Catecholaminergic polymorphic ventricular tachycardia is a form of 
exercise-induced sudden cardiac death that has been linked to mutations in the 
cardiac Ca2+ release channel/ryanodine receptor (RyR2) located on the 
sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic 
ventricular tachycardia-linked RyR2 mutations significantly decrease the binding 
affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state 
of the channel. We have proposed that RyR2-mediated diastolic SR Ca2+ leak 
triggers ventricular tachycardia (VT) and sudden cardiac death. In 
calstabin-2-deficient mice, we have now documented diastolic SR Ca2+ leak, 
monophasic action potential alternans, and bidirectional VT. Calstabin-deficient 
cardiomyocytes exhibited SR Ca2+ leak-induced aberrant transient inward currents 
in diastole consistent with delayed after-depolarizations. The 
1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 
for RyR2, inhibited the diastolic SR Ca2+ leak, monophasic action potential 
alternans and triggered arrhythmias. Our data suggest that calstabin-2 
deficiency is as a critical mediator of triggers that initiate cardiac 
arrhythmias.