Clinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Background-Mutations in the cardiac ryanodine receptor gene (RyR2) underlie catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disease occurring in the structurally intact heart. The proportion of patients with CPVT carrying RyR2 mutations is unknown, and the clinical features of RyR2-CPVT as compared with nongenotyped CPVT are undefined. Methods and Results-Patients with documented polymorphic ventricular arrhythmias occurring during physical or emotional stress with a normal heart entered the study. The clinical phenotype of the 30 probands and of 118 family members was evaluated, and mutation screening on the RyR2 gene was performed. Arrhythmias documented in probands were: 14 of 30 bidirectional ventricular tachycardia, 12 of 30 polymorphic ventricular tachycardia, and 4 of 30 catecholaminergic idiopathic ventricular fibrillation; RyR2 mutations were identified in 14 of 30 probands (36% bidirectional ventricular tachycardia, 58% polymorphic ventricular tachycardia, 50% catecholaminergic idiopathic ventricular fibrillation) 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 do patients with nongenotyped CPVT and that male sex is a risk factor for syncope in RyR2-CPVT (relative riskϭ4.2). Conclusions-CPVT is a clinically and genetically heterogeneous disease manifesting beyond pediatric age with a spectrum of polymorphic arrhythmias. ␤-Blockers reduce arrhythmias, but in 30% of patients an implantable defibrillator may be required. Genetic analysis identifies two groups of patients: Patients with nongenotyped 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. These data provide a rationale for prompt evaluation and treatment of young men with RyR2 mutations. (Circulation. 2002;106:69-74.)

CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity

“…Changes in cardiac function by the two steps coincided with changes in biomarkers including RyR2 and its modulator FKBP12.6, as well as SERCA2a and its modulator PLB. This is in line with other published findings on aggravating cardiac failure by ISO injection [5,[29][30][31] .…”

Double SCN5A mutation underlying asymptomatic Brugada syndrome

“…Because the double mutant channel showed a negative shift of the steady-state inactivation curve and an increased proportion of Na channels that enter an intermediate state of inactivation, there is a reduction in cardiac Na current, which is characteristic of SCN5A mutations in those with symptomatic Brugada syndrome 18,28 . These results suggest that asymptomatic individuals with "functionally proven" SCN5A mutations with loss-of-function properties should be carefully followed to avoid lethal events as was observed in the SUNDS 29 as well as in long-QT syndrome 30 . We previously found an SCN5A mutation R367H in a family with atrial standstill complicated with J wave elevation in the inferior leads 22 , while Hong et al found the same mutation in a typical Brugada syndrome family 31 .…”

Effective cascade screening through identification of a mutation in RYR2 in a large family with a history of sudden death

“…Exercise tests are often used in the diagnosis and monitoring of therapy in CPVT, however mutation carriers may display no features during testing [4]. As in our family, there are reports of symptomatic RYR2 mutation carriers who have inherited the pathogenic mutation from completely asymptomatic parents [5]. Clinical assessment is limited in the evaluation of at-risk individuals and therefore cascade genetic testing is a more sensitive and specific way of screening in families with CPVT.…”

“…The incomplete penetrance of the condition can make it difficult to identify at-risk individuals, hence molecular genetic testing can be of particular value [5]. We describe a large family with a history of sudden death highlighting the value and clinical utility of molecular genetic testing for CPVT.…”