Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations
Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations
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DOI：
10.1016/j.jacc.2018.08.2181
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发表时间：
2018-11-13
影响因子：
24
通讯作者：
Garcia-Pavia, Pablo
中科院分区：
文献类型：
--
作者：
Dominguez, Fernando;Cuenca, Sofia;Garcia-Pavia, Pablo
背景BAG3 （blc2相关的凋亡基因3）基因编码一种位于肌节z盘的抗凋亡蛋白。BAG3基因突变与扩张型心肌病（DCM）有关，但迄今为止只有少数病例报道，而且BAG3心肌病的自然历史尚不清楚。目的：本研究旨在描述一个大型多中心DCM队列中BAG3突变的表型和预后。方法：研究队列包括129名BAG3突变个体（62%为男性，年龄35.1±15.0岁），在18个欧洲中心进行随访。利用免疫组织化学分析BAG3突变截断患者心脏组织中BAG3的定位。结果首次评估时，有57.4%的患者存在DCM。中位随访38个月后（四分位数范围：7至95个月），68.4%的患者患有DCM， 26.1%最初表型阴性的患者发展为DCM。在最后一次评估中，bb0 - 40岁个体的疾病外显率为80%，男性DCM有早期发病的趋势（年龄34.6 +/- 13.2岁vs. 40.7 +/- 12.2岁；p = 0.053）。在DCM患者中，不良心脏事件（死亡、左心室辅助装置、心脏移植和持续性室性心律失常）的发生率为每年5.1%。配偶性行为，左心室射血分数降低。左心室舒张末期直径增大与心脏不良事件相关。BAG3突变患者的心肌组织显示肌原纤维紊乱和BAG3蛋白在肌聚体z盘的重新定位。结论BAG3基因突变引起的DCM在40岁携带者中具有高外显率和进行性心力衰竭的高风险。男性、左室射血分数降低和左室舒张末期内径增大与BAG3突变患者的不良结局相关。(C) 2018年美国心脏病学会基金会。Elsevier出版。版权所有。
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. Mate 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. (C) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.