Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Myocardial Biology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART).
Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Inherited cardiac diseases Unit, Department of Cardiology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
J Am Coll Cardiol. 2018 Nov 13;72(20):2471-2481. doi: 10.1016/j.jacc.2018.08.2181.
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.
This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort.
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.
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.
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.
BAG3（BLC2 相关抗细胞凋亡蛋白 3）基因编码位于肌节 Z 盘上的抗凋亡蛋白。BAG3 基因突变与扩张型心肌病（DCM）有关，但迄今为止仅报道了少数病例，BAG3 心肌病的自然病史尚不清楚。
本研究旨在描述大型多中心 DCM 队列中 BAG3 基因突变的表型和预后。
研究队列包括 18 个欧洲中心随访的 129 名 BAG3 突变患者（62%为男性，年龄 35.1±15.0 岁）。使用免疫组织化学分析携带截断 BAG3 突变的患者心脏组织中 BAG3 的定位。
在首次评估时，57.4%的患者患有 DCM。在中位数为 38 个月（四分位距：7 至 95 个月）的随访后，68.4%的患者患有 DCM，26.1%的初始表型阴性患者发展为 DCM。最后一次评估时，年龄>40 岁的个体疾病外显率为 80%，且男性 DCM 的发病年龄较早（34.6±13.2 岁比 40.7±12.2 岁；p=0.053）。患有 DCM 的个体每年发生不良心脏事件（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 5.1%。男性、左心室射血分数降低和左心室舒张末期直径增加与不良心脏事件相关。携带 BAG3 突变的患者心肌组织显示肌原纤维排列紊乱和 BAG3 蛋白在肌节 Z 盘上的重新定位。
由 BAG3 基因突变引起的 DCM 的特征是>40 岁携带者的高外显率和心力衰竭进行性恶化的高风险。男性、左心室射血分数降低和左心室舒张末期直径增加与 BAG3 突变患者的不良结局相关。
