Outcomes of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Treated With ß-Blockers.

Importance: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite ß-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated. Objective: To investigate the long-term outcomes of patients with RYR2 CPVT treated with ß-blockers only and the cost to benefit ratio of ICD. Design, Settings, and Participants: This prospective cohort study conducted from January 1988 to October 2020 with a mean (SD) follow-up of 9.4 (7.5) years included patients who were referred to the Molecular Cardiology Clinics of ICS Maugeri Hospital, Pavia, Italy. Participants included consecutive patients with CPVT who were carriers of a pathogenic or likely pathogenic RYR2 variant with long-term clinical follow-up. Exposures: Treatment with selective and nonselective ß-blocker only and ICD implant when indicated. Main Outcome and Measures: The main outcome was the occurrence of the first LTAE while taking a ß-blocker. LTAE was defined as a composite of 3 hard end points: sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated ventricular tachycardia. Results: The cohort included 216 patients with RYR2 CPVT (121 of 216 female [55%], median [IQR] age 14, [9-30] years). During a mean (SD) follow-up of 9.4 (7.5) years taking ß-blockers only, 28 of 216 patients (13%) experienced an LTAE (annual rate, 1.9%; 95% CI, 1.3-2.7). In multivariable analysis, experiencing either an LTAE (hazard ratio [HR], 3.3; 95% CI, 1.2-8.9; P = .02) or syncope before diagnosis (HR, 4.5; 95% CI, 1.8-11.1; P = .001) and carrying a C-terminal domain variant (HR, 18.1; 95% CI, 4.1-80.8; P < .001) were associated with an increased LTAE risk during ß-blocker therapy only. The risk of LTAE among those taking selective ß-blockers vs nadolol was increased 6-fold (HR, 5.8; 95% CI, 2.1-16.3; P = .001). Conversely, no significant difference was present between propranolol and nadolol (HR, 1.8; 95% CI, 0.4-7.3; P = .44). An ICD was implanted in 79 of 216 patients (37%) who were followed up for a mean (SD) of 8.6 (6.3) years. At the occurrence of LTAE, ICD carriers were more likely to survive (18 of 18 [100%]) than non-ICD carriers (6 of 10 [60%]; P = .01). Conclusions and Relevance: In this cohort study, selective ß-blockers were associated with a higher risk of LTAE as compared with nadolol. Independently from treatment, LTAE and syncope before diagnosis and C-terminal domain variants identified patients at higher risk of ß-blocker failure, and the ICD was associated with reduced mortality in high-risk patients with CPVT.

Role of CACNA1C in Brugada syndrome: Prevalence and phenotype of probands referred for genetic testing.

BACKGROUND: Evidence for the role of the CACNA1C gene, which encodes for the α-subunit of the cardiac L-type calcium channel CaV1.2, as a cause of the BrS3 variant of Brugada syndrome (BrS) is contradictory. OBJECTIVE: The purpose of this study was to define in a large BrS cohort the yield of molecular screening and to test whether appropriate patient selection could improve clinical utility. METHODS: A total of 709 patients were included in this study. BrS probands (n = 563, consecutively referred) underwent CACNA1C sequencing. Two matched cohorts where defined: discovery cohort (n = 200) and confirmation cohort (n = 363). In addition, the clinical phenotypes of a matched SCN5A-positive BrS cohort (n = 146) were included for comparative genotype-phenotype correlation. RESULTS: In the discovery cohort, we identified 11 different rare variants in 9 patients; 10 of the variants (5%) were considered potentially causative based on their frequency in the general population. However, American College of Medical Genetics criteria were unable to classify the majority (80%) of them, which eventually were labeled as variants of unknown significance (VUS). Functional studies revealed a loss of function for 9 variants, pointing to a prevalence of CACNA1C causative variants in 4% of the discovery cohort. Genotype-phenotype correlation showed that pathogenic variants are significantly more frequent in patients with shorter QTc (12.9% vs 2.2% in patients with QTc <390 ms). CONCLUSION: CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT. Functional studies are highly relevant to improve variant interpretation.

Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). OBJECTIVES: This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. METHODS: Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. RESULTS: The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). CONCLUSIONS: The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS.

Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined. OBJECTIVES: This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy. METHODS: We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals. RESULTS: A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated. CONCLUSIONS: The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management.