肥厚型心肌病的临床和预后分析及候选基因突变筛查
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摘要
肥厚型心肌病(Hypertrophic Cardiomyopathy,HCM)以心室肌非对称性肥厚为特征。HCM的临床表现多样,可无症状或轻度胸闷、胸痛、心悸,并发房颤、室性心律失常、心力衰竭、心源性猝死等。HCM是一种常染色体显性遗传病,且为单基因致病。目前,至少已发现20个基因的400余种突变与HCM发病相关。尽管多数HCM患者可长期存活,但亦可发生心源性猝死、心力衰竭死亡及致死性脑卒中等严重不良事件。其中,心源性猝死约占年轻人猝死原因的50%。因此,识别影响HCM预后的危险因素对预防严重不良事件的发生十分重要。目前,研究认为HCM相关死亡与多种危险因素相关,包括确诊时的年龄、临床症状、是否存在左室流出道梗阻、特殊基因缺失等。但不同种族在遗传特点和基因型-表型关系方面存在差异,目前资料大多来自国外,不一定适合中国人群。因此,有必要探索我国HCM患者临床预后及影响预后的高危因素,对病人进行危险分层,给予相应的预防措施,从而改善HCM患者的预后。
第一部分肥厚型心肌病的临床和预后分析
研究目的
探讨中国HCM的临床特点和预后及影响HCM预后的危险因素,为HCM的早期诊断和临床治疗策略的优化提供依据。
对象和方法
回顾性分析1999年6月～2006年3月期间收入院的234例HCM患者的病史资料,并对其中获得随访的199例患者的随访结果采用SPSS13.0软件包进行统计学处理。
结果
全部患者男158例、女76例,发病年龄女性(53.7±17.1岁)高于男性(49.4±14.6岁)(P＜0.05),女性心房颤动发生率高于男性(32.9%对14.6%,P＜0.05)。绝大多数患者(93.6%)临床症状无特异性,为胸闷、胸痛、心悸等,仅15例(6.4%)患者无临床症状,例行体检时检出该病。绝大多数患者(93.6%)ECG表现为非特异性ST—T改变,心肌肥厚累及心尖部者胸前导联见巨大倒置T波,仅少数患者(15例,6.4%)ECG未见异常;女性患者(25/76,32.9%)较男性患者(23/158,14.6%)更易发生心房颤动。共231例患者在我院行超声心动图(UCG)检查,另3例患者外院诊断为非梗阻性HCM,因胸痛行冠状动脉造影入住我院。UCG显示,梗阻性HCM者30例(13.0%),非梗阻性HCM者201例(87.0%);心尖HCM 57例(24.9%),男:女=3.4:1;肥厚累及右室6例;心室壁平均厚度为(19.5±4.6)mm。另3例患者外院诊断为非梗阻性HCM,冠状动脉造影有＞75%的狭窄者16例(15.5%)。长期治疗中,接受β-受体阻滞剂(美托洛尔或比索洛尔)和(或)非二氢吡啶类钙离子拮抗剂(维拉帕米或地尔硫卓)治疗者194例(82.9%),起博器植入者18例,经皮化学消融者6例,左室流出道疏通术5例。院内发生猝死事件(室速/室颤)者5例,其中3例患者经电复律或药物复律后存活,2例复苏失败死亡。
234例患者中,199例(85%)患者获得随访,35例(15%)患者失访,获得随访的患者的基本资料与失访患者基本相似。平均随访时间为(31.7±22.6)月,由确诊到随访结束时间中位数为35个月。随访中21例患者死亡,其中19例患者被确认为HCM相关性死亡,包括:心脏骤停11例(57.9%)、心力衰竭死亡7例(36.8%)、脑卒中死亡1例;另有2例患者分别因意外事故和急性胰腺炎死亡。患者自确诊后第1、2、3、4、5年生存率分别为96.7%、94.7%、94.7%、93.6%、89.0%。单因素分析显示,男性、心功能分级、合并心房颤动、持续或短阵室速、左房增大、左室流出道梗阻、HCM家族史7个变量与HCM预后相关;而多因素分析显示,仅持续或短阵室速(RR=2.234,P＜0.001)、心功能Ⅲ级以上(RR=1.964,P=0.003)是影响HCM预后的独立危险因素。心脑事件死亡患者中,超声心动图表现以MaronⅢ型为多见(14/19,73.7%),仅1例患者表现为心尖肥厚型心肌病(5.2%)。对心脏骤停者和心力衰竭死亡者进行分析显示,7例(63.6%)心脏骤停者发生在60岁以下的患者中(P=0.12,但仅1例患者小于35岁),5例(71.4%)心力衰竭死亡者发生在60岁以上的患者中(P=0.22);仅2例心脏骤停者和1例心力衰竭死亡者存在静息状态下左室流出道压差;7例(63.6%)心脏骤停者和2例(28.6%)心力衰竭死亡者合并阵发性室速;心脏骤停者与心力衰竭死亡者的室壁厚度分别为(20.4±4.7)mm和(22.7±6.3)mm。
结论
中国HCM的发病年龄较国外偏大,临床表现无特异性:女性比男性发病年龄偏大,且更易发生心房颤动;心肌肥厚以非梗阻性HCM最为常见(204/234),心尖HCM约占1/4,男性多于女性;绝大多数患者以药物治疗为主,住院转归良好。其中长期预后相对较好,5年生存率可达89%,以心肌肥厚仅累及心尖部者预后最佳;持续或短阵室速、心功能Ⅲ级以上是发生HCM相关心脑血管不良事件的独立危险因素;心脏骤停可发生在各年龄段,对其预防在年轻和中老年患者中同样重要。
第二部分肥厚型心肌病患者肌球蛋白连接蛋白C基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌球蛋白连接蛋白C基因(MYBPC3)突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为105例无血缘关系的汉族肥厚型心肌病先证者,其中家族性HCM20例、SHCM 85例。对照组为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病先证者及正常对照组的基因组DNA。根据文献报道设计MYBPC3基因2～35号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果
105例患者中,在10例(9.5%)患者中检出7种突变,分别位于第5、12、16、17、25、31、32号外显子,而120例正常对照中未发现相同突变。携带MYBPC3基因突变的10例患者中有3例为FHCM家系的先证者,占20例FHCM的15%;另2例患者的子女与患者携有相同位点突变,但目前超声心动图检查未见HCM表现;其余5例患者为散发病例,占85例散发患者的5.9%。
在7种MYBPC3基因突变中,1种为错义突变,6种为移码突变,分别为3810delG(Pro 186fs)、7420-7421insCGGCA(Arg346fs)、10739 delC(Pro459 fs)、10966G＞A(Gly507Arg)、16096-16098delAAG(Lys 814fs)、20700-20701insG(Tyr1119fs)和21078delC(Pro1208fs)。各突变的发生频率不相同,有1种突变(Pro459fs)见于4例先证者中,2例先证者的子女携带有相同的突变,但目前超声心动图检查未见HCM表现,2例先证者为散发患者;其他6种突变分别见于6例先证者中,其中Pro186fs、Lys814fs、Pro1208fs突变携带者为家族性HCM,Tyr1119fs突变携带者有可疑家族史,Arg346fs、Gly507Arg突变携带者为散发患者。Pro186fs、Pro459fs、Tyr1119fs突变为首次发现,国内外尚未见文献报道;Gly507Arg、Pro1208fs突变为国内首次报道,国外有过文献报道;Arg346fs突变仅国内有过文献报道;Lys814fs突变国内外均有过文献报道。携带MYBPC3基因突变的10个家系中,15个成员携带MYBPC3基因突变,11个成员已发病,4个成员携带目前无HCM临床表现,外显率73.3%。45%的患者35岁之前起病,63.6%患者(7/11)合并室速/室颤/左室流出道梗阻/充血性心力衰竭。
结论MYBPC3基因是我国HCM患者常见的致病基因,在FHCM中占的比例较高。MYBPC3基因突变的外显率较高,半数患者年轻时起病,并不像既往文献所报道的是HCM患者预后较好的因素,多数携带者的临床预后同样不良。Arg346fs、Pro459fs突变为我国HCM患者热点突变;Lys814fs为HCM患者的热点突变。
第三部分肥厚型心肌病患者肌钙蛋白T(TNNT2)基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌钙蛋白T(TNNT2)基因突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为95例无血缘关系的汉族肥厚型心肌病的先证者,其中家族性HCM16例、SHCM 79例。均经过MYBPC3基因突变的筛查,未发现MYBPC3基因突变。对照为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病患者及正常对照组的基因组DNA。根据文献报道设计TNNT2的第8、9、10、11、14、15、16号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果16例FHCM患者及79例SHCM患者均未发现TNNT2基因的错义突变、移码突变、剪接突变,仅在9号外显子检出一同义突变,为ATC→ATT,均编码异亮氨酸(Ile)。
结论TNNT2基因不是我国HCM患者的主要致病基因。
第四部分肥厚型心肌病患者肌钙蛋白I(TNNl3)基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌钙蛋白I(TNNl3)基因突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为95例无血缘关系的汉族肥厚型心肌病的先证者,其中家族性HCM16例、SHCM 79例。均经过MYBPC3基因和TNN2基因的8、9、10、11、14、15、16号外显子突变筛查,未发MYBPC3基因和TNN2基因突变。对照为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病患者及正常对照组的基因组DNA。根据文献报道设计TNNI基因第3、7、8号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果16例FHCM患者及79例SHCM患者均未发现TNNI3基因的错义突变、移码突变、剪接突变,仅在7号外显子检出一同义突变,为GAG→GAA,均编码谷氨酸(Glu)。
结论TNNI3基因不是我国HCM患者的主要致病基因。
PartⅠ:Clinical and Prognostic Analysis of Patients with Hypertrophic Cardiomyopathy
Objectives:To investigate the clinical characteristics,long-term prognosis and death hazards in patients with hypertrophic cardiomyopathy(HCM).
Methods:The medical record of the 234 patients with HCM recruited from June,1999 to March,2006 were retrospectively analyzed,199 patients were followed up and the outcome data was statistically analyzed by SPSS ver13.0.
Results:Two hundreds and thirty-four patients(158 males,76 females;symptomatic age[51.0±15.6]years) diagnosed with HCM were studied.Among the 234 patients, females symptomatic age was older than males and more females compared with atrial fibrillation than males(P＜0.05 ).Symptoms in most of patients were nonspecific and 6.4%patients did not have symptoms.Changes of electrocardiogram in HCM were nonspecific and 6.4%did not have changes,but inverted T waves were sawed in patients with thicker wall in apex of heart.M-mode,2D,and echocardiogram showed the average maximal thickness of ventricular wall were(19.5±4.6)mm; 57(24.9%) patients were diagnosed with apical hypertrophic cardiomyopathy (AHCM),and the ratio between male and female was 3.4.The 15.5%patients who underwent coronary angiography had stenosis of coronary artery.Most of the patients received treatment and sudden death occurred to 5 patients.Among the 234 patients with HCM,199 patients(85%) were followed up with the mean time of 31.7±22.6 months,and the time interval from the first diagnosis till the end of the research was 52.2±66.6 months.Twenty-one patients died in the follow-up duration,HCM-related death occurred in 19 patients including 11(57.9%) patients of cardiac arrest, 7(36.8%)patients of heart failure,1 patient of stroke;1 patient of misadventure and 1 patient of acute pancreatitis..The free survival rates of all the followed patients at 1,2, 3,4 and 5 years were 96.7%,94.7%,94.7%,93.6%and 89.0%in respective. One-way ANOVA analysis indicated that sex,cardiac function,atrial fibrillation, sustained or non-sustained ventricular tachycardia(SVT or NSVT),enlargement of left atrium,obstructive outflow of left ventricular(LVOT),family history were associated with prognosis of patients.In the Cox model,the multivariate analysis showed HCM related death risk ratios were 2.234 for SVT or NSVT(p＜0.001), 1.964 for cardiac function of NYHA classⅢ-Ⅳ(P=0.003).Among the death patients,Maron typeⅢwere more common(73.7%)and only one patient merely involving apical myocardial hypertrophy(5.2%).Cardiac arrest was most common in patients＜60 years old(P=0.12),whereas heart failure occurred more frequently in patients≥60 years old(p=0.22).As for the death patients with cardiac arrest and heart failure,(1) 7 patients with cardiac arrest occurred under the age of 60(P=0.12,only one patient with onset age before 35),the onset age of 5 patients with heart failure were above 60(P=0.22);(2) LVOT occurred in only two patients with cardiac arrest and one patient with heart failure;(3)seven patients with cardiac arrest and 2 patients with heart failure combined SVT or NSVT;(4) maximum wall thicknesses of the patients with cardiac arrest and heart failure were 20.4±4.7mm versus 22.7±6.3mm.
Conclusions:The clinical manifestations of HCM in china is nonspecific,but the symptomatic age is older than that in other countries.Symptomatic age was older in females than that in males,and the female patients were prone to atrial fibrillation. Non-obstructive hypertrophic cardiomyopathy was much more common(204/234). The incidence of apical hypertrophic cardiomyopathy was 1/4 and more common in males.The outcomes of most of patients were good.A relatively benign long-term prognosis was shown in this group of HCM patients,especially in patients merely involving apical myocardial hypertrophy;Sustained or non-sustained ventricular tachycardia,cardiac function of NYHA classⅢ-Ⅳare the independent risk factors for main adverse cardio-cerebral events;cardiac arrest may occur in all ages of patients.
PartⅡ:Screening of cardiac myosin-binding protein C gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac myosin-binding protein C(MYBPC3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:One hundred and five patients with HCM and 120 control individuals were chosen for the study.Thirty-four exons in the functional regions of the MYBPC3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:Among the 105 patients,20 patients were identified familial hypertrophic cardiomyopathy(FHCM) and 85 patients identified sporatic hypertrophic cardiomyopathy(SHCM).Seven mutations were identified in 10 patients which respectively located in exon 5,12,16,17,25,31and 32.And no mutations were not detected in A group of 120 anonymous healthy individuals.Among the 10 patients with mutations,3 patient were identified FHCM,accounted for 15%of the total 20 patients with FHCM.Although the same mutation was identified in 2 patients' children,their ultrasonic cardiogram examination was normal.The other 5 patients were identified SHCM, accounted for 5.9%of the total 85 patients with SHCM.The seven mutations included 1 missense mutation and 6 frame shift mutation.Mutation pro459fs was identified in 4 patients and the mutation was identified in 2 patients' children,but their ultrasonic cardiogram examination was normal.The other 6 mutations were respectively identified in 6 patients.Mutation Pro 186fs,Lys 814fs,Pro1208fs were identified in patients with FHCM.Mutation Arg346fs and Gly507Arg were identified in patients with SHCM.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Mutation Gly507Arg and Pro1208fs were identical to foreign reports.Mutation Arg346fs was identified in Chinese patients with HCM. Mutation Lys814fs was identified in Chinese patients and foreign patients with HCM. Among the 10 families with mutations,mutations were identified in 15 person. Eleven of the total 15 person with mutation were diagnosed patients with HCM, accounted for 73.3%.Five patients' symptomatic age was less than 35 years old, accounted for 45%of the total 11 patients.Seven patients were associated with ventricular tachycardia or ventricular fibrillation or left ventricular outflow tract obstru-cttion or congestive cardiac failure.
Conclusions:Cardiac myosin-binding protein C(cMYBPC3) was one of the main disease-causing genes,accounted for 15%of the total 20 patients with FHCM.The penetrance was high of the cMYBPC3 gene mutations,and the symptomatic age of 45%patients with the mutations was less than 35 years old.The outcomes of most of the patients with the MYBPC3 gene mutation were not good.This indicated that the MYBPC3 gene mutation was not a good factor for the outcomes of the patients with HCM unlike what ever reported.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Arg346fs and Pro459fs were hot spot mutation in Chinese patients with HCM.
PartⅢ:Screening of cardiac Troponin T gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac Troponin T(TNNT2) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:Ninety-five patients with HCM which had been scanned in MYBPC3 gene and had nomutaions found and 120 control individuals were chosen for the study. Seven exons(exon 8,9,10,11,14,15,16) in the functional regions of the TNNT2 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:The study could not find any mutation in TNNT2 gene.
Conclusion:This study did not find any HCM-caused mutation in TNNT2 gene, which was much lower than 10%-20%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.
PartⅣ:Screening of cardiac Troponin I gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac Troponin I(TNNI3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:Ninety-five patients with HCM and 120 control individuals were chosen for the study.The patients with HCM had been scanned in MYBPC3 gene and TNNT2 gene,and no mutaions had been found.Three exons in the functional regions of the TNNI3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:The study could not find any mutation in TNNI3 gene.
Conclusion:This study did not find any HCM-caused mutation in TNNI3 gene, which was much lower than 5%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.
第一部分肥厚型心肌病的临床和预后分析
研究目的
探讨中国HCM的临床特点和预后及影响HCM预后的危险因素,为HCM的早期诊断和临床治疗策略的优化提供依据。
对象和方法
回顾性分析1999年6月～2006年3月期间收入院的234例HCM患者的病史资料,并对其中获得随访的199例患者的随访结果采用SPSS13.0软件包进行统计学处理。
结果
全部患者男158例、女76例,发病年龄女性(53.7±17.1岁)高于男性(49.4±14.6岁)(P＜0.05),女性心房颤动发生率高于男性(32.9%对14.6%,P＜0.05)。绝大多数患者(93.6%)临床症状无特异性,为胸闷、胸痛、心悸等,仅15例(6.4%)患者无临床症状,例行体检时检出该病。绝大多数患者(93.6%)ECG表现为非特异性ST—T改变,心肌肥厚累及心尖部者胸前导联见巨大倒置T波,仅少数患者(15例,6.4%)ECG未见异常;女性患者(25/76,32.9%)较男性患者(23/158,14.6%)更易发生心房颤动。共231例患者在我院行超声心动图(UCG)检查,另3例患者外院诊断为非梗阻性HCM,因胸痛行冠状动脉造影入住我院。UCG显示,梗阻性HCM者30例(13.0%),非梗阻性HCM者201例(87.0%);心尖HCM 57例(24.9%),男:女=3.4:1;肥厚累及右室6例;心室壁平均厚度为(19.5±4.6)mm。另3例患者外院诊断为非梗阻性HCM,冠状动脉造影有＞75%的狭窄者16例(15.5%)。长期治疗中,接受β-受体阻滞剂(美托洛尔或比索洛尔)和(或)非二氢吡啶类钙离子拮抗剂(维拉帕米或地尔硫卓)治疗者194例(82.9%),起博器植入者18例,经皮化学消融者6例,左室流出道疏通术5例。院内发生猝死事件(室速/室颤)者5例,其中3例患者经电复律或药物复律后存活,2例复苏失败死亡。
234例患者中,199例(85%)患者获得随访,35例(15%)患者失访,获得随访的患者的基本资料与失访患者基本相似。平均随访时间为(31.7±22.6)月,由确诊到随访结束时间中位数为35个月。随访中21例患者死亡,其中19例患者被确认为HCM相关性死亡,包括:心脏骤停11例(57.9%)、心力衰竭死亡7例(36.8%)、脑卒中死亡1例;另有2例患者分别因意外事故和急性胰腺炎死亡。患者自确诊后第1、2、3、4、5年生存率分别为96.7%、94.7%、94.7%、93.6%、89.0%。单因素分析显示,男性、心功能分级、合并心房颤动、持续或短阵室速、左房增大、左室流出道梗阻、HCM家族史7个变量与HCM预后相关;而多因素分析显示,仅持续或短阵室速(RR=2.234,P＜0.001)、心功能Ⅲ级以上(RR=1.964,P=0.003)是影响HCM预后的独立危险因素。心脑事件死亡患者中,超声心动图表现以MaronⅢ型为多见(14/19,73.7%),仅1例患者表现为心尖肥厚型心肌病(5.2%)。对心脏骤停者和心力衰竭死亡者进行分析显示,7例(63.6%)心脏骤停者发生在60岁以下的患者中(P=0.12,但仅1例患者小于35岁),5例(71.4%)心力衰竭死亡者发生在60岁以上的患者中(P=0.22);仅2例心脏骤停者和1例心力衰竭死亡者存在静息状态下左室流出道压差;7例(63.6%)心脏骤停者和2例(28.6%)心力衰竭死亡者合并阵发性室速;心脏骤停者与心力衰竭死亡者的室壁厚度分别为(20.4±4.7)mm和(22.7±6.3)mm。
结论
中国HCM的发病年龄较国外偏大,临床表现无特异性:女性比男性发病年龄偏大,且更易发生心房颤动;心肌肥厚以非梗阻性HCM最为常见(204/234),心尖HCM约占1/4,男性多于女性;绝大多数患者以药物治疗为主,住院转归良好。其中长期预后相对较好,5年生存率可达89%,以心肌肥厚仅累及心尖部者预后最佳;持续或短阵室速、心功能Ⅲ级以上是发生HCM相关心脑血管不良事件的独立危险因素;心脏骤停可发生在各年龄段,对其预防在年轻和中老年患者中同样重要。
第二部分肥厚型心肌病患者肌球蛋白连接蛋白C基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌球蛋白连接蛋白C基因(MYBPC3)突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为105例无血缘关系的汉族肥厚型心肌病先证者,其中家族性HCM20例、SHCM 85例。对照组为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病先证者及正常对照组的基因组DNA。根据文献报道设计MYBPC3基因2～35号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果
105例患者中,在10例(9.5%)患者中检出7种突变,分别位于第5、12、16、17、25、31、32号外显子,而120例正常对照中未发现相同突变。携带MYBPC3基因突变的10例患者中有3例为FHCM家系的先证者,占20例FHCM的15%;另2例患者的子女与患者携有相同位点突变,但目前超声心动图检查未见HCM表现;其余5例患者为散发病例,占85例散发患者的5.9%。
在7种MYBPC3基因突变中,1种为错义突变,6种为移码突变,分别为3810delG(Pro 186fs)、7420-7421insCGGCA(Arg346fs)、10739 delC(Pro459 fs)、10966G＞A(Gly507Arg)、16096-16098delAAG(Lys 814fs)、20700-20701insG(Tyr1119fs)和21078delC(Pro1208fs)。各突变的发生频率不相同,有1种突变(Pro459fs)见于4例先证者中,2例先证者的子女携带有相同的突变,但目前超声心动图检查未见HCM表现,2例先证者为散发患者;其他6种突变分别见于6例先证者中,其中Pro186fs、Lys814fs、Pro1208fs突变携带者为家族性HCM,Tyr1119fs突变携带者有可疑家族史,Arg346fs、Gly507Arg突变携带者为散发患者。Pro186fs、Pro459fs、Tyr1119fs突变为首次发现,国内外尚未见文献报道;Gly507Arg、Pro1208fs突变为国内首次报道,国外有过文献报道;Arg346fs突变仅国内有过文献报道;Lys814fs突变国内外均有过文献报道。携带MYBPC3基因突变的10个家系中,15个成员携带MYBPC3基因突变,11个成员已发病,4个成员携带目前无HCM临床表现,外显率73.3%。45%的患者35岁之前起病,63.6%患者(7/11)合并室速/室颤/左室流出道梗阻/充血性心力衰竭。
结论MYBPC3基因是我国HCM患者常见的致病基因,在FHCM中占的比例较高。MYBPC3基因突变的外显率较高,半数患者年轻时起病,并不像既往文献所报道的是HCM患者预后较好的因素,多数携带者的临床预后同样不良。Arg346fs、Pro459fs突变为我国HCM患者热点突变;Lys814fs为HCM患者的热点突变。
第三部分肥厚型心肌病患者肌钙蛋白T(TNNT2)基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌钙蛋白T(TNNT2)基因突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为95例无血缘关系的汉族肥厚型心肌病的先证者,其中家族性HCM16例、SHCM 79例。均经过MYBPC3基因突变的筛查,未发现MYBPC3基因突变。对照为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病患者及正常对照组的基因组DNA。根据文献报道设计TNNT2的第8、9、10、11、14、15、16号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果16例FHCM患者及79例SHCM患者均未发现TNNT2基因的错义突变、移码突变、剪接突变,仅在9号外显子检出一同义突变,为ATC→ATT,均编码异亮氨酸(Ile)。
结论TNNT2基因不是我国HCM患者的主要致病基因。
第四部分肥厚型心肌病患者肌钙蛋白I(TNNl3)基因突变的筛查及其与表现型关系的研究
研究目的
研究中国肥厚型心肌病患者肌钙蛋白I(TNNl3)基因突变的特点,进一步阐明基因型-临床表型的关系。
研究对象和方法
研究对象为95例无血缘关系的汉族肥厚型心肌病的先证者,其中家族性HCM16例、SHCM 79例。均经过MYBPC3基因和TNN2基因的8、9、10、11、14、15、16号外显子突变筛查,未发MYBPC3基因和TNN2基因突变。对照为120例健康志愿者,均为汉族,性别、年龄均与患者相匹配,各项检查均未见异常。取外周静脉血,EDTA抗凝,采用QIAGEN公司试剂盒,从白细胞中提取肥厚型心肌病患者及正常对照组的基因组DNA。根据文献报道设计TNNI基因第3、7、8号外显子含侧翼内含子序列的引物。利用聚合酶链反应(PCR)扩增基因组DNA,将扩增的外显子的PCR产物按双脱氧末端终止法进行进行测序反应(美国ABI公司3730XL测序仪),应用Vector NTI 8.0分析软件分析测序结果。并与GenBank中的标准序列进行比对,确定可能的突变位点后,应用先证者发生突变的外显子的扩增引物序列扩增对照组相关基因片断,除外基因的多态性。与GenBank中收集的突变进行比对确定新发现的突变点。如确定为突变位点,则采用上述方法对先证者家族成员进行突变筛查。
结果16例FHCM患者及79例SHCM患者均未发现TNNI3基因的错义突变、移码突变、剪接突变,仅在7号外显子检出一同义突变,为GAG→GAA,均编码谷氨酸(Glu)。
结论TNNI3基因不是我国HCM患者的主要致病基因。
PartⅠ:Clinical and Prognostic Analysis of Patients with Hypertrophic Cardiomyopathy
Objectives:To investigate the clinical characteristics,long-term prognosis and death hazards in patients with hypertrophic cardiomyopathy(HCM).
Methods:The medical record of the 234 patients with HCM recruited from June,1999 to March,2006 were retrospectively analyzed,199 patients were followed up and the outcome data was statistically analyzed by SPSS ver13.0.
Results:Two hundreds and thirty-four patients(158 males,76 females;symptomatic age[51.0±15.6]years) diagnosed with HCM were studied.Among the 234 patients, females symptomatic age was older than males and more females compared with atrial fibrillation than males(P＜0.05 ).Symptoms in most of patients were nonspecific and 6.4%patients did not have symptoms.Changes of electrocardiogram in HCM were nonspecific and 6.4%did not have changes,but inverted T waves were sawed in patients with thicker wall in apex of heart.M-mode,2D,and echocardiogram showed the average maximal thickness of ventricular wall were(19.5±4.6)mm; 57(24.9%) patients were diagnosed with apical hypertrophic cardiomyopathy (AHCM),and the ratio between male and female was 3.4.The 15.5%patients who underwent coronary angiography had stenosis of coronary artery.Most of the patients received treatment and sudden death occurred to 5 patients.Among the 234 patients with HCM,199 patients(85%) were followed up with the mean time of 31.7±22.6 months,and the time interval from the first diagnosis till the end of the research was 52.2±66.6 months.Twenty-one patients died in the follow-up duration,HCM-related death occurred in 19 patients including 11(57.9%) patients of cardiac arrest, 7(36.8%)patients of heart failure,1 patient of stroke;1 patient of misadventure and 1 patient of acute pancreatitis..The free survival rates of all the followed patients at 1,2, 3,4 and 5 years were 96.7%,94.7%,94.7%,93.6%and 89.0%in respective. One-way ANOVA analysis indicated that sex,cardiac function,atrial fibrillation, sustained or non-sustained ventricular tachycardia(SVT or NSVT),enlargement of left atrium,obstructive outflow of left ventricular(LVOT),family history were associated with prognosis of patients.In the Cox model,the multivariate analysis showed HCM related death risk ratios were 2.234 for SVT or NSVT(p＜0.001), 1.964 for cardiac function of NYHA classⅢ-Ⅳ(P=0.003).Among the death patients,Maron typeⅢwere more common(73.7%)and only one patient merely involving apical myocardial hypertrophy(5.2%).Cardiac arrest was most common in patients＜60 years old(P=0.12),whereas heart failure occurred more frequently in patients≥60 years old(p=0.22).As for the death patients with cardiac arrest and heart failure,(1) 7 patients with cardiac arrest occurred under the age of 60(P=0.12,only one patient with onset age before 35),the onset age of 5 patients with heart failure were above 60(P=0.22);(2) LVOT occurred in only two patients with cardiac arrest and one patient with heart failure;(3)seven patients with cardiac arrest and 2 patients with heart failure combined SVT or NSVT;(4) maximum wall thicknesses of the patients with cardiac arrest and heart failure were 20.4±4.7mm versus 22.7±6.3mm.
Conclusions:The clinical manifestations of HCM in china is nonspecific,but the symptomatic age is older than that in other countries.Symptomatic age was older in females than that in males,and the female patients were prone to atrial fibrillation. Non-obstructive hypertrophic cardiomyopathy was much more common(204/234). The incidence of apical hypertrophic cardiomyopathy was 1/4 and more common in males.The outcomes of most of patients were good.A relatively benign long-term prognosis was shown in this group of HCM patients,especially in patients merely involving apical myocardial hypertrophy;Sustained or non-sustained ventricular tachycardia,cardiac function of NYHA classⅢ-Ⅳare the independent risk factors for main adverse cardio-cerebral events;cardiac arrest may occur in all ages of patients.
PartⅡ:Screening of cardiac myosin-binding protein C gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac myosin-binding protein C(MYBPC3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:One hundred and five patients with HCM and 120 control individuals were chosen for the study.Thirty-four exons in the functional regions of the MYBPC3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:Among the 105 patients,20 patients were identified familial hypertrophic cardiomyopathy(FHCM) and 85 patients identified sporatic hypertrophic cardiomyopathy(SHCM).Seven mutations were identified in 10 patients which respectively located in exon 5,12,16,17,25,31and 32.And no mutations were not detected in A group of 120 anonymous healthy individuals.Among the 10 patients with mutations,3 patient were identified FHCM,accounted for 15%of the total 20 patients with FHCM.Although the same mutation was identified in 2 patients' children,their ultrasonic cardiogram examination was normal.The other 5 patients were identified SHCM, accounted for 5.9%of the total 85 patients with SHCM.The seven mutations included 1 missense mutation and 6 frame shift mutation.Mutation pro459fs was identified in 4 patients and the mutation was identified in 2 patients' children,but their ultrasonic cardiogram examination was normal.The other 6 mutations were respectively identified in 6 patients.Mutation Pro 186fs,Lys 814fs,Pro1208fs were identified in patients with FHCM.Mutation Arg346fs and Gly507Arg were identified in patients with SHCM.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Mutation Gly507Arg and Pro1208fs were identical to foreign reports.Mutation Arg346fs was identified in Chinese patients with HCM. Mutation Lys814fs was identified in Chinese patients and foreign patients with HCM. Among the 10 families with mutations,mutations were identified in 15 person. Eleven of the total 15 person with mutation were diagnosed patients with HCM, accounted for 73.3%.Five patients' symptomatic age was less than 35 years old, accounted for 45%of the total 11 patients.Seven patients were associated with ventricular tachycardia or ventricular fibrillation or left ventricular outflow tract obstru-cttion or congestive cardiac failure.
Conclusions:Cardiac myosin-binding protein C(cMYBPC3) was one of the main disease-causing genes,accounted for 15%of the total 20 patients with FHCM.The penetrance was high of the cMYBPC3 gene mutations,and the symptomatic age of 45%patients with the mutations was less than 35 years old.The outcomes of most of the patients with the MYBPC3 gene mutation were not good.This indicated that the MYBPC3 gene mutation was not a good factor for the outcomes of the patients with HCM unlike what ever reported.Mutation Pro186fs,Pro459fs and Tyr1119fs were firstly identified in patients with HCM.Arg346fs and Pro459fs were hot spot mutation in Chinese patients with HCM.
PartⅢ:Screening of cardiac Troponin T gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac Troponin T(TNNT2) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:Ninety-five patients with HCM which had been scanned in MYBPC3 gene and had nomutaions found and 120 control individuals were chosen for the study. Seven exons(exon 8,9,10,11,14,15,16) in the functional regions of the TNNT2 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:The study could not find any mutation in TNNT2 gene.
Conclusion:This study did not find any HCM-caused mutation in TNNT2 gene, which was much lower than 10%-20%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.
PartⅣ:Screening of cardiac Troponin I gene mutations of Chinese HCM and study of the correlation between genotype and phenotype
Objective:To study the cardiac Troponin I(TNNI3) gene mutations in Chinese patients with hypertrophic cardiomyopathy(HCM),and to analyze the correlation between genotype and phenotype.
Methods:Ninety-five patients with HCM and 120 control individuals were chosen for the study.The patients with HCM had been scanned in MYBPC3 gene and TNNT2 gene,and no mutaions had been found.Three exons in the functional regions of the TNNI3 were amplified with polymerase chain reactions(PCR) respectively and the products were sequenced.The patients with positive results underwent family screen.
Results:The study could not find any mutation in TNNI3 gene.
Conclusion:This study did not find any HCM-caused mutation in TNNI3 gene, which was much lower than 5%that foreign reported.This research displayed that different race had different distribution of HCM-caused genes.
引文
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