RYR2 and catecholaminergic polymorphic ventricular tachycardia: In addition to causing altered glucose metabolism and providing triggers for cardiac arrhythmias (CPVT), the RyR2-mediated Ca2+ leak—by depleting Ca2+ stores—may also contribute to arrhythmia substrate creation via reduced IKs current, i.e., decreased Ca2+-dependent IKs activation (40) and consequently, impaired repolarization reserve (17).