Cardiac arrhythmia is an important cause of death in patients with heart failure (HF) and inherited arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) [1]. Recent studies indicate that alterations in intracellular calcium (Ca2+) release channels known as ryanodine receptors (RyR2) play an important role in triggering ventricular arrhythmias [2]. For example, inherited mutations in the RyR2 gene have been associated with exercise-induced ventricular arrhythmias and sudden cardiac death in patients with CPVT. Electrophysiological studies have revealed that CPVT-mutant RyR2 channels are more likely to open aberrantly during diastole, which may provide the trigger for delayed afterdepolarizations and premature ventricular contractions. Studies in cardiomyocytes isolated from knockin mice carrying a CPVT-mutation in RyR2 demonstrated an increased propensity towards spontaneous Ca2+ release events during diastole [3]. Some CPVT mutations are also thought to decrease the binding affinity of the channel-stabilizing subunit calstabin2 (FKBP12.6), which may further enhance diastolic Ca2+ release from the sarcoplasmic reticulum (SR) [2]. Interestingly, decreased binding of calstabin2 to RyR2 has also been reported in patients and animals with heart failure. Indeed, enhanced diastolic SR Ca2+ leak has been demonstrated in cardiomyocytes isolated from calstabin2-deficient mice [2,4]. Moreover, an increased open probability of RyR2 isolated has been reported in several animal models of heart failure [5]. Taken together, these findings show that reopening of RyR2 channels during diastole, when the channel normally remains closed, cause SR Ca2+ leak which may initiate delayed afterdepolarizations and triggered activity leading to ventricular arrhythmias.