Impact of Obesity on Atrial Fibrillation Pathogenesis and Treatment Options

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF increases the risk of stroke, heart failure, dementia, and hospitalization. Obesity significantly increases AF risk, both directly and indirectly, through related conditions, like hypertension, diabetes, and heart failure. Obesity-driven structural and electrical remodeling contribute to AF via several reported mechanisms, including adiposity, inflammation, fibrosis, oxidative stress, ion channel alterations, and autonomic dysfunction. In particular, expanding epicardial adipose tissue during obesity has been suggested as a key driver of AF via paracrine signaling and direct infiltration. Weight loss has been shown to reverse these changes and reduce AF risk and recurrence after ablation. However, studies on how obesity affects pharmacologic or interventional AF treatments are limited. In this review, we discuss mechanisms by which obesity mediates AF and treatment outcomes, aiming to provide insight into obesity-drug interactions and guide personalized treatment for this patient subgroup.

Keywords: antiarrhythmic drugs; atrial fibrillation; epicardial adipose tissue; ion channel; obesity.

Figure 1. Mechanisms of obesity‐mediated atrial fibrillation (AF).

Obesity‐mediated AF is multifactorial, encompassing hemodynamic, structural, and electrical remodeling, adiposity, metabolic dysfunction, inflammation, and neurohormonal changes. Epicardial adipose tissue accumulates during obesity and can mediate structural and electrical remodeling. Subsequent conduction and repolarization abnormalities lead to increased ectopic activity and wavelength reentry, causing AF. IL indicates interleukin; LA, left atrial; LV, left ventricular; RAAS, renin‐angiotensin‐aldosterone system; ROS, reactive oxygen species; TGF‐β, transforming growth factor‐β; and TNF‐α, tumor necrosis factor‐α. Figure created with BioRender.com.

Figure 2. The effect of left atrial (LA) epicardial adipose tissue (EAT) on myocardial structure and function in obesity.

Obesity causes EAT expansion, particularly around the posterior LA, and dysfunction. EAT is composed of adipocytes, fibroblasts, ganglionic plexi, macrophages, endothelial cells, and smooth muscle cells. In obesity, the expression and secretion of certain adipokines in EAT are increased. Alongside excess free fatty acids (FFAs) and ganglionic plexi hyperactivity‐induced autonomic dysfunction, this leads to LA fibrosis, inflammation, oxidative stress, and altered atrial electrophysiology. IL indicates interleukin; ROS, reactive oxygen species; TGF‐β, transforming growth factor‐β; and TNF‐α, tumor necrosis factor‐α. Figure created with BioRender.com.

Figure 3. The effect of obesity on atrial cardiomyocyte electrophysiology.

Obesity can induce excess free fatty acids, oxidative stress, inflammation, and myocardial remodeling. Electrical remodeling is subsequently triggered, through mechanisms not fully elucidated, causing altered expression and function of atrial ion channels and gap junctions. Subsequent abnormal atrial conduction and repolarization properties characterize arrhythmogenic substrate, increasing risk of atrial fibrillation. CaMKII indicates calmodulin kinase 2; Cx43, connexin 43; I_Ca,L, L‐type calcium current; I_Kur, ultrarapid potassium current; I_Na,L, late sodium current; I_Na,P, peak sodium current; P, phosphorylation; RyR2, ryanodine 2 receptor; SERCA2A, sarcoplasmic/endoplasmic reticulum Ca²⁺‐ATPase 2a; and SR, sarcoplasmic reticulum. Figure created with BioRender.com.

Figure 4. The effect of obesity on current atrial fibrillation (AF) treatments and potential recommendations for treatment of patients with obesity‐mediated AF.

Existing clinically used AF treatments with altered efficacy in obesity are shown in orange, altered pharmacokinetic/pharmacodynamic (PK/PD) properties in blue, and promising efficacy/safety in green. PVI indicates pulmonary vein isolation. Figure created with BioRender.com.