Effects of a high-affinity and selective RyR2 inhibitor on Ca2+ signals in cardiomyocytes and arrhythmias in CPVT model mice

Gain-of-function mutations in the type 2 ryanodine receptor (RyR2) are known to cause lethal arrhythmias such as catecholaminergic ventricular tachycardia (CPVT). In CPVT, reduction of RyR2 activity is thought to suppress arrhythmias, but there are no clinically available antiarrhythmic drugs with pure RyR2-specific inhibitory action. We developed a high-affinity (IC50 of ∼15 nM) and selective RyR2 inhibitor, TMDJ-035, based on a hit compound identified in a high-throughput screening. In isolated cardiomyocytes, TMDJ-035 suppressed Ca2+ waves and sparks without affecting action potential-induced Ca2+ transients. TMDJ-035 effectively suppressed arrhythmias in CPVT mouse models harboring mutant RyR2s. Unlike conventional antiarrhythmic drugs (i.e., Na channel inhibitors, Ca channel inhibitors, ß-blockers), TMDJ-035 did not affect ECG parameters or cardiac contractile function at the effective doses. Our results demonstrate that the specific suppression of RyR2 activity is highly effective in the prevention and treatment of arrhythmias caused by RyR2 hyperactivation.