Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The aim of the study was to define clinical characteristics of patients with mutations in RyR2 gene, compared to patients with non-genotyped CPVT.

The study population included subjects with documented polymorphic ventricular tachycardia (occurred during exercise or emotional stress) and a structurally normal heart. We evaluated the clinical phenotype of 30 probands and of 118 family members, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia (bVT), 12 of 30 polymorphic ventricular tachycardia (pVT), and 4 of 30 catecholaminergic idiopathic ventricular fibrillation (cIVF). Family history of sudden death was positive in 10 of 30 (19 subjects deceased suddenly). RyR2 mutations were identified in 14 of 30 probands (36% bVT, 58% pVT, 50% cIVF) and in 9 family members (4 silent gene carriers). Genotype-phenotype analysis showed that patients with RyR2-CPVT have events at a younger age than patients with non-genotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative risk=4.2).

Based on these results, CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. Beta-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: patients with non-genotyped CPVT are predominantly women and become symptomatic later in life; patients with RyR2 CPVT become symptomatic earlier, and men are at higher risk of cardiac events.