Maria A Restrepo-Cordoba1,2,3, Karim Wahbi4, Anca R Florian5, Juan Jiménez-Jáimez6, Luisa Politano7, Michael Arad8, Vicente Climent-Paya9, Ana Garcia-Alvarez2,10, Rasmus B Hansen11, José M Larrañaga-Moreira12, Milos Kubanek13, Luis R Lopes3,14,15, Andrea Ros16, Ruxandra Jurcut3,17, Torsten B Rasmussen18, Luis Ruiz-Guerrero19, Regina Pribe-Wolferts20, Julian Palomino-Doza2,21, Zofia Bilinska22, José F Rodríguez-Palomares2,23, Rosa L E Van Loon24, María Teresa Basurte Elorz25, Giovanni Quarta26, Maria Robledo Iñarritu27, Job A J Verdonschot28, Tanya Stojkovic29, Zornitsa Shomanova5, Francisco Bermudez-Jimenez6, Alberto Palladino7, Dov Freimark8, Maria I García-Álvarez9, Paloma Jorda10, Fernando Dominguez1,2,3, Juan Pablo Ochoa1,30, Francesca Girolami31, Ramon Brugada2,32,33, Benjamin Meder20,34, Roberto Barriales-Villa2,12, Jens Mogensen11, Pascal Laforêt35, Ali Yilmaz5, Perry Elliott3,14,15, Pablo Garcia-Pavia1,2,3,36,37. 1. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain. 2. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. 3. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN-GUARDHEART), Amsterdam, The Netherlands. 4. APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France. 5. Division of Cardiovascular Imaging, Department of Cardiology I, University Hospital Muenster, Muenster, Germany. 6. Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain. 7. Cardiomyology and Medical Genetics, University of Campania Luigi Vanvitelli, Naples, Italy. 8. Leviev Heart Center, Sheba Medical Center and The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 9. Cardiology Department, University General Hospital of Alicante, Alicante, Spain. Institute of Health and Biomedical Research (ISABIAL), Alicante, Spain. 10. Institut Clinic Cardiovascular, IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain. 11. Department of Cardiology, Odense University Hospital, Odense, Denmark. 12. Inherited Cardiovascular Diseases Unit, Cardiology Service, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Instituto de Investigación Biomédica de A Coruña (INIBIC), Universidade da Coruña, A Coruña, Spain. 13. Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. 14. Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK. 15. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK. 16. Cardiogenetics Unit, Clinical Genetics Department, University Hospital Germans Trias i Pujol, Badalona, Spain. 17. Expert Center for Rare Cardiovascular Genetic Diseases, 3rd Cardiology Department, Emergency Institute for Cardiovascular Diseases "Prof. Dr. C.C. Iliescu", Bucharest, Romania. 18. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark. 19. Department of Cardiology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. 20. Institute for Cardiomyopathies Heidelberg, University Hospital Heidelberg, Heidelberg, Germany. 21. Inherited cardiac diseases unit, Cardiology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Madrid, Spain. 22. Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, Warsaw, Poland. 23. Hospital Universitari Vall d'Hebron, Department of Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. 24. Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. 25. Heart Area, Complejo Hospitalario de Navarra, Pamplona, Spain. 26. Cardiology Department, ASST Papa Giovanni XXIII, Bergamo, Italy. 27. Hospital Universitario Araba - Txagorritxu, Vitoria, Spain. 28. Department of Cardiology and Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. 29. Referral Center of Neuromuscular Diseases, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France. 30. Cardiology Department, Health in Code, A Coruña, Spain. 31. Department of Paediatric Cardiology, Meyer Children's Hospital, Florence, Italy. 32. Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitari Dr Josep Trueta, Girona, Spain. 33. Medical Science Department, School of Medicine, University of Girona, Girona, Spain. 34. Stanford University School of Medicine, Department of Genetics, Stanford, CA, USA. 35. APHP, Hôpital Raymond Poincaré, Centre de Référence des Maladies Neuromusculaires Nord-Est-Île de France, Garches, France. 36. Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain. 37. Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Abstract
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.
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.
Authors: Jesús G Mirelis; Luis Escobar-Lopez; Juan Pablo Ochoa; María Ángeles Espinosa; Eduardo Villacorta; Marina Navarro; Guillem Casas; Nerea Mora-Ayestarán; Roberto Barriales-Villa; María Victoria Mogollón-Jiménez; José M García-Pinilla; Pablo E García-Granja; Vicente Climent; Julian Palomino-Doza; Ana García-Álvarez; María Álvarez-Barredo; Eva Cabrera-Borrego; Tomás Ripoll-Vera; María Luisa Peña-Peña; Elena Rodríguez-González; María Gallego-Delgado; Josefa Gonzalez-Carrillo; Ana Fernández-Ávila; José F Rodríguez-Palomares; Ramón Brugada; Antoni Bayes-Genis; Fernando Dominguez; Pablo García-Pavía Journal: Eur J Heart Fail Date: 2022-05-22 Impact factor: 17.349