Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable 
arrhythmia unmasked by exertion or stress, characterized by triggered activity 
and sudden cardiac death in affected patients. In this study we used a 
mathematical model to simulate two mutations linked toCPVT, in cardiac 
calsequestrin (CSQN2) and the ryanodine receptor (RyR2). The aim of the present 
study is to characterize the mutations responsible for CPVT and establish the 
mechanistic basis for spontaneous Ca2+ release events that lead to delayed 
afterdepolarizations (DADs) and triggered arrhythmias. Simulated calcium 
transients in the mutant CSQN2 model recapitulated the smaller amplitude and 
time to peak, as well as accelerated recovery from inactivation seen in 
experiments. When simulated CSQN2-mutant myocytes were paced in current-clamp 
mode, DADs were observed, suggesting that accelerated recovery of RyR2 induced 
by impaired luminal Ca2(+) sensing can lead to the triggered activity observed 
in the mutant CSQN2. Simulations of mutant RyR2 suggest that the hyperactive, 
"leaky" receptors characteristic of reduced FKBP12.6 function may be centrally 
involved in triggering DADs. These results provide plausible mechanisms by which 
defects in RyR2 gating may lead to the cellular triggers of CPVT, with 
implications for the development of targeted therapies.