多维信息融合对肥厚型心肌病MYH7基因突变携带者进行风险预测和危险分层的研究

Hypertrophic cardiomyopathy (HCM) is the most common inheritable myocardial disorder, which is inherited with the mutations identified in a range of cardiac sarcomere genes. Among them, beta-myosin heavy chain is the main pathogenic gene, whose mutation cause worse condition and higher risk of death. Most of them died of sudden cardiac death, heart failure and atrial fibrillation as well as the stroke. Therefore, identifying those with higher risk and evaluating risk factors, especially in HCM patients with MYH7 mutation are critical in improving prognosis. Recently, the HCM risk stratification has been revealed by the 2014 ESC guidelines. However, they were limited to use because of unsatisfied results reported by several researches. Accordingly, it is urgent to select more accurate, highly recognizable parameters and to build up the new risk assessment model. This program aims at investigating the cardiac structure, myocardial function, and myocardial fibrosis as well as the electrocardiographic features of HCM patients with MYH7 mutation, using multiple echocardiography, cardiac magnetic resonance and electrocardiography. Meanwhile, we collect the clinical data of these patients with regular follow-up. Finally, a multi-variable Cox regression model will be built on the basis of genetics, imaging and clinical data. We are also desired to find some independent parameters with higher sensitivity and specificity, to predict the incidence of sudden cardiac death and other adverse cardiovascular event in HCM, facilitating the risk stratification and guiding the individualized therapy.

肥厚型心肌病（HCM）是最常见遗传性心血管疾病，多与编码肌小节蛋白的基因突变有关。其中，β肌球蛋白重链基因（MYH7）是最主要致病基因，其突变引起临床表现通常较重、有较高的死亡风险，死因主要为心源性猝死、心衰及房颤并发栓塞性中风。因此，对高危患者的识别和危险因素的评估，特别是对MYH7基因突变携带者的风险预测和危险分层，是改善HCM预后的关键。目前指南提出的危险分层方法已被许多研究证明是不完善的。因此，找到更准确、更有辨识度的危险因素，建立新型危险评估模型非常紧迫。本课题拟采用多种心脏影像技术（超声心动图、心脏核磁共振和心电图）对MYH7基因突变携带者进行评估；收集临床资料，进行随访，记录临床转归；最后融合基因突变、心脏影像学和临床资料等多维信息建立多因素综合预测模型，找到能够敏感和特异地预测MYH7基因突变携带者猝死和其他不良临床结局的指标，对患者进行风险预测和危险分层，指导个体化治疗。

肥厚型心肌病（HCM）是最常见遗传性心血管疾病，多与编码肌小节蛋白的基因突变有关。其中，β肌球蛋白重链基因（MYH7）是最主要致病基因之一，其突变引起的HCM通常发病早、症状较重、猝死率较高。因此，对携带MYH7基因突变的HCM患者进行危险因素的评估，尽早识别高危患者并进行临床干预，是预防猝死和改善预后的关键。.本项目采用靶向基因外显子捕获测序筛选出200例携带MYH7基因突变的成人肥厚型心肌病患者及其一级亲属，采用多种心脏影像技术（超声心动图、心脏核磁共振和心电图）对MYH7基因突变携带者进行评估，同时对其进行定期随访。截止2019年4月30日共完成随访190例，平均随访时间（3.02±1.82）年，共发生一级随访终点10例（心源性猝死5例，ICD适当放电1例，心脏骤停抢救存活4例），二级随访终点18例（心力衰竭11例，HCM相关房颤引起的脑梗5例，室上速致血流动力学障碍1例，终末期HCM 1例），合计复合随访终点28例。.将所有MYH7基因突变携带者按是否发生一级或复合终点进行分组和统计。（1）与无一级终点组相较，发生一级终点事件患者晕厥较多，左房容积指数更大，二尖瓣环收缩期速度和三尖瓣环舒张早期速度更低，三维圆周、纵向、径向和面积应变的绝对值更低。多因素Cox回归分析显示：只有三维纵向应变是MYH7基因突变携带者发生一级随访终点的独立预测因素，且三维纵向应变绝对值<12.2%的MYH7基因突变携带者更易发生一级终点。（2）按是否发生复合终点进行分组发现：与无复合终点组相较，发生复合终点事件患者晕厥较多，NYHA III/IV所占比例较多，左房容积指数更大，二尖瓣环收缩期、舒张早期速度，三尖瓣环收缩期、舒张早期速度更低，三维圆周、纵向、径向和面积应变的绝对值更低。多因素Cox回归分析显示：晕厥、家族猝死史、左房容积指数以及三维纵向应变是MYH7基因突变携带者发生复合随访终点的独立预测因素，且有晕厥史、左房容积指数>46.6 ml/m2、三维纵向应变绝对值<14.1%的MYH7基因突变携带者更易发生复合终点。