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Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations

2018; Elsevier BV; Volume: 72; Issue: 20 Linguagem: Inglês

10.1016/j.jacc.2018.08.2181

1558-3597

Fernándo Domínguez, Sofía Cuenca, Zofia T. Bilińska, Rocío Toro, Eric Villard, Roberto Barriales‐Villa, Juan Pablo Ochoa, Folkert W. Asselbergs, Arjan Sammani, Maria Franaszczyk, Mohammed Akhtar, Maria José Coronado-Albi, Diego Rangel‐Sousa, José F. Rodríguez‐Palomares, Juan Jiménez‐Jáimez, José Manuel García‐Pinilla, Tomás Ripoll‐Vera, María Victoria Mogollón‐Jiménez, Ana Fontalba-Romero, Dolores García-Medina, Julián Palomino-Doza, David de Gonzalo‐Calvo, Marcos Cicerchia, Joel Salazar‐Mendiguchía, Clara Salas, Sabine Pankuweit, Thomas Morris Hey, Jens Mogensen, Paul J.R. Barton, Philippe Charron, Perry Elliott, Pablo García‐Pavía, Hans Eiskjær, Roberto Barriales‐Villa, Xusto Fernández, Marcos Cicerchia, Lorenzo Monserrat, Juan Pablo Ochoa, Joel Salazar‐Mendiguchía, María V. Mogollón, Tomás Ripoll, Philippe Charron, Pascale Richard, Eric Villard, Julián Palomino Doza, Ana Fontalba, Luis Alonso‐Pulpón, Marta Cobo Marcos, Fernándo Domínguez, Pablo García‐Pavía, Manuel Gómez‐Bueno, Esther González-López, A Hernández, Francisco Hernández‐Pérez, Ángela López‐Sainz, Maria Alejandra Restrepo‐Córdoba, Javier Segovia, Rocío Toro, David de Gonzalo‐Calvo, Félix Rosa Longobardo, Javier Limeres Freire, José F. Rodríguez‐Palomares, José Manuel García‐Pinilla, Miguel A. López-Garrido, Juan Jiménez‐Jáimez, Dolores García-Medina, Diego Rangel‐Sousa, María Luisa Peña Peña, Jens Mogensen, Thomas Morris-Hey, Paul J.R. Barton, Stuart A. Cook, William Midwinter, Angharad M. Roberts, James S. Ware, Roddy Walsh, Mohammed Akhtar, Perry Elliott, Luís R. Lopes, Konstantinos Savvatis, Petros Syrris, Ewa Michalak, Rafał Płoski, Małgorzata Sobieszczańska−Małek, Zofia T. Bilińska, Sabine Pankuweit, Folkert W. Asselbergs, Annette F. Baas, Dennis Dooijes, Arjan Sammani,

Heat shock proteins research

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. This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. 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. 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. 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.