Proarrhythmic Lipid Inflammatory Mediators: Mechanisms in Obesity Arrhythmias

Abstract

The prevalence of obesity and associated metabolic disorders such as diabetes is rapidly increasing; therefore, concerns regarding their cardiovascular consequences, including cardiac arrhythmias, are rising. As obesity progresses, the excessively produced lipids accumulate in unconventional areas such as the epicardial adipose tissue (EAT) around the myocardium. Metabolic alterations in obesity contribute to the transformation of these ectopic fat deposits into arrhythmogenic substrates. However, despite advances in therapeutic approaches, particularly in lowering EAT volume and thickness through sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, obese and diabetic patients still suffer from fatal arrhythmias that may lead to sudden cardiac death. Therefore, an investigation into how unappreciated underlying pathways such as lipid mediators contribute to the transformation of adipose tissues into proinflammatory and arrhythmogenic substrates is of significance. Leukotriene B4 (LTB4) is an eicosanoid derived from arachidonic acid and acts as a lipid mediator. LTB4 has recently been identified to be associated with cardiac ion channel modulations and arrhythmogenic conditions in diabetes. LTB4 increases circulatory free fatty acids (FFAs) and has been associated with adipocyte hypertrophy. LTB4 also interferes with insulin signaling pathways, instigating insulin resistance (IR). In addition, LTB4, as a potent chemoattractant, contributes to the mobilization of circulatory immune cells such as monocytes and promotes inflammatory macrophage polarization and macrophage dysfunction. Thus, this review provides a comprehensive overview of LTB4's underlying pathways in obesity; illustrates how these pathways might lead to alterations in cardiac ion channels, currents, and cardiac arrhythmias; and shows how they might pose a therapeutic target for metabolic-associated arrhythmias.