Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations
Por:
Cuenca S., Barriales-Villa R., Franaszczyk M., Coronado-Albi M.J., Rangel-Sousa D., Jiménez-Jáimez J., Ripoll-Vera T., Mogollón-Jiménez M.V., Fontalba-Romero A., Palomino-Doza J., Salas C., Hey T.M., Elliott P., Eiskjær H., Barriales R., Fernández Fernández X., Cicerchia M., Monserrat L., Ochoa J.P., Salazar-Mendiguchia J., Mogollón M.V., Ripoll T., Charron P., Richard P., Villard E., Palomino Doza J., Fontalba A., Alonso-Pulpón L., Cobo-Marcos M., Domínguez F., Garcia-Pavia P., Gómez-Bueno M., González-López E., Hernández-Hernández A., Hernández-Pérez F.J., López-Sainz Á., Restrepo-Córdoba A., Segovia-Cubero J., Toro R., de Gonzalo-Calvo D., Rosa Longobardo F., Limeres J., Rodriguez-Palomares J.F., Garcia-Pinilla J.M., López-Garrido M.A., Jiménez-Jaimez J., Garcia-Medina D., Rangel Sousa D., Peña M.L., Mogensen J., Morris-Hey T., Barton P.J., Cook S.A., Midwinter W., Roberts A.M., Ware J.S., Walsh R., Akhtar M., Elliott P.M., Rocha-Lopes L., Savvatis K., Syrris P., Michalak E., Ploski R., Sobieszczanska-Malek M., Bilinska Z., Pankuweit S., Asselbergs F., Baas A., Dooijes D., Sammani A.
Publicada:
1 ene 2018
Resumen:
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. © 2018 American College of Cardiology Foundation
Filiaciones:
Cuenca S.:
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
Barriales-Villa R.:
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
Franaszczyk M.:
Molecular Biology Laboratory, Department of Medical Biology, Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland
Coronado-Albi M.J.:
Confocal Microscopy Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain
Rangel-Sousa D.:
Heart Failure and Heart Transplantation Unit, Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain
Jiménez-Jáimez J.:
Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain
Ripoll-Vera T.:
Cardiology Department, Hospital Universitario Son Llatzer, Mallorca, Spain
Mogollón-Jiménez M.V.:
Cardiology Department, Hospital San Pedro de Alcántara, Cáceres, Spain
Fontalba-Romero A.:
Hospital Universitario Marqués de Valdecilla, Santander, Spain
Palomino-Doza J.:
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Hereditary Cardiopathies Unit, Hospital Universitario 12 de Octubre, Madrid, Spain
Salas C.:
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Department of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain
Hey T.M.:
Cardiology Department, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Elliott P.:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART), Spain
Saint Bartholomews’ Hospital, London, United Kingdom
Cicerchia M.:
Cardiology Department, Health in Code, A Coruña, Spain
Ochoa J.P.:
Cardiology Department, Health in Code, A Coruña, Spain
Grupo de Investigación Cardiovascular (GRINCAR), Universidad A Coruña, Spain
Salazar-Mendiguchia J.:
Cardiology Department, Health in Code, A Coruña, Spain
Charron P.:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART), Spain
APHP, Referral center for inherited cardiac diseases, ICAN, INSERM UMRS1166, Hôpital Pitié-Salpêtrière, Paris, France
Villard E.:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART), Spain
APHP, Referral center for inherited cardiac diseases, ICAN, INSERM UMRS1166, Hôpital Pitié-Salpêtrière, Paris, France
Palomino Doza J.:
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Hereditary Cardiopathies Unit, Hospital Universitario 12 de Octubre, Madrid, Spain
Domínguez F.:
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), Spain
Garcia-Pavia P.:
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), Spain
University Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain
Toro R.:
Medicine Department, School of Medicine, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), Cádiz, Spain
de Gonzalo-Calvo D.:
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
Rodriguez-Palomares J.F.:
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
Garcia-Pinilla J.M.:
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
Jiménez-Jaimez J.:
Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain
Garcia-Medina D.:
Cardiology Department, Hospital Universitario Virgen de Valme, Seville, Spain
Rangel Sousa D.:
Heart Failure and Heart Transplantation Unit, Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain
Mogensen J.:
Cardiology Department, Odense University Hospital, University of Southern Denmark, Odense, Denmark
Barton P.J.:
National Heart and Lung Institute, Imperial College London, London, United Kingdom
Cardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust LondonLondon, United Kingdom
Akhtar M.:
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART), Spain
Saint Bartholomews’ Hospital, London, United Kingdom
Bilinska Z.:
Unit for Screening Studies in Inherited Cardiovascular Diseases, Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland
Pankuweit S.:
Department of Cardiology, University Hospital Giessen and Marburg, Philipps-University Marburg, Marburg, Germany
Asselbergs F.:
Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University of UtrechtUtrecht, 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
Sammani A.:
Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University of UtrechtUtrecht, Netherlands
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