AIMS: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. METHODS AND RESULTS: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. CONCLUSIONS: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

APHP Cochin Hospital Cardiology Department FILNEMUS Paris Descartes Sorbonne Paris Cité University Paris France

APHP Hôpital Raymond Poincaré Centre de Référence des Maladies Neuromusculaires Nord Est Île de France Garches France

Barts Heart Centre St Bartholomew's Hospital Barts Health NHS Trust London UK

Cardiogenetics Unit Clinical Genetics Department University Hospital Germans Trias i Pujol Badalona Spain

Cardiology Department ASST Papa Giovanni XXIII Bergamo Italy

Cardiology Department Health in Code A Coruña Spain

Cardiology Department Hospital Universitario Virgen de las Nieves Granada Spain

Cardiology Department University General Hospital of Alicante Alicante Spain Institute of Health and Biomedical Research Alicante Spain

Cardiomyology and Medical Genetics University of Campania Luigi Vanvitelli Naples Italy

Centre for Heart Muscle Disease Institute of Cardiovascular Science University College London London UK

Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares Madrid Spain

Centro Nacional de Investigaciones Cardiovasculares Madrid Spain

Department of Cardiology Aarhus University Hospital Aarhus Denmark

Department of Cardiology and Department of Clinical Genetics Maastricht University Medical Center Maastricht The Netherlands

Department of Cardiology Hospital Universitario Marqués de Valdecilla IDIVAL Santander Spain

Department of Cardiology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Cardiology Odense University Hospital Odense Denmark

Department of Genetics University Medical Center Utrecht University of Utrecht Utrecht The Netherlands

Department of Paediatric Cardiology Meyer Children's Hospital Florence Italy

Division of Cardiovascular Imaging Department of Cardiology 1 University Hospital Muenster Muenster Germany

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart Amsterdam The Netherlands

Expert Center for Rare Cardiovascular Genetic Diseases 3rd Cardiology Department Emergency Institute for Cardiovascular Diseases Prof Dr C C Iliescu Bucharest Romania

Heart Area Complejo Hospitalario de Navarra Pamplona Spain

Heart Failure and Inherited Cardiac Diseases Unit Department of Cardiology Hospital Universitario Puerta de Hierro Madrid Spain

Hospital Universitari Vall d'Hebron Department of Cardiology Vall d'Hebron Institut de Recerca Universitat Autònoma de Barcelona Barcelona Spain

Hospital Universitario Araba Txagorritxu Vitoria Spain

Inherited cardiac diseases unit Cardiology Department Hospital Universitario 12 de Octubre Instituto de Investigación i 12 Madrid Spain

Inherited Cardiac Diseases Unit Department of Cardiology Hospital Universitari Dr Josep Trueta Girona Spain

Inherited Cardiovascular Diseases Unit Cardiology Service Complexo Hospitalario Universitario de A Coruña Servizo Galego de Saúde Universidade da Coruña A Coruña Spain

Institut Clinic Cardiovascular IDIBAPS Hospital Clínic University of Barcelona Barcelona Spain

Institute for Cardiomyopathies Heidelberg University Hospital Heidelberg Heidelberg Germany

Leviev Heart Center Sheba Medical Center and The Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Medical Science Department School of Medicine University of Girona Girona Spain

Referral Center of Neuromuscular Diseases Myology Institute Pitié Salpêtrière Hospital Paris France

Stanford University School of Medicine Department of Genetics Stanford CA USA

Unit for Screening Studies in Inherited Cardiovascular Diseases National Institute of Cardiology Warsaw Poland

Universidad Francisco de Vitoria Pozuelo de Alarcon Spain

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$a Restrepo-Cordoba, Maria A $u Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain $u Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain $u European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN-GUARDHEART), Amsterdam, The Netherlands

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$a Prevalence and clinical outcomes of dystrophin-associated dilated cardiomyopathy without severe skeletal myopathy / $c MA. Restrepo-Cordoba, K. Wahbi, AR. Florian, J. Jiménez-Jáimez, L. Politano, M. Arad, V. Climent-Paya, A. Garcia-Alvarez, RB. Hansen, JM. Larrañaga-Moreira, M. Kubanek, LR. Lopes, A. Ros, R. Jurcut, TB. Rasmussen, L. Ruiz-Guerrero, R. Pribe-Wolferts, J. Palomino-Doza, Z. Bilinska, JF. Rodríguez-Palomares, RLE. Van Loon, MT. Basurte Elorz, G. Quarta, M. Robledo Iñarritu, JAJ. Verdonschot, T. Stojkovic, Z. Shomanova, F. Bermudez-Jimenez, A. Palladino, D. Freimark, MI. García-Álvarez, P. Jorda, F. Dominguez, JP. Ochoa, F. Girolami, R. Brugada, B. Meder, R. Barriales-Villa, J. Mogensen, P. Laforêt, A. Yilmaz, P. Elliott, P. Garcia-Pavia, European Genetic Cardiomyopathies Initiative Investigators (see online supplementary Appendix S1)

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$a AIMS: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. METHODS AND RESULTS: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. CONCLUSIONS: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

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