Author + information
- Received June 7, 2018
- Revision received August 12, 2018
- Accepted August 13, 2018
- Published online November 12, 2018.
- Fernando Domínguez, MD, PhDa,b,c,d,
- Sofía Cuenca, MD, PhDc,e,
- Zofia Bilińska, MD, PhDf,
- Rocío Toro, MD, PhDg,
- Eric Villard, PhDd,h,
- Roberto Barriales-Villa, MD, PhDc,i,j,
- Juan Pablo Ochoa, MDk,l,
- Folkert Asselbergs, MD, PhDm,n,o,
- Arjan Sammani, MDm,
- Maria Franaszczyk, PhDp,
- Mohammed Akhtar, MDd,q,
- Maria José Coronado-Albi, PhDr,
- Diego Rangel-Sousa, MDs,
- Jose F. Rodriguez-Palomares, MD, PhDc,t,
- Juan Jiménez-Jáimez, MD, PhDu,
- José Manuel Garcia-Pinilla, MD, PhDc,v,
- Tomás Ripoll-Vera, MD, PhDw,
- Maria Victoria Mogollón-Jiménez, MDx,
- Ana Fontalba-Romero, MDy,
- Dolores Garcia-Medina, MDz,
- Julian Palomino-Doza, MD, PhDc,aa,
- David de Gonzalo-Calvo, PhDc,bb,cc,
- Marcos Cicerchia, MDk,
- Joel Salazar-Mendiguchia, MDk,
- Clara Salas, MDc,dd,
- Sabine Pankuweit, PhDee,
- Thomas Morris Hey, MDff,
- Jens Mogensen, MD, PhDff,
- Paul J. Barton, PhDgg,hh,
- Philippe Charron, MD, PhDd,h,
- Perry Elliott, MD, PhDd,q,
- Pablo Garcia-Pavia, MD, PhDa,c,d,ii,∗ (, )@cardiopdh,
- for the European Genetic Cardiomyopathies Initiative Investigators
- aHeart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain
- bMyocardial Biology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- cCentro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- dEuropean Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART)
- eInherited cardiac diseases Unit, Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- fUnit for Screening Studies in Inherited Cardiovascular Diseases, Cardinal Stefan Wyszyński Institute of Cardiology, Warsaw, Poland
- gMedicine Department, School of Medicine, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA), Cádiz, Spain
- hAPHP, Referral center for inherited cardiac diseases, ICAN, INSERM UMRS1166, Hôpital Pitié-Salpêtrière, Paris, France
- iInstituto de Investigación Biomédica de A Coruña (INIBIC), A Coruña, Spain
- jInherited Cardiovascular Diseases Unit, Cardiology Service, Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain
- kCardiology Department, Health in Code, A Coruña, Spain
- lGrupo de Investigación Cardiovascular (GRINCAR), Universidad A Coruña, Spain
- mDepartment of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
- nInstitute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom
- oFarr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, United Kingdom
- pMolecular Biology Laboratory, Department of Medical Biology, Cardinal Stefan Wyszyński Institute of Cardiology, Warsaw, Poland
- qSaint Bartholomews' Hospital, London, United Kingdom
- rConfocal Microscopy Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain
- sHeart Failure and Heart Transplantation Unit, Department of Cardiology, Virgen del Rocio University Hospital, Seville, Spain
- tHospital Universitari Vall d’Hebron, Department of Cardiology, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
- uCardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain
- vHeart Failure and Familial Cardiomyopathies Unit, Cardiology Department, Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain
- wCardiology Department, Hospital Universitario Son Llatzer, Mallorca, Spain
- xCardiology Department, Hospital San Pedro de Alcántara, Cáceres, Spain
- yHospital Universitario Marqués de Valdecilla, Santander, Spain
- zCardiology Department, Hospital Universitario Virgen de Valme, Seville, Spain
- aaHereditary Cardiopathies Unit, Hospital Universitario 12 de Octubre, Madrid, Spain
- bbInstitute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain
- ccBiomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
- ddDepartment of Pathology, Hospital Universitario Puerta de Hierro, Madrid, Spain
- eeDepartment of Cardiology, University Hospital Giessen and Marburg, Philipps-University Marburg, Marburg, Germany
- ffCardiology Department, Odense University Hospital, University of Southern Denmark, Odense, Denmark
- ggNational Heart and Lung Institute, Imperial College London, London, United Kingdom
- hhCardiovascular Research Centre, Royal Brompton and Harefield NHS Foundation Trust London, London, United Kingdom
- iiUniversity Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain
- ↵∗Address for correspondence:
Dr. Pablo Garcia-Pavia, Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2, 28222 Madrid, Spain.
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.
This work was supported by grants from the following institutions: Instituto de Salud Carlos III (ISCIII) (PI14/0967, PI15/01551, AC16/0014), CIBERCV (CB16/11/00403), Progreso and Salud Foundation (Junta de Andalucia) (PI-0011/201), Ministry of Economy, Industry and Competitiveness (IJCI-2016-29393), Mutual Medical (Research Award 2017), ERA-CVD Joint Transnational Call 2016 (Genprovic), British Heart Foundation (SP/10/10/28431), Wellcome Trust (107469/Z/15/), NIHR Royal Brompton Cardiovascular Biomedical Research Unit, NIHR Imperial Biomedical Research Center, Health Innovation Challenge Fund award from the Wellcome Trust and Department of Health, U.K. (HICF-R6-373), Danish Heart Foundation (16-R107-A6617), University of Southern Denmark, the Region of Southern Denmark, Odense University Hospital, German Competence Network Heart Failure, (TP9, FKZ 01GI0205), DETECTIN-HF project (ERA-CVD framework), and PROMEX Charitable Foundation. UCL Hospitals NIHR Biomedical Research Center and Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation, CVON2015-12 eDETECT and CVON2014-40 DOSIS. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from ISCIII and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016 – European Regional Development Fund (FEDER) “A way of making Europe.” The Hospital Universitario Puerta de Hierro Majadahonda, Hôpital Pitié-Salpêtrière, and Saint Bartholomews' Hospital are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). Drs. Ochoa, Cicerchia, and Salazar-Mendiguchia are employees of Health In Code. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 7, 2018.
- Revision received August 12, 2018.
- Accepted August 13, 2018.
- 2018 American College of Cardiology Foundation
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