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

摘要

BackgroundTheBAG3(BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations inBAG3are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history ofBAG3cardiomyopathy is poorly understood. ObjectivesThis study sought to describe the phenotype and prognosis ofBAG3mutations in a large multicenter DCM?cohort. MethodsThe study cohort comprised 129 individuals with aBAG3mutation (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 truncatingBAG3?mutations using immunohistochemistry. ResultsAt 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 aBAG3mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. ConclusionsDCM caused by mutations inBAG3is 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 withBAG3mutations.