Abstract 570: Catecholaminergic Polymorphic Ventricular Tachycardia - a Link between Mutation and Arrhythmia
In this study, we investigate the mechanistic underpinnings of catecholaminergic polymorphic ventricular tachycardia (CPVT), a hereditary arrhythmia that leads to exercise- and stress-induced sudden cardiac death in young adults with structurally normal hearts. Recently, several mutations in cardiac calsequestrin (CSQN2) and the cardiac ryanodine receptor (RyR2) have been linked to CPVT. These mutant genes have been shown to affect RyR2 gating, however, the precise mechanisms by which they give rise to triggered activity remain uncertain. We modified a detailed mathematical model of the human left-ventricular subepicardial myocyte, using recently obtained experimental data, to study the aberrant calcium release events observed in mutant myocytes. First, CSQN2 mutations were modeled, by simulating disrupted luminal SR Ca2+ sensing in the release process (the rate of release termination and rate of recovery from inactivation were increased). Second, a model for mutant RyR2 myocytes was formed by simulating the impaired coupled gating characteristic of reduced FKBP12.6 (calstabin) binding to the RyR2. Both models give rise to delayed afterdepolarizations (DADs) when paced in the presence of simulated isoproterenol. The mechanism for DADs in CSQN2 mutants appears to be secondary to premature recovery of receptors from a luminal calcium-dependent refractory state. In RyR2 mutants, DADs arise from receptors that activate with less synchrony, resulting in hyperactive, “leaky” receptors. Overall, these results provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers of arrhythmia, with implications for the development of targeted therapy.