Linking Arrhythmias and Adipocytes: Insights, Mechanisms, and Future Directions

Abstract

Obesity and atrial fibrillation have risen to epidemic levels worldwide and may continue to grow over the next decades. Emerging evidence suggests that obesity promotes atrial and ventricular arrhythmias. This has led to trials employing various strategies with the ultimate goal of decreasing the atrial arrhythmic burden in obese patients. The effectiveness of these interventions remains to be determined. Obesity is defined by the expansion of adipose mass, making adipocytes a prime candidate to mediate the pro-arrhythmogenic effects of obesity. The molecular mechanisms linking obesity and adipocytes to increased arrhythmogenicity in both the atria and ventricles remain poorly understood. In this focused review, we highlight areas of potential molecular interplay between adipocytes and cardiomyocytes. The effects of adipocytes may be direct, local or remote. Direct effect refers to adipocyte or fatty infiltration of the atrial and ventricular myocardium itself, possibly causing increased dispersion of normal myocardial electrical signals and fibrotic substrate of adipocytes that promote reentry or adipocytes serving as a direct source of aberrant signals. Local effects may originate from nearby adipose depots, specifically epicardial adipose tissue (EAT) and pericardial adipose tissue, which may play a role in the secretion of adipokines and chemokines that can incite inflammation given the direct contact and disrupt the conduction system. Adipocytes can also have a remote effect on the myocardium arising from their systemic secretion of adipokines, cytokines and metabolites. These factors may lead to mitochondrial dysfunction, oxidative stress, autophagy, mitophagy, autonomic dysfunction, and cardiomyocyte death to ultimately produce a pro-arrhythmogenic state. By better understanding the molecular mechanisms connecting dysfunctional adipocytes and arrhythmias, novel therapies may be developed to sever the link between obesity and arrhythmias.

Autophagy inhibition blunts PDGFRA adipose progenitors’ cell-autonomous fibrogenic response to high-fat diet

“…Whether such age-dependent changes rely on autophagy modulation in dermal progenitors as described here for subcutaneous fat has not been investigated, but autophagic decline is a well-known feature in ageing. Also, related to TGF-BMP pathway, obesity can promote heart arrhythmias through fibrosis accumulation [31], and TGFb is up regulated in the atria of rats fed a HFD which favors fibrosis [32].…”

Effects of Secretome from Fat Tissues on Ion Currents of Cardiomyocyte Modulated by Sodium-Glucose Transporter 2 Inhibitor

“…Mazurek et al investigated human epicardial adipose tissue and found that epicardial adipose tissue was a source of several cytokines, including monocyte chemotactic protein 1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, all of which may promote the genesis of atherosclerosis [7]. The adipocytokines and metabolites of pericardial fat also could result in mitochondrial dysfunction, autonomic nervous dysfunction, and cardiomyocyte death, all of which might lead to heart failure [8]. Our previous study also demonstrated that adipocytokines from pericardial fat could affect the ion currents of cardiomyocytes, which might contribute to the mechanisms of arrhythmogenesis [9].…”

Epicardial adipose tissue affects the efficacy of left atrial posterior wall isolation for persistent atrial fibrillation

“…For instance, increased leptin levels can lead to increased aldosterone secretion, endothelial dysfunction, increased vascular stiffness, hypertension, and cardiac hypertrophy, all of which could contribute for AF pathogenesis 22 . Moreover, adipokines and metabolites from EAT are associated with systemic inflammation, oxidative stress, and autonomic dysfunction, resulting in a pro‐arrhythmogenic state 14 …”

“…The local effect involves adipocyte infiltration into the atrial myocardium 9,10 and fibrosis of the neighboring atrial tissue by paracrine secretion of profibrotic adipokines 11‐13 . The remote effect, on the other hand, arises from the systemic secretion of adipokines and metabolites 14 . Furthermore, ganglionated plexuses are located in EAT, altering the electrophysiological properties of atrial remote areas 15,16 .…”