Genotype-Phenotype Correlation in ARVD/C | Journal Scan

Study Questions:

How does genotype influence outcome in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)?


ARVD/C genotype-positive subjects were sourced from ARVD/C registries at Johns Hopkins and the Interuniversity Cardiology Institute of the Netherlands. Prospectively collected registry data were used for phenotype characterization. The primary outcome was a composite of sudden cardiac arrest, sustained ventricular tachycardia/ventricular fibrillation, or appropriate implantable cardioverter-defibrillator intervention. Secondary outcome was death or cardiac transplant.


Out of 577 subjects, a single plakophilin-2 (PKP2) mutation was the most common genotype, occurring in 80%. Two or more mutations were present in 4%. Sudden cardiac death (SCD) was the presenting symptom in 6%, occurring at a median age of 23 years. Desmoplakin (DSP) mutation carriers accounted for 11% of SCD cases, but only 3% of the cohort. The 541 living subjects were followed for a mean of 6 years, during which 53% remained asymptomatic and 38% patients reached the primary outcome. Symptom onset for PKP2 mutation carriers occurred at a median age of 30 years; younger than those with phospholamban (PLN) mutations. Arrhythmic event-free survival at ages 40 and 60 years was 66% and 42%. Freedom from death/transplant at ages 40 and 60 years was 91% and 85%. Patients with >1 mutation were affected more severely, with median age of symptom onset at 23 years and arrhythmia-free survival at ages 20 and 40 years of 71% and 33%. Those with PLN, DSP, or >1 mutation had a higher incidence of left ventricular dysfunction. Men were more likely to reach the primary outcome or present with SCD.


The authors concluded that initial presentation of SCD occurs at a younger age than other arrhythmia symptoms. Genotype and sex influence outcomes.


This large cohort study of ARVD/C shows that presentation with SCD occurs at a younger age than other arrhythmia-related symptoms, and the incidence of SCD is disproportionately higher in patients with DSP mutations. Certain genotype-specific risks appear to exist. Patients with >1 mutation and men are more severely affected.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Heart Transplant, Interventions and Structural Heart Disease

Keywords: Arrhythmias, Cardiac, Arrhythmogenic Right Ventricular Dysplasia, Death, Sudden, Cardiac, Defibrillators, Implantable, Desmoplakins, Disease-Free Survival, Genotype, Heart Transplantation, Mutation, Phenotype, Plakophilins, Ventricular Dysfunction, Left, Ventricular Fibrillation, Tachycardia, Ventricular, Registries

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