扩张型心肌病患者的遗传学罕见变异特征对心脏再同步化治疗效果的潜在影响  

Potential Effects of Rare Genetic Variants on Cardiac Resynchronization Therapy in Patients with Dilated Cardiomyopathy

作　　者：陈旭华[1] 白慧[1] 胡奕然 井然 王靖[1] 楚建民[1] 华伟[1] 张澍[1] CHEN Xu-hua;BAI Hui;HU Yi-ran;JING Ran;WANG Jing;CHU Jian-min;HUA Wei;ZHANG Shu(Fuwai Hospital and National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100037,China)

机构地区：[1]中国医学科学院北京协和医学院国家心血管病中心阜外医院心律失常诊治中心

出　　处：《中国分子心脏病学杂志》2019年第5期3052-3057,共6页Molecular Cardiology of China

摘　　要：目的探讨扩张型心肌病患者的遗传学罕见变异特征对心脏再同步化治疗效果的潜在影响。方法连续入组2014年7月至2016年6月我院单中心诊断为扩张型心肌病且同时符合以下标准的患者:①窦性心律,伴完全性左束支传导阻滞且QRS时限≥150 ms;②纽约心功能Ⅱ~Ⅲ级;③左室射血分数(LVEF)≤35%;④年龄≥18岁;⑥接受了心脏再同步化装置植入治疗;⑥签署了知情同意书。抽取患者的外周静脉血进行高通量靶向测序,检测132个与原发性心肌病和心脏离子通道疾病相关的基因。术后随访至第12~15个月,根据患者超声心动图的结果及纽约心功能分级情况将患者分为心脏再同步化治疗有反应组及无反应组。结果58例患者中,57例(98.28%)为汉族,1例(1.72%)为蒙古族,男性38例(65.52%),平均年龄为(65.80±7.94)岁。58例(100.00%)患者均检测出基因罕见变异,变异率最高的基因依次为TTN(17.24%)、SYNE2(17.24%)、SYNE1(12.07%)、MYH6(10.34%)、SCN5A(10.34%)、TNNT2(10.34%)。53例(91.38%)患者检测出涉及1个基因以上的罕见变异,每例患者的罕见变异平均涉及(2.83±0.91)个基因。对心脏再同步化治疗无反应的患者共13例(22.41%)。无反应组与有反应组相比,罕见变异负荷[(3.32±1.06)个vs(2.59±0.86)个,P=0.04)]、罕见变异涉及心肌细胞内相关基因的比例(71.43%vs 55.45%,P=0.04),以及罕见变异涉及Z盘相关基因的比例(20.63%vs 8.91%,P=0.03)更高。两组间罕见变异位点分布方面也有差异,MYH6(9.52%vs 0.00%,P<0.01)、FLT1(6.35%vs 0.00%,P=0.01)和MYH7B(6.35%vs 0.00%,P=0.01)的变异频度在无反应组明显高于有反应组,而SYNE1(0.00%vs 6.93%,P=0.03)在有反应组显著高于无反应组。结论对心脏再同步化治疗有反应及无反应亚洲扩张型心肌病患者的遗传学特征有较大差异,可能是导致对心脏再同步化治疗反应不同的潜在机制。Objective To explore the potential effect of genetic characteristics of patients with dilated cardiomyopathy on the therapeutic effect of cardiac resynchronization.Methods Patients diagnosed with dilated cardiomyopathy in Fuwai Hospital and meeting the following criteria were consecutively enrolled in this study from July 2014 to June 2016:(1)with sinus rhythm,complete left bundle branch block and QRS duration≥150 ms,and(2)with NYHA classification of cardiac function grade II-III,and(3)with left ventricular ejection fraction(LVEF)≤35%,and(4)age≥18 years,and(5)received cardiac resynchronization therapy(CRT),and(6)informed consent was signed.Peripheral venous blood samples were collected from patients and Next generation sequencing were performed.One hundred thirty-two genes relative to primary cardiomyopathy and cardiac ion channel disease were examined.Patients were divided into two groups,responder group and non-responder group,after 12-15 months according to the change in echocardiographic results and the classification of cardiac function.Results Of the 58 patients,57(98.28%)were Han,1(1.72%)were Mongolian,and 38 were male(65.52%),with an average age of(65.80±7.94)years.Rare genetic variants were detected in all patients(100.00%).The top six genes with the highest mutation rate were TTN(17.24%),SYNE2(17.24%),SYNE1(12.07%),MYH6(10.34%),SCN5 A(10.34%)and TNNT2(10.34%).Multiple rare Variants involving≥2 genes were found in 53(91.38%)patients,with an average of 2.83±0.91 mutated genes per patient.Thirteen(22.41%)patients did not show response to CRT.Compared with the responder group,the non-responder group had a higher rare variant load(3.32±1.06 vs 2.59±0.86,P=0.04),a higher proportion of rare variants relative to genes encoding internal structure of myocytes(71.43%vs 55.45%,P=0.04),and a higher proportion of rare variants involving Z disk related genes(20.63%vs 8.91%,P=0.03).Distribution of mutated genes was also different between the two groups.MYH6(9.52%vs 0.00%,P<0.01),FLT1(6.35%vs 0.00%,P=0.01)an

关 键 词：扩张型心肌病 基因 心脏再同步化治疗 

分 类 号：R54[医药卫生—心血管疾病]