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Dilated cardiomyopathy due to BLC2-associated athanogene 3 (BAG3) mutations

AuthorsDomínguez, Fernando ; Cuenca, Sofía; Bilinska, Zofia; Toro, Rocío; Villard, Eric; Barriales-Villa, Roberto; Ochoa, Juan Pablo; Asselbergs, Folkert; Sammani, Arjan; Franaszczyk, Maria; Akhtar, Mohammed; Coronado-Albi, Maria José; Rangel-Sousa, Diego; Rodriguez-Palomares, Jose F.; Jiménez-Jáimez, Juan; Garcia-Pinilla, José Manuel; Ripoll-Vera, Tomás; Mogollón-Jiménez, Maria Victoria; Fontalba-Romero, Ana; Garcia-Medina, Dolores; Palomino-Doza, Julian; Gonzalo-Calvo, David de; Cicerchia, Marcos; Salazar-Mendiguchia, Joel; Salas, Clara; Pankuweit, Sabine; Morris Hey, Thomas; Mogensen, Jens; Barton, Paul J.; Charron, Philippe; Elliott, Perry; García-Pavía, Pablo
Issue DateNov-2018
CitationJournal of the American College of Cardiology 72(20): 2471-2481 (2018)
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.
Publisher version (URL)https://doi.org/10.1016/j.jacc.2018.08.2181
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