Macrophage-Dependent Interleukin-6-Production and Inhibition of Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart.

In the heart, the delayed rectifier K current, , composed of the rapid () and slow () components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel , elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered in the heart, using electrophysiology to evaluate changes in 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 isoproterenol 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 and densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of did a proarrhythmic phenotype of 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.