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. 2015 Apr 7;36(14):847-55.
doi: 10.1093/eurheartj/ehu509. Epub 2015 Jan 23.

Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

Aditya Bhonsale  1 , Judith A Groeneweg  2 , Cynthia A James  1 , Dennis Dooijes  3 , Crystal Tichnell  1 , Jan D H Jongbloed  4 , Brittney Murray  1 , Anneline S J M te Riele  5 , Maarten P van den Berg  6 , Hennie Bikker  7 , Douwe E Atsma  8 , Natasja M de Groot  9 , Arjan C Houweling  10 , Jeroen F van der Heijden  11 , Stuart D Russell  1 , Pieter A Doevendans  11 , Toon A van Veen  12 , Harikrishna Tandri  1 , Arthur A Wilde  13 , Daniel P Judge  1 , J Peter van Tintelen  14 , Hugh Calkins  1 , Richard N Hauer  15
Affiliations

Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

Aditya Bhonsale et al. Eur Heart J. .

Abstract

Aims: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.

Methods and results: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.

Conclusions: Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.

Keywords: Arrhythmia; Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Genetics; Prognosis.

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