Implications of SGLT Inhibition on Redox Signalling in Atrial Fibrillation

Abstract

Atrial fibrillation (AF) is the most common sustained (atrial) arrhythmia, a considerable global health burden and often associated with heart failure. Perturbations of redox signalling in cardiomyocytes provide a cellular substrate for the manifestation and maintenance of atrial arrhythmias. Several clinical trials have shown that treatment with sodium-glucose linked transporter inhibitors (SGLTi) improves mortality and hospitalisation in heart failure patients independent of the presence of diabetes. Post hoc analysis of the DECLARE-TIMI 58 trial showed a 19% reduction in AF in patients with diabetes mellitus (hazard ratio, 0.81 (95% confidence interval: 0.68–0.95), n = 17.160) upon treatment with SGLTi, regardless of pre-existing AF or heart failure and independent from blood pressure or renal function. Accordingly, ongoing experimental work suggests that SGLTi not only positively impact heart failure but also counteract cellular ROS production in cardiomyocytes, thereby potentially altering atrial remodelling and reducing AF burden. In this article, we review recent studies investigating the effect of SGLTi on cellular processes closely interlinked with redox balance and their potential effects on the onset and progression of AF. Despite promising insight into SGLTi effect on Ca2+ cycling, Na+ balance, inflammatory and fibrotic signalling, mitochondrial function and energy balance and their potential effect on AF, the data are not yet conclusive and the importance of individual pathways for human AF remains to be established. Lastly, an overview of clinical studies investigating SGLTi in the context of AF is provided.

Is the Risk of Diabetes Lower in Patients With Atrial Fibrillation Treated With Direct Oral Anticoagulant Compared to Warfarin?

“…Although available data is insufficient to support the effect of vitamin K in ameliorating prediabetes (the impaired glucose tolerance, fasting blood sugar, fasting serum insulin level would not be restored), the glucose and insulin levels of 2-h post-oral glucose tolerance test could be reduced by stable vitamin K support ( 10 , 30 , 31 ), which indicate that DOACs may not induce the rapid deterioration of prediabetes compared with warfarin. Also, the clinical trials have demonstrated that the new anti-diabetic drug sodium-glucose linked transporter inhibitors (SGLTi) with a beneficial effect on cardiovascular disease ( 32 – 34 ), regardless if diabetes exists or not ( 34 ). In the aspect of AF, SGLTi can counteract the production of cellular ROS in cardiomyocytes, which may change atrial remodeling and reduce the burden of AF ( 34 ).…”

“…Also, the clinical trials have demonstrated that the new anti-diabetic drug sodium-glucose linked transporter inhibitors (SGLTi) with a beneficial effect on cardiovascular disease ( 32 – 34 ), regardless if diabetes exists or not ( 34 ). In the aspect of AF, SGLTi can counteract the production of cellular ROS in cardiomyocytes, which may change atrial remodeling and reduce the burden of AF ( 34 ). This suggests that the new anti-diabetic drug SGLTi and new oral anticoagulants DOAC may have similar effects on the prevention of new-onset diabetes during AF treatment.…”

Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats

“…Importantly, AMPK tightly regulates endogenous cardioprotective signaling pathways ( 51 , 52 ). The activation (i.e., phosphorylation) of AMPK mitigates the impaired expression of proteins involved in mitochondrial homeostasis, as well as antioxidant genes ( 53 , 54 ), which influence the increase in mitochondrial biogenesis and the decrease in mitochondrial ROS generation ( 13 ). In addition, AMPK influences the homeostasis of mitochondrial dynamics through phosphorylation of the mitochondrial fission factor ( 13 , 55 ).…”

“…Oxidative stress refers to elevated intracellular levels of ROS, either due to excessive ROS generation or reduced ROS scavenging, which results in damage to lipids, proteins, and DNA ( 12 ). Oxidative stress and inflammation contribute to the pathogenesis of AF in patients with DM ( 4 , 13 ). Indeed, previous studies have demonstrated that the reduction of ROS generation reduces AF inducibility in several experimental AF models ( 14 , 15 ).…”

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…Ongoing experimental studies suggest that SGLTi not only attenuates HF but also counteracts cellular ROS production in cardiomyocytes, thereby potentially hampering myocardial remodeling and reducing AF and VF burden. This important feature of SGLT2i is linked to their impact on redox signaling in AF, and this has recently been comprehensively reviewed [133]. SGLT2i also exerts direct antiinflammatory and anti-oxidative effects on resting endothelial cells, and its anti-oxidative effect could be partly mediated by NADPH oxidase inhibition [134].…”