Palmitic acid-induced lipotoxicity and IL-6 exposure severely prolonged the QT interval and depressed IKr and IKs densities in adult guinea pig ventricular myocytes.
Does lipotoxicity-induced IL-6 production alter delayed rectifier potassium currents and prolong QT interval in guinea pig hearts?
Lipotoxicity-induced IL-6 production depresses delayed rectifier potassium currents (IKr and IKs), leading to acquired QT prolongation and increased vulnerability to fatal arrhythmias.
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 arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-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 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 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.
Chowdhury et al. (Mon,) conducted a other in Lipotoxicity and QT prolongation. Palmitic acid diet and IL-6 exposure vs. Low-fat diet fed controls was evaluated on QT interval, IKr and IKs densities, and action potential duration. Palmitic acid-induced lipotoxicity and IL-6 exposure severely prolonged the QT interval and depressed IKr and IKs densities in adult guinea pig ventricular myocytes.