Genes, exercise and sudden death: molecular basis of familial catecholaminergic polymorphic ventricular tachycardia

Familial catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disease manifesting with exercise- or stress-induced ventricular arrhythmias, syncope, and even sudden death. CPVT is inherited as an autosomal dominant or autosomal recessive trait, usually with high penetrance. We characterized in detail the clinical, structural and electrocardiographic findings in this disorder and by use of genome-wide linkage analysis, mapped the disease-causing gene to chromosome 1q42-q43. Thereafter, we and others demonstrated point mutations of the cardiac ryanodine receptor gene (RyR2) to underlie this life-threatening disease. In addition, RyR2 mutations were identified in patients affected with a variant form of arrhythmogenic right ventricular dysplasia (ARVD2), a phenotypically distinct disease entity. Identification of the causal mutations has enabled molecular diagnosis in the affected families, which is of major importance in identifying individuals at risk of an arrhythmia. Recently, several groups have delineated the functional effects of the RyR2 mutations associated with CPVT and ARVD2. The results are slightly contradictory, and further studies are thus needed to clarify the exact molecular mechanisms leading to arrhythmia induction.