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

Aditya Bhonsale, Judith A. Groeneweg, Cynthia A. James, Dennis Dooijes, Crystal Tichnell, Jan D.H. Jongbloed, Brittney Murray, Anneline S.J.M. Te Riele, Maarten P. Van Den Berg, Hennie Bikker, Douwe E. Atsma, Natasja M. De Groot, Arjan C. Houweling, Jeroen F. Van Der Heijden, Stuart D. Russell, Pieter A. Doevendans, Toon A. Van Veen, Harikrishna Tandri, Arthur A. Wilde, Daniel P. JudgeJ. Peter Van Tintelen, Hugh Calkins, Richard N. Hauer

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)847-855
Number of pages9
JournalEuropean heart journal
Issue number14
StatePublished - Apr 7 2015


  • Arrhythmia
  • Arrhythmogenic right ventricular dysplasia/cardiomyopathy
  • Genetics
  • Prognosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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