Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient
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Cardiovascular Diabetology Open Access
REVIEW
Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient Teerapat Nantsupawat1,2,3, Wanwarang Wongcharoen1,2,3, Siriporn C. Chattipakorn2,3 and Nipon Chattipakorn2,3,4*
Abstract Metformin has been shown to have various cardiovascular benefits beyond its antihyperglycemic effects, including a reduction in stroke, heart failure, myocardial infarction, cardiovascular death, and all-cause mortality. However, the roles of metformin in cardiac arrhythmias are still unclear. It has been shown that metformin was associated with decreased incidence of atrial fibrillation in diabetic patients with and without myocardial infarction. This could be due to the effects of metformin on preventing the structural and electrical remodeling of left atrium via attenuating intracellular reactive oxygen species, activating 5′ adenosine monophosphate-activated protein kinase, improving calcium homeostasis, attenuating inflammation, increasing connexin-43 gap junction expression, and restoring small conductance calcium-activated potassium channels current. For ventricular arrhythmias, in vivo reports demonstrated that activation of 5′ adenosine monophosphate-activated protein kinase and phosphorylated connexin-43 by metformin played a key role in ischemic ventricular arrhythmias reduction. However, metformin failed to show anti-ventricular arrhythmia benefits in clinical trials. In this review, in vitro and in vivo reports regarding the effects of metformin on both atrial arrhythmias and ventricular arrhythmias are comprehensively summarized and presented. Consistent and controversial findings from clinical trials are also summarized and discussed. Due to limited numbers of reports, further studies are needed to elucidate the mechanisms and effects of metformin on cardiac arrhythmias. Furthermore, randomized controlled trials are needed to clarify effects of metformin on cardiac arrhythmias in human. Keywords: Metformin, Arrhythmias, Atrial fibrillation, Atrial arrhythmias, Ventricular arrhythmias Introduction Metformin initially received approval from the U.S. Food and Drug Administration for type 2 diabetes in 1995 [1]. Since then, an accumulating body of evidence has shown various benefits of metformin beyond the antihyperglycemic effects [2]. In the case of cardiovascular protection, it has been shown that metformin exerted many benefits including a reduction in blood pressure, left ventricular mass [3], stroke [4], heart failure [5, 6], myocardial infarction (MI), cardiovascular death, and all-cause mortality *Correspondence: [email protected] 2 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Chiang Mai 50200, Thailand Full list of author information is available at the end of the article
[7–10]. Several mechanisms behind the cardioprotective effects have been proposed. Metformin is known as 5′ adenosine monophosphate-activated protein kinase (AMPK) activator. Metformin activates AMPK thr
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