80ms and 97.13±25.00 vs 67.88±3.80ms, respectively; P<.05). With PD prolonging, PCWP demonstrated a significant increase after three months (15.88±3.06 vs. 11.50±1.12mmHg; P=.029) but it failed to reach a significant level instantly after the ablation (15.25±3.15 vs. 11.50±1.12mmHg; P=.072). Compared to the studied swines previously untreated, mitral valve late diastolic velocity (MV AV) decreased significantly from the moment RFCA being done to the time three months later (64.54±8.17 vs. 53.79±5.25mmHg; P=.028). In the subgroups, PCWP increased greatly (11.2±1.3, 17.2±2.4, 18.0±1.8mmHg, respectively; P<.05) in the group with PD prolongation but was nearly the same as before in the group without PD dispersion.
Conclusions: Swine IACD model was successfully established with statistically significant PD prolongation. Our findings suggested that PD prolongation increased PCWP in the chronic phase.
[GW28-e0960]
Seipin deficiency causes renal injury and reversed both by adipose tissue transplantation and leptin respectively in mice
Xuejing Liu Wei Huang
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
Objectives: Seipin deficiency is responsible for type 2 Berardinelli–Seip Congenital lipodystrophy (BSCL2) with severe loss of adipose tissue (AT), hyperlipidemia, insulin resistance (IR) and hepatic steatosis. Some patients with Seipin deficiency were reported died due to the renal failure. However, the function of Seipin in kidney was poorly understood. We supposed loss of fat played important role in the renal injury. Here in this study we investigated the effects of Seipin deficiency on renal injury and used two treatments to improve the renal injury.
Methods: 3-month-old Seipin-/-(SKO) and wild-type (WT) mice were used in this study. The body weight, 24h urinary albumin excretion (UAE) and creatinine clearance were detected. For improve the renal injury, AT were transplanted to SKO mice (SKO-AT) for 3 months or SKO mice were injected by i.p. with leptin (SKO-Leptin) for 14 days respectively. Renal relative parameters, plasma leptin and adiponectin levels were studied. We evaluated glucose homeostasis and relevant genes expressions as well.
Results: Seipin mRNA expression levels in WT mice were higher in AT and testicles, and could also be found in kidney, which is mainly expression in glomeruli. SKO groups showed higher body weight, food intake and polyuria. Increased kidney weight/tibia length, 24 hours’ urinary excretion of Na+, K+, Cl-, Ca2+, UAE, creatinine clearance, surface areas of glomerulus and mesangial were also increased compared with WT control groups. A few glomerular lipids depositions and disappeared brush border of renal tubule were observed in SKO groups. Electron microscopy revealed moderate mesangial proliferation and segmental effacement of podocyte foot processes in SKO mice. SKO mice showed delayed glucose clearance, IR and decreased plasma leptin and adiponectin levels. Real-time PCR revealed genes in water reabsorption like aquaporin1(AQP1), aquaporin7(AQP7) and vasopressin receptor 2 (V2R) were significantly lower in SKO mice than that in WT mice. Genes involved in salt reabsorption such as Sodium-potassium-chloride cotransporter 2(NKCC2), Epithelial sodium channel (Scnn1α, Scnn1β, Scnn1γ) Sodium-potassium pump/Na+-K+-ATPase (Atp1a1) were decreased in SKO mice as well. After the transplantation of AT, plasma leptin levels increased in SKO mice. The glomerular hyperfiltration and plasma glucose tolerance were improved. The remarkable reduction of UAE, glomerular and mesangial surface area were observed as well. Then we treated SKO mice with leptin. The renal injury and IR were recovered. Some genes expressions involved in reabsorption (AQP1, V2R, NKCC2, Scnn1α, Scnn1β, Scnn1γ, Atp1a1) were reaching to normal levels.
Conclusions: In our study, we first noticed that the renal injury in SKO mice which improved by transplantation of the AT or leptin treatment. It suggested lack of AT was responsible to renal injury in SKO mice. AT transplantation and leptin could be two effective treatments for renal injury in Seipin deficiency.
[GW28-e0929]
Effects of Comprehensive Lifestyle Intervention on Cardiovascular Health Behaviors and Factors in Male Workers in Kailuan Community
Feng Wang Dayi Hu
Chongqing Medical University
Objectives: To observe the status of ideal cardiovascular behaviors and factors in male workers in Kailuan community. To investigate the effects of health education and comprehensive lifestyle intervention on cardiovascular health behaviors and factors in male workers.
Methods: Randomly selecte Tang Shan Kuang and Fan Ge Zhuang to participate in this study. To complete the first questionnaire survey (including birth date, marital status, telephone number, cultural level, monthly economic income, personal health information, history of hypertension, history of diabetes) and anthropometric measurements (including height, weight, blood pressure) and biochemical indicators collection (including fasting blood glucose, total cholesterol, triglycerides, high density lipoprotein, low density lipoprotein) from July 2013 to August 2013. Health education and multiple lifestyle interventions were conducted in the intervention community for 2 years from September 2013. To analyze the changes of cardiovascular health behaviors (smoking status, body mass index, physical exercise and healthy diet) and factors (total cholesterol, blood pressure and fasting blood glucose) in community male workers after intervention.
Results: In 2013, 1738 male workers participated in the survey and 1677 cases were included in the statistical analysis at the end of 2015.
(1) After intervention, the dietary habits, physical exercise, blood pressure and total cholesterol were improved, and the difference was statistically significant (P <0.01). There was no significant difference in smoking, body mass index and fasting blood glucose.
(2) The systolic blood pressure decreased from (140.75 ± 18.20) mmHg to (128.98 ± 15.27) mmHg and diastolic blood pressure decreased from (87.96±10.64) mmHg to (83.58±9.18)mmHg. The total cholesterol was decreased from (5.41 ± 2.72) mmol / L to (4.74 ± 1.06) mmol / L and the high-density lipoprotein cholesterol increased from (1.37 ± 0.35) mmol / L to (1.54 ± 0.41) mmol/L and low-density lipoprotein decreased from (3.29 ± 0.81) mmol / L to (2.38 ± 0.88) mmol / L. The difference was all statistically significant (P <0.01).
(3) The total number of ideal cardiovascular health behaviors and factors were increased from (2.58±1.11) to (3.01±1.09) in the male population after comprehensive intervention, and there was significant difference between the two groups (P <0.01);
(4) The average cardiovascular health score increased from (7.15±2.11) to (8.16±2.00) after the intervention, and there were significant differences between before and after the intervention (P <0.01).
Conclusions: The prevalence of ideal cardiovascular behaviors and factors of male workers in Kailuan community was low. Comprehensive lifestyle intervention could improve the cardiovascular health behaviors and factors.
[GW28-e0895]
Association of secreted frizzled-related protein 4 (SFRP4) expression in human epicardial adipose tissue with coronary atherosclerosis
Yu Du1 2 Qingwei Ji1 Yingxin Zhao1 2 Zhijian Wang1 Jianwei Zhang1 Yujie Zhou1 2
1. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University
2. Beijing Institute of Heart Lung and Blood Vessel Diseases
Objectives: Association of circulating secreted frizzled-related protein 4 (SFRP4) and β-cell dysfunction, insulin resistance and other metabolic disorders has been widely studied. We aimed at investigating the association between SFRP4 expression in human epicardial adipose tissue (EAT) and coronary atherosclerosis.
Methods: Serum samples and adipose biopsies from EAT and subcutaneous adipose tissue (SAT) were collected from patients with and without coronary artery disease (CAD, n = 40 and non-CAD, n = 30, respectively) during elective cardiac surgery. CAD presence was identified by coronary angiography. SFRP4 mRNA and protein expressions in adipose tissue were detected by quantitative real-time PCR and immunohistochemistry, respectively. Serum SFRP4 concentrations were measured by ELISA. Correlation analysis and multivariate linear regression analysis were to determine the association of SFRP4 expression with atherosclerosis as well as clinical risk factors.
Results: SFRP4 mRNA and protein expressions were significantly lower in EAT than paired SAT in patients with and without CAD (all P<0.05). Compared with non-CAD patients, CAD patients had higher SFRP4 expression in EAT (both mRNA and protein levels) and in serum. Multivariate linear regression analysis showed that CAD was an independent predictor for SFRP4 expression in EAT (beta = 0.442, 95% CI 0.030 – 0.814; P = 0.036) and in serum (beta = 0.300, 95% CI 0.056 – 0.545; P = 0.017). In addition, SAT derived SFRP4 mRNA levels were independently associated with fasting insulin levels (beta = 0.382, 95% CI 0.008 – 0.756; P = 0.045). Meanwhile, serum SFRP4 levels were positively correlated with BMI (r = 0.259, P = 0.030), fasting insulin levels (r = 0.306, P = 0.010) and HOMA-IR (r = 0.331, P = 0.005).
Conclusions: EAT-derived and circulating SFRP4 expressions were increased in patients with CAD. EAT SFRP4 mRNA levels and serum SFRP4 concentrations were independently associated with CAD presence, separately.
[GW28-e0926]
The impact of optimal medical therapy on prognosis of patients with coronary atherosclerosis
Jingwen Yong Yujie Zhou Zhijian Wang
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University
Objectives: To investigate the prevalence of OMT in patients with various coronary stenosis severities and its impact on clinical prognosis.
Methods: A total of 11490 patients undergoing invasive coronary angiography for suspected coronary artery disease (CAD) were grouped according to coronary stenosis severity: patients with obstructive CAD (luminal stensosis ≥50%, n=6416), non-obstructive CAD (stenosis <50%, n=3748) and angiographic normal patients (n=1326). The prevalence of OMT and its impact on prognosis were compared across three groups. OMT was defined as a combination of statin, β-blocker, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in patients with an American College of Cardiology/American Heart Association class I indication for each medication. The primary endpoint was the major adverse cardiovascular events, which was the composite of death, myocardial infarction, or repeat revascularization.
Results: With increasing coronary severity, we observed a progressively increased prevalence of risk factors, higher risk of MACE (MACE was 0.9% vs. 5.4% vs. 11.0% in patients with normal, non-obstructive and obstructive CAD, p < 0.001), and higher prevalence of OMT (95.1% vs. 98.2% vs. 99.4%, p < 0.001). Although there was an interaction between the impact of OMT on MACE and coronary severity (interaction p = 0.038), OMT was an independent predictor of improved MACE in patients with either obstructive CAD (HR: 0.72, 95% CI:0.62-0.84, p = 0.002) or non-obstructive CAD (HR: 0.87, 95% CI: 0.76-0.99, p = 0.046).
Conclusions: The prevalence of OMT is lower in patients with non-obstructive CAD compared with patients with obstructive CAD. Although the impact is weaker in non-obstructive CAD patients, OMT is an independent predictor of improved prognosis in patients with either non-obstructive or obstructive CAD.
[GW28-e0927]
The influence of social support on health outcomes in patients with acute coronary syndrome: a prospective study from China
Sha Lei1 DayiHu1 LiWang1 RongjingDing2
1. Department of cardiology, the First Affiliated Hospital of Chongqing Medical University
2. People’s Hospital of Peking University
Objectives: Social support is generally identified to associated with heath-related quality of life(HRQoL) and prognosis among patients with coronary heart disease(CHD). Few study described the changes of social support during follow-up. We evaluated the changes of social support at 12 months and taken anxiety into account for health outcomes of acute coronary syndrome(ACS) patients in mainland China.
Methods: 778 patients with ACS were consecutively enrolled in the study within 7 days after admission from 5 hospitals in Beijing China. Social support(ENRICHD Social Support Inventory),health status(Short Form-12 physical and mental component scores),anxiety(Anxiety Disorder-7 scale),depressive symptoms(Patients Health Questionnaire),and angina-related quality of life(Seattle Angina Questionaire) were investigated at baseline and 12 months. Mortality, recurrent angina, non-fatal myocardial infarction and re-hospitalization were observed during 12 months follow-up
Results: Patients with low social support at baseline presented more anxiety, worse mental functioning and angina-related quality of life than patients with moderate/high social support(all P<0.05).Mortality and non-fatal myocardial infarction were low in the overall cohort and not differ by social support(P>0.05).Whereas, patients with low social support at baseline were at greater risk of a recurrent angina(HR1.16,95%CI1.06-2.62, P<0.05) and rehospitalization(HR2.16,95%CI1.16-4.05, P<0.05) than those who had moderate/high social support over follow-up period.In average social support and health-related quality of life had been significantly improved regardless of baseline social support level at 12 month(all P<0.01)
Conclusions: Low social support was a predictor for worse health outcomes and recurrent angina, re-admission among Chinese ACS patients. Social support level experienced an improvement at 12 months post-ACS. Future studies is needed to figure out the mechanism of social support change and to develop the specific intervention for social support.
[GW28-e0988]
Berberine attenuates cardaic fibrosis via downregulating IGF1R in diabetic rats
Guohua Li Ling Dong Feng Gao
1. Department of Aerospace Medicine, Fourth Military Medical University, Xi’an 710032, China
Objectives: Diabetic cardiac fibrosis increases ventricular stiffness and facilitates occurrence of diastolic and systolic dysfunction. IGF 1R is a key receptor regulating cell growth, survival and differentiation. However, the role of IGF 1R and its downstream signaling in pathogenesis of diabetic cardiac fibrosis is rarely known. Berberine, a natural isoquinoline alkaloid, can yield benefits to cardiovascular system in diabetes. This study aimed to investigate whether berberine could alleviate interstitial fibrosis in diabetic heart and the underlying mechanisms.
Methods: Diabetes was induced by streptozotocin and high fat diet in male Sprague Dawley rats. Then, diabetes rats were gavaged with berberine or saline for 4 weeks. Cardiac function and fibrosis were measured. Effects of berberine on fibroblast proliferation and differentiation were studied in isolated neonatal cardiac fibroblasts cultured in high glucose medium.
Results: Diabetic rats presented cardiac systolic dysfunction and matrix collagen deposition, with decreased ejection fraction and fraction of shortening, increased expression of TGF beta, fibronectin, collagen 1, alpha SMA and MMP 2, MMP 9. Gavage of berberine for 4 weeks ameliorated cardiac systolic dysfunction and interstitial fibrosis in diabetic rats. Furthermore, the upregulation of IGF1R was inhibited by berberine in diabetic heart. In vitro data demonstrated that berberine inhibited proliferation of fibroblast and up-regulation of IGF1R and MMP 2, MMP 9 induced by high glucose. Furthermore, the inhibitory effects of berberine on MMP 2, MMP 9 were blunted by overexpression of IGF1R in myocardial fibroblasts.
Conclusions: Increased IGF1R contributes to cardiac fibrosis through up-regulating MMP 2, MMP 9 in diabetic rats, and berberine attenuates cardiac fibrosis through down-regulating IGF1R to decrease MMP 2, MMP 9 in diabetes.
[GW28-e0828]
Comparative Study of Thrombolysis with PCI and Primary PCI on Coronary Microcirculation in patients with Anterior STEMI
Yuyang Xiao Xiangming Li Xianghua Fu
The Second Hospital of Hebei Medical University
Objectives: Comparing thrombolysis combined with PCI and primary PCI on coronary microcirculation in patients with anterior ST-segment elevation myocardial infarction.
Methods: From March 2015 to December 2016, all anterior STEMI patients within 24 hours from symptom onset in Cardiology Department of our hospital were enrolled. All eligible STEMI patients were divided into two groups: post-thrombolysis PCI group (T-PCI group, patients have received thrombolytic agents in non-PCI capable hospital or ER in our hospital before. If IRA was thought to reopen, patients were transferred to receiving early PCI in 3-24 hours. If they failed to recover coronary flow, they must accept emergent PCI as soon as possible) and primary PCI group (P-PCI group, patients receiving primary CAG/PCI). All details were recorded, including baseline information, operative data, such as reperfusion time, TIMI flow of IRA before and after PCI, thrombus score and coronary microcirculation related indicators: CTFC and TMPG were analyzed. Both groups measured LVEF and WMS by taking echocardiography 7 days and 3 months after PCI. All patients were followed up for 3 months to assess bleeding implications and MACEs. SPSS 22.0 for was used for statistical analysis. Values of P < 0.05 were considered statistically significant.
Results: Totally 100 patients were enrolled in this trial with 32 in T-PCI group and 68 in P-PCI group.
1. Baseline characteristics such as gender distribution, age, BMI, the risk factors of coronary heart disease (hypertension, diabetes, dyslipidemia, smoking), laboratory index (serum BNP, SCr, Hb and LDL-C), Killip grade, GRACE score, CRUSADE score were similar between the two groups. In terms of myocardial necrosis marker enzymes the peal value of CK-MB and cTnI in T-PCI group higher than P-PCI group, while there was no statistical significance between two groups.
2. The mean time from symptom onset to thrombolysis was 3.4±2.05 h in T-PCI group. Compared with P-PCI group, the mean time from onset to PCI was longer in T-PCI group. There were no differences in the number of implanted stents, appliance of tirofiban as well as thrombus aspiration rate. Before PCI, rate of TIMI 0 and 3 flow has significant difference (P<0.001). Thrombus 0 and 5 scores in T-PCI group respectively were lower than that in P-PCI group (P<0.05). The level of LAD-CTFC in T-PCI group was higher than that in P-PCI group(P=0.043). TMPG 3 grade after PCI in T-PCI group higher, and there was a significant difference (P=0.045).
3. There was no significant difference in LVEF and WMS at 7 days after PCI between the two groups (LVEF: P=0.625; WMS: P=0.631). At 3 months after PCI, LVEF between the two groups has no difference either, whereas LVEF was improved significantly in each group(P<0.05).
4. There was no difference in the incidence of bleeding complications and MACEs. For major bleeding events, there was 2 case in T-PCI group and 2 in P-PCI group. For minor bleeding, there were 8 in T-PCI group and 7 in P-PCI. One patient in P-PCI group received transfusion in hospital.
Follow-up in 3 months, the incidences of MACEs in two groups showed no difference (All P>0.05).
Conclusions: 1. Coronary microcirculation in patients with anterior STEMI was better in patients undergoing thrombolysis combined with PCI.
2. It is safe and efficacious for anterior STEMI patients receiving thrombolysis with PCI, which shares the same advantage of improving left ventricular function, without increasing bleeding complications and MACEs incidence.
[GW28-e0959]
Advanced oxidation protein products exacerbates cardiac remodeling via cardiomyocyte apoptosis in chronic kidney disease
Weijing Feng1 2 Wanbing He1 2 Yinyin Zhang1 2 Mongheng Wang5 Jingfeng Wang1 2 Kun Zhang1 2 Yu Liu3 Jie Chen1 2 Qingqing Cai4 Hui Huang1 2
1. Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
2. Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, China
3. Department of Cardiology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
4. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
5. Department of Physiology, Augusta University, Augusta, GA30912, USA
Objectives: The accumulation of advanced oxidation protein products (AOPPs) is an established risk factor for cardiovascular events. Cardiomyocyte apoptosis has been implicated as a crucial process in cardiac remodeling during chronic kidney disease (CKD). However, whether AOPPs affect cardiomyocyte apoptosis and subsequent cardiac remodeling in CKD is still unclear. Thus, we aim to test the effects of AOPPs on cardiomyocyte apoptosis in CKD.
Methods: Rats were randomly divided into sham-operated group (n=10) and 5/6 nephrectomy (STNx) group (n=10). Characteristics in sham-operated rats and STNx rats were collected. The concentrations of serum AOPPs were determined by a multi-mode microplate reader with a 96 well microplate at different time courses. In vitro, cardiomyocytes were exposed to AOPPs (100 ug/ml) for various times. Expression of the related proteins was analyzed using Western blot. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect apoptotic cells.
Results: Serum concentrations of AOPPs in CKD rats increased in a time-dependent manner but no significant change in sham-operated rats over time. Compared with sham-operated rats, CKD rats showed a significant increase in serum AOPPs levels at the 6th week (42.32±4.12µmol/L vs. 66.49±6.20µmol/L, P<0.05), 9th week (41.67±3.65µmol/L vs. 88.12±7.36µmol/L, P<0.05) and 13th week (40.48±3.08µmol/L vs. 104.70±7.66µmol/L, P<0.05) after surgery, respectively. Additionally, the cardiomyocyte apoptosis, as indicating by TUNEL-staining, in CKD rats was nearly 3-fold higher than sham-operated rats at the 13th week after surgery by TUNEL-staining (1.36 ± 0.04% vs. 0.28±0.03%, P<0.05). Interestingly, the correlation analysis revealed that serum levels of AOPPs were positively correlated with apoptosis rates of cardiomyocyte in CKD rats (R2= 0.76, P<0.01). In vitro, AOPPs exacerbated cardiomyocyte apoptosis and up-regulated pro-apoptotic Bax and caspase-3 expression via activating JNK and endoplasmic reticulum stress. These effects were reversed by nicotinamide adenine dinucleotide phosphate oxidase inhibition.
Conclusions: These results demonstrate for the first time that AOPPs exacerbates cardiomyocyte apoptosis via activating JNK and endoplasmic reticulum stress, which suggests that targeting AOPPs may be a strategy for improving cardiac remodeling in CKD.
[GW28-e0919]
Associations between aldehyde dehydrogenase 2 (ALDH2) rs671 genetic polymorphisms, lifestyles and diabetes risk in Chinese Han people
Cong Ma Bingxiang Yu Qiang Zeng
Health Management Institute of Chinese PLA General Hospital
Objectives: Diabetes is a multiple factor disease which was influenced by gene, environment, and lifestyle. Several studies confirmed that the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism is associated with diabetes. However, the evidence remains inconclusive. Whether lifestyle affects the development of diabetes in different genotype groups have not been clarified, either. We sought to identify associations between ALDH2 rs671 polymorphism, lifestyles, and diabetes in Chinese Han people.
Methods: The subjects were adult Chinese Han people who received heath examination in the period from December 2015 to December 2016. Detection of the ALDH2 r671 polymorphism was determined by polymerase chain reaction. Lifestyle data were collected using self-administered questionnaires. Basic characteristics and fasting venous blood sample were collected at baseline.
Results: 3519 subjects were eligible for participation. The frequencies of the ALDH2 rs671 genotype were 67.1% (GG), 30.2%(GL), 2.7%(LL), respectively. ALDH2 rs671 polymorphism was significantly associated with diabetic risk (GG vs. GL+LL: OR=1.33, 95% CI=1.07-1.66, P=0.01). In different groups, the association between lifestyle and diabetic risk were also significant difference. In the homozygous group, smoking and drinking were significantly increased the risk of diabetes rather than in heterozygous group(smoking:OR=1.53, 95% CI:1.31–1.79, P<0.001; drinking:OR=1.62, 95% CI:1.33–1.99, P<0.001). Pickled foods intake was significantly increased the risk of diabetes in homozygous group (OR=1.71, 95% CI: 1.15–2.54,P=0.008). Fried foods intake was significantly decreased the risk of diabetes in heterozygous group(OR=0.45, 95% CI: 0.28–0.70,P=0.001).
Conclusions: Our study suggested that ALDH2 rs671 polymorphism might be able to be used as a predictor for the risk of diabetes in Chinese Han people. Smoking, drinking and pickled foods intake were risk factors for diabetes in the homozygous group, while fried food intake is a protective factor in heterozygous group.
[GW28-e1052]
The mechanism of α7nAChR mediated cholinergic anti-inflammatory pathway in the vagal nerve regulated atrial fibrillation
Shujuan Zhang1 2 3 Shudi Zhang4 Zixuan Dai1 2 3 Hongyi Zhao1 2 3 Yongsheng Qian1 2 3 Youjing Zhang1 2 3 Youcheng Wang1 2 3 Bo He1 2 3 Yanhong Tang1 2 3 Xi Wang1 2 3 Teng Wang1 2 3 He Huang1 2 3 Qingyan Zhao1 2 3 Congxin Huang1 2 3
1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
2. Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, China
3. Hubei Key Laboratory of Cardiology, Wuhan, Hubei 430060, China
4. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China
Objectives: To investigate the mechanism of α7nAChR mediated cholinergic anti-inflammatory pathway in the vagal nerve regulated atrial fibrillation
Methods: Eighteen beagles were randomized into control group (n=6), LL-VNS group (n=6) and MLA group (n=6). All the beagles were subjected to rapid atrial pacing at 800 beats/min for 6 hours. The effective refractory period (ERP) of atrium and pulmonary veins and induced AF were measured hourly during non-pacing. After cessation of 3 h pacing, the control group was injected with saline into four GPs, the LL-VNS group was given LL-VNS and saline injected into four GPs, and the MLA group was injected with methyllycaconitine (an α7nAChR inhibitor) into for GPs combined with LL-VNS. Then, the level of serum tumor mecrosis factor-alpah (TNF-α), interleukin-6 (IL-6), and acetylcholine (ACh) were measured at baseine condition, 3 h and 6 h. At the end of the experiment, atrial tissues were collected and the levels of TNF-α, IL-6, ACh, α7nAChR, STAT3 and NF-κB proteins were measured.
Results: During the first 3 h pacing, the ERPs were gradually decreased while the dERPs and AF inducibility were gradually increased in all three groups, there were not significant difference in the ERPs, dERPs and AF inducibility among the three groups. During the last 3 hours, when compared with the control group and MLA group, the ERPs in the LL-VNS group wer higher, and the dERPs and AF vulnerability were significant lower at the same time points. The levels of TNF-α and IL-6 in atrial tissues were all significant decreased in LL-VNS group when compared with the control group and MLA group, and the levels of ACh in plasma and atrial tissues in the LL-VNS group and MLA group were higher than in the control group. The concentrations of α7nAChR and STAT3 proteins in RA and LA were higher in the LL-VNS group than in the control group and MLA group, and the levels of NF-κB in those tissues were lower in the LL-VNS group than in the control group and MLA group.
Conclusions: Cholinergic anti-inflammatory pathway plays an important role in low-level vagal nerve regulated AF.
[GW28-e0939]
Discovery of dynamical network biomarkers (DNB) during the progression of atherosclerosis using multiple omic techniques and systems biology
Jing Ge1 2 Xiaoya Fan1 2 Xinli Xue2 3 Gaopeng Li1 2 Shanshan Zhong2 3 Xia Shen3 5 Huiyong Yin2 3 4 5 Luonan Chen1 2 5
1. Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
2. University of the Chinese Academy of Sciences, CAS, Beijing 100049, China
3. Key Laboratory of Food Safety Research, Institute for Nutritional Sciences (INS), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200031, China
4. Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China
5. School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
Objectives: Aim to develop a prediction model to identify the early signals of the critical transition in atherosclerosis, and define the major metabolic networks that regulate the homoestasis of blood vessel, which may help for the early detection and prevention of atherosclerosis.
Methods: Combining omics data and theoretical analysis to establish a theoretical model for early prediction of the dysregulation of blood vessel homeostasis and atherosclerotic lesion formation from the viewpoint of systems biology.
Results: First we used the LDLR-/- mouse model feeding western diet to mimic the onset and progression of atherosclerosis. The pathological characteristics of aortic roots by oil red and H&E staining showed that the atherosclerotic lesion gradually increased over time. Second, we integrated high throughput data including different-stage data of RNA-seq and metabolomics/lipidomics to discover regulatory networks of atherosclerosis and identify dynamical network biomarkers (DNB) to characterize the critical transition from normal vessel to atherosclerotic lesion. By analyzing the RNA-seq data of aortas, we identified the critical tipping point in the progression of atherosclerosis at the genetic level and discovered a group of DNB which appear to play driving roles in the progression of this disease. At last, we attempted to validate the theoretical results with biological experiments.
Conclusions: We develop a prediction model to identify the early signals of the critical transition in atherosclerosis, and discovered a group of DNB which appear to play driving roles in the progression of this disease. These may help for the early detection and prevention of atherosclerosis.
[GW28-e0914]
A Novel Mechanism Underlying Energy Metabolic Disorders in Failing Heart: Defective Branched Chain Amino Acid Catabolism-Induced Mitochondrial Metabolic Enzyme Hyper-Succinylation
Fuyang Zhang1 2 Xiyao Chen3 Xinliang Ma4 Jianming Pei2 Ling Tao1
1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University.
2. Department of Physiology, Basic Medical Science School, Fourth Military Medical University
3. Department of Geriatrics, Xijing Hospital, Fourth Military Medical University.
4. Emergency Medicine Department, Thomas Jefferson University.
Objectives: Cardiac energy metabolic disorders majorly contribute to heart failure (HF) progression following myocardial infarction (MI). We have previously shown that branched chain amino acid (BCAA) catabolism is obviously impaired in the mitochondrion isolated from the MI-induced failing heart. However, the role of cardiac BCAA catabolic defects in heart failure remain largely unknown.
Methods: MI was induced by coronary artery ligation in a mouse model of defective BCAA catabolism (protein phosphatase-2Cm [PP2Cm] knockout [KO]) or in wild type (WT) mice. Primary cardiomyocytes were isolated from KO or WT heart. Cardiac function and structure were analyzed respectively by echocardiography or masson trichrome staining at 4 weeks post-MI.
Results: Compared with WT group, MI-induced cardiac dysfunction and remodeling were obviously exacerbated in KO mice. In KO heart, chronic BCAA accumulation obviously suppressed cardiac glucose and lipid metabolism through inhibition of mitochondrial pyruvate dehydrogenase (PDH) and carnitine palmitoyltransferase-1 (CPT-1) activity. Furthermore, we found that defective BCAA catabolism caused succinyl-coenzyme A (succi-coA) accumulation, leading to excessive PDH and CPT-1 lysine succinylation and inactivation in the mitochondrion. Promoting cardiac BCAA catabolism or normalizing PDH and CPT-1 hyper-succinylation by SIRT5 (the specific desuccinylation enzyme) overexpression in the KO heart rescued metabolic, functional, and structural outcomes following MI.
Conclusions: The present study revealed a novel and crucial role of BCAA catabolism in the regulation of cardiac metabolism and stress response during HF progression following MI. These observations also for the first time provided direct evidence demonstrating that impaired BCAA catabolism-induced mitochondrial metabolic enzyme hyper-succinylation majorly contributes to energy metabolic disorders in MI-induced failing heart. Targeting defective BCAA catabolism or excessive mitochondrial metabolic enzyme lysine succinylation may be novel therapeutic strategies for post-MI HF management.
[GW28-e0192]
Preliminary study on the role of AKAP1 in the development of diabetes mellitus
Fengzhou Liu1 Lele JI2 Fei LI1
1. Department of Cardiology, Xijing Hospital, the Fourth Military Medical University
2. State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, the Fourth Military Medical University
Objectives: Diabetes mellitus (DM) is a chronic disease characterized by metabolic disorder. Emerging evidences have showed that mitochondrial dysfunction is associated with diabetes initiation and progression. A kinase anchoring protein1 (AKAP1), located in the mitochondrial outer membrane, has been proved to play an important role in maintaining the functional activity of the mitochondrial respiratory chain, regulating the division and integration of mitochondria. However, to date, the significance of AKAP1 in diabetes mellitus has never been investigated.
Methods: We first constructed AKAP1-/- knockout mice model by CRISPR/Cas9 technology. Then, we systematically explored the role of AKAP1 on the occurrence and development of diabetes mellitus and the underlying mechanism.
Results: Here, we showed that AKAP1-/- knockout mice constructed by CRISPR/Cas9 technology are prone to obesity, hepatic steatosis, and whole-body insulin resistance in diabetes induced by high-fat diet. Moreover, we demonstrated that the up-regulation of AKAP1 can improve the cardiac ejection function, reduce the collagen content of myocardial tissue, alleviate myocardial hypertrophy, and ameliorate myocardial ischemia injury in db/db mice. Finally, our results indicated that AKAP1 deficiency increased the mitochondrial morphological abnormalities in the major tissues of diabetic mice, and up-regulation of AKAP1 expression could significantly improve the mitochondrial morphology of db/db mice.
Conclusions: Our findings demonstrate that AKAP1 plays a critical role in the development of diabetes mellitus. Thereby, AKAP1 may represent an attractive therapeutic target in diabetes.
[GW28-e0558]
Inhibition of TRPA1 prevents Adriamycin-induced acute cardiotoxicity through suppression of oxidative stress and inflammation responses
Zhen Wang Menglong Wang Jianfang Liu Jing Ye Yao Xu Huimin Jiang Jun Wan
Renmin Hospital of Wuhan University
Objectives: To investigate the potential role of TRPA1 in the development of doxorubicin-induced acute cardiotoxicity
Methods: 80 experimental male C57BL/6J mice were randomly divided into four groups: sham + vehicle (n=20), sham + HC-030031(HC) (n=20), ADR + vehicle (n=20), and ADR + HC-030031(HC) (n=20). HC-030031 (10mg/kg, i.g.), a selective TRPA1 blocker, was administered from 0 to 10 d. Acute ADR cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg DOX in mice on the 5th day. Cardiotoxicity was assessed by measuring the levels of various antioxidant parameters in the heart and the release of marker enzymes in the serum. Cardiac function was assessed 5 days after ADR exposure through echocardiography. Thereafter, the hearts were harvested and weighed. Heart sections were evaluated for pathological lesions. The RT-PCR, western blotting, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed to check for ADRinduced damages.
Results: The results demonstrated that ADR treatment enhanced myocardial TRPA1 mRNA and protein levels. Next, we calculated the and body weight (BW) and heart weight (HW) of mice in each group. Compared to control mice, mice treated with ADR showed a decreased BW and HW. The HC alone group had similar BW and HW to those of the control animals. Meanwhile, HC treatment did not alter the BW and HW in ADR-treated animals. Interestingly, there was no differences in the HW/BW on day 10 among the 4 groups. Further, ejection fraction (EF) and fractional shortening (FS) were also reduced in the ADR+HC group, but the level was significantly higher than that observed in the ADR-only group at day 10. Histological examinations also revealed increased vacuolar and myofibrillar disorganization in mice with ADR treatment, while they were ameliorated in the ADR+HC group. Additionally, the significant increased biomarkers of cardiac injury including CK-MB, LDH, ALT and AST were further detected after ADR administration. Interestingly, administration of HC decreased the level of serum enzyme obviously, indicating the attenuated myocardial injury. Then, the administration of HC alone to mice had no effects on enzyme activities compared with control group. ADR treatment caused significant reduction in the activities of SOD and GSH as well as increase in the levels of MDA when compared with the sham groups. In addition, Treatment with HC indicated a statistically decrease in MDA levels and restored the activities of SOD and GSH antioxidant levels as compared with the ADR-treated group.
Furthermore, inhibition of TRPA1 with HC remarkable reduced the expression of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-17 and TNF-α, and suppressed the downstream inflammatory cascade. TUNEL staining showed an increase in cardiomyocyte apoptosis rate in the ADR group, whereas the increased apoptosis rate was reduced by HC treatment with the ADR injection. To confirm these findings, western blot analysis was applied to assess the expression levels of the apoptosis-related proteins. The expression levels of casepase-3, caspase-9 and Bax/Bcl-2 in myocardial tissue were significantly higher in the ADR group than the other three groups. Furthermore, HC-treat decreased casepase-3 and caspase-9 as well as the ratio of Bax/Bcl-2 protein expression in ADR plus HC group
Conclusions: Inhibition of TRPA1 could prevent ADRinduced acute cardiotoxicity in mice by inhibiting oxidative stress and inflammation.
[GW28-e0689]
Updating 10-year atherosclerotic cardiovascular risk assessment equation for Chinese adults
Miao Wang Jing Liu Wei Wang Jun Liu Jiayi Sun Yue Qi Ying Wang Yongchen Hao Lanping Qin Mengge Zhou Shen Gao Dong Zhao
Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing 100029, China
Objectives: To update 10-year first atherosclerotic cardiovascular disease (ASCVD) risk assessment equation for Chinese adults.
Methods: A total of 21265 Chinese aged 35 to 64 years without ASCVD who were from the Chinese Multi-Provincial Cohort Study were included in this study. The Chinese Multi-Provincial Cohort Study was a nationwide, multicenter, cohort study on the determinants in cardiovascular disease in China. The cohort was built by using multistage sampling method. The non-random and stratified random sampling methods were used, in turn, to select study centers and enroll participants. The ASCVD risk assessment equation was developed based on Cox proportional hazards regression model. The smoking status, diabetes, and natural logarithm of age, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (SBP) were included during the equation updating. The interaction between age and risk factors was also considered. The ability of discrimination (C statistic) and calibration (calibration χ2 from Hosmere-Lemeshow test) of the equation were evaluated. The equation was also validated internally by the method of 10×10-fold cross-validation.
Results: In this study, 822 individuals experienced a first ASCVD event during the 12-year follow up. The β values of smoking status, diabetes, and natural logarithm of age, TC, HDL-C, SBP, and interaction between age and SBP were 0.09 (P=0.716), 0.51 (P=0.003), 45.91 (P<0.001), 0.39 (P=0.200), -0.60 (P=0.009), 36.90 (P<0.001), and -8.72 (P<0.001) in the risk assessment equation for the female. Compared to the female, the risk assessment equation for the male had one more interaction item (age and TC). The C statistic of the risk assessment equation was 0.769 (95% confidence interval (CI), 0.634-0.823) in females and 0.768 (95% CI, 0. 695-0.824) in males. The Hosmere-Lemeshow χ2 was 5.022 (P=0.832) in females and 9.453 (P=0.397) in males. In internal validation the average calibration χ2 was 7.276 (95CI%, 2.537-14.446) in females and 9.331 (95CI, 3.067-21.162) in males.
Conclusions: The updated 10-year first ASCVD risk assessment equation showed good performance by evaluating the ability of discrimination and calibration. Next, the equation should be developed into risk assessment tools which would make it be easily applied in the practice of ASCVD prevention.
[GW28-e0646]
Echinacoside protects against high glucose-induced oxidative stress in vascular endothelial cells through Nrf2/HO-1 dependent pathway
Jiahong Xue Zhu canzhan Anqi Song Jiahong Xue
Department of Cardiology, Second Affiliated Hospital of Xi’an Jiaotong University
Objectives: Oxidative stress plays an important factor that is related to endothelial dysfunction in diabetes. Echinacoside, a compound derived from the medicinal plants Cistanche and Echinacea, has been found to effectively inhibit oxidative stress formation. The present study aimed to further implore the protective role of echinacoside in endothelial injury induced by high glucose and whether the endogenous antioxidant gene regulator, nuclear factor erythroid-2-related factor 2(Nrf2)/ heme oxygenase 1(HO-1)was involved in the effect of echinacoside against oxidative stress.
Methods: Human umbilical vein endothelial cells(HUVECs)were treated with D-glucose(5.6 mM and 30.0 mM) with or without echinacoside (200 µM) for 24 to72h. Intracellular reactive oxygen species (ROS) was measured using dihydroethidium (DHE) fluorescence. The nitric oxide synthase (NOS) activity and phosph-eNOS expression were measured by means of scintillation counting and western blot respectively. To determine Nrf2 activation,Nrf2 protein expressions in cytoplasm and nucleus were evaluated and Nrf2-antioxidant response element (ARE) binding activity was determined by electromobility shift assay. Furthermore, real time PCR and western blot were further employed to measure the expression of HO-1, one of antioxidative target gene of Nrf2.
Results: Compared with normal glucose, 30.0 mM high glucose significantly induced ROS production, which was significantly reversed by pretreatment echinacoside in high glucose cultured endothelial cells. Furthermore, decreased NOS activity and phosph-eNOS protein expression by high glucose were also attenuated by 50% and 40% respectively by echinacoside in endothelial cells. In addition, it has been found that echinacoside induced nuclear translocation of Nrf2 protein after 24 h and reduced nuclear protein levels of Fyn, a repressor of the antioxidant response element. Similarly, Nrf2-ARE binding activity was increased, which was along with increased HO-1 mRNA and protein expressions by 40% in echinacoside treated endothelial cells. However, the role of echinacoside in high glucose-induced oxidative stress formation was blocked by Nrf2 siRNA. Similarly, the effect of echinacoside on NOS activity and phosph-eNOS protein expression was also impeded by Nrf2 siRNA. Finally, it was also found that echinacoside promoted phosphorylation of Akt and increased Nrf2 transcription action by echinacoside was blocked by the Akt inhibitor MK2206 and Akt negative regulators PTEN, which was accompanied by increase in nuclear accumulation of Fyn.
Conclusions: It is suggested that echinacoside protects against high glucose-induced vascular endothelial dysfunction, which is associated with Nrf2/HO-1-dependent antioxidative passway, and regulated by Akt phosphorylation. It may be a useful therapeutic potential in preventing from endothelial dysfunction in diabetes.
[GW28-e0314]
Drug-Eluting Balloon Versus Bare-Mental Stent and Drug-Eluting Stent for De Novo Coronary Artery Disease: a Systematic Review and Meta-Analysis
Konyong Cui1 2 Shuzheng LYU1 2
1. Beijing Anzhen Hospital, Capital Medical University
2. Beijing Institute of Heart, Lung and Blood Vessel Diseases
Objectives: Drug-eluting balloon (DEB) has become an alternative option to drug-eluting stent (DES) for the treatment of in-stent restenosis (ISR). However, the effect of drug-eluting balloon with regular bare-mental stent (BMS) in de novo coronary artery disease (CAD) is unclear. This meta-analysis aimed to evaluate the efficacy of DEB with regular BMS compared to BMS or DES in de novo CAD.
Methods: Randomized controlled trials (RCTs) assessing the efficacy of DEB+BMS in comparison with BMS or DES were obtained by searching the PubMed, EMBASE, and Cochrane Library databases through January 2016. Primary endpoints were major adverse cardiac events (MACEs) and late lumen loss (LLL). Secondary endpoints included death, myocardial infarction (MI), target lesion revascularization (TLR), stent thrombosis (ST), binary restenosis, and minimum lumen diameter (MLD). Dichotomous and continuous data were presented as odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs), respectively, and analyzed using a random-effects model.
Results: A total of 14 RCTs involving 2281 patients were included in this meta-analysis. DEB+BMS showed significantly less MACEs (OR: 0.67, 95%CI 0.45 to 0.99, P=0.04) and reduced LLL (MD: -0.30 mm, 95%CI: -0.48 mm to -0.11 mm, P=0.001) compared with BMS. Meanwhile, treatment with DEB+BMS had disadvantages over DES in terms of MACEs (OR: 1.94, 95%CI 1.24 to 3.05, P=0.004), LLL (MD: 0.20 mm, 95%CI: 0.07 mm to 0.33 mm, P=0.003), TLR (OR: 2.53, 95% CI 1.36 to 4.72, P = 0.003), and MLD (MD: -0.25 mm, 95%CI: -0.42 mm to -0.09 mm, P=0.003).
Conclusions: This limited evidence demonstrated that treatment with DEB+BMS appears to be effective in de novo CAD. In addition, DEB+ BMS clearly showed superiority to BMS, but is inferior to DES in the treatment of patients with de novo CAD. Hence, DES (especially new generation DES) should be recommended for patients with de novo CAD.
[GW28-e0596]
Melatonin sustained-released cardiac patch improves functional survival of transplanted bone marrow mesenchymal stem cells after myocardial infarction in rats
Jiangwei Chen1 Dong Han1 Hongbing Deng2 Feng Cao3 1
1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
2. School of Resource and Environmental Science, Wuhan University, Wuhan 430079, China
3. Department of Cardiology, Chinese PLA General Hospital, Beijing 100039, China
Objectives: In the present study, we aimed to fabricate a type of novel melatonin sustained-released nanofibrous cardiac patch and explore its effect on functional survival of transplanted stem cells for heart repair after myocardial infarction (MI). Meanwhile, this study explored a novel noninvasive molecular imaging strategy to trace the stem cell differentiation.
Methods: Melatonin sustained-released cardiac patch was fabricated via electrospinning and layer-by-layer coating technique. Bone marrow mesenchymal stem cells (BMSCs) with Fluc/eGFP/cardiac troponin T (cTNT) promoter-driven ferritin heavy polypeptide (FTH) triple reporter genes were seed cells and engrafted to the patch. 5-Aza was used to induce BMSCs to differentiate into cardiomyocytes, and the relevance between expressions of cTNT and FTH was analyzed by Western Blot. Linear relationship between magnetic resonance imaging (MRI) signal and differentiation degree (cTNT expression level) of transplanted BMSCs was assessed in vitro. Wild type Sprague Dawley rats (male, 140-160g) were randomized into four groups (each n=10): Sham group, MI group (MI model was established by ligation of left anterior descending coronary artery), MI+patch/BMSCs group and MI+patch/melatonin/BMSCs group (Patches with or without sustained-released melatonin were adhered onto the epicardium over the infarcted region respectively, patch size:10×10 mm2, BMSCs count: 2×105). Myocardial apoptosis in the peri-infarct area was determined by TUNEL staining 24 hours post-operation. Viability of engrafted BMSCs was tracked using bioluminescence imaging (BLI) via built-in firefly luciferase (Fluc) in vivo 1, 3, 7, 14, 21 and 28 days post-operation. Cardiac function was monitored by transthoracic echocardiography (TTE). MRI was performed to detect cardiac structure and BMSCs differentiation in vivo. Histopathological stainings (Masson’s Trichrome, prussian blue, cTNT/GFP, CD68 and CD31 immunofluorescence) were performed to evaluate myocardium fibrosis, Fe distribution, BMSCs viability and differentiation, neovascularization and inflammatory reaction 4 weeks after operation.
Results: Melatonin sustained-released cardiac patch was fabricated and steadily released melatonin. MRI signal showed a linear correlation with FTH expression level in vitro. TUNEL staining showed reduced apoptotic index in MI+patch/melatonin/BMSCs group. BMSCs were detectable until 4 weeks after transplantation, and the Fluc signals of MI+patch/melatonin/BMSCs group decreased more lenitively than MI+ patch/BMSCs group. TTE showed increased cardiac functionin in MI+melatonin/patch/BMSCs group (EF value: sham: 76.3±4.7%, MI: 32.1±5.2%, MI+patch/BMSCs: 46.5±7.1%, MI+melatonin/patch/BMSCs: 57.8±6.3%, 4 weeks post-operation). MRI showed thickened left ventricles and remarkable low T2 signals of rats bearing melatonin/patch/BMSCs treatment in vivo. Histopathological stainings indicated patch/melatonin/BMSCs treatment decreased myocardial apoptosis and cardiac fibrosis, increased BMSCs viability and differentiation, promoted neovascularization, and caused minor immunological response.
Conclusions: Melatonin sustained-released cardiac patch improved viability and differentiation of implanted BMSCs, restrained ventricular remodeling, and prevented heart failure. In comparison to infarcted hearts with no treatment and patch/BMSCs therapy, hearts bearing patch/melatonin/BMSCs therapy showed significant anatomical and functional improvement.
[GW28-e0813]
Exercise-derived and exosome-mediated miR-342-5p: a novel exerokine protects against myocardial ischemia/reperfusion injury
Zuoxu Hou Feng Gao
Department of Aerospace Medicine, Fourth Military Medical University, Xi’an, 710032, China
Objectives: Exercise training, in addition to reducing cardiovascular risk factors, also confers direct cardioprotection against myocardial ischemia/reperfusion (MI/R) injury in animal models and has been associated with improved survival following a heart attack in humans. However, the underlying mechanisms are still unclear. Exosomes are nanometer-sized vesicles secreted by multiple cell types into the blood, where they can transmit signals throughout the body. This study sought to evaluate the functional effects of exercise-derived circulating exosomes in the context of MI/R injury and identify the molecular mechanisms involved.
Methods: Circulating exosomes were isolated from the serum of volunteers with or without exercise training and rats subjected to 4 weeks of swimming exercise or sedentary littermates. In vivo MI/R and in vitro neonatal rat ventricular cardiomyocytes hypoxia/reoxygenation (H/R) models were used to evaluate the cardioprotective actions of circulating exosomes. A miRNA profiling assay between circulating exosomes of exercised and sedentary rats was performed using Illumina HiSeq 2500 high-throughput sequencing. Western blot and luciferase reporter assay were used to identify target genes of miR-342-5p. Rats were intramyocardially injected with serotype 9 adeno-associated virus (AAV9) carrying specific sequence targeting miR-342-5p one week prior to 4 weeks of swimming exercise to inhibit miR-342-5p in hearts in vivo.
Results: Nanoparticle tracking analysis and Western blot showed no significant changes in total level of circulating exosomes in long-term exercise rats compared with sedentary ones. However, exercise-derived circulating exosomes afforded profound cardioprotective effects in MI/R rats as evidenced by reduced infarct size (from 57.8 ± 2.7% to 31.6 ± 4.0% in relation to the area at risk) and improved cardiac function. miRNA array and qRT-PCR analysis identified 12 differentially expressed miRNAs in exercise-derived circulating exosomes from exercised rats and rowing athletes, and miR-342-5p stood out as the most potent cardioprotective molecule in the context of H/R injury. Moreover, inhibition of miR-342-5p almost abolished the cardioprotective effects of exercise-derived circulating exosomes. More importantly, in vivo inhibition of miR-342-5p with AAV9 attenuated exercise-afforded cardioprotective effects in MI/R rats. Mechanistically, miR-342-5p significantly inhibited the apoptotic signaling via targeting Caspase9 and Jnk2, and enhanced the survival signaling (p-Akt) via targeting phosphatase Ppm1f in cardiomyocytes.
Conclusions: Our findings reveal a novel endogenous cardioprotective mechanism that exercise-derived circulating exosomes protect the heart against MI/R injury via miR-342-5p.
[GW28-e0097]
Application of genome-wide microarray analysis technology to explore the neuroprotection mechanism of hypothermia after cardiopulmonary resuscitation
Dezhi Zou Xuan Dai Chunlin Hu
The First Affiliated Hospital, Sun Yat-sen University, Emergency Department
Objectives: Hypothermia is one of the most robust experimental neuroprotective interventions against cerebral ischemia. Identification of molecular pathways together with single genes or gene families that are significantly associated with neuroprotection might help unravel the mechanisms of therapeutic hypothermia.
Methods: Total of 20 healthy adult male Wistar rats, were randomly divided into 4 groups, sham-operated plus nonthermia (NT1)(n=4), sham-operated plus hypothemia (NT2)(n=4), return of spontaneous circulation (ROSC) after ventricular fibrillation(VF) plus nonthermia (CPRT1)(n=6), ROSC after VF plus hypothemia (CPRT2)(n=6). 12 of CPRT were induced VF by an external trans-thoracic alternating current. After 7 minutes cardiac arrest, the animals received 2 minutes cardiopulmonary resuscitation and then defibrillation until ROSC. The animals in NT1 and CPRT1 Placed in the constant temperature box at 37oC and maintained esophageal temperature at 38 oC. The animals in NT2 and CPRT2 were treated by surface hypothermia, and maintained for 2 hrs of target temperature between 33 oC to 35 oC. The animals were sacrificed after ROSC 2h, the cerebral cortex were removed, then the RNA of samples were processed in extraction, quality inspection, purification and amplification. Data collection, inspection and analysis after The Mouse Genome Microarrays hybridization reaction. The gene expression profile of NT1, NT2, CPRT1, and CPRT2 were compared by analyzing changes of individual genes and pathways.
Results: All samples showed high consistency, and integrity of RNA sample was qualified. The microarray hybridization reaction process was good. The normalized data shows approximate normal distribution. The data of compare of two groups (p < 0.05) indicates differentially expressed genes in common. CPRT1 versus NT1, of 227 genes present on the array chip(p<0.05), compared with upregulated 150(66.1%) genes and down regulated 77(33.9%) genes equal or greater than twofold. CPRT2 versus NT2, of 108 genes present on the array chip(p<0.05), compared with upregulated 76(76.1%) genes and downregulated 32(33.3%) genes equal or greater than twofold. NT2 versus NT1, of 138 genes present on the array chip(p<0.05), compared with upregulated 96(69.6%) genes and downregulated 32(30.4%) genes equal or greater than twofold. CPRT2 VS NT2 compared with CPRT1 VS NT1, NT2 VS NT1 compared with CPRT2 VS CPRT1, there are 8 and 6 difference expression genes in common, respectively. Genes implicated in hyphothemia displayed significantly differential expression, such as p21, 14-3-3-sigma, GADD45, BDNF, c-fos, HSP72, c-JUN, Nur77, CXCL2, CCL3, IL4 and TSLP. On the pathway level, the MAPK signaling pathway and Cytokine-cytokine receptor interaction pathway in CPRT2 VS NT2, likewise the P53 signaling pathway in CPRT1 VS NT1, were identified to be significantly altered (p<0.05, fc>=1.5). The most significantly altered pathways contained genes above participating in cell cycle arrest, proliferation, differentiation, apoptosis and inflammation.
Conclusions: Our data suggest that Inflammation pathway, P53 apoptosis pathway and inflammatory factor receptor pathways that connected with MAPK, were associated with neronal injury after cardiopulmonary resuscitation. Hypothemia has remarkable effect on the expression of several of genes related to these pathways, which affect inflammatory response, apoptosis and cell inflammatory factor receptor mediated neronal injury pathways after CPR, thus play a role of neuroprotection.