Effects of metformin on atrial and ventricular arrhythmias: evidence from cell to patient

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: Arrhythmias; Atrial arrhythmias; Atrial fibrillation; Metformin; Ventricular arrhythmias.

Fig. 1

Effects of metformin on atrial arrhythmias. Atrial fibrillation, obesity, insulin resistance, and diabetes mellitus can cause atrial structural, electrical, electromechanical, and autonomic adverse remodeling. These remodelings become arrhythmogenic substrates and set out a vicious cycle known as “AF begets AF”. Metformin exerts protective effects through various mechanisms. Red arrow shows adverse effects from atrial fibrillation, obesity, insulin resistance, and diabetes. Green rectangle shows pathway that metformin blocked. Solid green arrow shows protective mechanisms of metformin directly demonstrated from the studies in Tables 1 and 2. Dotted green arrow indicates protective mechanism of metformin from other studies in the text

Fig. 2

Effects of metformin on ventricular arrhythmias. Ischemia causes reduction in myocardial ATP and finally results in ventricular fibrillation. Chronic metformin use exerts its energy guardian effects mainly via AMPK activation. Additionally, metformin prevents QT interval prolongation, QT dispersion, and conduction velocity delay by regulating microRNA-1 and L-type calcium channels. Only the combination of metformin and vildagliptin could increase p-Cx43 and subsequently reduce ventricular fibrillation. Green rectangle and arrow shows protective mechanisms of metformin