The Effect Of ALK7 On Cardiac Electrophysiology And Arrhythmogenesis

Part Ⅰ:The impact of ALK7 deletion for repolarizing K+ currents in ventricular cardiomyocytesWe 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 Ito and IK1 were profoundly reduced in Alk7-/-ventricular cardiomyocytes. 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.Part Ⅱ:The impact of ALK7 deletion for expression of cardiac ion channel subunitWe aimed to investigate the effects of activin receptor-like kinase (ALK7) on expression of cardiac ion channel subunit in mice. The expression of mRNA and protein of ion channel subunit were observed by RT-PCR and western blot technology in ventricular myocytes of ALK7-/- and control mice. We found the expressions of Kv4.2 (a major subunit of Ito carrying channel) and KCHIP2 (a key accessory subunit of Ito carrying channel), were markedly decreased in Alk7-/- hearts. These findings suggest that the molecular mechanism of prolonged repolarization and increased arrhythmia susceptibility caused by ALK7 deletion may be decreased expression of Kv4.2 and KCHIP2.Part Ⅲ:The impact of ALK7 deletion for atrial electrical remodelingWe aimed to elucidate the effects of activin receptor-like kinase (ALK7) on atrial repolarization and tachyarrhythmia in mice. ECG was recorded by Telemetry ECG and showed that sinus arrest and Atrioventricular block with escape rhythm, but the incidence of spontaneous arrhythmia in implantable telemetry ECG was no significantly different relative to control mice. The incidence of atrial tachyarrhythmia was increased in ALK7-/-Langendorff-perfused mouse hearts during burst pacing compared with control mice. Atrial prolonged repolarization was observed in ALK7-/-hearts by increased atrial effective refractory periods (AERP). Increased sinus node recovery time (SNRT) is showed in ALK7-/-isolated hearts relative to control mice. These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5-/-mice may contribute to abnormalities of atrial repolarization.