TY - JOUR
T1 - Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations
AU - Domínguez, Fernando
AU - Cuenca, Sofía
AU - Bilińska, Zofia
AU - Toro, Rocío
AU - Villard, Eric
AU - Barriales-Villa, Roberto
AU - Ochoa, Juan Pablo
AU - Asselbergs, Folkert
AU - Sammani, Arjan
AU - Franaszczyk, Maria
AU - Akhtar, Mohammed
AU - Coronado-Albi, Maria José
AU - Rangel-Sousa, Diego
AU - Rodriguez-Palomares, Jose F.
AU - Jiménez-Jáimez, Juan
AU - Garcia-Pinilla, José Manuel
AU - Ripoll-Vera, Tomás
AU - Mogollón-Jiménez, Maria Victoria
AU - Fontalba-Romero, Ana
AU - Garcia-Medina, Dolores
AU - Palomino-Doza, Julian
AU - de Gonzalo-Calvo, David
AU - Cicerchia, Marcos
AU - Salazar-Mendiguchia, Joel
AU - Salas, Clara
AU - Pankuweit, Sabine
AU - Hey, Thomas Morris
AU - Mogensen, Jens
AU - Barton, Paul J.
AU - Charron, Philippe
AU - Elliott, Perry
AU - Garcia-Pavia, Pablo
AU - European Genetic Cardiomyopathies Initiative Investigators
AU - Eiskjær, Hans
AU - Barriales, Roberto
AU - Fernández Fernández, Xusto
AU - Cicerchia, Marcos
AU - Monserrat, Lorenzo
AU - Ochoa, Juan Pablo
AU - Salazar-Mendiguchia, Joel
AU - Mogollón, Maria Victoria
AU - Ripoll, Tomás
AU - Charron, Philippe
AU - Richard, Pascale
AU - Villard, Eric
AU - Palomino Doza, Julian
AU - Fontalba, Ana
AU - Alonso-Pulpón, Luis
AU - Cobo-Marcos, Marta
AU - Walsh, Roddy
AU - Asselbergs, Folkert
PY - 2018/11/13
Y1 - 2018/11/13
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85056204123&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30442290
U2 - https://doi.org/10.1016/j.jacc.2018.08.2181
DO - https://doi.org/10.1016/j.jacc.2018.08.2181
M3 - Article
C2 - 30442290
SN - 0735-1097
VL - 72
SP - 2471
EP - 2481
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 20
ER -