SK 4 K + channels are therapeutic targets for the treatment of cardiac arrhythmias

Catecholaminergic polymorphic ventricular tachycardia ( CPVT ) is a stress‐provoked ventricular arrhythmia, which also manifests sinoatrial node ( SAN ) dysfunction. We recently showed that SK 4 calcium‐activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK 4 channels were identified in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐ CM s) from healthy and CPVT 2 patients bearing a mutation in calsequestrin 2 ( CASQ 2‐D307H) and in SAN cells from WT and CASQ 2‐D307H knock‐in ( KI ) mice. TRAM ‐34, a selective blocker of SK 4 channels, prominently reduced delayed afterdepolarizations and arrhythmic Ca 2+ transients observed following application of the β‐adrenergic agonist isoproterenol in CPVT 2‐derived hiPSC‐ CM s and in SAN cells from KI mice. Strikingly, in vivo ECG recording showed that intraperitoneal injection of the SK 4 channel blockers, TRAM ‐34 or clotrimazole, greatly reduced the arrhythmic features of CASQ 2‐D307H KI and CASQ 2 knockout mice at rest and following exercise. This work demonstrates the critical role of SK 4 Ca 2+ ‐activated K + channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT .