Macrophage‐dependent interleukin‐6‐production and inhibition of ik contributes to acquired qt prolongation in lipotoxic guinea pig heart

Abstract

In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro‐inflammatory cytokines may remodel IK, elevating the risk for ventricular ar-rythmias and sudden cardiac death. We investigated whether and how the pro‐inflammatory in-terleukin‐6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL‐6 in RAW264.7 cells. PA‐diet fed guinea pigs displayed a severely prolonged QT interval when compared to low‐fat diet fed controls. Exposure to isopro-terenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre‐exposure to IL‐6 with the soluble IL‐6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.