Molecular and Electrophysiological Bases of Catecholaminergic Polymorphic Ventricular Tachycardia

Uwais Mohamed, M.B.B.S., F.R.A.C.P.; Carlo Napolitano, M.D., Ph.D.; Silvia G. Priori, M.D., Ph.D.

Disclosures

J Cardiovasc Electrophysiol. 2007;18(7):791-797. 

In This Article

Abstract and Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. Genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2) and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2). Functional characterization of mutations identified in the RyR2 and CASQ2 genes has demonstrated that CPVT are caused by derangements of the control of intracellular calcium. Investigations in a knock-in mouse model have shown that CPVT arrhythmias are initiated by delayed afterdepolarizations and triggered activity. In the present article, we review clinical and molecular understanding of CPVT and discuss the most recent approaches to develop novel therapeutic strategies for the disease.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder characterized by adrenergically mediated polymorphic ventricular tachyarrhythmias. It is an important cause of syncope and sudden cardiac death in individuals with a structurally normal heart.[1,2] The first case of CPVT was described in 1975[3] and the disease was further characterized in 1978.[4] More recently, genetic investigations have identified two variants of the disease: an autosomal dominant form associated with mutations in the gene encoding the cardiac ryanodine receptor (RyR2)[5,6] and a recessive form associated with homozygous mutations in the gene encoding the cardiac isoform of calsequestrin (CASQ2).[7,8]

This article will review the current knowledge regarding the molecular and electrophysiological basis of CPVT. First, we will discuss the clinical aspects of the disease and, subsequently, we will provide an overview of the in vitro functional characterization of the mutations identified in CPVT patients and the data collected in a transgenic animal model of the disease. Finally, we will present the current hypothesis on the molecular and electrophysiological derangements leading to arrhythmias in CPVT patients.

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