四川省克山病病区55例扩张型心肌病患者临床特征、预后及基因突变分析

Clinical characteristics,prognosis and gene mutation of 55 patients with dilated cardiomyopathy in Keshan disease area of Sichuan Province

目的分析四川省克山病病区扩张型心肌病(扩心病)患者的临床特征、预后及基因突变情况,探讨扩心病患者全因死亡的危险因素。方法2016年6月在四川省克山病病区凉山彝族自治州冕宁县和攀枝花市仁和区,以当地疾病预防控制中心通过临床表现、心电图检查和超声心动图检查诊断的55例扩心病患者为调查对象,分析其基线临床资料并进行长期随访。随访时间截至2021年6月15日,随访终点为全因死亡。采用单因素Cox回归分析患者全因死亡的影响因素,Kaplan-Meier(K-M)生存曲线分析患者的生存时间。同时,采集其中27例扩心病患者外周静脉血,分离白细胞后提取DNA,进行全外显子组测序,筛选潜在的致病基因。结果55例扩心病患者中,男性40例、女性15例;年龄为(54.09±12.38)岁;美国纽约心脏病协会(NYHA)心功能分级以Ⅱ、Ⅲ级为主,占94.55%(52/55)。55例扩心病患者的随访时间为(7.02±2.96)年,17例患者发生全因死亡,占30.91%(17/55),其中男性15例、女性2例。与存活组患者比较,死亡组患者晕厥发生率较低(χ^(2)=6.57,P=0.010),而双下肢水肿(χ^(2)=6.43,P=0.017)、肺淤血(χ^(2)=7.61,P=0.006)、室内传导阻滞发生率(χ^(2)=6.41,P=0.011)及血管紧张素转化酶抑制剂(ACEI)使用比例(χ^(2)=6.57,P=0.010)均较高,左室内径增大(t=2.36,P=0.022)。单因素Cox回归分析结果显示,双下肢水肿[风险比(HR)=4.61,P=0.042]和室内传导阻滞(HR=3.20,P=0.019)是扩心病患者发生全因死亡的危险因素。K-M生存曲线分析结果显示,双下肢水肿及室内传导阻滞的患者全因死亡率均较高(log-rankχ^(2)=5.02、6.24,P=0.025、0.012)。全外显子组测序结果显示,4例患者检测到携带致病或疑似致病基因突变,阳性率为14.81%(4/27),涉及β-肌球蛋白重链7(MYH7)、钙网蛋白3(CALR3)、凝溶胶蛋白(GSN)3个基因。结论四川省克山病病区扩心病患者的全因死亡率较高,死亡患者易出现双下肢水肿、肺淤血和室内传导阻滞,并且左室内径增大。双下肢水肿和室内传导阻滞是扩心病患者全因死亡的独立预测危险因素。扩心病致病基因涉及MYH7、CALR3和GSN基因。

Objective To analyze the clinical characteristics,prognosis and gene mutation in patients with dilated cardiomyopathy(DCM)in Keshan disease area of Sichuan Province,and to explore the risk factors for all-cause death in DCM patients.Methods In June 2016,55 DCM patients diagnosed at the local disease prevention and control center through clinical manifestations,electrocardiogram examination,and echocardiography were selected as the survey subjects in Mianning County,Liangshan Yi Autonomous Prefecture,and Renhe District,Panzhihua City,Keshan disease areas of Sichuan Province.Baseline clinical data were analyzed and long-term follow-up was conducted.The follow-up period ended June 15,2021,with the endpoint of all-cause death.Univariate Cox regression was used to analyze the influencing factors of all-cause death in patients,and Kaplan-Meier(K-M)survival curve was used to analyze the survival time of patients.At the same time,peripheral venous blood was collected from 27 DCM patients.After separating white blood cells,DNA was extracted,and whole exome sequencing was performed to screen potential pathogenic genes.Results Among the 55 DCM patients,40 were males and 15 were females.The age was(54.09±12.38)years old.The heart function classification of New York Heart Association(NYHA)was mainly gradeⅡandⅢ,accounting for 94.55%(52/55).The follow-up time for 55 DCM patients was(7.02±2.96)years,and 17 patients experienced all-cause death,accounting for 30.91%(17/55),including 15 males and 2 females.Compared with the survival group,the death group had a lower incidence of syncope(χ^(2)=6.57,P=0.010),but higher rates of bilateral lower limb edema(χ^(2)=6.43,P=0.017),pulmonary congestion(χ^(2)=7.61,P=0.006),intraventricular conduction block(χ^(2)=6.41,P=0.011),and angiotensin-converting enzyme inhibitor(ACEI)use(χ^(2)=6.57,P=0.010),as well as increased left ventricular diameter(t=2.36,P=0.022).Univariate Cox regression analysis showed that bilateral lower limb edema[hazard ratio(HR)=4.61,P=0.042]and intraventricular conduction block(HR=3.20,P=0.019)were risk factors for all-cause death of DCM patients.The results of K-M survival curve analysis showed that patients with bilateral lower limb edema and intraventricular conduction block had higher all-cause death rates(log-rankχ^(2)=5.02,6.24,P=0.025,0.012).Whole exome sequencing results showed that 4 patients were detected to carry pathogenic or suspected pathogenic gene mutations,with a positive rate of 14.81%(4/27),involving three genes:β-myosin heavy chain 7(MYH7),calreticulin 3(CALR3),and gelsolin(GSN).Conclusions The all-cause death rate of DCM patients in the Keshan disease area of Sichuan Province is relatively high.Dead patients are prone to bilateral lower limb edema,pulmonary congestion,and intraventricular conduction block,as well as increased left ventricular diameter.Bilateral lower limb edema and intraventricular conduction block are independent predictive risk factors for all-cause death in DCM patients.MYH7,CALR3 and GSN are involved in the pathogenesis of DCM.