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Minciună IA, Tomoaia R, Mihăilă D, Cismaru G, Puiu M, Roșu R, Simu G, Frîngu F, Irimie DA, Caloian B, Zdrenghea D, Pop D. Recent Advances in Understanding the Molecular Mechanisms of SGLT2 Inhibitors in Atrial Remodeling. Curr Issues Mol Biol 2024; 46:9607-9623. [PMID: 39329923 PMCID: PMC11430639 DOI: 10.3390/cimb46090571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/26/2024] [Accepted: 08/30/2024] [Indexed: 09/28/2024] Open
Abstract
Atrial cardiomyopathy and remodeling play pivotal roles in the development of atrial fibrillation (AF) and heart failure (HF), involving complex changes in atrial structure and function. These changes facilitate the progression of AF and HF by creating a dynamic interplay between mechanical stress and electrical disturbances in the heart. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for the management of type 2 diabetes, have demonstrated promising cardiovascular benefits, being currently one of the cornerstone treatments in HF management. Despite recent data from randomized clinical trials indicating that SGLT2is may significantly influence atrial remodeling, their overall effectiveness in this context is still under debate. Given the emerging evidence, this review examines the molecular mechanisms through which SGLT2is exert their effects on atrial remodeling, aiming to clarify their potential benefits and limitations. By exploring these mechanisms, this review aims to provide insights into how SGLT2is can be integrated into strategies for preventing the progression of atrial remodeling and HF, as well as the development of AF.
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Affiliation(s)
- Ioan-Alexandru Minciună
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Raluca Tomoaia
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Dragos Mihăilă
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
| | - Gabriel Cismaru
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Mihai Puiu
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Radu Roșu
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Gelu Simu
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Florina Frîngu
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Diana Andrada Irimie
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Bogdan Caloian
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
| | - Dumitru Zdrenghea
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
| | - Dana Pop
- 5th Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania; (I.-A.M.); (D.M.); (G.C.); (R.R.); (F.F.); (D.A.I.); (B.C.); (D.Z.); (D.P.)
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania;
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Sarkar A, Fanous KI, Marei I, Ding H, Ladjimi M, MacDonald R, Hollenberg MD, Anderson TJ, Hill MA, Triggle CR. Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights. Vasc Health Risk Manag 2024; 20:255-288. [PMID: 38919471 PMCID: PMC11198029 DOI: 10.2147/vhrm.s391808] [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: 02/12/2024] [Accepted: 06/05/2024] [Indexed: 06/27/2024] Open
Abstract
Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.
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Affiliation(s)
- Aparajita Sarkar
- Department of Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Kareem Imad Fanous
- Department of Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Isra Marei
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
| | - Hong Ding
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
| | - Moncef Ladjimi
- Department of Biochemistry & Medical Education, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ross MacDonald
- Health Sciences Library, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Morley D Hollenberg
- Department of Physiology & Pharmacology, and Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Todd J Anderson
- Department of Cardiac Sciences and Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Michael A Hill
- Dalton Cardiovascular Research Center & Department of Medical Pharmacology & Physiology, School of Medicine, University of Missouri, Columbia, Missouri, USA
| | - Chris R Triggle
- Department of Pharmacology & Medical Education, Weill Cornell Medicine- Qatar, Doha, Qatar
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Lv C, Hu C, Zhu C, Wan X, Chen C, Ji X, Qin Y, Lu L, Guo X. Empagliflozin alleviates the development of autoimmune myocarditis via inhibiting NF-κB-dependent cardiomyocyte pyroptosis. Biomed Pharmacother 2024; 170:115963. [PMID: 38042114 DOI: 10.1016/j.biopha.2023.115963] [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: 08/24/2023] [Revised: 11/16/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023] Open
Abstract
Autoimmune myocarditis, which falls within the broad spectrum of myocarditis, is characterized by an excessive inflammatory response in the heart, and can progress into dilated cardiomyopathy and irreversible heart failure in all possibility. However, effective clinical therapeutics are limited due to its complex inflammatory reactions. Empagliflozin (EMPA) has been previously demonstrated to possess anti-inflammatory properties. This study aimed to determine the improvement effects of EMPA on cardiac dysfunction under the condition of autoimmune myocarditis, and to further investigate the potential mechanisms. In vivo, all male Balb/c mice were randomly divided into four groups: control, experimental autoimmune myocarditis (EAM), EAM+EMPA and EMPA. In vitro, the effects of EMPA on IL-18-stimulated H9C2 cells were explored and the underlying molecular mechanisms were further determined. EMPA treatment significantly inhibited the development of autoimmune myocarditis, and mice treated with EMPA exhibited improved cardiac function compared with that in the EAM group, potentially through modulating pyroptosis of myocardium. Specifically, the NF-κB pathway was activated in the hearts of the EAM mice, which further activated NLRP3 inflammasome-dependent pyroptosis. EMPA treatment significantly inhibited such activation, thus alleviating inflammatory reactions in the context of EAM. Moreover, in vitro, we also observed that EMPA significantly inhibited pyroptosis of IL-18-stimulated H9C2 cells, and reduced nuclear translocation of NF-κB and degradation of activated IκBα. This work provides the first direct evidence that EMPA can inhibit myocardial inflammation and improve cardiac function in EAM mice, partly attributed to the drug-induced suppression of cardiomyocyte pyroptosis via disrupting the NF-κB pathway.
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Affiliation(s)
- Chao Lv
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Chongqing Hu
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Chuanmeng Zhu
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Xiaoning Wan
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Chen Chen
- Department of Cardiology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China
| | - Xinyun Ji
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China
| | - Yating Qin
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
| | - Li Lu
- Department of Orthopedics, Union Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
| | - Xiaomei Guo
- Department of Cardiology, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China.
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Chan CS, Lin FJ, Chen YC, Lin YK, Higa S, Chen SA, Chen YJ. Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis. Int J Mol Sci 2023; 24:13100. [PMID: 37685906 PMCID: PMC10488086 DOI: 10.3390/ijms241713100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.
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Affiliation(s)
- Chao-Shun Chan
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-S.C.); (Y.-K.L.)
- Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Fong-Jhih Lin
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan;
| | - Yung-Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-S.C.); (Y.-K.L.)
- Division of Cardiology, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 9012131, Japan;
| | - Shih-Ann Chen
- Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Clinical Medicine and Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan
| | - Yi-Jen Chen
- Division of Cardiology, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
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Batta A, Hatwal J, Batta A, Verma S, Sharma YP. Atrial fibrillation and coronary artery disease: An integrative review focusing on therapeutic implications of this relationship. World J Cardiol 2023; 15:229-243. [PMID: 37274376 PMCID: PMC10237004 DOI: 10.4330/wjc.v15.i5.229] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/05/2023] [Accepted: 05/06/2023] [Indexed: 05/19/2023] Open
Abstract
The incidence of both atrial fibrillation (AF) and coronary artery disease (CAD) increases with advancing age. They share common risk factors and very often coexist. Evidence points to an intricate relationship between atrial tissue excitability and neuronal remodeling with ischemia at the microcirculatory level. In this review, we delineated this complex relationship, identified a common theme between the two, and discussed how the knowledge of this relationship translates into a positive and meaningful impact in patient management. Recent research indicates a high prevalence of CAD among AF patients undergoing coronary angiography. Further, the incidence of AF is much higher in those suffering from CAD compared to age-matched adults without CAD underlying this reciprocal relationship. CAD adversely affects AF by promoting progression via re-entry and increasing excitability of atrial tissue as a result of ischemia and electrical inhomogeneity. AF in turn accelerates atherosclerosis via endothelial dysfunctional and inflammation and together with enhanced thrombogenicity and hypercoagulability contribute to micro and macrothrombi throughout cardiovascular system. In a nutshell, the two form a vicious cycle wherein one disease promotes the other. Most AF recommendations focuses on rate/rhythm control and prevention of thromboembolism. Very few studies have discussed the importance of unmasking coexistent CAD and how the treatment of underlying ischemia will impact the burden of AF in these patients. Inflammation and endothelial dysfunction remain central to both disease processes and form a handsome therapeutic target in the management of the two diseases. The relationship between AF and CAD is complex and much more than mere coincidence. The two diseases share common risk factor and pathophysiology. Hence, it is impractical to treat them in isolation. Accordingly, we share the implications of managing underlying ischemia and inflammation to positively impact and improve quality of life among AF patients.
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Affiliation(s)
- Akash Batta
- Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Juniali Hatwal
- Department of Internal Medicine, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India
| | - Akshey Batta
- Department of Medicine and Surgery, Sohana Multi Super Specialty Hospital, Mohali 160062, Punjab, India.
| | - Samman Verma
- Department of Cardiology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India
| | - Yash Paul Sharma
- Department of Cardiology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, India
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Kim S, Park SY, Kim B, Min C, Cho W, Yon DK, Kim JY, Han KD, Rhee EJ, Lee WY, Rhee SY. Association between antidiabetic drugs and the incidence of atrial fibrillation in patients with type 2 diabetes: A nationwide cohort study in South Korea. Diabetes Res Clin Pract 2023; 198:110626. [PMID: 36933806 DOI: 10.1016/j.diabres.2023.110626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/08/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Although diabetes is a risk factor for atrial fibrillation (AF), studies on the AF risk according to the antidiabetic drugs are lacking. This study evaluated the effects of antidiabetic drugs on AF incidence in Korean patients with type 2 diabetes. METHODS We included 2,515,468 patients with type 2 diabetes from the Korean National Insurance Service database without a history of AF who underwent health check-ups between 2009 and 2012. Newly diagnosed AF incidence was recorded until December 2018 according to the main antidiabetic drug combinations used in the real world. RESULTS Of the patients included (mean age, 62 ± 11 years; 60 % men), 89,125 were newly diagnosed with AF. Metformin (MET) alone (hazard ratio [HR] 0.959, 95 % CI 0.935-0.985) and MET combination therapy (HR < 1) significantly decreased the risk of AF compared to the no-medication group. The antidiabetic drugs consistently showing a protective effect against AF incidence were MET (HR 0.977, 95 % CI 0.964-0.99) and thiazolidinedione (TZD; HR 0.926, 95 % CI 0.898-0.956), even after adjusting for various factors. Moreover, this protective effect was more remarkable with MET and TZD combination therapy (HR 0.802, 95 % CI 0.754-0.853) than with other drug combinations. In the subgroup analysis, the preventive effect of MET and TZD treatment against AF remained consistent, regardless of age, sex, duration, and diabetes severity. CONCLUSION The combination therapy of MET and TZD is the most effective antidiabetic drug for preventing AF in patients with type 2 diabetes.
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Affiliation(s)
- Sunyoung Kim
- Department of Family Medicine, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea; Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - So Young Park
- Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - Bongseong Kim
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chanyang Min
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - Wonyoung Cho
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - Dong Keon Yon
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
| | - Joo Young Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hanil General Hospital, Seoul, Republic of Korea
| | - Kyung-Do Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Youl Rhee
- Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea; Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea.
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Vergès B, Aboyans V, Angoulvant D, Boutouyrie P, Cariou B, Hyafil F, Mohammedi K, Amarenco P. Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms. Cardiovasc Diabetol 2022; 21:242. [PMID: 36380358 PMCID: PMC9667639 DOI: 10.1186/s12933-022-01686-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain.
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Affiliation(s)
- Bruno Vergès
- grid.5613.10000 0001 2298 9313Department of Endocrinology, Diabetes and Metabolic Disorders, Dijon University Hospital, INSERM Unit, LNC-UMR 1231, University of Burgundy, Dijon, France
| | - Victor Aboyans
- Department of Cardiology, EpiMaCT - INSERM UMR, Dupuytren University Hospital, Limoges University, 1094 & IRD 270, Limoges, France
| | - Denis Angoulvant
- EA4245 Transplantation, Immunity & Inflammation, Department of Cardiology, University of Tours, Tours University Hospital, Tours, France
| | - Pierre Boutouyrie
- Paris Cardiovascular Research CenterUMR-970Department of Pharmacology, INSERM, Georges-Pompidou European Hospital, Paris City University, Paris, France
| | - Bertrand Cariou
- grid.462318.aUniversity of Nantes, Nantes University Hospital Centre, CNRS, INSERM, L’institut du Thorax, Nantes, France
| | - Fabien Hyafil
- grid.414093.b0000 0001 2183 5849Department of Nuclear Medicine, DMU IMAGINA, Georges-Pompidou European Hospital, APHP, Paris City University, Paris, France
| | - Kamel Mohammedi
- grid.412041.20000 0001 2106 639XDepartment of Endocrinology, Diabetes, and Nutrition, University of Bordeaux, INSERM U1034, Pessac, France
| | - Pierre Amarenco
- Neurology and Stroke Center, SOS-TIA Clinic, Bichat Hospital, University of Paris, Paris, France
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Scheen AJ. Antidiabetic agents and risk of atrial fibrillation/flutter: A comparative critical analysis with a focus on differences between SGLT2 inhibitors and GLP-1 receptor agonists. DIABETES & METABOLISM 2022; 48:101390. [DOI: 10.1016/j.diabet.2022.101390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 09/22/2022] [Accepted: 09/22/2022] [Indexed: 04/11/2023]
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Iqbal A, Tekin Z, Kattan MW, Ji X, Milinovich A, Pantalone KM, Zimmerman RS, Chung MK, Kashyap SR. Association between first-line monotherapy with metformin and the risk of atrial fibrillation (AMRAF) in patients with type 2 diabetes. J Diabetes Complications 2022; 36:108315. [PMID: 36208567 PMCID: PMC10147560 DOI: 10.1016/j.jdiacomp.2022.108315] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 10/31/2022]
Abstract
BACKGROUND Type 2 diabetes (T2D) has a strong association with atrial fibrillation (AF) which increases risk of thromboembolic events, heart failure, and frequent hospitalizations. Metformin is the first-line medication for T2D with proposed anti-inflammatory, pro-metabolic, and cardio-protective benefits. Our objective was to investigate if initial therapy with metformin is associated with reduced incidence of AF in comparison to other non-insulin anti-hyperglycemic agents in patients with newly diagnosed T2D. METHODS This retrospective cohort analysis included adults with a new diagnosis of T2D who were started on monotherapy (except insulin) between 2007 and 2017, without prior anti-hyperglycemic agent use, history of arrhythmias, or estimated GFR (eGFR) ≤ 30 ml/min. A multivariate analysis was performed using a fine-gray regression competing risk analysis to control for confounding variables after which pooled hazard ratios and 95 % confidence intervals were reported. Patients were followed until the end of study date, development of AF, addition of more anti-hyperglycemic agents, or death, whichever occurred first. RESULTS Among 4584 metformin initiators compared to 1080 non-metformin monotherapy initiators, 10-year cumulative incidence of AF in metformin group was 5.2 % as compared to 8.1 % with other agents which was not statistically significant. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92, 95 % CI 0.69 to 1.21; P = 0.55). Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1.29, 95 % CI: 1.21 to 1.37; P ≤ 0.001; HR: 2.73, 95 % CI: 1.62 to 4.61; P ≤ 0.001, respectively). CONCLUSION Initiation of metformin as a first line monotherapy for T2D, when compared to other non-insulin monotherapies, was not associated with decreased risk of developing AF in this retrospective observational study.
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Affiliation(s)
- Anira Iqbal
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Zehra Tekin
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Michael W Kattan
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Xinge Ji
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Alex Milinovich
- Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Kevin M Pantalone
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Robert S Zimmerman
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Mina K Chung
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America
| | - Sangeeta R Kashyap
- Endocrinology, Diabetes and Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, United States of America.
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10
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Zhuo M, D’Andrea E, Paik JM, Wexler DJ, Everett BM, Glynn RJ, Kim SC, Patorno E. Association of Sodium-Glucose Cotransporter-2 Inhibitors With Incident Atrial Fibrillation in Older Adults With Type 2 Diabetes. JAMA Netw Open 2022; 5:e2235995. [PMID: 36219443 PMCID: PMC9554705 DOI: 10.1001/jamanetworkopen.2022.35995] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022] Open
Abstract
Importance Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point. Objective To examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice. Design, Setting, and Participants A population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021. Exposures To control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)-matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates. Main Outcomes and Measures The primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups. Results New users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, -3.7; 95% CI, -5.2 to -2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, -1.8; 95% CI, -3.2 to -0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses. Conclusions and Relevance The findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level-lowering agents in older adults with T2D.
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Affiliation(s)
- Min Zhuo
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Elvira D’Andrea
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Julie M. Paik
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
- Division of Renal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- New England Geriatric Research, Education and Clinical Center, VA Boston Healthcare System, Boston, Massachusetts
| | - Deborah J. Wexler
- Diabetes Center, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Brendan M. Everett
- Divisions of Cardiovascular and Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Robert J. Glynn
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Seoyoung C. Kim
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Elisabetta Patorno
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Boston, Massachusetts
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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11
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Lkhagva B, Lee TW, Lin YK, Chen YC, Chung CC, Higa S, Chen YJ. Disturbed Cardiac Metabolism Triggers Atrial Arrhythmogenesis in Diabetes Mellitus: Energy Substrate Alternate as a Potential Therapeutic Intervention. Cells 2022; 11:cells11182915. [PMID: 36139490 PMCID: PMC9497243 DOI: 10.3390/cells11182915] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/10/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022] Open
Abstract
Atrial fibrillation (AF) is the most common type of sustained arrhythmia in diabetes mellitus (DM). Its morbidity and mortality rates are high, and its prevalence will increase as the population ages. Despite expanding knowledge on the pathophysiological mechanisms of AF, current pharmacological interventions remain unsatisfactory; therefore, novel findings on the underlying mechanism are required. A growing body of evidence suggests that an altered energy metabolism is closely related to atrial arrhythmogenesis, and this finding engenders novel insights into the pathogenesis of the pathophysiology of AF. In this review, we provide comprehensive information on the mechanistic insights into the cardiac energy metabolic changes, altered substrate oxidation rates, and mitochondrial dysfunctions involved in atrial arrhythmogenesis, and suggest a promising advanced new therapeutic approach to treat patients with AF.
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Affiliation(s)
- Baigalmaa Lkhagva
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ting-Wei Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Yung-Kuo Lin
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yao-Chang Chen
- Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan
| | - Cheng-Chih Chung
- Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Satoshi Higa
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 901-2131, Japan
| | - Yi-Jen Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- Correspondence:
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12
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Song H, Kim YR, Lee SE, Nam H, Kim H, Kyoung DS, Kim KA. Effects of Sodium-Glucose Cotransporter-2 Inhibitors and Thiazolidinedione on New-Onset Atrial Fibrillation Risk to Patients with Type 2 Diabetes. Rev Cardiovasc Med 2022; 23:303. [PMID: 39077692 PMCID: PMC11262332 DOI: 10.31083/j.rcm2309303] [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: 06/24/2022] [Revised: 08/10/2022] [Accepted: 08/15/2022] [Indexed: 07/31/2024] Open
Abstract
Background and Objectives Type 2 diabetes (T2D) is an independent risk factor for the development of atrial fibrillation (AF). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently been shown to decrease the incidence of AF through several mechanisms, including the reduction of atrial dilatation via diuresis and the lowering of body weight. In observational studies of diabetic patients, the use of thiazolidinedione (TZD) was found to have a protective effect on new-onset AF. In this study, we aimed to compare the effect of SGLT-2i and TZD on the risk of AF in patients with T2D. Methods We enrolled 69,122 patients newly prescribed SGLT-2i and 94,262 patients prescribed TZD from January 2014 to December 2018, using the Korean National Health Insurance Service database. We compared new-onset AF events (hospitalizations and outpatient events) in SGLT-2i and TZD groups after having taken medication for greater than 90 days. Results During a mean follow-up of 1.8 years, 397 (0.72%) new-onset AF events occurred in the SGLT-2i group and 432 (0.79%) events in the TZD group following propensity score matching (each group n = 54,993). The hazard ratio (HR) of AF was 0.918 (95% confidence interval: 0.783-1.076, p = 0.29) in SGLT-2i-treated patients compared with TZD-treated patients. Conclusions In this study, the risk of new-onset AF is comparable in patients treated with SGLT-2i and TZD in T2D. Either SGLT-2i or TZD would be a reasonable choice for T2D patients who are at risk for AF.
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Affiliation(s)
- Haegeun Song
- Division of Cardiology, Department of Internal Medicine, Chung-Ang University, Gwang-Myong Hospital, 14353 Seoul, Republic of Korea
| | - Yoo Ri Kim
- Division of Cardiology, Department of Internal Medicine, Chonnam National University, 61469 Gwangju, Republic of Korea
| | - Seung Eun Lee
- Division of Endocrinology, Department of Internal Medicine, Dongguk University Ilsan Hospital, 10326 Goyang, Republic of Korea
| | - Hyewon Nam
- Data Science Team, Hanmi Pharm. Co. Ltd, 05545 Seoul, Republic of Korea
| | - Hoseob Kim
- Data Science Team, Hanmi Pharm. Co. Ltd, 05545 Seoul, Republic of Korea
| | - Dae-Sung Kyoung
- Data Science Team, Hanmi Pharm. Co. Ltd, 05545 Seoul, Republic of Korea
| | - Kyoung-Ah Kim
- Division of Endocrinology, Department of Internal Medicine, Dongguk University Ilsan Hospital, 10326 Goyang, Republic of Korea
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13
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.,Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium.,Department of Medicine, CHU Liège, Liège, Belgium
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14
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Yildiz M, Lavie CJ, Morin DP, Oktay AA. The complex interplay between diabetes mellitus and atrial fibrillation. Expert Rev Cardiovasc Ther 2022; 20:707-717. [PMID: 35984314 DOI: 10.1080/14779072.2022.2115357] [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] [Indexed: 10/15/2022]
Abstract
INTRODUCTION : A growing body of evidence suggests that diabetes mellitus (DM) is associated with an increased risk of new-onset atrial fibrillation (AF) and contributes to suboptimal arrhythmia control and poor prognosis in patients with AF. The high prevalence of AF among patients with DM is primarily attributed to common risk factors, shared pathophysiological mechanisms, and associated atrial remodeling and autonomic dysfunction. AREAS COVERED : This comprehensive review covers the current data on the role of DM in the development and prognosis of AF. In addition, we review the impact of anti-DM medications on AF prevention and the role of anticoagulation in patients with coexisting DM and AF. EXPERT OPINION : DM is independently associated with new-onset AF, and the coexistence of these two conditions contributes to poor outcomes, from reduced quality of life to increased risks of thromboembolic events, heart failure, and mortality. Despite this strong link, the current evidence is insufficient to recommend routine screening for AF in patients with DM. Although some observations exist on preventing AF with anti-DM medications, randomized controlled trials are warranted to explore the proposed benefits of novel anti-DM medicines in reducing the risk of incident AF.
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Affiliation(s)
- Mehmet Yildiz
- The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital, Cincinnati, OH
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, LA
| | - Daniel P Morin
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, LA
| | - Ahmet Afsin Oktay
- The Heart and Vascular Institute, Rush University Medical Center, Chicago, IL
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15
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Bourazana A, Giamouzis G, Skoularigis J, Triposkiadis F, Xanthopoulos A. Glucose lowering does not necessarily reduce cardiovascular risk in type 2 diabetes. World J Cardiol 2022; 14:266-270. [PMID: 35582467 PMCID: PMC9048273 DOI: 10.4330/wjc.v14.i4.266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/29/2021] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) is a health condition characterized by glucose dysregulation and affects millions of people worldwide. The presentation of heart failure in diabetic cardiomyopathy extends over a wide phenotypic spectrum, commencing from asymptomatic, subclinical structural abnormalities to severely symptomatic biventricular dysfunction with increased mortality risk. Similarly, the spectrum of systolic dysfunction in diabetic-induced heart failure is diverse. DM leads also to cardiac electrical remodeling reacting on various targets. Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce glucagon and blood glucose levels by raising levels of the endogenous hormones glucagon-like-peptide 1 and glucose-dependent insulinotropic peptide and constitute a safe and effective glucose lowering treatment option in patients with type 2 DM. Despite DPP-4 inhibitors' efficacy regarding glycemic control, their effect on cardiovascular outcomes (myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization, and cardiovascular death) in diabetic patients has been neutral. The potential correlation between atrial flutter and DPP-4 inhibitors administration needs further investigation.
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Affiliation(s)
- Angeliki Bourazana
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - Grigorios Giamouzis
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | - John Skoularigis
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece
| | | | - Andrew Xanthopoulos
- Department of Cardiology, University Hospital of Larissa, Larissa 41110, Greece.
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16
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Andelova K, Bacova BS, Sykora M, Hlivak P, Barancik M, Tribulova N. Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress. Int J Mol Sci 2022; 23:1416. [PMID: 35163340 PMCID: PMC8835881 DOI: 10.3390/ijms23031416] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 01/27/2023] Open
Abstract
The prevention of cardiac life-threatening ventricular fibrillation and stroke-provoking atrial fibrillation remains a serious global clinical issue, with ongoing need for novel approaches. Numerous experimental and clinical studies suggest that oxidative stress and inflammation are deleterious to cardiovascular health, and can increase heart susceptibility to arrhythmias. It is quite interesting, however, that various cardio-protective compounds with antiarrhythmic properties are potent anti-oxidative and anti-inflammatory agents. These most likely target the pro-arrhythmia primary mechanisms. This review and literature-based analysis presents a realistic view of antiarrhythmic efficacy and the molecular mechanisms of current pharmaceuticals in clinical use. These include the sodium-glucose cotransporter-2 inhibitors used in diabetes treatment, statins in dyslipidemia and naturally protective omega-3 fatty acids. This approach supports the hypothesis that prevention or attenuation of oxidative and inflammatory stress can abolish pro-arrhythmic factors and the development of an arrhythmia substrate. This could prove a powerful tool of reducing cardiac arrhythmia burden.
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Affiliation(s)
- Katarina Andelova
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Dúbravská Cesta 9, 84104 Bratislava, Slovakia; (K.A.); (M.S.); (M.B.)
| | - Barbara Szeiffova Bacova
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Dúbravská Cesta 9, 84104 Bratislava, Slovakia; (K.A.); (M.S.); (M.B.)
| | - Matus Sykora
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Dúbravská Cesta 9, 84104 Bratislava, Slovakia; (K.A.); (M.S.); (M.B.)
| | - Peter Hlivak
- Department of Arrhythmias and Pacing, National Institute of Cardiovascular Diseases, Pod Krásnou Hôrkou 1, 83348 Bratislava, Slovakia;
| | - Miroslav Barancik
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Dúbravská Cesta 9, 84104 Bratislava, Slovakia; (K.A.); (M.S.); (M.B.)
| | - Narcis Tribulova
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Dúbravská Cesta 9, 84104 Bratislava, Slovakia; (K.A.); (M.S.); (M.B.)
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17
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Lee DI, Murninkas M, Elyagon S, Etzion Y, Anderson HD. Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model. Front Pharmacol 2021; 12:642398. [PMID: 33967775 PMCID: PMC8100753 DOI: 10.3389/fphar.2021.642398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/16/2021] [Indexed: 12/17/2022] Open
Abstract
Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR. Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis. Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13. Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study.
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Affiliation(s)
- Danielle I Lee
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Canadian Centre for Agri-Food Research in Health and Medicine (CCARM), Albrechtsen Research Centre, St Boniface Hospital, Winnipeg, MB, Canada
| | - Michael Murninkas
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Sigal Elyagon
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yoram Etzion
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hope D Anderson
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Canadian Centre for Agri-Food Research in Health and Medicine (CCARM), Albrechtsen Research Centre, St Boniface Hospital, Winnipeg, MB, Canada
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