Obesity Arrhythmias: Role of IL-6 Trans-Signaling

Obesity is a chronic disease that is rapidly increasing in prevalence and affects more than 600 million adults worldwide, and this figure is estimated to increase by at least double by 2030. In the United States, more than one-third of the adult population is either overweight or obese. The global obesity epidemic is a major risk factor for the development of life-threatening arrhythmias occurring in patients with long QT, particularly in conditions where multiple heart-rate-corrected QT-interval-prolonging mechanisms are simultaneously present. In obesity, excess dietary fat in adipose tissue stimulates the release of immunomodulatory cytokines such as interleukin (IL)-6, leading to a state of chronic inflammation in patients. Over the last decade, increasing evidence has been found to support IL-6 signaling as a powerful predictor of the severity of heart diseases and increased risk for ventricular arrhythmias. IL-6's pro-inflammatory effects are mediated via trans-signaling and may represent a novel arrhythmogenic risk factor in obese hearts. The first selective inhibitor of IL-6 trans-signaling, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 trans-signaling and obesity-linked ventricular arrhythmias remains unexplored. Therefore, understanding how IL-6 trans-signaling elicits a cellular pro-arrhythmic phenotype and its use as an anti-arrhythmic target in a model of obesity remain unmet clinical needs.