Beta2-adrenergic receptor activation increases susceptibility to arrhythmogenesis in aging heart by impairing repolarization reserve via Giβγ–PLC signaling pathway

In this study, age-related alterations in cardiac electrophysiology and the response to β2-adrenergic receptor (β2AR) activation were examined. Experiments were conducted in guinea pig hearts (in vivo, in vitro) and in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using a multielectrode array. Heart rate–corrected QT interval (QTc) and action potential duration (APD) were prolonged in aging hearts. The shortening of APD in response to increased pacing rates was markedly blunted in aged ventricular myocytes compared with young myocytes. β2AR agonist salbutamol (SAL) shortened QTc in a concentration-dependent manner in young hearts, whereas this response was absent in aging hearts, with susceptibility to ventricular tachyarrhythmias. In D-galactose–induced aging hiPSC-CMs, SAL-induced repolarization delay and cell arrhythmias, consistent with findings in aging hearts. In both aging hearts and hiPSC-CMs, the Gi inhibitor pertussis toxin, Gβγ inhibitor gallein, and the phospholipase C inhibitor U73122 reduced arrhythmogenesis. Furthermore, the slow delayed rectifier potassium channel (IKs) activator ML277 exerted a protective effect against aging-related arrhythmias. Overall, these findings indicate that β2AR activation increases susceptibility to arrhythmogenesis in aging hearts and D-galactose–induced aging hiPSC-CMs, whereas suppression of Giβγ–PLC signaling or activation of IKs may provide potential protection against aging-related repolarization delay and arrhythmias.