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Li T, Luo CJ, Yi ZQ, Li L. Dapagliflozin Attenuates Myocardial Inflammation and Apoptosis after Coronary Microembolization in Rats by Regulating the SIRT1/NF-κB Signaling Pathway. FRONT BIOSCI-LANDMRK 2025; 30:27082. [PMID: 40152380 DOI: 10.31083/fbl27082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/30/2024] [Accepted: 12/09/2024] [Indexed: 03/29/2025]
Abstract
BACKGROUND Coronary microembolization (CME) often occurs as a serious complication during or after percutaneous coronary intervention (PCI), leading to an impairment in heart function, inflammation, and cell death. Dapagliflozin (DAPA) has been shown to have cardioprotective effects. However, its role and exact mechanism in CME remains unclear. METHODS A preclinical CME model was developed via the administration of microspheres into the left ventricle. In an in vitro model, the CME-created microenvironment was observed by using lipopolysaccharide (LPS) with hypoxic induction on H9C2 cardiomyocytes. Before developing both experimental models, DAPA or the sirtuin 1 (SIRT1) inhibitor "EX-527" was administered. Echocardiography, histological examination, and molecular and immunological assays were carried out to assess the levels of cardiac tissue or cardiomyocyte damage, inflammation, and apoptosis. RESULTS Heart dysfunction and tissue damage caused by CME can be alleviated by pre-treatment with DAPA, which also reduces myocardial inflammation and apoptosis. Moreover, both experimental studies have depicted that DAPA can upregulate the SIRT1 level and downregulate the acetylation and phosphorylation levels of nuclear factor kappa-B (NF-κB) p65. This effect inhibits the induction of NF-κB signaling and mitigates cardiomyocyte damage. However, DAPA's cardioprotective effect was reversed when co-treated with EX-527. CONCLUSIONS DAPA reduces myocardial damage caused by CME by suppressing myocarditis and apoptosis via the SIRT1/NF-κB axis.
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Affiliation(s)
- Tao Li
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China
| | - Chang-Jun Luo
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China
- Department of Cardiology, Affiliated Liutie Central Hospital of Guangxi Medical University, 545007 Liuzhou, Guangxi, China
| | - Ze-Qiang Yi
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China
| | - Lang Li
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China
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Erdogan BR, Arioglu-Inan E. SGLT2 inhibitors: how do they affect the cardiac cells. Mol Cell Biochem 2025; 480:1359-1379. [PMID: 39160356 DOI: 10.1007/s11010-024-05084-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 08/01/2024] [Indexed: 08/21/2024]
Abstract
The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.
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Affiliation(s)
| | - Ebru Arioglu-Inan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, Emniyet District, Dogol Street, No:4, 06560, Yenimahalle, Ankara, Turkey.
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Harris DD, Stone C, Broadwin M, Kanuparthy M, Sabe SA, Nho JW, Hamze J, Abid MR, Sellke FW. Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia. J Pharmacol Exp Ther 2025; 392:100532. [PMID: 40023609 DOI: 10.1016/j.jpet.2024.100532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 03/04/2025] Open
Abstract
Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.
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Affiliation(s)
- Dwight Douglas Harris
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Christopher Stone
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Sharif A Sabe
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Ju-Woo Nho
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Jad Hamze
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - M Ruhul Abid
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Frank W Sellke
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
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Coelho Meine M, Santo P, Dolovitsch de Oliveira F, Lenci Marques G, Spadoni Barboza J. Sodium-glucose cotransporter-2 inhibitors in acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials. Heart Fail Rev 2025; 30:219-226. [PMID: 39467963 DOI: 10.1007/s10741-024-10457-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/17/2024] [Indexed: 10/30/2024]
Abstract
We aimed to assess the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo, initiated within the hospitalization period, in addition to habitual treatment, for treating adult patients with confirmed acute myocardial infarction (AMI). We also conducted subgroup analysis by diabetes mellitus (DM) status and type of AMI. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcome was hospitalization for heart failure (HF). The secondary outcomes were all-cause death, cardiovascular death, and serious adverse events (AEs). We pooled risk ratios (RR) with a 95% confidence interval (CI) for binary outcomes. The between-study variance was assessed using tau2 statistics. We included five RCTs, encompassing 11,211 patients. SGLT2i significantly reduced the risk of hospitalization for HF compared to placebo (RR 0.73; 95% CI [0.61, 0.88]). However, the risk of all-cause death (RR 1.05; 95% CI [0.78, 1.41]) and cardiovascular death (RR 1.04; 95% CI [0.84, 1.29]) was similar between the groups, as well as the risk of serious AEs (RR 1.01; 95% CI [0.90, 1.14]). In the subgroup analysis by DM status and type of AMI, there were no significant subgroup differences for the outcomes of hospitalization for HF and all-cause death. In patients with AMI, treatment with SGLT2i is safe and significantly reduces the risk of hospitalization for HF, but it has no impact on all-cause death and cardiovascular death compared to placebo.
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Affiliation(s)
| | - Paula Santo
- Diagnostic Imaging and Specialized Diagnosis Unit, University Hospital of Federal University of São Carlos, 111, Luís Vaz de Camões Street - Vila Celina, São Carlos, SP, 13566-448, Brazil.
| | | | - Gustavo Lenci Marques
- Postgraduate Program in Internal Medicine and Health Sciences, Federal University of Paraná, Curitiba, Brazil
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Stone C, Harris DD, Broadwin M, Sabe SA, Bellam K, Kanuparthy M, Abid MR, Sellke FW. Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium. J Surg Res 2024; 303:600-612. [PMID: 39437599 DOI: 10.1016/j.jss.2024.09.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 07/30/2024] [Accepted: 09/01/2024] [Indexed: 10/25/2024]
Abstract
INTRODUCTION Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration. METHODS Thirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis. RESULTS SGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes. CONCLUSIONS SGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.
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Affiliation(s)
- Christopher Stone
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Dwight D Harris
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Sharif A Sabe
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Krishna Bellam
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - M Ruhul Abid
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Frank W Sellke
- Division of Cardiothoracic Surgery, Department of Surgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
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Soares RR, Viggiani LF, Reis Filho JM, Joviano-Santos JV. Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies. Chem Biol Interact 2024; 403:111229. [PMID: 39244185 DOI: 10.1016/j.cbi.2024.111229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/12/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.
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Affiliation(s)
- Rayla Rodrigues Soares
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil
| | - Larissa Freitas Viggiani
- Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil
| | - Juliano Moreira Reis Filho
- Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Julliane V Joviano-Santos
- Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Investigações NeuroCardíacas, Ciências Médicas de Minas Gerais (LINC CMMG), Belo Horizonte, Minas Gerais, Brazil.
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Karakasis P, Fragakis N, Kouskouras K, Karamitsos T, Patoulias D, Rizzo M. Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Acute Coronary Syndrome: A Modern Cinderella? Clin Ther 2024; 46:841-850. [PMID: 38991865 DOI: 10.1016/j.clinthera.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 06/11/2024] [Accepted: 06/11/2024] [Indexed: 07/13/2024]
Abstract
PURPOSE Atherosclerotic cardiovascular disease remains a prominent global cause of mortality, with coronary artery disease representing its most prevalent manifestation. Recently, a novel class of antidiabetic medication, namely sodium-glucose cotransporter-2 (SGLT2) inhibitors, has been reported to have remarkable cardiorenal advantages for individuals with type 2 diabetes mellitus (DM), and they may reduce cardiorenal risk even in individuals without pre-existing DM. Currently, there is no evidence regarding the safety and efficacy of these drugs in acute coronary syndrome (ACS), regardless of diabetes status. This review aims to comprehensively present the available preclinical and clinical evidence regarding the potential role of SGLT2 inhibitors in the context of ACS, as adjuncts to standard-of-care treatment for this patient population, while also discussing potential short- and long-term cardiovascular benefits. METHODS A literature search was performed through MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, and Scopus until February 26, 2024. Eligible were preclinical and clinical studies, comprising randomized controlled trials (RCTs), real-world studies, and meta-analyses. FINDINGS Evidence from preclinical models indicates that the use of SGLT2 inhibitors is associated with a blunted ischemia-reperfusion injury and decreased myocardial infarct size, particularly after prior treatment. Although RCTs and real-world data hint at a potential benefit in acute ischemic settings, showing improvements in left ventricular systolic and diastolic function, decongestion, and various cardiometabolic parameters such as glycemia,body weight, and blood pressure, the recently published DAPA-MI (Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure) trial did not establish a clear advantage regarding surrogate cardiovascular end points of interest. SGLT2 inhibitors appear to provide a benefit in reducing contrast-induced acute kidney injury events in patients with ACS undergoing percutaneous coronary intervention. However, data on other safety concerns, such as treatment discontinuation because of hypotension, hypovolemia, or ketoacidosis, are currently limited. IMPLICATIONS Despite the well-established cardiovascular benefits observed in the general population with type 2 DM and, more recently, in other patient groups irrespective of diabetes status, existing evidence does not support the use of SGLT2 inhibitors in the context of ACS. Definitive answers to this intriguing research question, which could potentially expand the therapeutic indications of this novel drug class, require large-scale, well-designed RCTs.
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Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.
| | - Nikolaos Fragakis
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Kouskouras
- Department of Radiology, Aristotle University of Thessaloniki, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Theodoros Karamitsos
- First Department of Cardiology, Aristotle University Medical School, AHEPA University General Hospital, Thessaloniki, Greece
| | - Dimitrios Patoulias
- Second Department of Cardiology, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Manfredi Rizzo
- School of Medicine, Department of Health Promotion, Mother and Child Care (Promise), Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
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Liao L, Wang T, Zhang L, Wei Y, Fan X. Protective Mechanisms of SGLTi in Ischemic Heart Disease. J Cardiovasc Transl Res 2024; 17:1018-1035. [PMID: 38767796 DOI: 10.1007/s12265-024-10513-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 04/11/2024] [Indexed: 05/22/2024]
Abstract
Ischemic heart disease (IHD) is a common clinical cardiovascular disease with high morbidity and mortality. Sodium glucose cotransporter protein inhibitor (SGLTi) is a novel hypoglycemic drug. To date, both clinical trials and animal experiments have shown that SGLTi play a protective role in IHD, including myocardial infarction (MI) and ischemia/reperfusion (I/R). The protective effects may be involved in mechanisms of energy metabolic conversion, anti-inflammation, anti-fibrosis, ionic homeostasis improvement, immune cell development, angiogenesis and functional regulation, gut microbiota regulation, and epicardial lipids. Thus, this review summarizes the above mechanisms and aims to provide theoretical evidence for therapeutic strategies for IHD.
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Affiliation(s)
- Lei Liao
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Tong Wang
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lu Zhang
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Yan Wei
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
| | - Xinrong Fan
- Department of Cardiology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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Hayashida T, Kuroko Y, Shimizu S, Akiyama T, Suezawa T, Kioka Y, Kotani Y, Shishido T, Kasahara S. Effects of dapagliflozin on myoglobin efflux from cardiomyocyte during myocardial ischemia/reperfusion in anesthetized rats. Sci Rep 2024; 14:16337. [PMID: 39014025 PMCID: PMC11253006 DOI: 10.1038/s41598-024-67195-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024] Open
Abstract
It has been suggested that sodium-glucose cotransporter 2 (SGLT2) inhibitors have cardioprotective effects during myocardial ischemia/reperfusion (I/R) independent of glucose-lowering action. However, the effects of SGLT2 inhibitors on structural damage to cardiomyocytes in the ischemic region during I/R remain unknown. We applied a microdialysis technique to the heart of anesthetized rats and investigated the effects of an SGLT2 inhibitor, dapagliflozin, on myocardial interstitial myoglobin levels in the ischemic region during coronary occlusion followed by reperfusion. Dapagliflozin was administered systemically (40 μg/body iv) or locally via a dialysis probe (100 μM and 1 mM) 30 min before coronary occlusion. In the vehicle group, coronary occlusion increased the dialysate myoglobin concentration in the ischemic region. Reperfusion further increased the dialysate myoglobin concentration. Intravenous administration of dapagliflozin reduced dialysate myoglobin concentration during ischemia and at 0-15 min after reperfusion, but local administration (100 μM and 1 mM) did not. Therefore, acute systemic administration of dapagliflozin prior to ischemia has cardioprotective effects on structural damage during I/R.
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Affiliation(s)
- Tomohiro Hayashida
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
- Department of Cardiovascular Surgery, Fukuyama City Hospital, Fukuyama, Hiroshima, 721-8511, Japan
| | - Yosuke Kuroko
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, Okayama, 700-8558, Japan
| | - Shuji Shimizu
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan.
| | - Tsuyoshi Akiyama
- Department of Cardiac Physiology, National Cerebral and Cardiovascular Center, Suita, Osaka, 564-8565, Japan
| | - Takanori Suezawa
- Department of Cardiovascular Surgery, Fukuyama City Hospital, Fukuyama, Hiroshima, 721-8511, Japan
| | - Yukio Kioka
- Department of Cardiovascular Surgery, Fukuyama City Hospital, Fukuyama, Hiroshima, 721-8511, Japan
| | - Yasuhiro Kotani
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, Okayama, 700-8558, Japan
| | - Toshiaki Shishido
- Department of Research Promotion and Management, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
| | - Shingo Kasahara
- Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, Okayama, 700-8558, Japan
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Akamine MAV, Ferreira Soares BMA, Telles JPM, Cicupira Rodrigues de Assis A, Rodriguez GNV, Soares PR, Chalela WA, Scudeler TL. Role of Dapagliflozin in Ischemic Preconditioning in Patients with Symptomatic Coronary Artery Disease-DAPA-IP Study Protocol. Pharmaceuticals (Basel) 2024; 17:920. [PMID: 39065769 PMCID: PMC11280174 DOI: 10.3390/ph17070920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 07/28/2024] Open
Abstract
Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5'-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.
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Affiliation(s)
| | | | | | | | | | | | | | - Thiago Luis Scudeler
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 44, Cerqueira César, São Paulo 05403-000, Brazil; (M.A.V.A.); (B.M.A.F.S.); (J.P.M.T.); (A.C.R.d.A.); (G.N.V.R.); (P.R.S.); (W.A.C.)
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11
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Madonna R, Biondi F, Alberti M, Ghelardoni S, Mattii L, D'Alleva A. Cardiovascular outcomes and molecular targets for the cardiac effects of Sodium-Glucose Cotransporter 2 Inhibitors: A systematic review. Biomed Pharmacother 2024; 175:116650. [PMID: 38678962 DOI: 10.1016/j.biopha.2024.116650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/21/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new class of glucose-lowering drugs traditionally used to control blood glucose levels in patients with type 2 diabetes mellitus, have been proven to reduce major adverse cardiovascular events, including cardiovascular death, in patients with heart failure irrespective of ejection fraction and independently of the hypoglycemic effect. Because of their favorable effects on the kidney and cardiovascular outcomes, their use has been expanded in all patients with any combination of diabetes mellitus type 2, chronic kidney disease and heart failure. Although mechanisms explaining the effects of these drugs on the cardiovascular system are not well understood, their effectiveness in all these conditions suggests that they act at the intersection of the metabolic, renal and cardiac axes, thus disrupting maladaptive vicious cycles while contrasting direct organ damage. In this systematic review we provide a state of the art of the randomized controlled trials investigating the effect of SGLT2i on cardiovascular outcomes in patients with chronic kidney disease and/or heart failure irrespective of ejection fraction and diabetes. We also discuss the molecular targets and signaling pathways potentially explaining the cardiac effects of these pharmacological agents, from a clinical and experimental perspective.
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Affiliation(s)
- Rosalinda Madonna
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy.
| | - Filippo Biondi
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Mattia Alberti
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, Pisa 56124, Italy
| | - Sandra Ghelardoni
- Department of Pathology, Laboratory of Biochemistry, University of Pisa, Italy
| | - Letizia Mattii
- Department of Clinical and Experimental Medicine, Histology Division, University of Pisa, Pisa, Italy
| | - Alberto D'Alleva
- Cardiac Intensive Care and Interventional Cardiology Unit, Santo Spirito Hospital, Pescara, Italy
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12
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Mondal S, Pramanik S, Khare VR, Fernandez CJ, Pappachan JM. Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives. World J Cardiol 2024; 16:240-259. [PMID: 38817648 PMCID: PMC11135334 DOI: 10.4330/wjc.v16.i5.240] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/23/2024] Open
Abstract
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Subhodip Pramanik
- Department of Endocrinology, Neotia Getwel Multispecialty Hospitals, Siliguri 734010, West Bengal, India
| | - Vibhu Ranjan Khare
- Department of Endocrinology, NRS Medical College, Kolkata 700020, West Bengal, India
| | - Cornelius James Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom.
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13
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Egashira T, Ichinomiya T, Yokoyama A, Matsumoto S, Higashijima U, Sekino M, Murata H, Yoshitomi O, Sato S, Hara T. Cardioprotective Effects of Sodium-Glucose Cotransporter Subtype Inhibition on Ischemic and Pharmacological Preconditioning. Cureus 2024; 16:e59757. [PMID: 38841006 PMCID: PMC11152766 DOI: 10.7759/cureus.59757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Sodium-glucose cotransporter (SGLT) 2 inhibitors partially inhibit SGLT1 expression; however, whether a clinical dose of SGLT2 inhibitor abrogates ischemic preconditioning (IPC) is unknown, and the pharmacological cardioprotective effect under SGLT1 inhibition has not been examined. In this study, we investigated whether a clinical dose of tofogliflozin abrogates IPC and whether pharmacological preconditioning with olprinone has cardioprotective effects under SGLT1 inhibition. METHODS Male Wistar rats were divided into seven groups (seven rats per group) and subjected to the following treatments before inducing ischemia/reperfusion (I/R; 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion): saline infusion control treatment (Con); ischemic preconditioning (IPC); IPC after phlorizin infusion (IPC+Phl); IPC after low-dose tofogliflozin infusion (IPC+L-Tof); IPC after high-dose tofogliflozin infusion (IPC+H-Tof); olprinone infusion (Olp); and Olp infusion after phlorizin infusion (Olp+Phl). RESULTS The infarct size was significantly decreased in the IPC group, but not in the IPC+Phl group. In contrast, the infarct size decreased in the IPC+L-Tof and IPC+H-Tof groups. Additionally, Olp reduced the infarct size, and the effect was preserved in Olp+Phl groups. Phosphorylated AMP-activated protein kinase (AMPK) expression was lower in the IPC+Phl group compared to that in the IPC group. CONCLUSION The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition.
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Affiliation(s)
- Takashi Egashira
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Taiga Ichinomiya
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Akihiro Yokoyama
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Sojiro Matsumoto
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Ushio Higashijima
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Motohiro Sekino
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Hiroaki Murata
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Osamu Yoshitomi
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
| | - Shuntaro Sato
- Clinical Research Center, Nagasaki University Hospital, Nagasaki, JPN
| | - Tetsuya Hara
- Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, JPN
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14
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Huang X, Dannya E, Liu X, Yu Y, Tian P, Li Z. Effect of sodium-glucose cotransporter-2 inhibitors on myocardial infarction incidence: A systematic review and meta-analysis of randomized controlled trials and cohort studies. Diabetes Obes Metab 2024; 26:1040-1049. [PMID: 38086546 DOI: 10.1111/dom.15405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/22/2023] [Accepted: 11/25/2023] [Indexed: 02/06/2024]
Abstract
AIM To assess whether sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce myocardial infarction (MI) incidence in patients with or without type 2 diabetes. METHODS PubMed, Embase, Web of Science, the Cochrane library, and https://ClinicalTrials.gov were searched up to 7 May 2022. Randomized controlled trials (RCTs) and cohort studies reporting the effects of SGLT2 inhibitor treatment on MI incidence were included. Relative risks (RRs) with a 95% confidence interval (CI) for MI incidence were extracted and pooled. Subgroup analysis and meta-regression were performed to explore the heterogeneity. RESULTS This meta-analysis included 54 RCTs and 32 cohort studies, with data from six SGLT2 inhibitors and 3 394 423 individuals. In the overall analysis, SGLT2 inhibitors significantly reduced MI incidence in RCTs (RR 0.9, 95% CI 0.84-0.96) and cohort studies (RR 0.89, 95% CI 0.83-0.94). In RCTs, the results of the subgroup analysis revealed no significant alterations in outcomes based on different SGLT2 inhibitor types, control drug types, cardiovascular disease (CVD) status and sources of outcome extraction (p for interaction >0.05). In cohort studies, the presence or absence of CVD led to similar effects of SGLT2 inhibitors on decreasing MI incidence (p for interaction = 0.179). However, variations in results were observed based on the type of control group in cohort studies (p for interaction = 0.036). Meta-regression results did not reveal an association between baseline cardiovascular risk factors, follow-up length, or MI incidence. CONCLUSIONS In both RCTs and cohort studies, SGLT2 inhibitors reduced MI incidence. The cardioprotective effects of SGLT2 inhibitors were observed in patients with and without a history of CVD.
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Affiliation(s)
- Xiaoru Huang
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
| | - Estau Dannya
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
| | - Xuening Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
| | - Yang Yu
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
| | - Panhui Tian
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
| | - Zijian Li
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing, China
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
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15
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García-Peña LM, Abel ED, Pereira RO. Mitochondrial Dynamics, Diabetes, and Cardiovascular Disease. Diabetes 2024; 73:151-161. [PMID: 38241507 PMCID: PMC10796300 DOI: 10.2337/dbi23-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/06/2023] [Indexed: 01/21/2024]
Abstract
Mitochondria undergo repeated cycles of fusion and fission that regulate their size and shape by a process known as mitochondrial dynamics. Numerous studies have revealed the importance of this process in maintaining mitochondrial health and cellular homeostasis, particularly in highly metabolically active tissues such as skeletal muscle and the heart. Here, we review the literature on the relationship between mitochondrial dynamics and the pathophysiology of type 2 diabetes and cardiovascular disease (CVD). Importantly, we emphasize divergent outcomes resulting from downregulating distinct mitochondrial dynamics proteins in various tissues. This review underscores compensatory mechanisms and adaptive pathways that offset potentially detrimental effects, resulting instead in improved metabolic health. Finally, we offer a perspective on potential therapeutic implications of modulating mitochondrial dynamics proteins for treatment of diabetes and CVD. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Luis Miguel García-Peña
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
| | - E. Dale Abel
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Renata O. Pereira
- Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
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16
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Wang Z, Liu Q, Wang X, Wang P, Wang Z, Zhang F. Empagliflozin improves cardiac function in rats with chronic heart failure. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1037-1044. [PMID: 37566305 DOI: 10.1007/s00210-023-02655-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 07/30/2023] [Indexed: 08/12/2023]
Abstract
The objective of this study is to examine the effect of empagliflozin on cardiac function in rats with chronic heart failure and the possible mechanism. Forty 6-week-old male SD rats were randomly divided into the control group, empagliflozin treatment group, and sham-operated group. SD rats in the control group and empagliflozin treatment group were subjected to ligation of the anterior descending coronary artery to induce an acute myocardial infarction model. SD rats in the sham-operated group were only subjected to threading of the anterior descending branch of the coronary artery without ligation. On the second day after surgery, the control group and sham operation group were given physiological saline by gavage, while the empagliflozin treatment group was given empagliflozin (30 mg/kg/day) by gavage. Sixteen weeks later, cardiac function, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), serum brain natriuretic peptide, hypersensitive C-reactive protein (hs-CRP), iNOS expression levels, and myocardial morphological changes were observed. Compared with that in the control group, heart function in the empagliflozin-treated group was significantly improved, MMP was increased, intracellular ROS levels were decreased, and NT-proBNP and hs-CRP were significantly reduced, and HE staining showed that the cell oedema was less than that in the control group, tissue arrangement was more orderly, and iNOS expression was inhibited. Empagliflozin can improve cardiac function in rats with chronic heart failure, and the mechanism may involve inhibiting inflammation, reducing myocardial oxidative stress, and improving myocardial fibrosis.
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Affiliation(s)
- Zhenzhen Wang
- Department of Cardiology, Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), No. 317, Dong Cheng Nan Yi Road, Dongying, 257091, Shandong Province, China.
| | - Qian Liu
- Department of Cardiology, Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), No. 317, Dong Cheng Nan Yi Road, Dongying, 257091, Shandong Province, China
| | - Xiaofang Wang
- Department of Cardiology, Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), No. 317, Dong Cheng Nan Yi Road, Dongying, 257091, Shandong Province, China
| | - Pengpeng Wang
- Department of Obstetrics, Dezhou Municipal Hospital, Dezhou, Shandong Province, China
| | - Zhuwen Wang
- Department of Cardiology, Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), No. 317, Dong Cheng Nan Yi Road, Dongying, 257091, Shandong Province, China
| | - Fenglei Zhang
- Department of Cardiology, Dongying People's Hospital (Dongying Hospital of Shandong Provincial Hospital Group), No. 317, Dong Cheng Nan Yi Road, Dongying, 257091, Shandong Province, China
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17
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Abdel-Wahab BA, El-Shoura EAM, Habeeb MS, Zaafar D. Dapagliflozin alleviates arsenic trioxide-induced hepatic injury in rats via modulating PI3K/AkT/mTOR, STAT3/SOCS3/p53/MDM2 signaling pathways and miRNA-21, miRNA-122 expression. Int Immunopharmacol 2024; 127:111325. [PMID: 38070468 DOI: 10.1016/j.intimp.2023.111325] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 01/18/2024]
Abstract
Dapagliflozin (DPG) is a sodium-glucose co-transporter 2 inhibitor that is commonly used in the treatment of type 2 diabetes. However, studies have shown that DPG has a protective effect under a variety of experimental conditions through its antioxidative and anti-inflammatory properties. DPG's effect on experimental hepatotoxicity caused by arsenic trioxide (ATO) has yet to be investigated. The purpose of this study was to investigate the protective effect of DPG in preventing hepatic damage caused by ATO and discover the underlying mechanisms. The effect of DPG (1 mg/kg, orally) on ATO (5 mg/kg, i.p.)-induced hepatic injury was evaluated in rats. Serum liver function parameters, as well as oxidative stress biomarkers and inflammatory cytokine levels were assessed. Histopathological changes in the liver were detected using H&E staining. Using Western blotting and PCR techniques, the molecular mechanisms of DPG in ameliorating hepatic injury were investigated. DPG improved liver function by inhibiting histopathological changes, decreasing levels of hepatic function and toxicity parameters measured in both serum and tissues, and exhibiting antioxidant and anti-inflammatory effects, according to the findings. Consistent with the PCR results, DPG also decreased the expression of LC3-II, micro-RNA-122, and micro-RNA-21 while increased the expression of SOCS3. Furthermore, according to western blotting results, DPG was able to reduce the protein expression of AKT, mTOR, PI3K, and STAT3. Although further clinical research is necessary, this study highlights the potential of DPG in preventing liver damage in a rat model of hepatotoxicity induced by ATO.
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Affiliation(s)
- Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran P.O. Box 1988, Saudi Arabia.
| | - Ehab A M El-Shoura
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | - Mohammed S Habeeb
- Department of Pharmacology, College of Pharmacy, Najran University, Najran P.O. Box 1988, Saudi Arabia.
| | - Dalia Zaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology, and Information, Cairo, Egypt.
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18
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Elsayed M, Moustafa YM, Mehanna ET, Elrayess RA, El-Sayed NM, Hazem RM. Empagliflozin protects against isoprenaline-induced fibrosis in rat heart through modulation of TGF-β/SMAD pathway. Life Sci 2024; 337:122354. [PMID: 38110076 DOI: 10.1016/j.lfs.2023.122354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/09/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
AIM Cardiac fibrosis is characterized by excessive accumulation of fibrous tissue, particularly collagens, in the myocardium. Accumulated fibrous tissue renders myocardium stiffer and reduces its contractility. Empagliflozin is an oral hypoglycemic agent with extra-diabetic functional profile toward maintaining cardiac functions. The present study aimed to examine protective effect of empagliflozin against an in-vivo model of cardiac fibrosis induced by isoprenaline and targeting TGF-β/SMAD signaling as a possible pathway responsible for such effect. MAIN METHODS Sixty animals were divided into six groups; the first was normal, and the second was treated with isoprenaline only (5 mg/kg/day I.P.) as a control. The third received pirfenidone (500 mg/kg/day P.O.), and the remaining groups received graded doses (5, 10, 20 mg/kg respectively) of empagliflozin for 14 days before fibrosis induction by isoprenaline (5 mg/kg/day) for 30 days. KEY FINDINGS Isoprenaline increased cardiac enzymes, and cardiac tissues revealed elevated concentrations of transforming growth factor β (TGF-β1), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor α (TNF-α), and c-jun N-terminal kinase (JNK) proteins. Expression of nuclear factor kappa B (NF-κB), alpha smooth muscle actin (α-SMA), collagens, suppressor of mothers against decapentaplegic (SMADs), connective tissue growth factor (CTGF), and fibronectin was upregulated. Empagliflozin improved the histological picture of heart tissue in comparison to fibrosis developed in controls, and protected against fibrosis through significant modulation of all mentioned parameters' concentrations and expressions. SIGNIFICANCE Empagliflozin demonstrated a promising protective approach against biological model of cardiac fibrosis through an anti-fibrotic effect through targeting TGF-β signaling pathways.
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Affiliation(s)
- Mohammed Elsayed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University in Cairo, Cairo 11829, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Biochemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt.
| | - Ranwa A Elrayess
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Norhan M El-Sayed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Reem M Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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19
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Zuo W, Wang L, Tian R, Wang L, Liu Y, Qian H, Yang X, Liu Z. Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway. Curr Vasc Pharmacol 2024; 22:203-217. [PMID: 38141195 DOI: 10.2174/0115701611269801231211104905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 12/25/2023]
Abstract
INTRODUCTION Myocardial ischaemia reperfusion injury (MIRI) determines infarct size and long-term outcomes after acute myocardial infarction (AMI). Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, alleviates MIRI in animal models. METHOD We investigated the potential mechanisms underlying the cardioprotective effect of dapagliflozin against MIRI, focusing on mitochondrial injury and mitophagy. MIRI mouse and H9C2 cell models were established. RESULTS 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed a significant alleviation of MIRI after pre-treatment of dapagliflozin compared to the model group (14.91 ± 1.76 vs. 40.47 ± 3.69%). Data from the pre-treatment dapagliflozin group showed a significant decrease in left ventricular ejection fraction (LVEF) (44.8 ± 2.7 vs. 28.5 ± 5.3%, P<0.01), left ventricular end-diastolic volume (LVEDV) (70.6 ± 9.5 vs. 93.5 ± 13.8 ul, P<0.05), and left ventricular end-systolic volume (LVESV) (39.0 ± 8.3 vs. 67.9 ± 13.7 ul, P<0.05) compared to the model group. Dapagliflozin also reduced the levels of reactive oxygen species (ROS) and fragmented mitochondrial DNA, reversed the decrease in mitochondrial membrane potential, and suppressed apoptosis. Further study showed that dapagliflozin could protect against mitochondrial injury by rapidly clearing damaged mitochondria via mitophagy in a phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/parkindependent manner. Dapagliflozin regulated mitophagy in cardiomyocytes by suppressing the adenosine 5'monophosphate-activated protein kinase (AMPK)-PINK1/parkin signalling pathway, resulting in attenuated MIRI. CONCLUSION Dapagliflozin alleviated MIRI by activating mitophagy via the AMPK-PINK1/parkin signalling pathway.
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MESH Headings
- Animals
- Glucosides/pharmacology
- Mitophagy/drug effects
- Myocardial Reperfusion Injury/pathology
- Myocardial Reperfusion Injury/drug therapy
- Myocardial Reperfusion Injury/physiopathology
- Myocardial Reperfusion Injury/prevention & control
- Myocardial Reperfusion Injury/metabolism
- Signal Transduction/drug effects
- Protein Kinases/metabolism
- Benzhydryl Compounds/pharmacology
- Ubiquitin-Protein Ligases/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/metabolism
- AMP-Activated Protein Kinases/metabolism
- Disease Models, Animal
- Male
- Ventricular Function, Left/drug effects
- Cell Line
- Mice, Inbred C57BL
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/pathology
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/enzymology
- Myocardial Infarction/drug therapy
- Myocardial Infarction/pathology
- Myocardial Infarction/physiopathology
- Myocardial Infarction/metabolism
- Sodium-Glucose Transporter 2 Inhibitors/pharmacology
- Mice
- Rats
- Reactive Oxygen Species/metabolism
- Apoptosis/drug effects
- Stroke Volume/drug effects
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Affiliation(s)
- Wei Zuo
- Department of Pharmacy, Peking Union Medical College Hospital, Beijing, China
| | - Liang Wang
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Ran Tian
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Lun Wang
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Yifan Liu
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Hao Qian
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Xinglin Yang
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
| | - Zhenyu Liu
- Department of Cardiology, Peking Union Medical College Hospital, Beijing, China
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20
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Zhang L, Lin H, Yang X, Shi J, Sheng X, Wang L, Li T, Quan H, Zhai X, Li W. Effects of dapagliflozin monotherapy and combined aerobic exercise on skeletal muscle mitochondrial quality control and insulin resistance in type 2 diabetes mellitus rats. Biomed Pharmacother 2023; 169:115852. [PMID: 37944441 DOI: 10.1016/j.biopha.2023.115852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/31/2023] [Accepted: 11/05/2023] [Indexed: 11/12/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a prevalent, chronic metabolic disease. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and aerobic exercise (AE) have shown promise in mitigating insulin resistance (IR) and T2DM. This study investigated the effects of dapagliflozin (Dapa) monotherapy and combined AE on mitochondrial quality control (MQC) in skeletal muscle and IR in T2DM rats. T2DM rats, induced by a high-fat diet/streptozotocin model, were randomly assigned to the following groups: T2DM+vehicle group (DMV), T2DM rats treated with Dapa (DMDa, 10 mg/kg/d), T2DM rats subjected to combined Dapa treatment and AE (DMDa+AE), and the standard control group (CON). Blood and skeletal muscle samples were collected after 6 weeks of intragastric administration and treadmill exercise. The results showed that DMDa monotherapy could reduce the accumulation of white adipose tissue and skeletal muscle lipid droplets and improve HOMA-IR. While the combined AE led to further reductions in subcutaneous white adipose tissue and fasting glucose levels, it did not confer additional benefits in terms of HOMA-IR. Furthermore, Dapa monotherapy enhanced skeletal muscle mitochondrial biogenesis (PGC-1α, NRF1, TFAM, and COX IV), mitochondrial dynamics (OPA1, DRP1, and MFN2), and mitophagy (PGAM5 and PINK1) related protein levels. Nevertheless, the combination of Dapa with AE treatment did not yield an additive effect. In conclusion, this study highlights the potential of SGLT2 inhibitors, specifically Dapa, in ameliorating IR and maintaining MQC in skeletal muscle in rats with T2DM. However, combined AE did not produce an additive effect, indicating the need for further research.
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Affiliation(s)
- Liangzhi Zhang
- Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
| | - Hengjun Lin
- Department of Colorectal anal Surgery, Jinhua People's Hospital, Jinhua, Zhejiang, China
| | - Xudong Yang
- Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
| | - Jipeng Shi
- Exercise Capacity Assessment and Promotion Research Center, School of Physical Education, Northeast Normal University, Changchun, Jilin, China
| | - Xiusheng Sheng
- Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua, Zhejiang, China
| | - Lifeng Wang
- Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
| | - Ting Li
- Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China
| | - Helong Quan
- Exercise Capacity Assessment and Promotion Research Center, School of Physical Education, Northeast Normal University, Changchun, Jilin, China.
| | - Xia Zhai
- Medical Molecular Biology Laboratory, School of Medicine, Jinhua Polytechnic, Jinhua, Zhejiang, China.
| | - Wei Li
- Exercise and Metabolism Research Center, College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China.
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21
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Abd Elmaaboud MA, Estfanous RS, Atef A, Kabel AM, Alnemari KA, Naguib TM, Alsufyani SE, Darwish HW, Arab HH. Dapagliflozin/Hesperidin Combination Mitigates Lipopolysaccharide-Induced Alzheimer's Disease in Rats. Pharmaceuticals (Basel) 2023; 16:1370. [PMID: 37895841 PMCID: PMC10609711 DOI: 10.3390/ph16101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/19/2023] [Accepted: 09/24/2023] [Indexed: 10/29/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of neurodegenerative disorders worldwide. Its pathologic features include massive neuroinflammation with abnormal deposition of β-amyloid peptide in the cerebral tissues leading to degeneration of the brain neurons. Adverse effects associated with the traditional drugs used for the treatment of this pathological condition have directed the research efforts towards searching for alternative effective agents with minimal adverse effects. The aim of this study was to elucidate the potential ameliorative effects of dapagliflozin and/or hesperidin on Alzheimer's disease (AD) induced by lipopolysaccharide (LPS) injection in rats. In a rodent model of AD, the effect of dapagliflozin with or without hesperidin on the biochemical parameters and the behavioral tests as well as the histopathological parameters was determined. Each of dapagliflozin and hesperidin restored the behavioral tests to the reference values, augmented the antioxidant defense mechanisms, ameliorated the neuronal inflammatory responses, combatted the changes in Toll-like receptor-4 (TLR-4)/High-mobility group box 1 (HMGB1) protein signaling and receptors of advanced glycation end products (RAGE) levels, and restored the balance between the apoptotic signals and autophagy in the hippocampal tissues. Additionally, both agents exhibited an outstanding ability to combat LPS-induced perturbations in the histopathological and electron microscopic image of the brain tissues. These favorable effects were significantly encountered in the group treated with dapagliflozin/hesperidin combination when compared versus animals treated with either dapagliflozin or hesperidin. In conclusion, inhibition of the hippocampal HMGB1/TLR4/RAGE signaling, the pro-inflammatory axis, and apoptosis alongside augmentation of the antioxidant defenses and autophagy can be regarded as beneficial effects by which dapagliflozin/hesperidin combination may combat LPS-triggered AD.
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Affiliation(s)
| | - Remon S. Estfanous
- Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | - Aliaa Atef
- Department of Pathology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | - Ahmed M. Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | | | - Tamer M. Naguib
- Anesthesia and ICU Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt;
| | - Shuruq E. Alsufyani
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia; (S.E.A.); or (H.H.A.)
| | - Hany W. Darwish
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Hany H. Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia; (S.E.A.); or (H.H.A.)
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
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22
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Forzano I, Wilson S, Lombardi A, Jankauskas SS, Kansakar U, Mone P, Varzideh F, Santulli G. SGLT2 inhibitors: an evidence-based update on cardiovascular implications. Expert Opin Investig Drugs 2023; 32:839-847. [PMID: 37740906 PMCID: PMC10591907 DOI: 10.1080/13543784.2023.2263354] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/22/2023] [Indexed: 09/25/2023]
Abstract
INTRODUCTION Sodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as 'gliflozins') represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors. AREA COVERED We critically examine the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many pending questions in the field of gliflozins and cardiovascular disease. EXPERT OPINION The favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.
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Affiliation(s)
| | - Scott Wilson
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Angela Lombardi
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | | | - Urna Kansakar
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Pasquale Mone
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Fahimeh Varzideh
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
| | - Gaetano Santulli
- University of Naples “Federico II”
- Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA
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23
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Huang K, Luo X, Liao B, Li G, Feng J. Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms. Cardiovasc Diabetol 2023; 22:86. [PMID: 37055837 PMCID: PMC10103501 DOI: 10.1186/s12933-023-01816-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/27/2023] [Indexed: 04/15/2023] Open
Abstract
Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy.
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Affiliation(s)
- Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Xianling Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Bin Liao
- Department of Cardiovascular Surgery, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Guang Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
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24
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Attimarad M, Munirul Islam M, Shafi S, David M, Rahman A, II Plaza Molina E. Eco-friendly mathematically manipulated UV spectroscopic procedures to resolve severely overlapped spectra of a binary mixture of Dapagliflozin with Sitagliptin and Vildagliptin. Microchem J 2023. [DOI: 10.1016/j.microc.2023.108700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
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25
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Liu X, Guo C, Zhang Q. Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies. Cell Stress Chaperones 2023; 28:133-144. [PMID: 36652120 PMCID: PMC10050249 DOI: 10.1007/s12192-023-01321-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/04/2023] [Accepted: 01/08/2023] [Indexed: 01/19/2023] Open
Abstract
Mitochondria are dynamic organelles that alter their morphology through fission (fragmentation) and fusion (elongation). These morphological changes correlate highly with mitochondrial functional adaptations to stressors, such as hypoxia, pressure overload, and inflammation, and are important in the setting of heart failure. Pathological mitochondrial remodeling, characterized by increased fission and reduced fusion, is associated with impaired mitochondrial respiration, increased mitochondrial oxidative stress, abnormal cytoplasmic calcium handling, and increased cardiomyocyte apoptosis. Considering the impact of the mitochondrial morphology on mitochondrial behavior and cardiomyocyte performance, altered mitochondrial dynamics could be expected to induce or exacerbate the pathogenesis and progression of heart failure. However, whether alterations in mitochondrial fission and fusion accelerate or retard the progression of heart failure has been the subject of intense debate. In this review, we first describe the physiological processes and regulatory mechanisms of mitochondrial fission and fusion. Then, we extensively discuss the pathological contributions of mitochondrial fission and fusion to heart failure. Lastly, we examine potential therapeutic approaches targeting mitochondrial fission/fusion to treat patients with heart failure.
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Affiliation(s)
- Xinxin Liu
- Department of First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Chenchen Guo
- Neck, Shoulder, Waist and Leg Pain Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiming Zhang
- Department of First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China.
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Empagliflozin-Pretreated Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Attenuated Heart Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:7747727. [PMID: 36852325 PMCID: PMC9966826 DOI: 10.1155/2023/7747727] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/20/2023]
Abstract
Objective Small extracellular vesicles derived from mesenchymal stem cells (MSCs) play important roles in cardiac protection. Studies have shown that the cardiovascular protection of sodium-glucose cotransporter 2 inhibitor (SGLT2i) is independent of its hypoglycemic effect. This study is aimed at investigating whether small extracellular vesicles derived from MSCs pretreated with empagliflozin (EMPA) has a stronger cardioprotective function after myocardial infarction (MI) and to explore the underlying mechanisms. Methods and Results We evaluated the effects of EMPA on MSCs and the effects of EMPA-pretreated MSCs-derived small extracellular vesicles (EMPA-sEV) on myocardial apoptosis, angiogenesis, and cardiac function after MI in vitro and in vivo. The small extracellular vesicles of control MSCs (MSC-sEV) and EMPA-pretreated MSCs were extracted, respectively. Small extracellular vesicles were cocultured with apoptotic H9c2 cells induced by H2O2 or injected into the infarcted area of the Sprague-Dawley (SD) rat myocardial infarction model. EMPA increased the cell viability, migration ability, and inhibited apoptosis and senescence of MSCs. In vitro, EMPA-sEV inhibited apoptosis of H9c2 cells compared with the control group (MSC-sEV). In the SD rat model of MI, EMPA-sEV inhibited myocardial apoptosis and promoted angiogenesis in the infarct marginal areas compared with the MSC-sEV. Meanwhile, EMPA-sEV reduced infarct size and improved cardiac function. Through small extracellular vesicles (miRNA) sequencing, we found several differentially expressed miRNAs, among which miR-214-3p was significantly elevated in EMPA-sEV. Coculture of miR-214-3p high expression MSC-derived small extracellular vesicles with H9c2 cells produced similar protective effects. In addition, miR-214-3p was found to promote AKT phosphorylation in H9c2 cells. Conclusions Our data suggest that EMPA-sEV significantly improve cardiac repair after MI by inhibiting myocardial apoptosis. miR-214-3p at least partially mediated the myocardial protection of EMPA-sEV through the AKT signaling pathway.
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27
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Maneechote C, Kerdphoo S, Jaiwongkam T, Chattipakorn SC, Chattipakorn N. Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia-Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis. Cardiovasc Drugs Ther 2023; 37:89-105. [PMID: 34515894 DOI: 10.1007/s10557-021-07250-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2021] [Indexed: 01/14/2023]
Abstract
PURPOSE There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated. METHODS Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min. RESULTS Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats. CONCLUSION Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.
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Affiliation(s)
- Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sasiwan Kerdphoo
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Thidarat Jaiwongkam
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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28
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Xiong S, Mo D, Wu Y, Wu P, Hu Y, Gong F. The effect of dapagliflozin on myocardial ischemia-reperfusion injury in diabetic rats. Can J Physiol Pharmacol 2023; 101:80-89. [PMID: 36621925 DOI: 10.1139/cjpp-2022-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The incidence of ischemic heart disease is 2-3 times higher in diabetic patients. However, the effect of dapagliflozin on ischemia-reperfusion myocardial injury in diabetic rats has not been studied. We examined the effects of dapagliflozin on myocardial IR injury in streptozotocin-nicotinamide-induced diabetic rats. Rats were divided into four groups (n = 7 in each group): control, control-dapagliflozin, diabetes, and diabetes-dapagliflozin. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water for 2 months. The hearts were perfused in a Langendorff's apparatus at 2 months and assessed before (baseline) and after myocardial IR for the following parameters: left ventricular developed pressure (LVDP), minimum and maximum rates of pressure change in the left ventricle (±dP/dt), endothelial nitric oxide (NO) synthase (eNOS) and inducible NO synthase (iNOS) mRNA expressions, creatine kinase MB (CK-MB) and troponin imyocardial enzyme extravasation, and lactate dehydrogenase. The recovery of LVDP and ±dP/dt in diabetic rats was lower than that in controls but near normal after dapagliflozin treatment. Diabetic rats had decreased eNOS expression and increased iNOS expression at baseline and after IR, whereas dapagliflozin normalized these parameters after IR. Compared with controls, cardiac NOx levels were initially lower in diabetic patients but higher after IR. Baseline MDA levels were higher in diabetic rats after IR, whereas cardiac NOx levels decreased after treatment with dapagliflozin. Dapagliflozin protects the diabetic rat heart from ischemia-reperfusion myocardial injury by regulating the expression of eNOS and iNOS and inhibiting cardiac lipid peroxidation.
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Affiliation(s)
- Shilong Xiong
- Department of Laboratory Diagnostics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, People's Republic of China
| | - Donghua Mo
- Department of Laboratory Diagnostics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, People's Republic of China
| | - Yingjun Wu
- Department of Laboratory Diagnostics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, People's Republic of China
| | - Peng Wu
- Department of Laboratory Diagnostics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, People's Republic of China
| | - YuanMing Hu
- Department of Laboratory Diagnostics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 511447, People's Republic of China
| | - Fang Gong
- ECG Lab, The Second Affiliated Hospital of Guangzhou Medical University, Panyu, Guangzhou, Guangdong 511447, People's Republic of China
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29
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Satyam SM, Bairy LK, Shetty P, Sainath P, Bharati S, Ahmed AZ, Singh VK, Ashwal AJ. Metformin and Dapagliflozin Attenuate Doxorubicin-Induced Acute Cardiotoxicity in Wistar Rats: An Electrocardiographic, Biochemical, and Histopathological Approach. Cardiovasc Toxicol 2023; 23:107-119. [PMID: 36790727 PMCID: PMC9950216 DOI: 10.1007/s12012-023-09784-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023]
Abstract
Doxorubicin is a widely used anticancer drug whose efficacy is limited due to its cardiotoxicity. There is no ideal cardioprotection available against doxorubicin-induced cardiotoxicity. This study aimed to investigate the anticipated cardioprotective potential of metformin and dapagliflozin against doxorubicin-induced acute cardiotoxicity in Wistar rats. At the beginning of the experiment, cardiac screening of experimental animals was done by recording an electrocardiogram (ECG) before allocating them into the groups. Thereafter, a total of thirty healthy adult Wistar rats (150-200 g) were randomly divided into five groups (n = 6) and treated for eight days as follows: group I (normal control), group II (doxorubicin control), group III (metformin 250 mg/kg/day), group IV (metformin 180 mg/kg/day), and group V (dapagliflozin 0.9 mg/kg/day). On the 7th day of the treatment phase, doxorubicin 20 mg/kg was administered intraperitoneal to groups II, III, IV, and V. On the 9th day (immediately after 48 h of doxorubicin administration), blood was collected from anesthetized animals for glucose, lipid profile, CK-MB & AST estimation, and ECG was recorded. Later, animals were sacrificed, and the heart was dissected for histopathological examination. We found that compared to normal control rats, CK-MB, AST, and glucose were significantly increased in doxorubicin control rats. There was a significant reversal of doxorubicin-induced hyperglycemia in the rats treated with metformin 250 mg/kg compared to doxorubicin control rats. Both metformin (180 mg/kg and 250 mg/kg) and dapagliflozin (0.9 mg/kg) significantly altered doxorubicin-induced ECG changes and reduced the levels of cardiac injury biomarkers CK-MB and AST compared to doxorubicin control rats. Metformin and dapagliflozin protected the cellular architecture of the myocardium from doxorubicin-induced myocardial injury. Current study revealed that both metformin and dapagliflozin at the FDA-recommended antidiabetic doses mitigated doxorubicin-induced acute cardiotoxicity in Wistar rats. The obtained data have opened the perspective to perform chronic studies and then to clinical studies to precisely consider metformin and dapagliflozin as potential chemoprotection in the combination of chemotherapy with doxorubicin to limit its cardiotoxicity, especially in patients with comorbid conditions like type II diabetes mellitus.
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Affiliation(s)
- Shakta Mani Satyam
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | - Laxminarayana Kurady Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | - Prakashchandra Shetty
- Department of Anatomy, Faculty of Medicine, Manipal University College Malaysia, Melaka, Malaysia
| | - P Sainath
- Department of Perfusion Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India.
| | - Sanjay Bharati
- Department of Nuclear Medicine, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Akheruz Zaman Ahmed
- Department of Anatomy, Melaka Manipal Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Varun Kumar Singh
- Department of Pathology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - A J Ashwal
- Sahyadri Narayana Multispecialty Hospital, Shimoga, Karnataka, India
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30
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Paolisso P, Bergamaschi L, Gragnano F, Gallinoro E, Cesaro A, Sardu C, Mileva N, Foà A, Armillotta M, Sansonetti A, Amicone S, Impellizzeri A, Esposito G, Morici N, Andrea OJ, Casella G, Mauro C, Vassilev D, Galie N, Santulli G, Marfella R, Calabrò P, Pizzi C, Barbato E. Outcomes in diabetic patients treated with SGLT2-Inhibitors with acute myocardial infarction undergoing PCI: The SGLT2-I AMI PROTECT Registry. Pharmacol Res 2023; 187:106597. [PMID: 36470546 PMCID: PMC9946774 DOI: 10.1016/j.phrs.2022.106597] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/27/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
AIMS To investigate in-hospital and long-term prognosis in T2DM patients presenting with acute myocardial infarction (AMI) treated with SGLT2-I versus other oral anti-diabetic agents (non-SGLT2-I users). METHODS In this multicenter international registry all consecutive diabetic AMI patients undergoing percutaneous coronary intervention between 2018 and 2021 were enrolled and, based on the admission anti-diabetic therapy, divided into SGLT-I users versus non-SGLT2-I users. The primary endpoint was defined as a composite of cardiovascular death, recurrent AMI, and hospitalization for HF (MACE). Secondary outcomes included i) in-hospital cardiovascular death, recurrent AMI, occurrence of arrhythmias, and contrast-induced acute kidney injury (CI-AKI); ii) long-term cardiovascular mortality, recurrent AMI, heart failure (HF) hospitalization. RESULTS The study population consisted of 646 AMI patients (with or without ST-segment elevation): 111 SGLT2-I users and 535 non-SGLT-I users. The use of SGLT2-I was associated with a significantly lower in-hospital cardiovascular death, arrhythmic burden, and occurrence of CI-AKI (all p < 0.05). During a median follow-up of 24 ± 13 months, the primary composite endpoint, as well as cardiovascular mortality and HF hospitalization were lower for SGLT2-I users compared to non-SGLT2-I patients (p < 0.04 for all). After adjusting for confounding factors, the use of SGLT2-I was identified as independent predictor of reduced MACE occurrence (HR=0.57; 95%CI:0.33-0.99; p = 0.039) and HF hospitalization (HR=0.46; 95%CI:0.21-0.98; p = 0.041). CONCLUSIONS In T2DM AMI patients, the use of SGLT2-I was associated with a lower risk of adverse cardiovascular outcomes during index hospitalization and long-term follow-up. Our findings provide new insights into the cardioprotective effects of SGLT2-I in the setting of AMI. REGISTRATION Data are part of the observational international registry: SGLT2-I AMI PROTECT. CLINICALTRIALS gov Identifier: NCT05261867.
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Affiliation(s)
- Pasquale Paolisso
- Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium; Dept. of Advanced Biomedical Sciences, University Federico II, Naples, Italy
| | - Luca Bergamaschi
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Felice Gragnano
- Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy; Division of Cardiology, A.O.R.N. "Sant'Anna e San Sebastiano", Caserta, Italy
| | - Emanuele Gallinoro
- Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium; Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy
| | - Arturo Cesaro
- Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy; Division of Cardiology, A.O.R.N. "Sant'Anna e San Sebastiano", Caserta, Italy
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Niya Mileva
- Cardiology Clinic, "Alexandrovska" University Hospital, Medical University of Sofia, Sofia, Bulgaria
| | - Alberto Foà
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Matteo Armillotta
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Angelo Sansonetti
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Sara Amicone
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Andrea Impellizzeri
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Giuseppe Esposito
- Dept. of Advanced Biomedical Sciences, University Federico II, Naples, Italy; Interventional Cardiology Unit, De Gasperis Cardio Center, Niguarda Hospital, Milan, Italy
| | - Nuccia Morici
- IRCCS S. Maria Nascente - Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
| | - Oreglia Jacopo Andrea
- Interventional Cardiology Unit, De Gasperis Cardio Center, Niguarda Hospital, Milan, Italy
| | | | - Ciro Mauro
- Department of Cardiology, Hospital Cardarelli, Naples, Italy
| | | | - Nazzareno Galie
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy
| | - Gaetano Santulli
- Dept. of Advanced Biomedical Sciences, University Federico II, Naples, Italy; International Translational Research and Medical Education (ITME) Consortium, Naples, Italy; Department of Medicine (Division of Cardiology) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, USA
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Mediterranea Cardiocentro, Naples, Italy
| | - Paolo Calabrò
- Department of Translational Medical Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy; Division of Cardiology, A.O.R.N. "Sant'Anna e San Sebastiano", Caserta, Italy
| | - Carmine Pizzi
- Unit of Cardiology, Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy.
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31
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Ferdinandy P, Andreadou I, Baxter GF, Bøtker HE, Davidson SM, Dobrev D, Gersh BJ, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier CJ, Hausenloy DJ, Schulz R. Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning. Pharmacol Rev 2023; 75:159-216. [PMID: 36753049 PMCID: PMC9832381 DOI: 10.1124/pharmrev.121.000348] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 08/07/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022] Open
Abstract
Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. SIGNIFICANCE STATEMENT: Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.
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Affiliation(s)
- Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Ioanna Andreadou
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Gary F Baxter
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Hans Erik Bøtker
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Sean M Davidson
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Dobromir Dobrev
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Bernard J Gersh
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Gerd Heusch
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Sandrine Lecour
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Marisol Ruiz-Meana
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Coert J Zuurbier
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Derek J Hausenloy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
| | - Rainer Schulz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (I.A.); Division of Pharmacology, Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK (G.F.B.); Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark (H.E.B.); The Hatter Cardiovascular Institute, University College London, London, UK (S.M.D.); Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.); Department of Medicine, Montreal Heart Institute and Université de Montréal, Montréal, Québec, Canada (D.D.); Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas (D.D.); Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota (B.J.G.); Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.); Cape Heart Institute and Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa (S.L.); Cardiovascular Diseases Research Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Spain (M.R-M.); Laboratory of Experimental Intensive Care Anesthesiology, Department Anesthesiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands (C.J.Z.); Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore (D.J.H.); National Heart Research Institute Singapore, National Heart Centre, Singapore (D.J.H.); Yong Loo Lin School of Medicine, National University Singapore, Singapore (D.J.H.); Cardiovascular Research Center, College of Medical and Health Sciences, Asia University, Taiwan (D.J.H.); and Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.)
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Gao Z, Bao J, Hu Y, Tu J, Ye L, Wang L. Sodium-glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy. Curr Drug Targets 2023; 24:1009-1022. [PMID: 37691190 PMCID: PMC10879742 DOI: 10.2174/1389450124666230907115831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.
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Affiliation(s)
- Zhicheng Gao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiaqi Bao
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yilan Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junjie Tu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
| | - Lifang Ye
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lihong Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China
- Heart Center, Department of Cardiovascular Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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Liarakos AL, Tran P, Keegan M, Robbins T, Chaudhuri N, Murthy N, Randeva H, Gholap NN. Real-world evaluation of glucose-lowering therapies and the use of weight-adjusted variable rate intravenous insulin infusion in the management of hyperglycaemia in patients with acute coronary syndrome (REGULATE-ACS). Int J Cardiol 2023; 370:26-34. [PMID: 36441073 DOI: 10.1016/j.ijcard.2022.10.158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 10/25/2022] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Admission hyperglycaemia in acute coronary syndromes (ACS) is a strong independent predictor of adverse clinical outcomes post-ACS. We examined the safety, efficacy, and feasibility of a modified, weight-adjusted variable rate intravenous insulin infusion (VRIII) and evaluated current practice of prescribing novel cardio-protective glucose-lowering therapies in patients presenting with acute hyperglycaemia across the ACS spectrum. METHODS REGULATE-ACS was an observational single-centre study of consecutive patients admitted with acute hyperglycaemia post-ACS between 2020 and 2021. Following updated local guidance on a modified VRIII, we evaluated its safety and efficacy in glycaemic control, cardio-metabolic complications including hypoglycaemia (blood glucose <3 mmol/L) and 30-day mortality. We also determined the prescription of glucose-lowering therapies pre-discharge. RESULTS Out of 107 patients, mean age was 64.9 ± 12.2 years, 82% had known diabetes, and 15% newly diagnosed diabetes. 86.9% (n = 93) had an admission glucose ≥11 mmol/L. In patients treated with VRIII (n = 63/93, 67.7%), glucose improved from 17.5 to 9.0 mmol/L (IQR 7.1-12.1), which was 3 mmol/L lower (p = 0.03) than in patients not treated with VRIII (n = 30/93, 32.3%) where median glucose reduced from 12.6 to 12 mmol/L (IQR 8.6-13.9). No significant hypoglycaemia, arrhythmia or worsening pulmonary oedema associated with VRIII was found. Novel glucose-lowering therapies were initiated in 20/71 (28.2%) and 3/15 (20.0%) of patients with prior and newly diagnosed diabetes, respectively. CONCLUSION This real-world analysis provides further support of efficacy, safety, and feasibility of a modified, weight-adjusted VRIII in managing acute hyperglycaemia in ACS. Despite established cardio-protective benefits of novel glucose-lowering therapies, <1/3 of eligible patients received such agents pre-discharge, demanding further research and awareness.
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Affiliation(s)
- Alexandros Leonidas Liarakos
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Patrick Tran
- Cardiology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Michelle Keegan
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Tim Robbins
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Nadia Chaudhuri
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Narasimha Murthy
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Harpal Randeva
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
| | - Nitin Narayan Gholap
- Diabetes and Endocrinology, Clifford Bridge Road, University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom.
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Mahmoud Refaie MM, Bayoumi AM, Mokhemer SA, Shehata S, Abd El-Hameed NM. Role of hypoxia inducible factor/vascular endothelial growth factor/endothelial nitric oxide synthase signaling pathway in mediating the cardioprotective effect of dapagliflozin in cyclophosphamide-induced cardiotoxicity. Hum Exp Toxicol 2023; 42:9603271231193392. [PMID: 37526264 DOI: 10.1177/09603271231193392] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
BACKGROUND Cyclophosphamide (CP) is a commonly used chemotherapeutic and immunosuppressive alkylating agent. However, cardiac adverse effects of CP interfere with its clinical benefit. Cardio-oncology research is currently an important issue and finding effective cardiopreserving agents is a critical need. For the first time, we aimed to detect if dapagliflozin (DAP) could ameliorate CP-induced cardiac injury and investigated the role of hypoxia inducible factor α (HIF1α)/vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) pathway. METHODS Forty male Wistar albino rats were included in the current model. Studied groups are: control group; CP-induced cardiotoxicity group; CP group treated with DAP; CP group treated with DAP and administered a nitric oxide synthase inhibitor; nitro-ω-L-arginine (L-NNA) before DAP to explore the role of eNOS. RESULTS Our data revealed that CP could induce cardiac damage as manifested by significant increases in cardiac enzymes, blood pressure, malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), HIF1α, sodium glucose co-transporter 2 (SGLT2) and cleaved caspase-3 levels with toxic histopathological changes. However, there are significant decreases in reduced glutathione (GSH), total antioxidant capacity (TAC), VEGF, and eNOS. On the opposite side, co-administration of DAP showed marked improvement of CP-induced cardiac damage that may be due to its ability to inhibit SGLT2, antioxidant, anti-inflammatory and anti-apoptotic properties. Results showed decreasing the cardioprotective effect of DAP on administration of L-NNA, reflecting the critical effect of eNOS in mediating such protection. CONCLUSION DAP could reduce CP cardiotoxicity based upon its ability to modulate SGLT2 and HIF1α/VEGF/eNOS signaling pathway.
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Affiliation(s)
| | - Asmaa Ma Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Sahar Ahmed Mokhemer
- Department of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia, Egypt
| | - Sayed Shehata
- Department of Cardiology, Faculty of Medicine, Minia University, El-Minia, Egypt
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Bețiu AM, Noveanu L, Hâncu IM, Lascu A, Petrescu L, Maack C, Elmér E, Muntean DM. Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed. Int J Mol Sci 2022; 23:13653. [PMID: 36362438 PMCID: PMC9656474 DOI: 10.3390/ijms232113653] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/20/2022] [Accepted: 10/28/2022] [Indexed: 07/25/2023] Open
Abstract
Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.
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Affiliation(s)
- Alina M. Bețiu
- Doctoral School Medicine-Pharmacy, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Lavinia Noveanu
- Department of Functional Sciences—Pathophysiology, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Iasmina M. Hâncu
- Doctoral School Medicine-Pharmacy, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Ana Lascu
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
- Department of Functional Sciences—Pathophysiology, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Lucian Petrescu
- Doctoral School Medicine-Pharmacy, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
| | - Christoph Maack
- Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, 97078 Würzburg, Germany
- Department of Internal Medicine 1, University Clinic Würzburg, 97078 Würzburg, Germany
| | - Eskil Elmér
- Mitochondrial Medicine, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, BMC A13, 221 84 Lund, Sweden
- Abliva AB, Medicon Village, 223 81 Lund, Sweden
| | - Danina M. Muntean
- Center for Translational Research and Systems Medicine, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
- Department of Functional Sciences—Pathophysiology, “Victor Babeș” University of Medicine and Pharmacy from Timișoara, Eftimie Murgu Sq. No. 2, 300041 Timișoara, Romania
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Wu YJ, Wang SB, Wang LS. SGLT2 Inhibitors: New Hope for the Treatment of Acute Myocardial Infarction? Am J Cardiovasc Drugs 2022; 22:601-613. [PMID: 35947249 DOI: 10.1007/s40256-022-00545-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 11/01/2022]
Abstract
Among all of the new antidiabetic drugs, an increasing number of studies have evaluated the relationship between the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and acute myocardial infarction (AMI). Since SGLT2i like empagliflozin, canagliflozin, and recently, dapagliflozin have shown impressive positive effects in patients with chronic heart failure with reduced ejection fraction (HFrEF), it has increased research interest to explore the cardiac molecular mechanisms underlying the clinical benefits and attracted more attention to the effects of SGLT2i on a series of cardiovascular events. Experimental and clinical data on SGLT2i treatment after AMI is limited. This is a review of the clinical and preclinical effects of SGLT2i, focusing on available data on the effects of SGLT2i in AMI patients with a brief overview of ongoing trials.
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Affiliation(s)
- Yu-Jie Wu
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Si-Bo Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Lian-Sheng Wang
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Chang X, Toan S, Li R, Zhou H. Therapeutic strategies in ischemic cardiomyopathy: Focus on mitochondrial quality surveillance. EBioMedicine 2022; 84:104260. [PMID: 36122552 PMCID: PMC9490489 DOI: 10.1016/j.ebiom.2022.104260] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/12/2022] [Accepted: 08/24/2022] [Indexed: 11/23/2022] Open
Abstract
Despite considerable efforts to prevent and treat ischemic cardiomyopathy (ICM), effective therapies remain lacking, in part owing to the complexity of the underlying molecular mechanisms, which are not completely understood yet. It is now widely thought that mitochondria serve as “sentinel” organelles that are capable of detecting cellular injury and integrating multiple stress signals. These pathophysiological activities are temporally and spatially governed by the mitochondrial quality surveillance (MQS) system, involving mitochondrial dynamics, mitophagy, and biogenesis. Dysregulation of MQS is an early and critical process contributing to mitochondrial bioenergetic dysfunction and sublethal injury to cardiomyocytes during ICM. An improved understanding of the pathogenesis of ICM may enable the development of novel preventive and therapeutic strategies aimed at overcoming the challenge of myocardial ischemia and its cardiovascular sequelae. This review describes recent research on the protective effects of MQS in ICM and highlights promising therapeutic targets.
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38
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Quentin V, Singh M, Nguyen LS. A review of potential mechanisms and uses of SGLT2 inhibitors in ischemia-reperfusion phenomena. World J Diabetes 2022; 13:683-695. [PMID: 36188147 PMCID: PMC9521445 DOI: 10.4239/wjd.v13.i9.683] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/13/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Recently added to the therapeutic arsenal against chronic heart failure as a first intention drug, the antidiabetic drug-class sodium-glucose cotransporter-2 inhibitors (SGLT2i) showed efficacy in decreasing overall mortality, hospitalization, and sudden death in patients of this very population, in whom chronic or acute ischemia count among the first cause. Remarkably, this benefit was observed independently from diabetic status, and benefited both preserved and altered ventricular ejection fraction. This feature, observed in several large randomized controlled trials, suggests additional effects from SGLT2i beyond isolated glycemia control. Indeed, both in-vitro and animal models suggest that inhibiting the Na+/H+ exchanger (NHE) may be key to preventing ischemia/ reperfusion injuries, and by extension may hold a similar role in ischemic damage control and ischemic preconditioning. Yet, several other mechanisms may be explored which may help better target those who may benefit most from SGLT2i molecules. Because of a large therapeutic margin with few adverse events, ease of prescription and potential pharmacological efficacity, SGLT2i could be candidate for wider indications. In this review, we aim to summarize all evidence which link SGLT2i and ischemia/reperfusion injuries modulation, by first listing known mechanisms, including metabolic switch, prevention of lethal arrythmias and others, which portend the latter, and second, hypothesize how the former may interact with these mechanisms.
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Affiliation(s)
- Victor Quentin
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
| | - Manveer Singh
- Intensive Care Medicine, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
| | - Lee S Nguyen
- Research and Innovation, CMC Ambroise Paré, Neuilly-sur-Seine 92200, France
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de Paula LJC, Uchida AH, Rezende PC, Soares P, Scudeler TL. Protective or Inhibitory Effect of Pharmacological Therapy on Cardiac Ischemic Preconditioning: A Literature Review. Curr Vasc Pharmacol 2022; 20:409-428. [PMID: 35986546 DOI: 10.2174/1570161120666220819163025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/23/2022] [Accepted: 05/31/2022] [Indexed: 01/25/2023]
Abstract
Ischemic preconditioning (IP) is an innate phenomenon, triggered by brief, non-lethal cycles of ischemia/reperfusion applied to a tissue or organ that confers tolerance to a subsequent more prolonged ischemic event. Once started, it can reduce the severity of myocardial ischemia associated with some clinical situations, such as percutaneous coronary intervention (PCI) and intermittent aortic clamping during coronary artery bypass graft surgery (CABG). Although the mechanisms underlying IP have not been completely elucidated, several studies have shown that this phenomenon involves the participation of cell triggers, intracellular signaling pathways, and end-effectors. Understanding this mechanism enables the development of preconditioning mimetic agents. It is known that a range of medications that activate the signaling cascades at different cellular levels can interfere with both the stimulation and the blockade of IP. Investigations of signaling pathways underlying ischemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. This review aims to present and discuss the effects of several medications on myocardial IP.
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Affiliation(s)
| | | | - Paulo Cury Rezende
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Paulo Soares
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Thiago Luis Scudeler
- Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Tao LC, Wang TT, Zheng L, Hua F, Li JJ. The Role of Mitochondrial Biogenesis Dysfunction in Diabetic Cardiomyopathy. Biomol Ther (Seoul) 2022; 30:399-408. [PMID: 35410981 PMCID: PMC9424338 DOI: 10.4062/biomolther.2021.192] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is described as abnormalities of myocardial structure and function in diabetic patients without other well-established cardiovascular factors. Although multiple pathological mechanisms involving in this unique myocardial disorder, mitochondrial dysfunction may play an important role in its development of DCM. Recently, considerable progresses have suggested that mitochondrial biogenesis is a tightly controlled process initiating mitochondrial generation and maintaining mitochondrial function, appears to be associated with DCM. Nonetheless, an outlook on the mechanisms and clinical relevance of dysfunction in mitochondrial biogenesis among patients with DCM is not completely understood. In this review, hence, we will summarize the role of mitochondrial biogenesis dysfunction in the development of DCM, especially the molecular underlying mechanism concerning the signaling pathways beyond the stimulation and inhibition of mitochondrial biogenesis. Additionally, the evaluations and potential therapeutic strategies regarding mitochondrial biogenesis dysfunction in DCM is also presented.
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Affiliation(s)
- Li-Chan Tao
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Ting-ting Wang
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Lu Zheng
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Fei Hua
- The Third Affiliated Hospital of Soochow University, Juqian Road, Changzhou 213000, China
| | - Jian-Jun Li
- State Key Laboratory of Cardiovascular Diseases, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
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Sullivan RD, McCune ME, Hernandez M, Reed GL, Gladysheva IP. Suppression of Cardiogenic Edema with Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Mechanisms and Insights from Pre-Clinical Studies. Biomedicines 2022; 10:2016. [PMID: 36009562 PMCID: PMC9405937 DOI: 10.3390/biomedicines10082016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
In heart failure with reduced ejection fraction (HFrEF), cardiogenic edema develops from impaired cardiac function, pathological remodeling, chronic inflammation, endothelial dysfunction, neurohormonal activation, and altered nitric oxide-related pathways. Pre-clinical HFrEF studies have shown that treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) stimulates natriuretic and osmotic/diuretic effects, improves overall cardiac function, attenuates maladaptive cardiac remodeling, and reduces chronic inflammation, oxidative stress, and endothelial dysfunction. Here, we review the mechanisms and effects of SGLT-2i therapy on cardiogenic edema in various models of HFrEF. Overall, the data presented suggest a high translational importance of these studies, and pre-clinical studies show that SGLT-2i therapy has a marked effect on suppressing the progression of HFrEF through multiple mechanisms, including those that affect the development of cardiogenic edema.
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Affiliation(s)
| | | | | | | | - Inna P. Gladysheva
- Department of Medicine, University of Arizona College of Medicine–Phoenix, Phoenix, AZ 85004, USA
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Zakaria EM, Tawfeek WM, Hassanin MH, Hassaballah MY. Cardiovascular protection by DPP-4 inhibitors in preclinical studies: an updated review of molecular mechanisms. Naunyn Schmiedebergs Arch Pharmacol 2022; 395:1357-1372. [PMID: 35945358 PMCID: PMC9568460 DOI: 10.1007/s00210-022-02279-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 07/26/2022] [Indexed: 11/29/2022]
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are a class of antidiabetic medications that cause glucose-dependent increase in incretins in diabetic patients. One of the two incretins, glucagon-like peptide-1 (GLP-1), beside its insulinotropic activity, has been studied for extra pancreatic effects. Most of DPP4 inhibitors (DPP4i) have been investigated in in vivo and in vitro models of diabetic and nondiabetic cardiovascular diseases including heart failure, hypertension, myocardial ischemia or infarction, atherosclerosis, and stroke. Results of preclinical studies proved prominent therapeutic potential of DPP4i in cardiovascular diseases, regardless the presence of diabetes. This review aims to present an updated summary of the cardiovascular protective and therapeutic effects of DPP4 inhibitors through the past 5 years focusing on the molecular mechanisms beneath these effects. Additionally, based on the results summary presented here, future studies may be conducted to elucidate or illustrate some of these findings which can add clinical benefits towards management of diabetic cardiovascular complications.
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Affiliation(s)
- Esraa M Zakaria
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Walaa M Tawfeek
- Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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Voorrips SN, Saucedo-Orozco H, Sánchez-Aguilera PI, De Boer RA, Van der Meer P, Westenbrink BD. Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure? Int J Mol Sci 2022; 23:8631. [PMID: 35955784 PMCID: PMC9369142 DOI: 10.3390/ijms23158631] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.
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Affiliation(s)
- Suzanne N. Voorrips
- Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.S.-O.); (P.I.S.-A.); (R.A.D.B.); (P.V.d.M.)
| | | | | | | | | | - B. Daan Westenbrink
- Department of Cardiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.S.-O.); (P.I.S.-A.); (R.A.D.B.); (P.V.d.M.)
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Ma S, He LL, Zhang GR, Zuo QJ, Wang ZL, Zhai JL, Zhang TT, Wang Y, Ma HJ, Guo YF. Canagliflozin mitigates ferroptosis and ameliorates heart failure in rats with preserved ejection fraction. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:945-962. [PMID: 35476142 PMCID: PMC9276585 DOI: 10.1007/s00210-022-02243-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Recently, hypoglycemic drugs belonging to sodium-glucose cotransporter 2 inhibitors (SGLT2i) have generated significant interest due to their clear cardiovascular benefits for heart failure with preserved ejection fraction (HFpEF) since there are no effective drugs that may improve clinical outcomes for these patients over a prolonged period. But, the underlying mechanisms remain unclear, particularly its effects on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death during heart failure (HF). Here, with proteomics, we demonstrated that ferroptosis might be a key mechanism in a rat model of high-salt diet-induced HFpEF, characterized by iron overloading and lipid peroxidation, which was blocked following treatment with canagliflozin. Data are available via ProteomeXchange with identifier PXD029031. The ferroptosis was evaluated with the levels of acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, ferritin heavy chain 1, transferrin receptor, Ferroportin 1, iron, glutathione, malondialdehyde, and 4-hydroxy-trans-2-nonenal. These findings highlight the fact that targeting ferroptosis may serve as a cardioprotective strategy for HFpEF prevention and suggest that canagliflozin may exert its cardiovascular benefits partly via its mitigation of ferroptosis.
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Affiliation(s)
- Sai Ma
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Li-Li He
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Guo-Rui Zhang
- Department of Cardiology, The Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, Hebei, China
| | - Qing-Juan Zuo
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Zhong-Li Wang
- Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Jian-Long Zhai
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Ting-Ting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yan Wang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Hui-Juan Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Yi-Fang Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, China.
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, Hebei, China.
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He S, Yao Y, Yang N, Wang Y, Liu D, Cao Z, Chen H, Fu Y, Yang M, Wang S, He G, Zhao Q. Dapagliflozin Protects Methamphetamine-Induced Cardiomyopathy by Alleviating Mitochondrial Damage and Reducing Cardiac Function Decline in a Mouse Model. Front Pharmacol 2022; 13:925276. [PMID: 35873593 PMCID: PMC9301370 DOI: 10.3389/fphar.2022.925276] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Methamphetamine (METH)-induced cardiovascular toxicity has been attributed to its destructive effect on mitochondrial function at least to some extent. Previous studies highlighted the benefits of dapagliflozin (DAPA) on the cardiovascular system, but the response of METH-induced cardiomyopathy to DAPA is never addressed before. The present study aimed to investigate the potential ability of DAPA in preventing METH-induced cardiomyopathy.Materials and Methods: C57BL/6 mice were randomly divided into control group (n = 24), METH group (n = 24), and METH + DAPA group (n = 24). The METH-induced cardiomyopathy group received intraperitoneal METH injections at gradually increasing doses thrice weekly for 14 weeks. Mice in the METH + DAPA group were simultaneously treated with DAPA 1 mg/kg/day by intragastric administration. Echocardiography was performed to assess cardiac function. Reactive oxygen species (ROS), JC-1, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were performed to evaluate oxidative stress, mitochondrial damage, and apoptosis, respectively. Mitochondrial and apoptosis-related protein expression was measured by western blotting.Results: Mice exposed to METH exhibited reduced cardiac function (left ventricular ejection fraction [LVEF]: 56.51 ± 6.49 vs. 73.62 ± 1.42, p < 0.01), fibrotic remodeling, and mitochondrial dysfunction, leading to apoptosis (apoptotic cells%: 7.4 ± 1.3 vs. 1.3 ± 0.5, p < 0.01). DAPA significantly reduced mitochondrial dynamics and function, ROS, apoptosis (apoptotic cells%: 2.4 ± 0.8 vs. 7.4 ± 1.3, p < 0.01), cardiac function decline (LVEF: 70.99 ± 4.936 vs. 56.51 ± 6.49, p < 0.01), and fibrotic remodeling. These results indicated that DAPA could be considered as an effective therapeutic agent in the protection against METH-associated cardiomyopathy.Conclusion: DAPA protects against METH-induced cardiomyopathy in mice by decreasing mitochondrial damage and apoptosis.
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Affiliation(s)
- Shanqing He
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yajun Yao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Nan Yang
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Youcheng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Dishiwen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Zhen Cao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Huiyu Chen
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yuntao Fu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mei Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Songjun Wang
- Hebei Key Laboratory of Forensic Medicine, Hebei Medical University, Shijiazhuang, China
| | - Guangjie He
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Qingyan Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
- *Correspondence: Qingyan Zhao,
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Fan ZG, Xu Y, Chen X, Ji MY, Ma GS. Appropriate Dose of Dapagliflozin Improves Cardiac Outcomes by Normalizing Mitochondrial Fission and Reducing Cardiomyocyte Apoptosis After Acute Myocardial Infarction. Drug Des Devel Ther 2022; 16:2017-2030. [PMID: 35789742 PMCID: PMC9250321 DOI: 10.2147/dddt.s371506] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/21/2022] [Indexed: 01/01/2023] Open
Abstract
Objective Dapagliflozin (DAPA) has been reported to have significant cardiac protective effects on heart failure (HF). However, the dose and time, as well as the underlying mechanisms, for DAPA treatment in acute myocardial infarction (AMI) remain controversial. The aim of this study aimed to assess the efficacy and safety of DAPA treatment along with an increased concentration gradient for AMI and explore the potential mechanisms. Methods Non-diabetic Sprague-Dawley rats were used for establishing AMI models and then were treated with three different concentrations of DAPA [0.5 mg/kg, 1 mg/kg and 1.5 mg/kg, described as AMI+DAPA Low, AMI+DAPA Medium (Med) and AMI+DAPA High, respectively] for six weeks from the onsetting of AMI. Echocardiography, histological staining and Western blot were performed to assess the relevant cardiac protective effects. Mitochondrial biogenesis and myocardial apoptosis were evaluated via the electron microscopy and TUNEL assay, respectively, as well as the Immunoblotting. In vitro, H9c2 cells were subjected to hypoxic treatment to assess the efficacy of DAPA on mitochondrial biogenesis and apoptosis. Results The medium dose of DAPA treatment could significantly reduce the infarct size (P < 0.01) and the echocardiography results showed that the MI-induced damage in cardiac function got partly repaired, showing no significant difference in left ventricle ejection fraction (LVEF) versus the Sham group (Sham vs AMI+DAPA Med group: 70.47% vs 61.73%). The Western blotting results confirmed the relevant benefits and the underlying mechanisms might be through the activation of PGAM5/Drp1 signaling pathway to normalize the mitochondrial fission and reduce cardiomyocyte apoptosis. Moreover, a medium dose of DAPA treatment could avoid increased damage to the bladder endothelium following higher treatment doses. Conclusion Appropriate dose of DAPA treatment could improve the cardiac remodeling and reduce the cardiomyocyte apoptosis after AMI, without increased damage to bladder endothelium, which might be more preferred for MI patients without diabetes.
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Affiliation(s)
- Zhong-guo Fan
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Yang Xu
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Xi Chen
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
| | - Ming-yue Ji
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
- Department of Cardiology, Lianshui People’s Hospital, Huaian, People’s Republic of China
| | - Gen-shan Ma
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China
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Ma L, Zou R, Shi W, Zhou N, Chen S, Zhou H, Chen X, Wu Y. SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways. Am J Cancer Res 2022; 12:5034-5050. [PMID: 35836807 PMCID: PMC9274739 DOI: 10.7150/thno.75121] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 06/13/2022] [Indexed: 01/12/2023] Open
Abstract
Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI. Methods: DAPA effects were evaluated both in vivo, in mice subjected to IRI, and in vitro, in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R). DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice. Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation. Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs. DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R. Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice. Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.
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Affiliation(s)
- Li Ma
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Rongjun Zou
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Wanting Shi
- Department of Paediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Na Zhou
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Shaoxian Chen
- Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Hao Zhou
- Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.,✉ Corresponding authors: Hao Zhou, E-mail: ; Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China. Xinxin Chen, E-mail: ; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Yueheng Wu, E-mail: ; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Xinxin Chen
- Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,✉ Corresponding authors: Hao Zhou, E-mail: ; Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China. Xinxin Chen, E-mail: ; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Yueheng Wu, E-mail: ; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yueheng Wu
- Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.,✉ Corresponding authors: Hao Zhou, E-mail: ; Senior Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China. Xinxin Chen, E-mail: ; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Heart Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. Yueheng Wu, E-mail: ; Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China
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Jing Y, Yang R, Chen W, Ye Q. Anti-Arrhythmic Effects of Sodium-Glucose Co-Transporter 2 Inhibitors. Front Pharmacol 2022; 13:898718. [PMID: 35814223 PMCID: PMC9263384 DOI: 10.3389/fphar.2022.898718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/04/2022] [Indexed: 12/11/2022] Open
Abstract
Arrhythmias are clinically prevalent with a high mortality rate. They impose a huge economic burden, thereby substantially affecting the quality of life. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) is a new type of hypoglycemic drug, which can regulate blood glucose level safely and effectively. Additionally, it reduces the occurrence and progression of heart failure and cardiovascular events significantly. Recently, studies have found that SGLT2i can alleviate the occurrence and progression of cardiac arrhythmias; however, the exact mechanism remains unclear. In this review, we aimed to discuss and summarize new literature on different modes in which SGLT2i ameliorates the occurrence and development of cardiac arrhythmias.
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Singhanat K, Apaijai N, Sumneang N, Maneechote C, Arunsak B, Chunchai T, Chattipakorn SC, Chattipakorn N. Therapeutic potential of a single-dose melatonin in the attenuation of cardiac ischemia/reperfusion injury in prediabetic obese rats. Cell Mol Life Sci 2022; 79:300. [PMID: 35588335 PMCID: PMC11072751 DOI: 10.1007/s00018-022-04330-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 04/24/2022] [Accepted: 04/27/2022] [Indexed: 01/05/2023]
Abstract
Although acute melatonin treatment effectively reduces cardiac ischemia/reperfusion (I/R) injury in lean rats by modulating melatonin receptor 2 (MT2), there is no information regarding the temporal effects of melatonin administration during cardiac I/R injury in prediabetic obese rats. Prediabetic obese rats induced by chronic consumption of a high-fat diet (HFD) were used. The rats underwent a cardiac I/R surgical procedure (30-min of ischemia, followed by 120-min of reperfusion) and were randomly assigned to receive either vehicle or melatonin treatment. In the melatonin group, rats were divided into 3 different subgroups: (1) pretreatment, (2) treatment during ischemic period, (3) treatment at the reperfusion onset. In the pretreatment subgroup either a nonspecific MT blocker (Luzindole) or specific MT2 blocker (4-PPDOT) was also given to the rats prior to melatonin treatment. Pretreatment with melatonin (10 mg/kg) effectively reduced cardiac I/R injury by reducing infarct size, arrhythmia, and LV dysfunction. Reduction in impaired mitochondrial function, mitochondrial dynamic balance, oxidative stress, defective autophagy, and apoptosis were observed in rats pretreated with melatonin. Unfortunately, the cardioprotective benefits were not observed when 10-mg/kg of melatonin was acutely administered to the rats after cardiac ischemia. Thus, we increased the dose of melatonin to 20 mg/kg, and it was administered to the rats during ischemia or at the onset of reperfusion. The results showed that 20-mg/kg of melatonin effectively reduced cardiac I/R injury to a similar extent to the 10-mg/kg pretreatment regimen. The MT2 blocker inhibited the protective effects of melatonin. Acute melatonin treatment during cardiac I/R injury exerted protective effects in prediabetic obese rats. However, a higher dose of melatonin is required when given after the onset of cardiac ischemia. These effects of melatonin were mainly mediated through activation of MT2.
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Affiliation(s)
- Kodchanan Singhanat
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nattayaporn Apaijai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Natticha Sumneang
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Chayodom Maneechote
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Busarin Arunsak
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Titikorn Chunchai
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Yin Z, Zheng H, Guo Z. Effect of Sodium-Glucose Co-transporter Protein 2 Inhibitors on Arrhythmia in Heart Failure Patients With or Without Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Front Cardiovasc Med 2022; 9:902923. [PMID: 35665272 PMCID: PMC9157597 DOI: 10.3389/fcvm.2022.902923] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 05/04/2022] [Indexed: 01/10/2023] Open
Abstract
Aim Arrhythmic events such as atrial fibrillation (AF) are tightly associated with an increased risk of heart failure (HF). Previous studies have shown inconsistent results regarding the association between sodium-glucose co-transporter 2 inhibitors (SGLT2i) and the risk of arrhythmia. The purpose of this study was to investigate the association of SGLT2i treatment with arrhythmia outcomes in clinical trials of patients with HF. Methods We searched Embase, PubMed, Web of Science, Medline, The Cochrane Library, and JAMA databases to identify appropriate randomized controlled trials (RCTs) of SGLT2i interventions. Endpoint outcomes included AF, atrial flutter (AFL), AF/AFL, ventricular fibrillation (VF), ventricular tachycardia (VT), VF/VT, and bradycardia. A random-effects model was used for the meta-analysis of all outcomes. The risk of bias and quality of evidence was assessed by using the Cochrane tool and assessment framework. Results Out of 1,725 citations, 9 trials were included in this study, with follow-up from 4 weeks to 52 weeks for 10,344 participants (mean age 68.27 years; 69.62% of participants were men). Compared with placebo, SGLT2i reduced the incidence of AF by 37% [ratio risk (RR) 0.63; 95% confidence interval (CI) 0.45–0.87; p < 0.05] and AF/AFL by 34% (RR 0.66; 95% CI 0.49–0.90; p < 0.05). Conclusions SGLT2i can reduce the risk of cardiac arrhythmias, particularly the AF. Our study provides strong evidence for recommending the use of SGLT2i in patients with HF. Systematic Review Registration PROSPERO, identifier: CRD42022296696.
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Affiliation(s)
- Ziwei Yin
- Department of Cardiology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Huizhen Zheng
- Department of Cardiology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Zhihua Guo
- College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Zhihua Guo
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