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

Domínguez, F; Cuenca, S; Bilińska, Z; Toro, R; Villard, E; Barriales-Villa, R; Ochoa, JP; ... European Genetic Cardiomyopathies Initiative Investigators, .; + view all (2018) Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations. Journal of the American College of Cardiology , 72 (20) pp. 2471-2481. 10.1016/j.jacc.2018.08.2181.

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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.

Type: Article
Title: Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations
Location: United States
DOI: 10.1016/j.jacc.2018.08.2181
Publisher version: https://doi.org/10.1016/j.jacc.2018.08.2181
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: BAG3, dilated cardiomyopathy, genetics, prognosis
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Health Informatics
URI: http://discovery.ucl.ac.uk/id/eprint/10063467
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