Sudden cardiac death (SCD) can occur in young, otherwise healthy individuals suffering frominherited gene mutations. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is aninherited arrhythmogenic disease characterized by adrenergically mediated rounds of bidirectional(biVT) and polymorphic (PVT)ventricular tachycardias, leading to syncope and/or SCD in theabsence of structural heart disease; mortality is ~30% by the age of 40 years. As many as 40 pointmutations in the human cardiac sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodinereceptor type 2 [RyR2]), linked to defective SR Ca2+ channel function, have been reported inindividuals affected by CPVT and arrhythmogenic right ventricular cardiomyopathy type 2(ARVC2).Our central objective is to determine the electrophysiological mechanisms of CPVT. We takeadvantage of a unique knock-in mouse model (RyR2+/RyR2R4496C), which carries the murineequivalent of a human missense mutation (R4497C) in RyR2 that results in CPVT. Recent datashow that administration of caffeine and of adrenergic agonists predisposes the RyR2+/RyR2R4496cmouse heart to biVT, PVT and VF, which suggests the involvement of increased Ca2+ releasethrough the defective RyR2 channels. It is our hypothesis that arrhythmias in this model, and byinference in CPVT patients, are triggered by delayed afterdepolarizations (DADs) occurring atPurkinje fibers on the right and left branches of the specialized ventricular conducting system. Wewill test this hypothesis using an integrative approach from the molecule to the organ level.
Our Specific Aims are:1. To investigate the mechanisms underlying the occurrence of SR-Ca2+ leak incardiac Purkinje fibers and ventricular myocytes of the RyR2+/RyR2R4496C mouse heart. 2. Todetermine whether ventricular myocytes and Purkinje cells obtained from RyR2+/RyR2R4496C heartundergo DADs and triggered activity in the presence of increased extracellular Ca2+ or duringsuperfusion with caffeine and/or isoproterenol. 3. To determine the electrophysiologicalmechanisms of biVT and PVT in the RyR2+/RyR2R4496C mouse heart. The results derived from theproposed studies should provide fundamental understanding to the CPVT phenotype and giveinsight into mechanisms in conditions such as heart failure and others in which there is anincreased vulnerability to arrhythmias due to abnormal SR Ca2* release.
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