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      Prognostic value of HbA1c for in-hospital and short-term mortality in patients with acute coronary syndrome: a systematic review and meta-analysis

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          Abstract

          Background

          HbA1c, the most commonly used indicator of chronic glucose metabolism, is closely associated with cardiovascular disease. However, the relationship between HbA1c and the mortality of acute coronary syndrome (ACS) patients has not been elucidated yet. Here, we aim to conduct a systematic review assessing the effect of HbA1c on in-hospital and short-term mortality in ACS patients.

          Methods

          Relevant studies reported before July 2019 were retrieved from databases including PubMed, Embase, and Central. Pooled relative risks (RRs) and the corresponding 95% confidence interval (CI) were calculated to evaluate the predictive value of HbA1c for the in-hospital mortality and short-term mortality.

          Results

          Data from 25 studies involving 304,253 ACS patients was included in systematic review. The pooled RR of in-hospital mortality was 1.246 (95% CI 1.113–1.396, p: 0.000, I 2 = 48.6%, n = 14) after sensitivity analysis in studies reporting HbA1c as categorial valuable. The pooled RR was 1.042 (95% CI 0.904–1.202, p: 0.57, I 2 = 82.7%, n = 4) in random-effects model for studies reporting it as continuous valuable. Subgroup analysis by diabetic status showed that elevated HbA1c is associated increased short-term mortality in ACS patients without diabetes mellitus (DM) history and without DM (RR: 2.31, 95% CI (1.81–2.94), p = 0.000, I 2 = 0.0%, n = 5; RR: 2.56, 95% CI 1.38–4.74, p = 0.003, I 2 = 0.0%, n = 2, respectively), which was not the case for patients with DM and patients from studies incorporating DM and non-DM individuals (RR: 1.16, 95% CI 0.79–1.69, p = 0.451, I 2 = 31.9%, n = 3; RR: 1.10, 95% CI 0.51–2.38), p = 0.809, I 2 = 47.4%, n = 4, respectively).

          Conclusions

          Higher HbA1c is a potential indicator for in-hospital death in ACS patients as well as a predictor for short-term mortality in ACS patients without known DM and without DM.

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          Most cited references45

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          Diabetic Hyperglycemia activates CaMKII and Arrhythmias by O linked Glycosylation

          Summary Ca2+-Calmodulin dependent protein kinase II (CaMKII) is a regulatory node in heart and brain, and its chronic activation can be pathological. CaMKII activation seen in heart failure can directly induce pathological changes in ion channels, Ca2+ handling and gene transcription. 1 Here we discover a novel mechanism linking CaMKII and hyperglycemic signaling in diabetes mellitus, which is a key risk factor for heart 2 and neurodegenerative diseases. 3,4 Acute hyperglycemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser-279 activates CaMKII autonomously, creating molecular memory even after [Ca2+] declines. O-GlcNAc modified CaMKII is increased in heart and brain from diabetic humans and rats. In cardiomyocytes, increased [glucose] significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum (SR) Ca2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias. 1 These effects were prevented by pharmacological inhibition of O-GlcNAc signaling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were enhanced by increased [glucose] via O-GlcNAc-and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signaling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.
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            Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

            The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.
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              Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study.

              Glycometabolic state at hospital admission is an important risk marker for long-term mortality in patients with acute myocardial infarction, whether or not they have known diabetes mellitus. Our aim was to ascertain the prevalence of impaired glucose metabolism in patients without diagnosed diabetes but with myocardial infarction, and to assess whether such abnormalities can be identified in the early course of a myocardial infarction. We did a prospective study, in which we enrolled 181 consecutive patients admitted to the coronary care units of two hospitals in Sweden with acute myocardial infarction, no diagnosis of diabetes, and a blood glucose concentration of less than 11.1 mmol/L. We recorded glucose concentrations during the hospital stay, and did standardised oral glucose tolerance tests with 75 g of glucose at discharge and again 3 months later. The mean age of our cohort was 63.5 years (SD 9) and the mean blood glucose concentration at admission was 6.5 mmol/L (1.4). The mean 2-h postload blood glucose concentration was 9.2 mmol/L (2.9) at hospital discharge, and 9.0 mmol/L (3.0) 3 months later. 58 of 164 (35%, 95% CI 28-43) and 58 of 144 (40%, 32-48) individuals had impaired glucose tolerance at discharge and after 3 months, respectively, and 51 of 164 (31%, 24-38) and 36 of 144 (25%, 18-32) had previously undiagnosed diabetes mellitus. Independent predictors of abnormal glucose tolerance at 3 months were concentrations of HbA(1c) at admission (p=0.024) and fasting blood glucose concentrations on day 4 (p=0.044). Previously undiagnosed diabetes and impaired glucose tolerance are common in patients with an acute myocardial infarction. These abnormalities can be detected early in the postinfarction period. Our results suggest that fasting and postchallenge hyperglycaemia in the early phase of an acute myocardial infarction could be used as early markers of high-risk individuals.
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                Author and article information

                Contributors
                minzhouzhang@aliyun.com
                Journal
                Cardiovasc Diabetol
                Cardiovasc Diabetol
                Cardiovascular Diabetology
                BioMed Central (London )
                1475-2840
                11 December 2019
                11 December 2019
                2019
                : 18
                : 169
                Affiliations
                [1 ]ISNI 0000 0000 8848 7685, GRID grid.411866.c, Guangzhou University of Chinese Medicine, ; Guangzhou, 510405 China
                [2 ]ISNI 0000 0000 8848 7685, GRID grid.411866.c, The Second Clinical College of Guangzhou University of Chinese Medicine, ; Guangzhou, 510120 China
                [3 ]GRID grid.413402.0, Guangdong Provincial Hospital of Chinese Medicine, ; No 111 Dade Road, Guangzhou, 510120 China
                Author information
                http://orcid.org/0000-0001-5959-8367
                Article
                970
                10.1186/s12933-019-0970-6
                6905004
                31829179
                a6c8d6c7-cf6d-42db-a548-7571cdf3978d
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 October 2019
                : 22 November 2019
                Funding
                Funded by: Project of Administration of Traditional Chinese Medicine of Guangdong Province of China
                Award ID: No. 20181126
                Award Recipient :
                Funded by: The Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine
                Award ID: No. YN2018QL06
                Award Recipient :
                Funded by: National Natural Scientific Foundation
                Award ID: 81703848
                Award ID: 81703877
                Award Recipient :
                Funded by: Natural Scientific Foundation of Guangzhou Province
                Award ID: 2017A030310123
                Award Recipient :
                Funded by: The specific Research Fund for TCM Science and Technology of Guangzhou Provincial Hospital of Chinese Medicine
                Award ID: YN10101915
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Endocrinology & Diabetes
                glycated hemoglobin a,acute coronary syndrome,mortality,predictor
                Endocrinology & Diabetes
                glycated hemoglobin a, acute coronary syndrome, mortality, predictor

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