PROJECT ABSTRACT Obesity is associated with a higher risk for the development of malignant ventricular tachyarrhythmias (VT), particularly under conditions of repolarization disorders and QT interval prolonging mechanisms (an established risk factor for VT), and sometimes tragically transitions to sudden cardiac death. In obesity, excess dietary fat in adipose tissues stimulates the release of immunomodulatory cytokines such as interleukin(IL)-6, leading to a state of chronic inflammation in patients. In the past decade, IL-6 trans-signaling has emerged as a powerful predictor of risk for VT. The first selective inhibitor of IL-6, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 and VT remains undiscovered. The long-term goal is to help inform the development of therapeutically novel anti-cytokine drugs for the clinical treatment of life-threatening malignant VT. The overall objectives in this application are to (i) elucidate the molecular mechanism(s) by which IL-6 signaling triggers dramatic and arrhythmogenic electrical changes in vitro and (ii) determine in vivo anti-IL-6 signaling anti-arrhythmic efficacy using a guinea pig high-fat diet-induced inflammation model. Our central hypothesis is that over-activation of IL-6 trans-signaling triggers proarrhythmogenic changes in the rapidly activating delayed rectifier K channel (IKr) and calcium (Ca) handling in vitro and promotes lethal VT in vivo by promoting electrical disturbances in the ventricular myocardium. The rationale for this project is that a determination of the therapeutic potential of IL-6 signaling inhibition and associated cellular mechanisms is likely to reveal a strong mechanistic basis whereby new strategies to treat lethal ventricular arrhythmias in patients can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) determine anti-arrhythmic effects of IL-6 signaling inh