TY - JOUR
T1 - Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers
AU - Bhonsale, Aditya
AU - Groeneweg, Judith A.
AU - James, Cynthia A.
AU - Dooijes, Dennis
AU - Tichnell, Crystal
AU - Jongbloed, Jan D.H.
AU - Murray, Brittney
AU - Te Riele, Anneline S.J.M.
AU - Van Den Berg, Maarten P.
AU - Bikker, Hennie
AU - Atsma, Douwe E.
AU - De Groot, Natasja M.
AU - Houweling, Arjan C.
AU - Van Der Heijden, Jeroen F.
AU - Russell, Stuart D.
AU - Doevendans, Pieter A.
AU - Van Veen, Toon A.
AU - Tandri, Harikrishna
AU - Wilde, Arthur A.
AU - Judge, Daniel P.
AU - Van Tintelen, J. Peter
AU - Calkins, Hugh
AU - Hauer, Richard N.
N1 - Funding Information:
The authors wish to acknowledge funding from the Dr Francis P. Chiaramonte Private Foundation, St. Jude Medical Inc. and Medtronic Inc. The Johns Hopkins ARVD/C Program is supported by the Leyla Erkan Family Fund for ARVD Research, the Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments. The study is supported by the Interuniversity Cardiology Institute of the Netherlands (project 06901), the Netherlands Heart Foundation (grants 2007B132 and 2007B139), the Alexandre Suerman Stipend (to A.T.), and the Netherlands Heart Foundation Dr E. Dekker grant (J.A.G., 2013T033). We furthermore acknowledge the support from the Netherlands CardioVascular Research Initiative: the Netherlands Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences.
Publisher Copyright:
© 2015 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015.
PY - 2015/4/7
Y1 - 2015/4/7
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Arrhythmogenic right ventricular dysplasia/cardiomyopathy
KW - Genetics
KW - Prognosis
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U2 - 10.1093/eurheartj/ehu509
DO - 10.1093/eurheartj/ehu509
M3 - Article
C2 - 25616645
AN - SCOPUS:84925968579
VL - 36
SP - 847
EP - 855
JO - European Heart Journal
JF - European Heart Journal
SN - 0195-668X
IS - 14
ER -