Aditya Bhonsale1, Judith A Groeneweg2, Cynthia A James1, Dennis Dooijes3, Crystal Tichnell1, Jan D H Jongbloed4, Brittney Murray1, Anneline S J M te Riele5, Maarten P van den Berg6, Hennie Bikker7, Douwe E Atsma8, Natasja M de Groot9, Arjan C Houweling10, Jeroen F van der Heijden11, Stuart D Russell1, Pieter A Doevendans11, Toon A van Veen12, Harikrishna Tandri1, Arthur A Wilde13, Daniel P Judge1, J Peter van Tintelen14, Hugh Calkins1, Richard N Hauer15. 1. Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA. 2. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands. 3. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 4. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 5. Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, USA Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 6. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 7. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 8. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 9. Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. 10. Department of Genetics, VU Medical Center, Amsterdam, The Netherlands. 11. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 12. Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands. 13. Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands. 14. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands Durrer Center for Cardiogenetic Research, Utrecht, The Netherlands. 15. Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands (ICIN), PO Box 19258, 3501 DG Utrecht, The Netherlands r.n.w.hauer@umcutrecht.nl.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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%) patientsdied, 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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