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Kjaergaard J, Møller CH, Wiberg S, Mikkelsen AD, Møller-Sørensen H, Ravn HB, Ravn J, Olsen PS, Høfsten DE, Boesgaard S, Køber L, Nilsson JC, Hassager C. Efficacy of the Glucagon-Like Peptide-1 Agonist Exenatide in Patients Undergoing CABG or Aortic Valve Replacement: A Randomized Double-Blind Clinical Trial. Circ Cardiovasc Interv 2025; 18:e014961. [PMID: 40265262 DOI: 10.1161/circinterventions.124.014961] [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: 01/06/2025] [Accepted: 03/28/2025] [Indexed: 04/24/2025]
Abstract
BACKGROUND GLP-1 (glucagon-like peptide-1) agonists have been proven beneficial in reducing the risk of and injury associated with several cardiovascular diseases. The efficacy in cardiopulmonary bypass-assisted cardiac surgery is unknown. This trial aimed to investigate the efficacy of an infusion of the GLP-1 agonist exenatide during and after open-heart surgery in reducing the risk of death and major organ failure. METHODS Randomized, double-blinded, 2-by-2 factorial design, single-center clinical trial, also including liberal (FiO2 of 100%) or restrictive (FiO2 of 50%) oxygenation during and after bypass. The present article presents the results of the exenatide intervention. We included adult patients undergoing elective cardiopulmonary bypass-assisted coronary artery bypass grafting or aortic valve replacement. Patients were predominantly low risk. The intervention was an infusion of 17.4 µg of exenatide or placebo during cardiopulmonary bypass and the first hour after weaning thereof. The main outcome was time to a composite end point consisting of death, stroke, renal failure requiring dialysis, or new/worsening heart failure during follow-up. Secondary end points included occurrence of prespecified adverse events. RESULTS A total of 1389 patients were included in the analyses. Within a follow-up period of a median of 5.9 years (min-max; 2.5-8.3 years), 170 (24%) patients in the exenatide group and 165 (24%) patients experienced a primary end point. We found no difference in time to the first event between patients randomized to FiO2 50% versus FiO2 100% (hazard ratio, 1.0 [95% CI, 0.83-1.3]; P=0.80). We found no significant difference in rates of adverse events between the 2 groups. CONCLUSIONS Exenatide during cardiopulmonary bypass and weaning thereof did not significantly reduce the incidence of death, stroke, renal failure, or new/worsening heart failure in patients undergoing coronary artery bypass grafting and aortic valve replacement. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT02673931.
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Affiliation(s)
- Jesper Kjaergaard
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark (J.K., S.W., L.K., C.H.)
| | - Christian Holdflod Møller
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Denmark (C.H.M., J.R., P.S.O.)
| | - Sebastian Wiberg
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark (J.K., S.W., L.K., C.H.)
- Department of Cardiothoracic Anesthesiology, Copenhagen University Hospital Rigshospitalet, Denmark (S.W., H.M.-S., J.C.N.)
| | - Astrid Duus Mikkelsen
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
| | - Hasse Møller-Sørensen
- Department of Cardiothoracic Anesthesiology, Copenhagen University Hospital Rigshospitalet, Denmark (S.W., H.M.-S., J.C.N.)
| | - Hanne Berg Ravn
- Department of Anesthesiology and Intensive Care, Odense University Hospital, Copenhagen, Denmark (H.B.R.)
| | - Jesper Ravn
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Denmark (C.H.M., J.R., P.S.O.)
| | - Peter Skov Olsen
- Department of Cardiothoracic Surgery, Copenhagen University Hospital Rigshospitalet, Denmark (C.H.M., J.R., P.S.O.)
| | - Dan E Høfsten
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
| | - Søren Boesgaard
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark (J.K., S.W., L.K., C.H.)
| | - Jens Christian Nilsson
- Department of Cardiothoracic Anesthesiology, Copenhagen University Hospital Rigshospitalet, Denmark (S.W., H.M.-S., J.C.N.)
| | - Christian Hassager
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Denmark (J.K., A.D.M., D.E.H., S.B., L.K., C.H.)
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark (J.K., S.W., L.K., C.H.)
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Biondi F, Madonna R. The Potential Role of GLP1-RAs Against Anticancer-Drug Cardiotoxicity: A Scoping Review. J Clin Med 2025; 14:2705. [PMID: 40283534 PMCID: PMC12027986 DOI: 10.3390/jcm14082705] [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] [Received: 02/15/2025] [Revised: 04/05/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Background: GLP1 receptor agonists (GLP1-RAs) have become a central component in the treatment of type 2 diabetes mellitus (T2DM) and are gaining prominence in the cardiovascular field. Semaglutide and other GLP1-RA molecules possess cardioprotective properties. Cardiotoxicity, a term used to refer to cardiovascular disease caused by anticancer treatment, is a collection of common and severe conditions. Its pharmacological prevention or mitigation is a clinical unmet need as options are few and limited to some specific clinical settings. GLP1-RAs have a promising pharmacological profile given their activity on a number of pathophysiological targets and signaling pathways including oxidative stress, autophagy, and STAT3 activation. Interestingly, abnormalities in some of the GLP-1-modulated pathways have been linked to cardiotoxicity. This scoping review aims to map the extent and assess the main characteristics of research on the role of GLP1-RAs in the prevention and/or mitigation of anticancer-related cardiotoxicity. Methods: The selection process led to the inclusion of thirteen studies chosen from reports retrieved through the search string: ("semaglutide" OR "exenatide" OR "liraglutide" OR "dulaglutide" OR "tirzepatide" OR "GLP1 receptor agonist" OR "GLP1RA" OR "GLP1-RA" OR "GLP1" OR "Glucagon-like Peptide-1 Agonists") AND ("cardioncology" OR "cardiotoxicity" OR "chemotherapy" OR "anti-cancer treatment" OR "anti-cancer therapy"). The study complied with the PRISMA guidelines on scoping reviews. Results: Two studies were clinical and conducted on registries, eight used animal models, two were conducted on cell cultures, and one was conducted on both animal models and cell cultures. Evidence in favor of cardioprotection and a number of putative mechanisms emerged. Conclusions: Evidence on GLP1-RAs' effect on cardiotoxicity is limited in both quantity and quality and suffers from poor study standardization. However, most included studies documented a rigorously defined cardioprotective effect and demonstrated changes in several pathophysiologically relevant targets and pathways, including NF-κB, IL-6, reactive oxygen species, and caspase-3. Further clinical studies are warranted.
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Affiliation(s)
- Filippo Biondi
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, 56124 Pisa, Italy
| | - Rosalinda Madonna
- Department of Pathology, Cardiology Division, University of Pisa, Via Paradisa, 56124 Pisa, Italy
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Theofilis P, Vlachakis PK, Mantzouranis E, Sakalidis A, Chrysohoou C, Leontsinis I, Lazaros G, Dimitriadis K, Drakopoulou M, Vordoni A, Oikonomou E, Tsioufis K, Tousoulis D. Acute Coronary Syndromes in Women: A Narrative Review of Sex-Specific Characteristics. Angiology 2025; 76:209-224. [PMID: 37995282 DOI: 10.1177/00033197231218331] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2023]
Abstract
Acute coronary syndromes (ACSs) encompass a spectrum of life-threatening cardiovascular conditions, including unstable angina (UA) and myocardial infarction. While significant progress has been made in the understanding and management of ACS over the years, it has become increasingly evident that sex-based differences play a pivotal role in the pathophysiology, presentation, and outcomes of these conditions. Despite this recognition, the majority of clinical research in the field has historically focused on male populations, leading to a significant knowledge gap in understanding the unique aspects of ACS in women. This review article aims to comprehensively explore and synthesize the current body of literature concerning the sex-specific characteristics of ACS, shedding light on the epidemiology, risk factors, clinical presentation, diagnostic challenges, treatment strategies, and prognosis in women. By elucidating the distinct aspects of ACS in women, this review intends to foster greater awareness and improved clinical management, ultimately contributing to enhanced cardiovascular care for female patients.
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Affiliation(s)
- Panagiotis Theofilis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panayotis K Vlachakis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Emmanouil Mantzouranis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Sakalidis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Chrysohoou
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Leontsinis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George Lazaros
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Kyriakos Dimitriadis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Drakopoulou
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Vordoni
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, "Sotiria" Chest Disease Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Tsioufis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Tousoulis
- 1st Department of Cardiology, "Hippokration" General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Wang M, Wang L, Sun H, Yuan H, Li Y. Mechanisms of ferroptosis and glucagon-like peptide-1 receptor agonist in post-percutaneous coronary intervention restenosis. Mol Cell Biochem 2025; 480:1465-1480. [PMID: 39283562 DOI: 10.1007/s11010-024-05118-6] [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: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 02/21/2025]
Abstract
Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.
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Affiliation(s)
- Miao Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Liren Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Huanxin Sun
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hong Yuan
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yonghong Li
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
- Department of Cardiology, The Affiliated Cardiovascular Hospital of Qingdao University, No.59 Haier Road, Qingdao, 266071, China.
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Stone C, Harris DD, Broadwin M, Kanuparthy M, Nho JW, Yalamanchili K, Hamze J, Abid MR, Sellke FW. Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. Arterioscler Thromb Vasc Biol 2025; 45:285-297. [PMID: 39665144 PMCID: PMC11748899 DOI: 10.1161/atvbaha.124.321850] [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: 09/18/2024] [Accepted: 11/25/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking. METHODS Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. RESULTS SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both P<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both P<0.03); reduced perivascular and interstitial fibrosis (both P<0.03); and apoptosis (P=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (P=0.005), coupled with downstream increases in eNOS (endothelial NO synthase; P=0.014). CONCLUSIONS This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
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Affiliation(s)
- Christopher Stone
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | - Dwight D. Harris
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | - Mark Broadwin
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | | | - Ju-Woo Nho
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | | | - Jad Hamze
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | - M. Ruhul Abid
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
| | - Frank W. Sellke
- Department of Cardiothoracic Surgery, Brown University, Providence, RI
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Skrobucha A, Pindlowski P, Krajewska N, Grabowski M, Jonik S. Anti-inflammatory effects of glucagon-like peptide-1 (GLP-1) in coronary artery disease: a comprehensive review. Front Cardiovasc Med 2024; 11:1446468. [PMID: 39741663 PMCID: PMC11685754 DOI: 10.3389/fcvm.2024.1446468] [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] [Received: 06/09/2024] [Accepted: 11/21/2024] [Indexed: 01/03/2025] Open
Abstract
Coronary artery disease (CAD)-cardiovascular condition occuring due to atherosclerotic plaque accumulation in the epicardial arteries-is responsible for disabilities of millions of people worldwide and remains the most common single cause of death. Inflammation is the primary pathological mechanism underlying CAD, since is involved in atherosclerotic plaque formation. Glucagon-like peptide-1 (GLP-1) is a peptide hormone which role extends beyond well-known carbohydrates metabolism. In in vitro studies GLP-1 receptor agonism is associated with regulation of several inflammatory pathways, including cytokine production, lypotoxicity and macrophages differentiation. In this review, we aimed to provide a comprehensive summary of the potential relationship between anti-inflammatory effects of GLP-1 and CAD. We have described a well-established association of anti-inflammatory properties of GLP-1 and atherosclerosis in animals. Pre-clinical studies showed that anti-atherogenic effect of GLP-1 is independent of modulation of plasma lipid levels and depends on anti-inflammatory response. Human studies in this area are limited by small sample size and often nonrandomized character. However, beneficial impact of GLP-1 on endothelial function and microcirculatory integrity in patients with CAD have been described. Understanding atherosclerosis as a chronic inflammatory disease offers new opportunities for the prevention and treatment of CAD. Therefore, we emphasize the need for larger randomized controlled trials focusing on cardiovascular morbidity and mortality to verify the cardioprotective properties of GLP-1R agonists in patients with CAD.
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Affiliation(s)
- Alicja Skrobucha
- 1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
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Zarei M, Sahebi Vaighan N, Farjoo MH, Talebi S, Zarei M. Incretin-based therapy: a new horizon in diabetes management. J Diabetes Metab Disord 2024; 23:1665-1686. [PMID: 39610543 PMCID: PMC11599551 DOI: 10.1007/s40200-024-01479-3] [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: 05/05/2024] [Accepted: 07/22/2024] [Indexed: 11/30/2024]
Abstract
Diabetes mellitus, a metabolic syndrome characterized by hyperglycemia and insulin dysfunction, often leads to serious complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Incretins, gut peptide hormones released post-nutrient intake, have shown promising therapeutic effects on these complications due to their wide-ranging biological impacts on various body systems. This review focuses on the role of incretin-based therapies, particularly Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, in managing diabetes and its complications. We also discuss the potential of novel agents like semaglutide, a recently approved oral compound, and dual/triple agonists targeting GLP-1/GIP, GLP-1/glucagon, and GLP-1/GIP/glucagon receptors, which are currently under investigation. The review aims to provide a comprehensive understanding of the beneficial impacts of natural incretins and the therapeutic potential of incretin-based therapies in diabetes management.
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Affiliation(s)
- Malek Zarei
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navideh Sahebi Vaighan
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Farjoo
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soosan Talebi
- Department of Pharmacology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Zarei
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
- John B. Little Center for Radiation Sciences, Harvard T.H Chan School of Public Health, Boston, MA USA
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Bosa Ojeda F, Méndez Vargas C, Lacalzada Almeida J, Izquierdo Gómez MM, Jiménez Sosa A, Rodríguez Jiménez C, Sánchez‐Grande Flecha A, Bosa Santana M, Yanes Bowden G. Efficacy and safety of levosimendan in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: The LEVOCEST trial. Catheter Cardiovasc Interv 2024; 104:1414-1422. [PMID: 39425551 PMCID: PMC11667407 DOI: 10.1002/ccd.31267] [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: 08/09/2024] [Revised: 09/30/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND Primary angioplasty is the standard procedure for patients with ST-segment elevation myocardial infarction (STEMI). However, myocardial reperfusion results in additional cell damage. Levosimendan, due to its pleiotropic effects, may be a therapeutic alternative to prevent this damage. The objective of this study was to evaluate whether this drug can reduce infarct size in patients with STEMI. METHODS Patients were randomized to receive a 24-h infusion of either levosimendan (0.1 μg/kg/min) or placebo after the primary angioplasty. The main objective was to assess the size of the infarct by cardiac resonance at 30 days and 6 months after the event. Other variables such as left ventricular ejection fraction (LVEF) and adverse ventricular remodeling (AVR) were assessed by speckle-tracking echocardiography and magnetic resonance. Major adverse cardiovascular events (MACE) were also collected. RESULTS 157 patients were analysed (levosimendan, n = 79; placebo, n = 78). We found that after 6 months, patients treated with levosimendan had a greater reduction in infarct size (13.19% ± 9.5% vs.11.79% ± 9%, p = 0.001), compared with those in the placebo group (13.35% ± 7.1% vs. 13.43% ± 7.8%, p = 0.38). There were no significant differences in MACE between both groups. CONCLUSIONS Levosimendan is a safe and effective therapeutic option for reducing infarct size in patients with STEMI.
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Affiliation(s)
- Francisco Bosa Ojeda
- Department of Interventional CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - Corabel Méndez Vargas
- Department of Interventional CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - Juan Lacalzada Almeida
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - María M. Izquierdo Gómez
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - Alejandro Jiménez Sosa
- Research UnitUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - Consuelo Rodríguez Jiménez
- Clinical Pharmacology ServiceClinical Research and Clinical Trials Unit of the University Hospital of the Canary IslandsCanary IslandsSpain
| | - Alejandro Sánchez‐Grande Flecha
- Department of Interventional CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
| | - Marta Bosa Santana
- Emergency DepartmentUniversity Hospital Nuestra Señora de CandelariaCanary IslandsSpain
| | - Geoffrey Yanes Bowden
- Department of Interventional CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
- Department of CardiologyUniversity Hospital of the Canary IslandsLa Laguna, Santa Cruz de TenerifeCanary IslandsSpain
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Yan H, Yao W, Li Y, Li T, Song K, Yan P, Dang Y. Cardiometabolic Modulation by Semaglutide Contributes to Cardioprotection in Rats with Myocardial Infarction. Drug Des Devel Ther 2024; 18:5485-5500. [PMID: 39640291 PMCID: PMC11618856 DOI: 10.2147/dddt.s491970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
Background Acute myocardial infarction (AMI) is a significant clinical challenge. Semaglutide has therapeutic potential in cardiovascular disease management, but its specific impact and mechanisms in AMI are not fully understood. Methods Twenty-four male Sprague-Dawley rats were divided into three groups: control (Control), infarction-only (MI), and semaglutide-treated (SEMA). Weight, blood glucose, and lipid profiles were analyzed. Cardiac function was evaluated via echocardiography. Histopathological assessment and immunohistochemical analysis were performed. Untargeted metabolomic analysis using LC-MS/MS was utilized. Results Semaglutide treatment was associated with a reduction in body weight, blood glucose, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), as well as an enhancement in the left ventricular ejection fraction (Control vs MI vs SEMA, 69.13±4.30 vs 30.16±3.17 vs 39.81±6.13, P < 0.05). It also had a lower collagen volume fraction (3.05 vs 34.05 vs 17.73, P < 0.05) and ameliorated the accumulation of glycogen in the myocardium. Metabolomic profiling revealed differentially expressed metabolites between the control/MI and MI/SEMA groups, predominantly within benzenoid, lipid, and organic acid categories. Pathway enrichment analysis highlighted amino sugar and nucleotide sugar metabolism, chlorocyclohexane and chlorobenzene degradation, and phenylalanine, tyrosine, and tryptophan biosynthesis. Random forest analysis identified key metabolites, including downregulated Docusate sodium, 1-(2-Thienyl)-1-heptanone, and Adenylyl-molybdopterin, alongside upregulated Methylenediphosphonic acid, Choline sulfate, and Lactosamine. Conclusion Semaglutide significantly ameliorated myocardial fibrosis and metabolic dysregulation in rats post-myocardial infarction. Its mechanism involves modulating glucose metabolism, lipid metabolism, and organic acid metabolism. Targeted metabolites, including Docusate sodium, 1-(2-Thienyl)-1-heptanone, Adenylyl-molybdopterin, Methylenediphosphonic acid, Choline sulfate, and Lactosamine, are implicated in the metabolic reprogramming induced by semaglutide.
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Affiliation(s)
- Haihao Yan
- Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Wenjing Yao
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China
| | - Yanhong Li
- Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China
| | - Tianxing Li
- Department of Graduate School of Hebei North University, Zhangjiakou, Hebei, 075000, People’s Republic of China
| | - Kexin Song
- Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China
| | - Pan Yan
- Department of Internal Medicine, Yongnian District Traditional Chinese Medicine Hospital, Handan, Hebei, 057150, People’s Republic of China
| | - Yi Dang
- Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China
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10
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Koirala S, Sunnaa M, Bernier T, Oktay AA. The Role of Obesity as a Cardiac Disease Risk Factor in Patients with Type 2 Diabetes. Curr Cardiol Rep 2024; 26:1309-1320. [PMID: 39235729 DOI: 10.1007/s11886-024-02129-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: 08/23/2024] [Indexed: 09/06/2024]
Abstract
PURPOSE OF REVIEW Cardiovascular disease (CVD) is the leading cause of death globally and is closely associated with obesity and type 2 diabetes mellitus (T2DM). This review examines the interplay between obesity, T2DM, and CVD, highlighting the increasing prevalence and economic burden of these conditions. RECENT FINDINGS Pharmacologic therapies, particularly glucagon-like peptide-1 receptor agonists, show promise in substantial weight loss and subsequent reduction of adverse cardiovascular events in obese individuals with and without diabetes. Obesity significantly contributes to the development of insulin resistance and T2DM, further escalating CVD risk. The common co-occurrence of these three conditions may involve several other pathophysiological mechanisms, such as chronic inflammation, increased visceral adiposity, and endothelial dysfunction. Until recently, lifestyle modifications and bariatric surgery had been the primary methods for weight loss and mitigating obesity-associated cardiovascular risk. Newer pharmacological options have led to a paradigm shift in our approach to obesity management as they provide substantial benefits in weight loss, glycemic control, and cardiovascular risk reduction.
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Affiliation(s)
- Sushant Koirala
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Michael Sunnaa
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Thomas Bernier
- Division of Cardiology, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Ahmet Afsin Oktay
- Division of Cardiology, Rush University Medical Center, Chicago, IL, 60612, USA.
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11
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Zhao X, Wang Z, Wang L, Jiang T, Dong D, Sun M. The PINK1/Parkin signaling pathway-mediated mitophagy: a forgotten protagonist in myocardial ischemia/reperfusion injury. Pharmacol Res 2024; 209:107466. [PMID: 39419133 DOI: 10.1016/j.phrs.2024.107466] [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: 06/05/2024] [Revised: 10/12/2024] [Accepted: 10/12/2024] [Indexed: 10/19/2024]
Abstract
Myocardial ischemia causes extensive damage, further exacerbated by reperfusion, a phenomenon called myocardial ischemia/reperfusion injury (MIRI). Nowadays, the pathological mechanisms of MIRI have received extensive attention. Oxidative stress, multiple programmed cell deaths, inflammation and others are all essential pathological mechanisms contributing to MIRI. Mitochondria are the energy supply centers of cells. Numerous studies have found that abnormal mitochondrial function is an essential "culprit" of MIRI, and mitophagy mediated by the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1)/Parkin signaling pathway is an integral part of maintaining mitochondrial function. Therefore, exploring the association between the PINK1/Parkin signaling pathway-mediated mitophagy and MIRI is crucial. This review will mainly summarize the crucial role of the PINK1/Parkin signaling pathway-mediated mitophagy in MIR-induced several pathological mechanisms and various potential interventions that affect the PINK1/Parkin signaling pathway-mediated mitophagy, thus ameliorating MIRI.
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Affiliation(s)
- Xiaopeng Zhao
- College of Exercise and Health, Shenyang Sport University, Shenyang 110102, China.
| | - Zheng Wang
- School of Medicine, Qilu Institute of Technology, Jinan 250200, China.
| | - Lijie Wang
- Department of Cardiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110033, China.
| | - Tao Jiang
- Rehabilitation Medicine Center, The Second Hospital of Shandong University, Jinan 250033, China.
| | - Dan Dong
- Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang 110122, China.
| | - Mingli Sun
- College of Exercise and Health, Shenyang Sport University, Shenyang 110102, China.
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12
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Bykova A, Serova M, Chashkina M, Kosharnaya R, Salpagarova Z, Andreev D, Giverts I. Glucagon-like Peptide-1 Receptor Agonists in the Context of Pathophysiology of Diverse Heart Failure with Preserved Ejection Fraction Phenotypes: Potential Benefits and Mechanisms of Action. Card Fail Rev 2024; 10:e14. [PMID: 39507374 PMCID: PMC11539042 DOI: 10.15420/cfr.2024.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/26/2024] [Indexed: 11/08/2024] Open
Abstract
This review examines the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on different heart failure phenotypes with preserved ejection fraction (HFpEF). Traditional heart failure treatment modalities have shown limited success in improving outcomes for patients with HFpEF, but new evidence suggests that GLP-1RAs could be beneficial. The positive effects of GLP-1RAs are likely due to their ability to reduce systemic inflammation, enhance metabolism and directly affect the cardiovascular system, addressing critical aspects of HFpEF pathology. However, the exact impact of GLP-1RAs on clinical outcomes for different HFpEF phenotypes is still unclear. This review highlights both the potential benefits and the current limitations of GLP-1RA therapy, suggesting a careful approach for their application in clinical practice.
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Affiliation(s)
- Aleksandra Bykova
- Department of Cardiology, Functional and Ultrasound Diagnostics of NV Sklifosovsky Institute for Clinical Medicine, IM Sechenov First Moscow State Medical University (Sechenov University)Moscow, Russia
- Department of Medical Informatics, Scientific Research Institute for System Analysis of the Russian Academy of SciencesMoscow, Russia
| | - Maria Serova
- Department of Cardiology, Functional and Ultrasound Diagnostics of NV Sklifosovsky Institute for Clinical Medicine, IM Sechenov First Moscow State Medical University (Sechenov University)Moscow, Russia
- Department of Surgical Treatment of Complex Rhythm Disorders and Pacing, City Clinical Hospital No 1 Named after NI Pirogov, Moscow State Healthcare InstitutionMoscow, Russia
| | - Maria Chashkina
- Department of Cardiology, Functional and Ultrasound Diagnostics of NV Sklifosovsky Institute for Clinical Medicine, IM Sechenov First Moscow State Medical University (Sechenov University)Moscow, Russia
| | - Raisa Kosharnaya
- Department of Cardiology and Vascular Surgery, Endocrinology Research CentreMoscow, Russia
| | | | - Denis Andreev
- Department of Cardiology, Functional and Ultrasound Diagnostics of NV Sklifosovsky Institute for Clinical Medicine, IM Sechenov First Moscow State Medical University (Sechenov University)Moscow, Russia
| | - Ilya Giverts
- Department of Internal Medicine, Maimonides Medical CenterNew York, NY, US
- Cardiovascular Research Center, Massachusetts General Hospital BostonMA, US
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13
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Shchendrygina A, Rakisheva A, Giverts I, Rustamova Y, Soloveva A. Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiac Function, Exercise Capacity and Quality of Life. Card Fail Rev 2024; 10:e10. [PMID: 39309521 PMCID: PMC11413987 DOI: 10.15420/cfr.2024.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 06/23/2024] [Indexed: 09/25/2024] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are emerging glucose-lowering agents primarily used in managing diabetes and obesity. Recently, GLP-1 RAs have garnered attention for their cardiovascular benefits beyond glycaemic control in patients with type 2 diabetes, exhibiting patterns previously seen in cardiovascular outcomes trials on sodium-glucose cotransporter 2 inhibitors, which now receive a high level of recommendation for the treatment of heart failure (HF). GLP-1 RAs have been increasingly investigated in HF cohorts, but mainly in small-scale studies reporting inconclusive findings regarding clinical outcomes and different safety profiles in HF patients with reduced and preserved ejection fractions. This review discusses the effects of GLP-1 RAs on surrogate HF outcomes, such as cardiac structure and function, exercise capacity and quality of life, in HF patients across the spectrum of left ventricular ejection fraction, to provide insights into the potential of these agents to be investigated in large clinical trials to evaluate clinical outcomes.
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Affiliation(s)
- Anastasia Shchendrygina
- Department of Hospital Therapy No. 2, IM Sechenov First Moscow State Medical UniversityMoscow, Russia
| | - Amina Rakisheva
- Department of Cardiology, City Cardiology CenterAlmaty, Kazakhstan
| | - Ilya Giverts
- Department of Internal Medicine, Maimonides Medical CenterBrooklyn, NY, US
- The Cardiovascular Research Center, Massachusetts General CenterBoston, MA, US
| | - Yasmin Rustamova
- Department of Internal Medicine, Educational-Surgery Clinic, Azerbaijan Medical UniversityBaku, Azerbaijan
| | - Anzhela Soloveva
- Department of Cardiology, Almazov National Medical Research CentreSt Petersburg, Russia
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Stone CR, Harris DD, Broadwin M, Kanuparthy M, Nho JW, Yalamanchili K, Hamze J, Abid MR, Sellke FW. Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.15.608191. [PMID: 39211263 PMCID: PMC11361037 DOI: 10.1101/2024.08.15.608191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Objective Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking. Approach and Results Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014). Conclusion This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
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15
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Huang XD, Jiang DS, Feng X, Fang ZM. The benefits of oral glucose-lowering agents: GLP-1 receptor agonists, DPP-4 and SGLT-2 inhibitors on myocardial ischaemia/reperfusion injury. Eur J Pharmacol 2024; 976:176698. [PMID: 38821168 DOI: 10.1016/j.ejphar.2024.176698] [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: 03/09/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/02/2024]
Abstract
Myocardial infarction (MI) is a life-threatening cardiovascular disease that, on average, results in 8.5 million deaths worldwide each year. Timely revascularization of occluded vessels is a critical method of myocardial salvage. However, reperfusion paradoxically leads to the worsening of myocardial damage known as myocardial ischaemia/reperfusion injury (MI/RI). Therefore, reducing the size of myocardial infarction after reperfusion is critical and remains an important therapeutic goal. The susceptibility of the myocardium to MI/RI may be increased by diabetes. Currently, some traditional antidiabetic agents such as metformin reduce MI/RI by decreasing inflammation, inhibiting oxidative stress, and improving vascular endothelial function. This appears to be a new direction for the treatment of MI/RI. Recent cardiovascular outcome trials have shown that several oral antidiabetic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose-linked transporter-2 inhibitors (SGLT-2is), not only have good antidiabetic effects but also have a protective effect on myocardial protection. This article aims to discuss the mechanisms and effects of oral antidiabetic agents, including GLP-1RAs, DPP-4is, and SGLT-2is, on MI/RI to facilitate their clinical application.
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Affiliation(s)
- Xu-Dong Huang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Cardiothoracic Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Ding-Sheng Jiang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China
| | - Xin Feng
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Ze-Min Fang
- Division of Cardiovascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Cardiothoracic Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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16
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Ben Nasr M, Usuelli V, Dellepiane S, Seelam AJ, Fiorentino TV, D'Addio F, Fiorina E, Xu C, Xie Y, Balasubramanian HB, Castillo-Leon E, Loreggian L, Maestroni A, Assi E, Loretelli C, Abdelsalam A, El Essawy B, Uccella S, Pastore I, Lunati ME, Sabiu G, Petrazzuolo A, Ducci G, Sacco E, Centofanti L, Venturini M, Mazzucchelli S, Mattinzoli D, Ikehata M, Castellano G, Visner G, Kaifeng L, Lee KM, Wang Z, Corradi D, La Rosa S, Danese S, Yang J, Markmann JF, Zuccotti GV, Abdi R, Folli F, Fiorina P. Glucagon-like peptide 1 receptor is a T cell-negative costimulatory molecule. Cell Metab 2024; 36:1302-1319.e12. [PMID: 38838642 DOI: 10.1016/j.cmet.2024.05.001] [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: 07/27/2023] [Revised: 12/06/2023] [Accepted: 05/02/2024] [Indexed: 06/07/2024]
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of glucose metabolism known to be expressed by pancreatic β cells. We herein investigated the role of GLP-1R on T lymphocytes during immune response. Our data showed that a subset of T lymphocytes expresses GLP-1R, which is upregulated during alloimmune response, similarly to PD-1. When mice received islet or cardiac allotransplantation, an expansion of GLP-1Rpos T cells occurred in the spleen and was found to infiltrate the graft. Additional single-cell RNA sequencing (scRNA-seq) analysis conducted on GLP-1Rpos and GLP-1Rneg CD3+ T cells unveiled the existence of molecular and functional dissimilarities between both subpopulations, as the GLP-1Rpos are mainly composed of exhausted CD8 T cells. GLP-1R acts as a T cell-negative costimulatory molecule, and GLP-1R signaling prolongs allograft survival, mitigates alloimmune response, and reduces T lymphocyte graft infiltration. Notably, GLP-1R antagonism triggered anti-tumor immunity when tested in a preclinical mouse model of colorectal cancer.
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Affiliation(s)
- Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Sergio Dellepiane
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andy Joe Seelam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Emma Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Cong Xu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - Yanan Xie
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - Hari Baskar Balasubramanian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Eduardo Castillo-Leon
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lara Loreggian
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Anna Maestroni
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Emma Assi
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Ahmed Abdelsalam
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Basset El Essawy
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Medicine, Al-Azhar University, Cairo, Egypt
| | - Silvia Uccella
- Humanitas University and IRCCS Humanitas Research Hospital, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli Sacco, Milan, Italy
| | | | - Gianmarco Sabiu
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Adriana Petrazzuolo
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Giacomo Ducci
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy; Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | - Elena Sacco
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy; Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | - Lucia Centofanti
- Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy
| | | | | | - Deborah Mattinzoli
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Masami Ikehata
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Castellano
- Nephrology, dialysis and renal transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Gary Visner
- Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Liu Kaifeng
- Pulmonary Medicine, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Kang Mi Lee
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhimin Wang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Domenico Corradi
- Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Technological innovation, University of Insubria, Varese, Italy; Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele, Milan, Italy
| | - Jun Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science, Wuhan, China
| | - James F Markmann
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Gian Vincenzo Zuccotti
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Department of Pediatrics, Children's Hospital Buzzi, University of Milan, Milan, Italy
| | - Reza Abdi
- Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Franco Folli
- Department of Health Sciences, Universita'degli Studi di Milano, Milan, Italy.
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Endocrinology, ASST Fatebenefratelli Sacco, Milan, Italy.
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17
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Wong SY, Lee ARYB, Sia AHJ, Wo YJ, Teo YH, Teo YN, Syn NL, Ong CC, Teo LL, Yeo TC, Poh KK, Kong WK, Wong RC, Sia CH. Effects of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1RA) on Cardiac Structure and Function: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials. Cardiovasc Drugs Ther 2024; 38:371-389. [PMID: 35819544 DOI: 10.1007/s10557-022-07360-w] [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: 06/10/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE Recent trials suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a cardioprotective role by reducing major adverse cardiac events, stroke mortality and heart failure-related hospitalisations. We examined whether and how GLP-1RAs affect cardiac function in cardiovascular and metabolic diseases including type 2 diabetes, heart failure and post-myocardial infarction. METHODS In this PRISMA-adherent systematic review and meta-analysis, three databases were searched from inception to July 2021 and registered on PROSPERO (CRD42021259661). RESULTS 20 reports of 19 randomized placebo-controlled trials including 2062 participants were meta-analyzed. Among type 2 diabetes patients, GLP-1RA resulted in improved systolic function measured by circumferential strain (mean difference [MD]= -5.48; 95% CI: -10.47 to -0.49; P= 0.03; I2= 89%) and diastolic dysfunction measured by E / A (MD= -0.15; 95% CI: -0.25 to -0.05; P= 0.003; I2= 0%). For post-myocardial infarction patients, GLP-1RA reduced infarct size (g) (MD= -5.36; 95% CI: -10.68 to -0.04; P= 0.05; I2= 78%). Liraglutide, but not exenatide, demonstrated improved systolic function, by increasing left ventricular ejection fraction (MD= 4.89; 95% CI: 3.62 to 6.16; P< 0.00001; I2= 0%) and reducing left ventricular end-systolic volume (MD= -4.15; 95% CI: -7.49 to -0.81; P = 0.01; I2= 0%). Among heart failure patients, no significant changes were noted. CONCLUSION GLP-1RA drugs may improve systolic and diastolic function in type 2 diabetes and reduce infarct size post-acute myocardial infarction with no demonstrable effect on cardiac function in heart failure. Tailored recommendations for the use of GLP-1RAs for cardioprotection should be considered for each patient's condition.
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Affiliation(s)
- Shi Yin Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Aaron Hon Jiun Sia
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yu Jun Wo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Hao Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yao Neng Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas L Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ching-Ching Ong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Diagnostic Imaging, National University Hospital, Singapore, Singapore
| | - Lynette L Teo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Diagnostic Imaging, National University Hospital, Singapore, Singapore
| | - Tiong-Cheng Yeo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Kian-Keong Poh
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - William K Kong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Raymond C Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore
| | - Ching-Hui Sia
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore.
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18
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Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, Gao F, Wang S, Tan R, Yuan J. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:12. [PMID: 38185705 PMCID: PMC10772178 DOI: 10.1038/s41392-023-01688-x] [Citation(s) in RCA: 151] [Impact Index Per Article: 151.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 08/29/2023] [Accepted: 10/18/2023] [Indexed: 01/09/2024] Open
Abstract
Ischemia-reperfusion (I/R) injury paradoxically occurs during reperfusion following ischemia, exacerbating the initial tissue damage. The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions. The Wnt signaling pathway exhibits extensive crosstalk with various other pathways, forming a network system of signaling pathways involved in I/R injury. This review article elucidates the underlying mechanisms involved in Wnt signaling, as well as the complex interplay between Wnt and other pathways, including Notch, phosphatidylinositol 3-kinase/protein kinase B, transforming growth factor-β, nuclear factor kappa, bone morphogenetic protein, N-methyl-D-aspartic acid receptor-Ca2+-Activin A, Hippo-Yes-associated protein, toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β, and hepatocyte growth factor/mesenchymal-epithelial transition factor. In particular, we delve into their respective contributions to key pathological processes, including apoptosis, the inflammatory response, oxidative stress, extracellular matrix remodeling, angiogenesis, cell hypertrophy, fibrosis, ferroptosis, neurogenesis, and blood-brain barrier damage during I/R injury. Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery, while activation of the non-canonical Wnt pathways exacerbates injury. Moreover, we explore novel therapeutic approaches based on these mechanistic findings, incorporating evidence from animal experiments, current standards, and clinical trials. The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction, to facilitate the development of innovative therapeutic agents for I/R injury.
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Affiliation(s)
- Meng Zhang
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
| | - Qian Liu
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hui Meng
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Hongxia Duan
- Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Xin Liu
- Second Clinical Medical College, Jining Medical University, Jining, Shandong, 272067, China
| | - Jian Wu
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Fei Gao
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Shijun Wang
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Rubin Tan
- Department of Physiology, Basic medical school, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jinxiang Yuan
- The Collaborative Innovation Center, Jining Medical University, Jining, Shandong, 272067, China.
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19
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Karakasis P, Patoulias D, Kassimis G, Koufakis T, Klisic A, Doumas M, Fragakis N, Rizzo M. Therapeutic Potential of Sodium-glucose Co-transporter-2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists for Patients with Acute Coronary Syndrome: A Review of Clinical Evidence. Curr Pharm Des 2024; 30:2109-2119. [PMID: 38910481 PMCID: PMC11475097 DOI: 10.2174/0113816128304097240529053538] [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: 01/12/2024] [Accepted: 04/29/2024] [Indexed: 06/25/2024]
Abstract
Atherosclerotic Cardiovascular Disease (ASCVD) is still one of the leading causes of death globally, with Coronary Artery Disease (CAD) being the most prevalent form of ASCVD. Patients with type 2 Diabetes Mellitus (DM) experience an increased risk for ASCVD during the disease course, with CAD being the most common cause of death among affected individuals, resulting in shorter life expectancy and increased morbidity among survivors. Recently, 2 novel classes of anti-diabetic drugs, namely Sodium-Glucose Co-Transporter- 2 (SGLT-2) inhibitors and Glucagon-Like Peptide-1 (GLP-1) receptor agonists, have shown impressive cardio-renal benefits for patients with type 2 DM, while they might decrease cardio-renal risk even in the absence of baseline DM. However, there is no evidence to date regarding their safety and efficacy in the setting of an acute coronary syndrome (ACS) event, regardless of concomitant DM. This study aims to provide a detailed, updated presentation of currently available clinical evidence concerning the potential role of SGLT-2 inhibitors and GLP-1 receptor agonists in the setting of an ACS, and to highlight whether those drug classes could be utilized as adjuncts to standard-of-care treatment in this specific patient population, along with a presentation of the potential short- and long-term cardiovascular benefits.
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Affiliation(s)
- Paschalis Karakasis
- Second Department of Cardiology, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - George Kassimis
- Second Department of Cardiology, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aleksandra Klisic
- Faculty of Medicine, Primary Health Care Center, University of Montenegro, Podgorica, Montenegro
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Fragakis
- Second Department of Cardiology, General Hospital “Hippokration”, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care (Promise), School of Medicine, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
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20
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Stampouloglou PK, Anastasiou A, Bletsa E, Lygkoni S, Chouzouri F, Xenou M, Katsarou O, Theofilis P, Zisimos K, Tousoulis D, Vavuranakis M, Siasos G, Oikonomou E. Diabetes Mellitus in Acute Coronary Syndrome. Life (Basel) 2023; 13:2226. [PMID: 38004366 PMCID: PMC10671950 DOI: 10.3390/life13112226] [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: 10/14/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
The global prevalence of diabetes mellitus (DM) has led to a pandemic, with significant microvascular and macrovascular complications including coronary artery disease (CAD), which worsen clinical outcomes and cardiovascular prognosis. Patients with both acute coronary syndrome (ACS) and DM have worse prognosis and several pathophysiologic mechanisms have been implicated including, insulin resistance, hyperglycemia, endothelial dysfunction, platelet activation and aggregations as well as plaque characteristics and extent of coronary lesions. Therefore, regarding reperfusion strategies in the more complex anatomies coronary artery bypass surgery may be the preferred therapeutic strategy over percutaneous coronary intervention while both hyperglycemia and hypoglycemia should be avoided with closed monitoring of glycemic status during the acute phase of myocardial infraction. However, the best treatment strategy remains undefined. Non-insulin therapies, due to the low risk of hypoglycemia concurrently with the multifactorial CV protective effects, may be proved to be the best treatment option in the future. Nevertheless, evidence for the beneficial effects of glucagon like peptide-1 receptor agonists, dipeptidyl-peptidase 4 inhibitors and sodium glycose cotransporter 2 inhibitors, despite accumulating, is not robust and future randomized control trials may provide more definitive data.
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Affiliation(s)
- Panagiota K. Stampouloglou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Artemis Anastasiou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Evanthia Bletsa
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Stavroula Lygkoni
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Flora Chouzouri
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Maria Xenou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Ourania Katsarou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Panagiotis Theofilis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (D.T.)
| | - Konstantinos Zisimos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Dimitris Tousoulis
- 1st Department of Cardiology, “Hippokration” General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.T.); (D.T.)
| | - Manolis Vavuranakis
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Gerasimos Siasos
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, Thoracic Diseases General Hospital “Sotiria”, National and Kapodistrian University of Athens, 11527 Athens, Greece; (P.K.S.); (A.A.); (E.B.); (S.L.); (F.C.); (M.X.); (K.Z.); (M.V.); (G.S.)
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21
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Solini A, Tricò D, Del Prato S. Incretins and cardiovascular disease: to the heart of type 2 diabetes? Diabetologia 2023; 66:1820-1831. [PMID: 37542009 PMCID: PMC10473999 DOI: 10.1007/s00125-023-05973-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 06/22/2023] [Indexed: 08/06/2023]
Abstract
Major cardiovascular outcome trials and real-life observations have proven that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), regardless of structural GLP-1 homology, exert clinically relevant cardiovascular protection. GLP-1RAs provide cardioprotective benefits through glycaemic and non-glycaemic effects, including improved insulin secretion and action, body-weight loss, blood-pressure lowering and improved lipid profile, as well as via direct effects on the heart and vasculature. These actions are likely combined with anti-inflammatory and antioxidant properties that translate into robust and consistent reductions in atherothrombotic events, particularly in people with type 2 diabetes and established atherosclerotic CVD. GLP-1RAs may also have an impact on obesity and chronic kidney disease, conditions for which cardiovascular risk-reducing options are limited. The available evidence has prompted professional and medical societies to recommend GLP-1RAs for mitigation of the cardiovascular risk in people with type 2 diabetes. This review summarises the clinical evidence for cardiovascular protection with use of GLP-1RAs and the main mechanisms underlying this effect. Moreover, it looks into how the availability of upcoming dual and triple incretin receptor agonists might expand the possibility for cardiovascular protection in people with type 2 diabetes.
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Affiliation(s)
- Anna Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy.
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22
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Ndrepepa G, Kastrati A. Coronary No-Reflow after Primary Percutaneous Coronary Intervention-Current Knowledge on Pathophysiology, Diagnosis, Clinical Impact and Therapy. J Clin Med 2023; 12:5592. [PMID: 37685660 PMCID: PMC10488607 DOI: 10.3390/jcm12175592] [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: 07/10/2023] [Revised: 08/17/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic, develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infarct size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently, the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research.
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Affiliation(s)
- Gjin Ndrepepa
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany;
| | - Adnan Kastrati
- Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse 36, 80636 Munich, Germany;
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany
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23
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Bernardini F, Nusca A, Coletti F, La Porta Y, Piscione M, Vespasiano F, Mangiacapra F, Ricottini E, Melfi R, Cavallari I, Ussia GP, Grigioni F. Incretins-Based Therapies and Their Cardiovascular Effects: New Game-Changers for the Management of Patients with Diabetes and Cardiovascular Disease. Pharmaceutics 2023; 15:1858. [PMID: 37514043 PMCID: PMC10386670 DOI: 10.3390/pharmaceutics15071858] [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: 05/31/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Atherosclerosis is the leading cause of death worldwide, especially in patients with type 2 diabetes mellitus (T2D). GLP-1 receptor agonists and DPP-4 inhibitors were demonstrated to play a markedly protective role for the cardiovascular system beyond their glycemic control. Several cardiovascular outcome trials (CVOT) reported the association between using these agents and a significant reduction in cardiovascular events in patients with T2D and a high cardiovascular risk profile. Moreover, recent evidence highlights a favorable benefit/risk profile in myocardial infarction and percutaneous coronary revascularization settings. These clinical effects result from their actions on multiple molecular mechanisms involving the immune system, platelets, and endothelial and vascular smooth muscle cells. This comprehensive review specifically concentrates on these cellular and molecular processes mediating the cardiovascular effects of incretins-like molecules, aiming to improve clinicians' knowledge and stimulate a more extensive use of these drugs in clinical practice as helpful cardiovascular preventive strategies.
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Affiliation(s)
- Federico Bernardini
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Annunziata Nusca
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Federica Coletti
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Ylenia La Porta
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Mariagrazia Piscione
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Francesca Vespasiano
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Fabio Mangiacapra
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Elisabetta Ricottini
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Rosetta Melfi
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Ilaria Cavallari
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Gian Paolo Ussia
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
| | - Francesco Grigioni
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy
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24
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Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: cardiovascular benefits and mechanisms of action. Nat Rev Cardiol 2023; 20:463-474. [PMID: 36977782 DOI: 10.1038/s41569-023-00849-3] [Citation(s) in RCA: 201] [Impact Index Per Article: 100.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 03/30/2023]
Abstract
Type 2 diabetes mellitus (T2DM) and obesity are metabolic disorders characterized by excess cardiovascular risk. Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists reduce body weight, glycaemia, blood pressure, postprandial lipaemia and inflammation - actions that could contribute to the reduction of cardiovascular events. Cardiovascular outcome trials (CVOTs) have demonstrated that GLP1R agonists reduce the rates of major adverse cardiovascular events in patients with T2DM. Separate phase III CVOTs of GLP1R agonists are currently being conducted in people living with heart failure with preserved ejection fraction and in those with obesity. Mechanistically, GLP1R is expressed at low levels in the heart and vasculature, raising the possibility that GLP1 might have both direct and indirect actions on the cardiovascular system. In this Review, we summarize the data from CVOTs of GLP1R agonists in patients with T2DM and describe the actions of GLP1R agonists on the heart and blood vessels. We also assess the potential mechanisms that contribute to the reduction in major adverse cardiovascular events in individuals treated with GLP1R agonists and highlight the emerging cardiovascular biology of novel GLP1-based multi-agonists currently in development. Understanding how GLP1R signalling protects the heart and blood vessels will optimize the therapeutic use and development of next-generation GLP1-based therapies with improved cardiovascular safety.
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Affiliation(s)
- John R Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
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25
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d'Aiello A, Bonanni A, Vinci R, Pedicino D, Severino A, De Vita A, Filomia S, Brecciaroli M, Liuzzo G. Meta-Inflammation and New Anti-Diabetic Drugs: A New Chance to Knock Down Residual Cardiovascular Risk. Int J Mol Sci 2023; 24:ijms24108643. [PMID: 37239990 DOI: 10.3390/ijms24108643] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/28/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Type 2 diabetes mellitus (DM) represents, with its macro and microvascular complications, one of the most critical healthcare issues for the next decades. Remarkably, in the context of regulatory approval trials, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) proved a reduced incidence of major adverse cardiovascular events (MACEs), i.e., cardiovascular death and heart failure (HF) hospitalizations. The cardioprotective abilities of these new anti-diabetic drugs seem to run beyond mere glycemic control, and a growing body of evidence disclosed a wide range of pleiotropic effects. The connection between diabetes and meta-inflammation seems to be the key to understanding how to knock down residual cardiovascular risk, especially in this high-risk population. The aim of this review is to explore the link between meta-inflammation and diabetes, the role of newer glucose-lowering medications in this field, and the possible connection with their unexpected cardiovascular benefits.
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Affiliation(s)
- Alessia d'Aiello
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Alice Bonanni
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Ramona Vinci
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Daniela Pedicino
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Anna Severino
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Antonio De Vita
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Simone Filomia
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Mattia Brecciaroli
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Giovanna Liuzzo
- Department of Cardiovascular Sciences, Fondazione Policlinico A. Gemelli, IRCCS, 00168 Rome, Italy
- Department of Cardiovascular and Pneumological Sciences, Catholic University of Sacred Heart, 00168 Rome, Italy
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26
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Yang T, Zhang D. Research progress on the effects of novel hypoglycemic drugs in diabetes combined with myocardial ischemia/reperfusion injury. Ageing Res Rev 2023; 86:101884. [PMID: 36801379 DOI: 10.1016/j.arr.2023.101884] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/08/2023] [Accepted: 02/14/2023] [Indexed: 02/18/2023]
Abstract
Acute myocardial infarction (AMI) reperfusion is associated with ischemia/reperfusion (I/R) injury, which leads to enlarged myocardial infarction size, poor healing of the infarcted myocardium, and poor left ventricular remodeling, thus increasing the risk of major adverse cardiovascular events (MACEs). Diabetes increases myocardial susceptibility to I/R injury, decreases myocardial responsiveness to cardioprotective strategies, exacerbates myocardial I/R injury, and expands the infarct size of AMI, thereby increasing the incidence of malignant arrhythmias and heart failure. Currently, evidence regarding pharmacological interventions for diabetes combined with AMI and I/R injury is lacking. Traditional hypoglycemic drugs have a limited role in the prevention and treatment of diabetes combined with I/R injury. Current evidence suggests that novel hypoglycemic drugs may exert a preventive effect on diabetes combined with myocardial I/R injury, especially glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-dependent glucose transporter protein 2 inhibitors (SGLT2i), which may increase coronary blood flow, reduce acute thrombosis, attenuate I/R injury, decrease myocardial infarction size, inhibit structural and functional remodeling of the ischemic heart, improve cardiac function, and reduce the occurrence of MACEs of diabetes patients combined with AMI via mechanisms such as reduction of inflammatory response, inhibition of oxidative stress, and improvement of vascular endothelial function. This paper will systematically elaborate the protective role and molecular mechanisms of GLP-1 RA and SGLT2i in diabetes combined with myocardial I/R injury, aiming to provide clinical assistance.
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Affiliation(s)
- Tiangui Yang
- Department of Cardiology, Shengjing Hospital of China Medical University, China.
| | - Daqing Zhang
- Department of Cardiology, Shengjing Hospital of China Medical University, China.
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27
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Exendin-4 alleviates myocardial ischemia reperfusion injury by enhancing autophagy through promoting nuclear translocation of TFEB. Exp Cell Res 2023; 423:113469. [PMID: 36627100 DOI: 10.1016/j.yexcr.2023.113469] [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: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/09/2023]
Abstract
Ischemia-reperfusion (I/R) injury (IRI) is a common clinical consequence of myocardial infarction. Exendin-4 is a glucagon-like peptide-1 (GLP-1) analog that has been demonstrated to alleviate myocardial IRI. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in myocardial IRI. However, whether exendin-4 exerts a protective effect on myocardial IRI by modulating autophagy remains elusive. Herein, we investigated the effect of exendin-4 on autophagic flux and explored the underlying molecular mechanisms. Our data revealed that the autophagic flux was blocked in the human ventricular cardiomyocyte cell lines (AC16) subjected to oxygen glucose deprivation/reoxygenation (OGD/R) in vitro. Exendin-4 pre-treatment markedly restored the blocked autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB and transcription of genes involving autophagy initiation, the effect of which was reversed by TFEB knockdown. The restoration of autophagic flux contributed to multiple beneficial effects of exendin-4 in cardiomyocytes, including reduction of oxidative stress, preservation of mitochondrial network as well as inhibition of cytochrome c leakage from mitochondrial permeability transition pore (MPTP) and the resulting apoptosis. Moreover, the administration of exendin-4 reduced infarct size and preserved cardiac function through its anti-apoptosis and antioxidative effects in vivo. These results shed some light on understanding the novel mechanism of exendin-4 as a protective agent against myocardial IRI.
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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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Huixing L, Di F, Daoquan P. Effect of Glucagon-like Peptide-1 Receptor Agonists on Prognosis of Heart Failure and Cardiac Function: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin Ther 2023; 45:17-30. [PMID: 36604209 DOI: 10.1016/j.clinthera.2022.12.006] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 01/04/2023]
Abstract
PURPOSE Whether an antidiabetic drug, glucagon-like peptide-1 receptor agonist (GLP-1RA), could improve the prognosis of heart failure and cardiac function remains controversial. We conducted a systematic review and meta-analysis of randomized controlled trials to explore the influence of GLP-1RAs on heart failure in patients regardless of diabetes diagnosis. METHODS Literature in English from the PubMed, EMBASE, and Cochrane Library databases was searched from inception to July 2022. The study aim was to identify published, randomized, placebo-controlled trials testing GLP-1RAs in patients with or without diabetes. Outcomes were heart failure hospitalization, cardiac function, and structure measures. FINDINGS Twenty-two randomized controlled trials involving 61,412 patients are included in the meta-analysis. Overall, compared with the placebo group, GLP-1RA treatment could not significantly decrease heart failure hospitalization in patients with a history of heart failure (hazard ratio [HR], 1.07; 95% CI, 0.91 to 1.25; P = 0.422). Six-minute walking test distances (WMD, 19.08 m; 95% CI, 4.81 to 33.36; P = 0.01), E-wave (SMD, -0.40; 95% CI, -0.60 to -0.20; P < 0.001), early diastolic to late diastolic velocities ratio (WMD, -0.10; 95% CI, -0.18 to -0.02; P = 0.01), mitral inflow E velocity to tissue Doppler e' ratio (WMD, -0.97; 95% CI, -1.54 to -0.41; P < 0.001), and E-wave deceleration time (WMD, -9.96 milliseconds; 95% CI, -18.52 to -1.41; P = 0.02) increased significantly after administration of GLP-1RAs. However, GLP-1RAs do not significantly influence N-terminal pro-B-type natriuretic peptide levels (WMD, -20.02 pg/mL; 95% CI, -53.12 to 13.08; P = 0.24), Minnesota Living with Heart Failure Questionnaire quality of life scores (WMD, -1.08; 95% CI, -3.99 to 1.84; P = 0.47), or left ventricular ejection fractions (WMD, -0.37%; 95% CI, -1.19 to 0.46; P = 0.38). IMPLICATIONS GLP-1RAs did not reduce heart failure readmissions in patients with a history of heart failure and elevated N-terminal pro-B-type natriuretic peptide levels. Thus, the prognosis of heart failure was not improved, although GLP-1RAs did significantly improve left ventricular diastolic function in patients. PROSPERO identifier: CRD42021226231.
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Affiliation(s)
- Liu Huixing
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Fu Di
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Peng Daoquan
- Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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McLean BA, Wong CK, Kabir MG, Drucker DJ. Glucagon-like Peptide-1 receptor Tie2+ cells are essential for the cardioprotective actions of liraglutide in mice with experimental myocardial infarction. Mol Metab 2022; 66:101641. [PMID: 36396031 PMCID: PMC9706177 DOI: 10.1016/j.molmet.2022.101641] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the rates of major cardiovascular events, including myocardial infarction in people with type 2 diabetes, and decrease infarct size while preserving ventricular function in preclinical studies. Nevertheless, the precise cellular sites of GLP-1R expression that mediate the cardioprotective actions of GLP-1 in the setting of ischemic cardiac injury are uncertain. METHODS Publicly available single cell RNA sequencing (scRNA-seq) datasets on mouse and human heart cells were analyzed for Glp1r/GLP1R expression. Fluorescent activated cell sorting was used to localize Glp1r expression in cell populations from the mouse heart. The importance of endothelial and hematopoietic cells for the cardioprotective response to liraglutide in the setting of acute myocardial infarction (MI) was determined by inactivating the Glp1r in Tie2+ cell populations. Cardiac gene expression profiles regulated by liraglutide were examined using RNA-seq to interrogate mouse atria and both infarcted and non-infarcted ventricular tissue after acute coronary artery ligation. RESULTS In mice, cardiac Glp1r mRNA transcripts were exclusively detected in endocardial cells by scRNA-seq. In contrast, analysis of human heart by scRNA-seq localized GLP1R mRNA transcripts to populations of atrial and ventricular cardiomyocytes. Moreover, very low levels of GIPR, GCGR and GLP2R mRNA transcripts were detected in the human heart. Cell sorting and RNA analyses detected cardiac Glp1r expression in endothelial cells (ECs) within the atria and ventricle in the ischemic and non-ischemic mouse heart. Transcriptional responses to liraglutide administration were not evident in wild type mouse ventricles following acute MI, however liraglutide differentially regulated genes important for inflammation, cardiac repair, cell proliferation, and angiogenesis in the left atrium, while reducing circulating levels of IL-6 and KC/GRO within hours of acute MI. Inactivation of the Glp1r within the Tie2+ cell expression domain encompassing ECs revealed normal cardiac structure and function, glucose homeostasis and body weight in Glp1rTie2-/- mice. Nevertheless, the cardioprotective actions of liraglutide to reduce infarct size, augment ejection fraction, and improve survival after experimental myocardial infarction (MI), were attenuated in Glp1rTie2-/- mice. CONCLUSIONS These findings identify the importance of the murine Tie2+ endothelial cell GLP-1R as a target for the cardioprotective actions of GLP-1R agonists and support the importance of the atrial and ventricular endocardial GLP-1R as key sites of GLP-1 action in the ischemic mouse heart. Hitherto unexplored species-specific differences in cardiac GLP-1R expression challenge the exclusive use of mouse models for understanding the mechanisms of GLP-1 action in the normal and ischemic human heart.
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Glycaemic Control in Patients Undergoing Percutaneous Coronary Intervention: What Is the Role for the Novel Antidiabetic Agents? A Comprehensive Review of Basic Science and Clinical Data. Int J Mol Sci 2022; 23:ijms23137261. [PMID: 35806265 PMCID: PMC9266811 DOI: 10.3390/ijms23137261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 11/17/2022] Open
Abstract
Coronary artery disease (CAD) remains one of the most important causes of morbidity and mortality worldwide, and revascularization through percutaneous coronary interventions (PCI) significantly improves survival. In this setting, poor glycaemic control, regardless of diabetes, has been associated with increased incidence of peri-procedural and long-term complications and worse prognosis. Novel antidiabetic agents have represented a paradigm shift in managing patients with diabetes and cardiovascular diseases. However, limited data are reported so far in patients undergoing coronary stenting. This review intends to provide an overview of the biological mechanisms underlying hyperglycaemia-induced vascular damage and the contrasting actions of new antidiabetic drugs. We summarize existing evidence on the effects of these drugs in the setting of PCI, addressing pre-clinical and clinical studies and drug-drug interactions with antiplatelet agents, thus highlighting new opportunities for optimal long-term management of these patients.
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Almutairi M, Chan JSF, Ussher JR. New Therapeutic Options for Type 2 Diabetes Mellitus and Their Impact Against Ischemic Heart Disease. Front Physiol 2022; 13:904626. [PMID: 35832485 PMCID: PMC9271769 DOI: 10.3389/fphys.2022.904626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/08/2022] [Indexed: 11/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) greatly increases risk for cardiovascular disease, including ischemic heart disease and myocardial infarction. With the completion of several cardiovascular outcomes trials (CVOTs) for new glucose-lowering therapies, including the sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists, we now have strong evidence alluding to the cardioprotective nature of these agents in people with T2DM. These agents have frequently been observed to reduce rates for 3-point major adverse cardiovascular events, which encompass death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Herein we will provide an overview on whether reductions in nonfatal myocardial infarction and ischemic heart disease status are a key component of the improved cardiovascular outcomes in people with T2DM treated with either SGLT2 inhibitors or GLP-1R agonists. Observations from preclinical studies will be compared to their clinical counterparts, while being further interrogated to define potential mechanisms that may account for SGLT2 inhibitor or GLP-1R agonist-induced cardioprotection against ischemic heart disease. A better understanding of the role these agents have in impacting the progression of ischemic heart disease in individuals with T2DM will have a substantial impact in our management of this patient population.
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Affiliation(s)
| | - Jordan S. F. Chan
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
| | - John R. Ussher
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada
- *Correspondence: John R. Ussher,
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Kobara M, Toba H, Nakata T. A Glucagon-like Peptide 1 Analog Protects Mitochondria and Attenuates Hypoxia-Reoxygenation Injury in Cultured Cardiomyocytes. J Cardiovasc Pharmacol 2022; 79:568-576. [PMID: 34983916 DOI: 10.1097/fjc.0000000000001218] [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] [Received: 07/04/2021] [Accepted: 12/17/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Glucagon-like peptide 1 (GLP-1) analogs improve glycemic control in diabetes and protect the heart against ischemia-reperfusion injury. However, the mechanisms underlying this protection remain unclear. Mitochondria are essential for myocyte homeostasis. Therefore, we herein examined the effects of a GLP-1 analog on mitochondria after the hypoxia-reoxygenation of rat neonatal cultured cardiomyocytes. Cardiomyocytes were subjected to hypoxia for 5 hours followed by reoxygenation for 30 minutes in the presence or absence of exendin-4 (50 nmol/L), a GLP-1 analog. Hypoxia-reoxygenation increased lactate dehydrogenase and caspase-3 activities, indicators of lethal myocyte injury and apoptosis, respectively, and exendin-4 attenuated these increases. The content of ATP in myocytes decreased after hypoxia-reoxygenation but was preserved by exendin-4. The membrane potential and shape of mitochondria were assessed using a fluorescent probe. Exendin-4 attenuated the hypoxia-reoxygenation-induced disruption of the mitochondrial membrane potential and shortening. Mitochondrial quality control-related factors, such as optic atrophy protein 1, mitofusin 2, dynamin-related protein 1, and parkin, were examined by Western blotting. Exendin-4 significantly increased the expression of the fusion proteins, optic atrophy protein 1 and mitofusin 2, and decreased that of the mitophagy-related protein, parkin, without altering dynamin-related protein 1 expression levels. Exendin-4 also preserved Akt phosphorylation levels after hypoxia-reoxygenation, whereas wortmannin, an inhibitor of the phosphoinositide 3-kinase-Akt pathway, blunted exendin-4-induced myocyte protection and its effects on mitochondrial quality control factors. In conclusion, exendin-4 protected mitochondria by preserving the phosphorylation of Akt and fusion proteins, leading to the attenuation of hypoxia-reoxygenation-induced injury in cultured myocytes.
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Affiliation(s)
- Miyuki Kobara
- Department of Clinical Pharmacology, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan
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Fernandez Rico C, Konate K, Josse E, Nargeot J, Barrère-Lemaire S, Boisguérin P. Therapeutic Peptides to Treat Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med 2022; 9:792885. [PMID: 35252383 PMCID: PMC8891520 DOI: 10.3389/fcvm.2022.792885] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular diseases (CVD) including acute myocardial infarction (AMI) rank first in worldwide mortality and according to the World Health Organization (WHO), they will stay at this rank until 2030. Prompt revascularization of the occluded artery to reperfuse the myocardium is the only recommended treatment (by angioplasty or thrombolysis) to decrease infarct size (IS). However, despite beneficial effects on ischemic lesions, reperfusion leads to ischemia-reperfusion (IR) injury related mainly to apoptosis. Improvement of revascularization techniques and patient care has decreased myocardial infarction (MI) mortality however heart failure (HF) morbidity is increasing, contributing to the cost-intense worldwide HF epidemic. Currently, there is no treatment for reperfusion injury despite promising results in animal models. There is now an obvious need to develop new cardioprotective strategies to decrease morbidity/mortality of CVD, which is increasing due to the aging of the population and the rising prevalence rates of diabetes and obesity. In this review, we will summarize the different therapeutic peptides developed or used focused on the treatment of myocardial IR injury (MIRI). Therapeutic peptides will be presented depending on their interacting mechanisms (apoptosis, necroptosis, and inflammation) reported as playing an important role in reperfusion injury following myocardial ischemia. The search and development of therapeutic peptides have become very active, with increasing numbers of candidates entering clinical trials. Their optimization and their potential application in the treatment of patients with AMI will be discussed.
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Affiliation(s)
- Carlota Fernandez Rico
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Karidia Konate
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Emilie Josse
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channel Science and Therapeutics, Valbonne, France
| | - Prisca Boisguérin
- PHYMEDEXP, Université de Montpellier, CNRS, INSERM, Montpellier, France
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Jonik S, Marchel M, Grabowski M, Opolski G, Mazurek T. Gastrointestinal Incretins-Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) beyond Pleiotropic Physiological Effects Are Involved in Pathophysiology of Atherosclerosis and Coronary Artery Disease-State of the Art. BIOLOGY 2022; 11:biology11020288. [PMID: 35205155 PMCID: PMC8869592 DOI: 10.3390/biology11020288] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/03/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023]
Abstract
Simple Summary The presented manuscript contains the most current and extensive summary of the role of the most predominant gastrointestinal hormones—GIP and GLP-1 in the pathophysiology of atherosclerosis and coronary artery disease both in animals and humans. We have described GIP and GLP-1 as (1) expressed in many human tissues, (2) emphasized relationship between GIP and GLP-1 and inflammation, (3) highlighted importance of GIP and GLP-1-dependent pathways in atherosclerosis and coronary artery disease and (4) proved that GIP and GLP-1 could be used as markers of incidence, clinical course and recurrence of coronary artery disease, and related to extent and severity of atherosclerosis and myocardial ischemia. Our initial review may state a cornerstone for the future, however, there are still many unknowns and understatements on this topic. Due to the widespread growing interest for the potential use of incretins in cardiovascular diseases, we think that further research in this direction is desirable. For the future, we would like to recognize GIP and GLP-1 as widely implemented into clinical practice as new biomarkers of atherosclerosis and coronary artery disease. Abstract Coronary artery disease (CAD), which is the manifestation of atherosclerosis in coronary arteries, is the most common single cause of death and is responsible for disabilities of millions of people worldwide. Despite numerous dedicated clinical studies and an enormous effort to develop diagnostic and therapeutic methods, coronary atherosclerosis remains one of the most serious medical problems of the modern world. Hence, new markers are still being sought to identify and manage CAD optimally. Trying to face this problem, we have raised the question of the most predominant gastrointestinal hormones; glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), mainly involved in carbohydrates disorders, could be also used as new markers of incidence, clinical course, and recurrence of CAD and are related to extent and severity of atherosclerosis and myocardial ischemia. We describe GIP and GLP-1 as expressed in many animal and human tissues, known to be connected to inflammation and related to enormous noncardiac and cardiovascular (CV) diseases. In animals, GIP and GLP-1 improve endothelial function and lead to reduced atherosclerotic plaque macrophage infiltration and stabilize atherosclerotic lesions by directly blocking monocyte migration. Moreover, in humans, GIPR activation induces the pro-atherosclerotic factors ET-1 (endothelin-1) and OPN (osteopontin) but also has anti-atherosclerotic effects through secretion of NO (nitric oxide). Furthermore, four large clinical trials showed a significant reduction in composite of CV death, MI, and stroke in long-term follow-up using GLP-1 analogs for DM 2 patients: liraglutide in LEADER, semaglutide in SUSTAIN-6, dulaglutide in REWIND and albiglutide in HARMONY. However, very little is known about GIP metabolism in the acute phase of myocardial ischemia or for stable patients with CAD, which constitutes a direction for future research. This review aims to comprehensively discuss the impact of GIP and GLP-1 on atherosclerosis and CAD and its potential therapeutic implications.
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Wiberg S, Kjaergaard J, Møgelvang R, Møller CH, Kandler K, Ravn H, Hassager C, Køber L, Nilsson JC. Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial. BMJ Open 2021; 11:e052340. [PMID: 34740932 PMCID: PMC8573662 DOI: 10.1136/bmjopen-2021-052340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are associated with risk of death, as well as brain, heart and kidney injury. Glucagon-like peptide-1 (GLP-1) analogues are approved for treatment of type 2 diabetes, and GLP-1 analogues have been suggested to have potential organ-protective and anti-inflammatory effects. During cardiopulmonary bypass (CPB), consensus on the optimal fraction of oxygen is lacking. The objective of this study is to determine the efficacy of the GLP-1-analogue exenatide versus placebo and restrictive oxygenation (50% fractional inspired oxygen, FiO2) versus liberal oxygenation (100% FiO2) in patients undergoing open heart surgery. METHODS AND ANALYSIS A randomised, placebo-controlled, double blind (for the exenatide intervention)/single blind (for the oxygenation strategy), 2×2 factorial designed single-centre trial on adult patients undergoing elective or subacute CABG and/or surgical AVR. Patients will be randomised in a 1:1 and 1:1 ratio to a 6-hour and 15 min infusion of 17.4 µg of exenatide or placebo during CPB and to a FiO2 of 50% or 100% during and after weaning from CPB. Patients will be followed until 12 months after inclusion of the last participant. The primary composite endpoint consists of time to first event of death, renal failure requiring renal replacement therapy, hospitalisation for stroke or heart failure. In addition, the trial will include predefined sub-studies applying more advanced measures of cardiac- and pulmonary dysfunction, renal dysfunction and cerebral dysfunction. The trial is event driven and aims at 323 primary endpoints with a projected inclusion of 1400 patients. ETHICS AND DISSEMINATION Eligible patients will provide informed, written consent prior to randomisation. The trial is approved by the local ethics committee and is conducted in accordance with Danish legislation and the Declaration of Helsinki. The results will be presented in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT02673931.
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Affiliation(s)
| | | | | | | | - Kristian Kandler
- Department of Cardiothoracic Surgery, Rigshospitalet, Copenhagen, Denmark
| | - Hanne Ravn
- Department of Cardiothoracic Anesthesiology, Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Køber
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
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Natali A, Nesti L, Tricò D, Ferrannini E. Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence. Cardiovasc Diabetol 2021; 20:196. [PMID: 34583699 PMCID: PMC8479881 DOI: 10.1186/s12933-021-01385-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/17/2021] [Indexed: 02/08/2023] Open
Abstract
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.
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Affiliation(s)
- Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy.
| | - Lorenzo Nesti
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
| | - Domenico Tricò
- Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100, Pisa, Italy
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
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Xiao F, Zha Q, Zhang Q, Wu Q, Chen Z, Yang Y, Yang K, Liu Y. Decreased Glucagon-Like Peptide-1 Is Associated With Calcific Aortic Valve Disease: GLP-1 Suppresses the Calcification of Aortic Valve Interstitial Cells. Front Cardiovasc Med 2021; 8:709741. [PMID: 34513952 PMCID: PMC8428521 DOI: 10.3389/fcvm.2021.709741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/23/2021] [Indexed: 12/25/2022] Open
Abstract
Objectives: This study explores the concentration and role of glucagon-like peptide-1 (GLP-1) in calcific aortic valve disease (CAVD). Background: Calcific aortic valve disease is a chronic disease presenting with aortic valve degeneration and mineralization. We hypothesized that the level of GLP-1 is associated with CAVD and that it participates in the calcification of aortic valve interstitial cells (AVICs). Methods: We compared the concentration of GLP-1 between 11 calcific and 12 normal aortic valve tissues by immunohistochemical (IHC) analysis. ELISA was used to measure GLP-1 in serum of the Control (n = 197) and CAVD groups (n = 200). The effect of GLP-1 on the calcification of AVICs and the regulation of calcific gene expression were also characterized. Results: The GLP-1 concentration in the calcific aortic valves was 39% less than that in the control non-calcified aortic valves. Its concentration in serum was 19.3% lower in CAVD patients. Multivariable regression analysis demonstrated that GLP-1 level was independently associated with CAVD risk. In vitro, GLP-1 antagonized AVIC calcification in a dose- and time-dependent manner and it down-regulated RUNX2, MSX2, BMP2, and BMP4 expression but up-regulated SOX9 expression. Conclusions: A reduction in GLP-1 was associated with CAVD, and GLP-1 participated in the mineralization of AVICs by regulating specific calcific genes. GLP-1 warrants consideration as a novel treatment target for CAVD.
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Affiliation(s)
- Fan Xiao
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Zha
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qianru Zhang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qihong Wu
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhongli Chen
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ying Yang
- Department of Endocrinology, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Ke Yang
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yan Liu
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Begic E, Causevic M. Glucagon-Like Peptide-1 Receptor Agonists and Brain Vascular Function. Heart Lung Circ 2021; 30:1675-1680. [PMID: 34479819 DOI: 10.1016/j.hlc.2021.07.024] [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: 05/03/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022]
Abstract
Prevention of cardiovascular events and regression of atherosclerotic changes are the primary aims of preventive cardiovascular medicine. Arterial thrombosis is caused by endothelial dysfunction, which disrupts vascular haemostasis. Glucagon-like peptide 1 (GLP-1) receptor agonists have been initially used as glucose lowering agents, but over time have been used for other indications due to their cardiorenal benefit, as well as their benefit in the regression of atherosclerosis process. The aim of this paper is to present the benefits of GLP-1 receptor agonists in the prevention of atherosclerotic changes, in the preservation of brain vascular function, and to show the possible role in the treatment of neurodegenerative diseases.
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Affiliation(s)
- Edin Begic
- Department of Cardiology, General Hospital "Prim.Dr. Abdulah Nakas", Sarajevo, Bosnia and Herzegovina; Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina.
| | - Mirsada Causevic
- Department of Pharmacology, Sarajevo Medical School, Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
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Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS. Cells 2021; 10:cells10092188. [PMID: 34571836 PMCID: PMC8468909 DOI: 10.3390/cells10092188] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/18/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.
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Heliste J, Jokilammi A, Vaparanta K, Paatero I, Elenius K. Combined genetic and chemical screens indicate protective potential for EGFR inhibition to cardiomyocytes under hypoxia. Sci Rep 2021; 11:16661. [PMID: 34404849 PMCID: PMC8371130 DOI: 10.1038/s41598-021-96033-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/27/2021] [Indexed: 12/30/2022] Open
Abstract
The return of blood flow to ischemic heart after myocardial infarction causes ischemia-reperfusion injury. There is a clinical need for novel therapeutic targets to treat myocardial ischemia-reperfusion injury. Here we screened for targets for the treatment of ischemia-reperfusion injury using a combination of shRNA and drug library analyses in HL-1 mouse cardiomyocytes subjected to hypoxia and reoxygenation. The shRNA library included lentiviral constructs targeting 4625 genes and the drug library 689 chemical compounds approved by the Food and Drug Administration (FDA). Data were analyzed using protein-protein interaction and pathway analyses. EGFR inhibition was identified as a cardioprotective mechanism in both approaches. Inhibition of EGFR kinase activity with gefitinib improved cardiomyocyte viability in vitro. In addition, gefitinib preserved cardiac contractility in zebrafish embryos exposed to hypoxia-reoxygenation in vivo. These findings indicate that the EGFR inhibitor gefitinib is a potential candidate for further studies of repurposing the drug for the treatment of myocardial infarction.
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Affiliation(s)
- Juho Heliste
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland.,Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
| | - Anne Jokilammi
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland.,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6B, 20520, Turku, Finland
| | - Katri Vaparanta
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland.,Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland.,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6B, 20520, Turku, Finland.,MediCity Research Laboratories, University of Turku, Tykistökatu 6A, 20520, Turku, Finland
| | - Ilkka Paatero
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6B, 20520, Turku, Finland.
| | - Klaus Elenius
- Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20014, Turku, Finland. .,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Tykistökatu 6B, 20520, Turku, Finland. .,MediCity Research Laboratories, University of Turku, Tykistökatu 6A, 20520, Turku, Finland. .,Department of Oncology, Turku University Hospital, PO Box 52, 20521, Turku, Finland.
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Eid RA, Bin-Meferij MM, El-Kott AF, Eleawa SM, Zaki MSA, Al-Shraim M, El-Sayed F, Eldeen MA, Alkhateeb MA, Alharbi SA, Aldera H, Khalil MA. Exendin-4 Protects Against Myocardial Ischemia-Reperfusion Injury by Upregulation of SIRT1 and SIRT3 and Activation of AMPK. J Cardiovasc Transl Res 2021; 14:619-635. [PMID: 32239434 DOI: 10.1007/s12265-020-09984-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 03/02/2020] [Indexed: 10/24/2022]
Abstract
This study evaluated if the cardioprotective effect of Exendin-4 against ischemia/reperfusion (I/R) injury in male rats involves modulation of AMPK and sirtuins. Adult male rats were divided into sham, sham + Exendin-4, I/R, I/R + Exendin-4, and I/R + Exendin-4 + EX-527, a sirt1 inhibitor. Exendin-4 reduced infarct size and preserved the function and structure of the left ventricles (LV) of I/R rats. It also inhibited oxidative stress and apoptosis and upregulated MnSOD and Bcl-2 in their infarcted myocardium. With no effect on SIRTs 2/6/7, Exendin-4 activated and upregulated mRNA and protein levels of SIRT1, increased levels of SIRT3 protein, activated AMPK, and reduced the acetylation of p53 and PGC-1α as well as the phosphorylation of FOXO-1. EX-527 completely abolished all beneficial effects of Exendin-4 in I/R-induced rats. In conclusion, Exendin-4 cardioprotective effect against I/R involves activation of SIRT1 and SIRT3. Graphical Abstract Exendin-4 could scavenge free radical directly, upregulate p53, and through upregulation of SIRT1 and stimulating SIRT1 nuclear accumulation. In addition, Exendin-4 also upregulates SIRT3 which plays an essential role in the upregulation of antioxidants, inhibition of reactive oxygen species (ROS) generation, and prevention of mitochondria damage. Accordingly, SIRT1 induces the deacetylation of PGC-1α and p53 and is able to bind p-FOXO-1. This results in inhibition of cardiomyocyte apoptosis through increasing Bcl-2 levels, activity, and levels of MnSOD; decreasing expression of Bax; decreasing cytochrome C release; and improving mitochondria biogenesis through upregulation of Mfn-2.
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Affiliation(s)
- Refaat A Eid
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
| | | | - Attalla Farag El-Kott
- Department of Biology, College of Science, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia
- Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Samy M Eleawa
- Department of Applied Medical Sciences, College of Health Sciences, PAAET, Shuwaikh, Kuwait
| | - Mohamed Samir Ahmed Zaki
- Department of Anatomy, College of Medicine, King Khalid University, P.O. 641, Abha, 61421, Saudi Arabia
- Department of Histology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Mubarak Al-Shraim
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Fahmy El-Sayed
- Department of Pathology, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Muhammad Alaa Eldeen
- Biology Department, Physiology Section, Faculty of Science, Zagazig University, Zagazig, Egypt
| | - Mahmoud A Alkhateeb
- Department of Basic Medical Sciences/College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Samah A Alharbi
- Department of Physiology, College of Medicine, Umm Al-Qura University, Mekkah, Saudi Arabia
| | - Hussain Aldera
- Department of Basic Medical Sciences/College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mohammad A Khalil
- Department of Basic Medical Sciences, Faculty of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia
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Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy. J Clin Med 2021; 10:jcm10132968. [PMID: 34279451 PMCID: PMC8268641 DOI: 10.3390/jcm10132968] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/22/2021] [Accepted: 06/27/2021] [Indexed: 02/06/2023] Open
Abstract
The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.
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Yaribeygi H, Farrokhi FR, Abdalla MA, Sathyapalan T, Banach M, Jamialahmadi T, Sahebkar A. The Effects of Glucagon-Like Peptide-1 Receptor Agonists and Dipeptydilpeptidase-4 Inhibitors on Blood Pressure and Cardiovascular Complications in Diabetes. J Diabetes Res 2021; 2021:6518221. [PMID: 34258291 PMCID: PMC8263148 DOI: 10.1155/2021/6518221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are a class of newly introduced antidiabetic medications that potentially lower blood glucose by several molecular pathways. DPP-4 inhibitors are the other type of novel antidiabetic medications which act by preventing GLP-1 inactivation and thereby increasing the activity levels of GLP-1, leading to more glucose-induced insulin release from islet β-cells and suppression of glucagon release. Most patients with diabetes have concurrent hypertension and cardiovascular disorder. If antihyperglycemic agents can attenuate the risk of hypertension and cardiovascular disease, they will amplify their overall beneficial effects. There is conflicting evidence on the cardiovascular benefits of GLP-1R induction in laboratory studies and clinical trials. In this study, we have reviewed the main molecular mechanisms by which GLP-1R induction may modulate the cardiovascular function and the results of cardiovascular outcome clinical trials.
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Affiliation(s)
- Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Farin Rashid Farrokhi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, UK
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, Lodz, Poland
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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45
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Kahles F, Rückbeil MV, Mertens RW, Foldenauer AC, Arrivas MC, Moellmann J, Lebherz C, Biener M, Giannitsis E, Katus HA, Marx N, Lehrke M. Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction. Eur Heart J 2021; 41:882-889. [PMID: 31620788 DOI: 10.1093/eurheartj/ehz728] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/04/2019] [Accepted: 10/04/2019] [Indexed: 12/17/2022] Open
Abstract
AIMS Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. METHODS AND RESULTS In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. CONCLUSION In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.
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Affiliation(s)
- Florian Kahles
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Marcia V Rückbeil
- Department of Medical Statistics, University Hospital Aachen, Pauwelsstraße 19, Aachen 52074, Germany
| | - Robert W Mertens
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Ann C Foldenauer
- Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Translational Medicine and Pharmacology (TMP), Theodor-Stern-Kai 7, Frankfurt am Main 60596, Germany
| | - Maria C Arrivas
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Julia Moellmann
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Corinna Lebherz
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Moritz Biener
- Department of Cardiology, Angiology, and Pneumology, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany
| | - Evangelos Giannitsis
- Department of Cardiology, Angiology, and Pneumology, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany
| | - Hugo A Katus
- Department of Cardiology, Angiology, and Pneumology, Heidelberg University Hospital, Im Neuenheimer Feld 410, Heidelberg 69120, Germany
| | - Nikolaus Marx
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
| | - Michael Lehrke
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Pauwelsstraße 30, Aachen 52074, Germany
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46
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Helmstädter J, Keppeler K, Küster L, Münzel T, Daiber A, Steven S. Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor. Br J Pharmacol 2021; 179:659-676. [PMID: 33764504 PMCID: PMC8820186 DOI: 10.1111/bph.15462] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/12/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP‐1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP‐1 and receptor agonists, and the GLP‐1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP‐1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP‐1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP‐1 receptor‐dependent versus independent effects secondary of GLP‐1 metabolites. We conclude that the favourable cardiovascular profile of GLP‐1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non‐diabetic populations.
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Affiliation(s)
- Johanna Helmstädter
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Karin Keppeler
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Leonie Küster
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.,Partner Site Rhine-Main, German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Sebastian Steven
- Department of Cardiology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.,Center of Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany
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Dambrova M, Zuurbier CJ, Borutaite V, Liepinsh E, Makrecka-Kuka M. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic Biol Med 2021; 165:24-37. [PMID: 33484825 DOI: 10.1016/j.freeradbiomed.2021.01.036] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/13/2021] [Accepted: 01/14/2021] [Indexed: 12/12/2022]
Abstract
The heart is the most metabolically flexible organ with respect to the use of substrates available in different states of energy metabolism. Cardiac mitochondria sense substrate availability and ensure the efficiency of oxidative phosphorylation and heart function. Mitochondria also play a critical role in cardiac ischemia/reperfusion injury, during which they are directly involved in ROS-producing pathophysiological mechanisms. This review explores the mechanisms of ROS production within the energy metabolism pathways and focuses on the impact of different substrates. We describe the main metabolites accumulating during ischemia in the glucose, fatty acid, and Krebs cycle pathways. Hyperglycemia, often present in the acute stress condition of ischemia/reperfusion, increases cytosolic ROS concentrations through the activation of NADPH oxidase 2 and increases mitochondrial ROS through the metabolic overloading and decreased binding of hexokinase II to mitochondria. Fatty acid-linked ROS production is related to the increased fatty acid flux and corresponding accumulation of long-chain acylcarnitines. Succinate that accumulates during anoxia/ischemia is suggested to be the main source of ROS, and the role of itaconate as an inhibitor of succinate dehydrogenase is emerging. We discuss the strategies to modulate and counteract the accumulation of substrates that yield ROS and the therapeutic implications of this concept.
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Affiliation(s)
- Maija Dambrova
- Latvian Institute of Organic Synthesis, Riga, Latvia; Riga Stradins University, Riga, Latvia.
| | - Coert J Zuurbier
- Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, AZ 1105, Amsterdam, the Netherlands
| | - Vilmante Borutaite
- Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI). Basic Res Cardiol 2021; 116:4. [PMID: 33495853 DOI: 10.1007/s00395-021-00842-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/04/2021] [Indexed: 01/03/2023]
Abstract
Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3-7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI.
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Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A SIRT1-Dependent Mechanism. Cardiovasc Toxicol 2021; 20:401-418. [PMID: 32193876 DOI: 10.1007/s12012-020-09567-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.
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50
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Bellis A, Mauro C, Barbato E, Ceriello A, Cittadini A, Morisco C. Stress-Induced Hyperglycaemia in Non-Diabetic Patients with Acute Coronary Syndrome: From Molecular Mechanisms to New Therapeutic Perspectives. Int J Mol Sci 2021; 22:E775. [PMID: 33466656 PMCID: PMC7828822 DOI: 10.3390/ijms22020775] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 01/08/2023] Open
Abstract
Stress-induced hyperglycaemia (SIH) at hospital admission for acute coronary syndrome is associated with poor outcome, especially in patients without known diabetes. Nevertheless, insulin treatment in these subjects was not correlated with the reduction of mortality. This is likely due to the fact that SIH in the context of an acute coronary syndrome, compared to that in known diabetes, represents an epiphenomenon of other pathological conditions, such as adrenergic and renin-angiotensin system over-activity, hyperglucagonaemia, increase of circulating free fatty acids and pancreatic beta-cell dysfunction, which are not completely reversed by insulin therapy and so worsen the prognosis. Thus, SIH may be considered not only as a biomarker of organ damage, but also as an indicator of a more complex therapeutic strategy in these subjects. The aim of this review is to analyse the molecular mechanisms by which SIH may favour a worse prognosis in non-diabetic patients with acute coronary syndrome and identify new therapeutic strategies, in addition to insulin therapy, for a more appropriate treatment and improved outcomes.
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Affiliation(s)
- Alessandro Bellis
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy; (A.B.); (C.M.)
| | - Ciro Mauro
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy; (A.B.); (C.M.)
| | - Emanuele Barbato
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, 80131 Napoli, Italy;
| | - Antonio Ceriello
- Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni, 20099 Milan, Italy;
| | - Antonio Cittadini
- Dipartimento di Scienze Mediche Traslazionali, Università Federico II, 80131 Napoli, Italy;
| | - Carmine Morisco
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, 80131 Napoli, Italy;
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