Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7(-/-) mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7(-/-) hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K(+) currents I(to) and I(K1) were profoundly reduced in Alk7(-/-) ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of I(to) carrying channel) and KCHIP2 (a key accessory subunit of I(to) carrying channel), was markedly decreased in Alk7(-/-) hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K(+) currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia.