Fernando Domínguez1, Sofía Cuenca2, Zofia Bilińska3, Rocío Toro4, Eric Villard5, Roberto Barriales-Villa6, Juan Pablo Ochoa7, Folkert Asselbergs8, Arjan Sammani9, Maria Franaszczyk10, Mohammed Akhtar11, Maria José Coronado-Albi12, Diego Rangel-Sousa13, Jose F Rodriguez-Palomares14, Juan Jiménez-Jáimez15, José Manuel Garcia-Pinilla16, Tomás Ripoll-Vera17, Maria Victoria Mogollón-Jiménez18, Ana Fontalba-Romero19, Dolores Garcia-Medina20, Julian Palomino-Doza21, David de Gonzalo-Calvo22, Marcos Cicerchia23, Joel Salazar-Mendiguchia23, Clara Salas24, Sabine Pankuweit25, Thomas Morris Hey26, Jens Mogensen26, Paul J Barton27, Philippe Charron5, Perry Elliott11, Pablo Garcia-Pavia28. 1. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Myocardial Biology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART). 2. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Inherited cardiac diseases Unit, Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 3. Unit for Screening Studies in Inherited Cardiovascular Diseases, Cardinal Stefan Wyszyński Institute of Cardiology, Warsaw, Poland. 4. Medicine Department, School of Medicine, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), Cádiz, Spain. 5. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART); APHP, Referral center for inherited cardiac diseases, ICAN, INSERM UMRS1166, Hôpital Pitié-Salpêtrière, Paris, France. 6. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Instituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain; Inherited Cardiovascular Diseases Unit, Cardiology Service, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain. 7. Cardiology Department, Health in Code, A Coruña, Spain; Grupo de Investigación Cardiovascular (GRINCAR), Universidad A Coruña, Spain. 8. Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom; Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, United Kingdom. 9. Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands. 10. Molecular Biology Laboratory, Department of Medical Biology, Cardinal Stefan Wyszyński Institute of Cardiology, Warsaw, Poland. 11. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART); Saint Bartholomews' Hospital, London, United Kingdom. 12. Confocal Microscopy Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain. 13. Heart Failure and Heart Transplantation Unit, Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain. 14. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Hospital Universitari Vall d'Hebron, Department of Cardiology, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. 15. Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain. 16. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Heart Failure and Familial Cardiomyopathies Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain. 17. Cardiology Department, Hospital Universitario Son Llatzer, Mallorca, Spain. 18. Cardiology Department, Hospital San Pedro de Alcántara, Cáceres, Spain. 19. Hospital Universitario Marqués de Valdecilla, Santander, Spain. 20. Cardiology Department, Hospital Universitario Virgen de Valme, Seville, Spain. 21. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Hereditary Cardiopathies Unit, Hospital Universitario 12 de Octubre, Madrid, Spain. 22. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain. 23. Cardiology Department, Health in Code, A Coruña, Spain. 24. Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain. 25. Department of Cardiology, University Hospital Giessen and Marburg, Philipps-University Marburg, Marburg, Germany. 26. Cardiology Department, Odense University Hospital, University of Southern Denmark, Odense, Denmark. 27. National Heart and Lung Institute, Imperial College London, London, United Kingdom; Cardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust London, London, United Kingdom. 28. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART); University Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain. Electronic address: pablogpavia@yahoo.es.
Abstract
BACKGROUND: The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood. OBJECTIVES: This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. METHODS: The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. RESULTS: At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. CONCLUSIONS: DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.
BACKGROUND: The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3cardiomyopathy is poorly understood. OBJECTIVES: This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. METHODS: The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. RESULTS: At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. CONCLUSIONS:DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.
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