心脏型肌球蛋白结合蛋白C基因缺失突变导致肥厚型心肌病特点分析

目的观察肥厚型心肌病（HCM）患者心脏型肌球蛋白结合蛋白C基因（MYBPC3）缺失突变及其表型的特点。方法在100例HCM患者中对MYBPC3的所有外显子及其侧翼内含子序列进行基因扫描,聚合酶链反应（PCR）扩增目的片段,双脱氧末段终止法测序。对突变患者进行家系调查,分析其表型特点。结果在两例先证者中分别发现两个缺失突变14262_14264delAAG和14364delG,均位于外显子25。表型分析发现两例先证者均有劳力性胸闷、胸痛和晕厥史,超声心动图表现为不对称性肥厚（室间隔/左室后壁分别为2.5、3.2）,但SAM征阴性,发病年龄分别为38岁和29岁。结论缺失突变是MYBPC3基因突变的常见形式,14262_14264delAAG或14364delG突变导致的HCM表现为不对称性心肌肥厚,患者容易出现晕厥等症状,应该警惕心源性猝死的发生。     

Two novel mutations of the MYBPC3 gene identified in Chinese families with hypertrophic cardiomyopathy

BACKGROUND:

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiovascular disorders. Mutations in the MYBPC3 gene are one of the most frequent genetic causes of HCM.

OBJECTIVES:

To screen MYBPC3 gene mutations in Chinese patients with HCM, and analyze the correlation between the genotype and the phenotype.

METHODS:

The 35 exons of the MYBPC3 gene were amplified by polymerase chain reaction in the 11 consecutive unrelated Chinese pedigrees. The sequences of the products were analyzed and the mutation sites were determined. The clinical data of genotype-positive families were collected, and the correlation between genotype and phenotype was analyzed.

RESULTS:

Two mutations of the MYBPC3 gene were confirmed among 11 pedigrees. A frameshift mutation (Pro459fs) was identified in exon 17 in family H8, and a splice mutation (IVS5+5G→C) was identified in intron 5 in family H3. These two mutations were first identified in Chinese patients with familial HCM and were absent in 110 chromosomes of healthy controls. Seven known polymorphisms were found in the cohort.

CONCLUSIONS:

Compared with what was reported abroad, the MYBPC3 gene is a common pathogenic gene responsible for HCM in Chinese patients, and the phenotypes of these two mutations in their respective families may have their own clinical characteristics.     

一个家族性肥厚型心肌病家系基因突变位点分析

目的:研究一个家族性肥厚型心肌病家系的基因突变,并初步分析临床表型与其基因突变的关系。方法:家系调查收集临床资料,采集家系成员外周血,提取基因组DNA,进行高通量测序确定突变基因位点,并结合生物信息学技术分析。结果:此家系3代7人中,确诊为肥厚型心肌病的患者有4例,只有两例临床症状明显且发病较晚,另外两例均无明显临床症状。系谱中每一代均有患者,男女均可患病。家系中明确两例患者MYBPC3基因上第16外显子存在c.1504位置上胞嘧啶到胸腺嘧啶的杂合改变。经生物信息学分析,此位点突变可能有害。结论:肥厚型心肌病为常染色体显性遗传病,同一家族患者之间其临床表型存在明显的异质性,MYBPC3基因上c.1504C>Tp.(Arg502Trp)的突变可能是该家系的致病原因。     

心脏肌球蛋白结合蛋白C基因1811518116insGCAGG突变导致肥厚型心肌病特点分析

目的观察肥厚型心肌病（HCM）患者中心脏肌球蛋白结合蛋白C基因（MYBPC3）插入突变的特点。方法在100例HCM患者中对MYBPC3的所有外显子及其侧翼内含子序列进行基因扫描,聚合酶链反应（PCR）扩增目的片段,双脱氧末段终止法测序。对突变患者进行家系调查,分析其表型特点。结果在一先证者及其一个家系成员中发现一个位于外显子29的五核苷酸插入突变（18115-18116ins-GCAGG）,序列分析发现1032位缬氨酸后发生了移码突变（p.Vall032fs）,造成先证者60岁发病,超声心动图上表现为室间隔重度不对称性心肌肥厚（35mm）。结论插入突变是MYBPC3基因突变的特点,18115-18116insGCAGG导致的HCM表型发病晚,心肌肥厚程度重。     

MYBPC3基因p.Ile852Val突变与家族性肥厚型心肌病的相关性研究

目的:MYBPC3基因突变是肥厚性心肌病(HCM)的常见原因,本研究对导致HCM的一种新型的MYBPC3基因突变进行研究。方法:纳入了1例HCM患者及其家系中的8个亲属,同时纳入13名健康志愿者作为对照。对HCM患者家系及对照组成员进行基因测序,同时对HCM患者家系进行谱系分析、临床评估和基因分型。结果:在患者家系中,患者母亲及外祖父为肥厚型心肌病患者,基因测序发现患者及该2名亲属均存在MYBPC3基因p.Ile852Val杂合突变,其余5名亲属及健康对照组均无此突变。患者及其母亲临床症状相对较轻,但表现并不相同,外祖父长期卧床,症状较重,有严重胸闷气喘,在研究过程中猝死。结论:MYBPC3基因p.Ile852Val杂合突变与肥厚型心肌病相关,该突变为一种新型的导致HCM的基因突变,且携带该突变的HCM患者临床症状存在一定差异性。     

Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy

Mutations causing familial hypertrophic cardiomyopathy (HCM) have been described in at least 11 genes encoding cardiac sarcomeric proteins. In this study, three previously unknown deletions have been identified in the human cardiac genes coding for beta-myosin heavy chain (MYH7 on chromosome 14) and myosin-binding protein-C (MYBPC3 on chromosome 11). In family MM, a 3-bp deletion in MYH7 was detected to be associated with loss of glutamic acid in position 927 (DeltaE927) of the myosin rod. In two other families (HH and NP, related by a common founder) a 2-bp loss in codon 453 (exon 16) of MYBPC3 was identified as the presumable cause of a translation reading frame shift. Taken together 15 living mutation carriers were investigated. Six deceased family members (with five cases of premature sudden cardiac death (SCD) in families MM and NP) were either obligate or suspected mutation carriers. In addition to these mutations a 25-bp deletion in intron 32 of MYBPC3 was identified in family MM (five carriers) and in a fourth family (MiR, one HCM patient, three deletion carriers). In agreement with the loss of the regular splicing branch point in the altered intron 32, a splicing deficiency was observed in an exon trapping experiment using MYBPC3 exon 33 as a test substrate. Varying disease profiles assessed using standard clinical, ECG and echocardiographic procedures in conjunction with mutation analysis led to the following conclusions: (1) In family MM the DeltaE927 deletion in MYH7 was assumed to be associated with complete penetrance. Two cases of reported SCD might have been related to this mutation. (2) The two families, HH and NP, distantly related by a common founder, and both suffering from a 2-bp deletion in exon 16 of MYBPC3 differed in their average phenotypes. In family NP, four cases of cardiac death were documented, whereas no cardiac-related death was reported from family HH. These results support the notion that mutations in HCM genes may directly determine disease penetrance and severity; however, a contribution of additional, unidentified factors (genes) to the HCM phenotype can-at least in some cases-not be excluded. (3) The deletion in intron 32 of MYBPC3 was seen in two families, but in both its relation to disease was not unequivocal. In addition, this deletion was observed in 16 of 229 unrelated healthy individuals of the population of the South Indian states of Kerala and Tamil Nadu. It was not seen in 270 Caucasians from Russia and western Europe. Hence, it is considered to represent a regional genetic polymorphism restricted to southern India. The association of the deletion with altered splicing in transfected cells suggests that this deletion may create a "modifying gene", which is per se not or only rarely causing HCM, but which may enhance the phenotype of a mutation responsible for disease.     

A large conus artery in patients with hypertrophic cardiomyopathy

Summary We retrospectively analyzed coronary arteriograms in 66 patients with hypertrophic cardiomyopathy (HCM) who underwent coronary arteriography. Four of these patients showed a large conus artery supplying the interventricular septum, and the characteristics of their echocardiograms revealed a marked interventricular septal hypertropy.It is suggested that in some patients with HCM, the conus artery may develop in compensation for the relatively reduced coronary blood flow which is due to the hypertrophied myocardium.     

80例肥厚型心肌病的临床分型

对经磁共振检查确诊的80例肥厚型心肌病（HCM）进行分析，全心肥厚型10例（12．50％），厚度为25．60±6．93mm。局限肥厚型70例（87.50％），平均厚度为22．98±5．64mm，其中室间隔肥厚型31例（38．75％），平均厚度为22．66±5．85mm;游离壁肥厚型20例（25．00％），20.65±4．07mm；心尖肥厚型11例（13．75％），28．27±5．90mm；室间隔并游离壁肥厚型6例（7．50％），22．33±3．14mm；心尖并游离壁肥厚型及乳头肌肥厚型各1例。合并流出道狭窄者29例，占36．25％。心电图T波倒置者60例，占75．95％（60／79），而S-T段下降者仅9例，占11．39％（9／79），与冠心病心电图变化规律不同。左室肥厚型以全心HCM多见（80．00％）；非室间隔肥厚型TV5倒置最多（50．00％），T波倒置最深者多出现在全心HCM，而不是心尖肥厚型。异常Q波在各型间的分布无显著性差异。     

肥厚型心肌病冠状动脉造影特征

目的　了解肥厚型心肌病患者冠状动脉造影有何特征性改变。方法　对我院自 1987年 8月至 1999年 8月 5 0例肥厚型心肌病患者冠状动脉造影资料进行分析。结果　 5 0例中 6例冠状动脉为左优势型 ,占 12 %。本组冠状动脉近端平均血管内径测量值 :LM :(5 1± 1 0 )mm ,LADp :(4 2±1 0 )mm ,LCXp :(3 8± 0 9)mm ,RAp :(3 8± 0 9)mm ,与正常左冠状动脉近端平均血管内径 (LM :(4 6±0 6 )mm ,LADp :(3 7± 0 6 )mm ,LCXp :(3 4± 0 6 )mm比较 ,明显增粗 ,P≤ 0 0 5 ,而本组病例右冠状动脉与之比较差异无显著性。冠状动脉肌桥 14例 ,发生率为 2 8% (14 5 0 ) ,其中 12例位于前降支 ,且大多位于其中段。 13例冠状动脉有单支或多支≥ 5 0 %的狭窄病变 ,占 2 6 %。结论　本组冠状动脉造影特点 :冠状动脉左优势型的比例明显增高 ;冠状动脉血管粗大 ,以左冠状动脉增粗为主 ;冠状动脉肌桥发生率高 ,大多出现于前降支中段 ;约 1 4的患者合并冠状动脉狭窄 (≥ 5 0 % )。     

Elevated carbohydrate antigen 125 levels in hypertrophic cardiomyopathy patients with heart failure

Carbohydrate antigen 125 (CA 125), known as a tumor marker for ovarian cancer, has been reported to increase and relate to severity in heart failure patients with systolic dysfunction. Hypertrophic cardiomyopathy (HCM) has a wide clinical spectrum that often includes heart failure symptoms. The aim of this study was to evaluate the role of CA 125 in HCM patients, its relation to severity of symptoms, and degree of diastolic dysfunction. CA 125 blood levels were determined in 32 HCM patients (21 male; age 51.3 +/- 18.4 years) and in 30 healthy volunteers (19 male; age 49.6 +/- 16.1 years). Echocardiographic examinations were performed in all patients. The results were grouped according to clinical status (New York Heart Association class) of the patients. The mean serum level of CA 125 was 14.6 +/- 23.8 U/ml in the study group and 7.6 +/- 4.8 U/ml in the control group. There was no significant difference between the groups (P = 0.12). CA 125 levels increased as the New York Heart Association functional class increased (class I/II: 6.2 +/- 2.4 U/ml; class III: 30.6 +/- 36.4 U/ml; P < 0.001). The mean CA 125 level in functional class III patients (30.6 +/- 36.4 U/ml) was significantly higher than that of the control group (7.6 +/- 4.8 U/ml) (P < 0.001) and the functional class I/II group (6.2 +/- 2.4 U/ml) (P < 0.001). There was a significant difference over all three diastolic dysfunction groups with respect to CA 125 levels (4.9 +/- 1.3 U/ml in impaired relaxation group, 11.8 +/- 6.9 U/ml in pseudonormal group, and 52.6 +/- 45.6 U/ml in restrictive filling group; P < 0.0001). Serum CA 125 is related to the clinical severity of HCM. Whether CA 125 has a specific biological role in HCM requires further investigation.     

肥厚型心肌病的心电图改变

目的 探讨肥厚型心肌病患者心电图变化及其临床意义。方法 对44例肥厚型心肌病(Ⅰ型前间隔肥大14例，Ⅱ型前间隔、后间隔均肥大18例，Ⅲ型左心室前壁或／和侧壁、后壁肥大7例，Ⅳ型心尖部肥大5例)行常规12导联心电图检查。结果 心电图异常(ST-T改变、异常Q波、心室肥大等)发生率为93．2％。Ⅳ型ST-T改变多见于前侧壁、高侧壁，具有特殊性。其它三型患者异常Q波、ST-T改变发生率及部位差异均无显著性意义。结论 肥厚型心肌病患者大多存在不同程度的心电图异常，但除心尖肥厚型心肌病外，其他各型心电图改变无特异性。     

肥厚型心肌病合并心房颤动的射频导管消融治疗

目的评价肥厚型心肌病合并心房颤动（房颤）射频导管消融的安全性和疗效。方法入选2005年至2012年共57例肥厚型心肌病合并房颤患者,采用Carto三维标测系统引导环肺静脉消融电隔离术,附加二尖瓣、三尖瓣峡部线性消融及左心房碎裂电位消融以改良基质。结果57例患者均顺利完成导管消融术,平均手术时间（192±36）min,X线曝光时间（28±8）min,随访时间（3．1±2．0）年,单次消融成功率42．1％,多次消融成功率61．4％,其中梗阻性肥厚型心肌病患者消融成功率36．4％,非梗阻性患者成功率67．4％（P=0．031）。结论环肺静脉消融结合基质改良治疗肥厚型心肌病合并房颤在有经验的治疗中心安全有效。     

老年肥厚型心肌病与高血压左室肥厚患者临床特点的比较

目的 分析老年肥厚型心肌病与老年高血压左室肥厚患者的临床特点.方法 回顾性分析老年肥厚型心肌病患者(35例)与老年高血压左室肥厚患者(35例)的症状和体征及心电图、超声心动图的差异.结果 老年肥厚型心肌病患者均无高血压史.两组年龄、性别、脑血管病史及肥厚型心肌病家族史比较,差异均无统计学意义(均为P＞0.05).老年肥厚型心肌病患者中,晕厥者5例(14.3%),高血压左室肥厚患者中,无晕厥者,2组比较,差异有统计学意义(P＜0.05).老年肥厚型心肌病患者中无心脏杂音者9例(25.7%),明显少于高血压左室肥厚患者[23例(65.7%),P＜0.05].心电图示:老年肥厚型心肌病患者中,有异常Q波者10例(28.6%),较高血压左室肥厚患者的1例(2.9%)多(P＜0.05).老年肥厚型心肌病患者中心房颤动(房颤)及ST-T改变者分别为11例(31.4%)及34例(97.1%),明显多于高血压左室肥厚患者的3例(8.6%)及26例(74.3%),均为P＜0.05.超声心动图示:老年肥厚型心肌病患者的左室后壁厚度为(9.5±1.1)mm,明显薄于高血压左室肥厚患者的(12.6±1.0)mm(P＜0.01),左房内径老年肥厚型心肌病患者为(41.6±6.3)mm,高血压左室肥厚患者为(38.6±5.5)mm,两组差异有统计学意义(P＜0.05);老年肥厚型心肌病患者二尖瓣血流频谱E/A＜1者15例(42.9%),明显少于高血压左室肥厚患者的32例(91.4%),P＜0.05.老年肥厚型心肌病患者有主动脉瓣钙化者7例(20.0%),高血压左室肥厚患者20例(57.1%),二者差异有统计学意义(P＜0.05),室间隔厚度、左室内径与射血分数2组相似(均为P＞0.05).结论 老年肥厚型心肌病患者临床表现有晕厥者多,心脏有明显的杂音,心电图有异常Q波及房颤者较多,超声心动图显示左室不对称性肥厚多;高血压左室肥厚患者左室肥厚多为对称性,合并主动脉瓣钙化者多.     

The role of impaired sympathetic nerve function in enhancing coronary vasoconstriction in patients with hypertrophic cardiomyopathy

Coronary vasospasm and diminished coronary blood flow reserve have often been reported in patients with hypertrophic cardiomyopathy (HCM). However, the mechanism of coronary spasm in HCM is unknown. Thus, coronary endothelial function and sympathetic nerve function in 11 patients with HCM and 11 control patients matched for age and sex were examined. The diameter of the left anterior descending coronary artery was assessed by quantitative coronary angiography, and the change in coronary blood flow was estimated using an intracoronary Doppler flow wire. To assess myocardial sympathetic nerve function, metaiodobenzylguanidine images - 15 min and 180 min after the injection of (123)I-metaiodoben-zylguanidine at a dosage of 111 MBq - were obtained, and the heart to mediastinum (H/M) count ratio and the washout rate (WR) were calculated. The H/M ratio was significantly lower in patients with HCM (2.1+/-0.3) than in control patients (2.6+/-0.4) (P<0.01). In addition, the WR was higher in patients with HCM (35+/-6%) than in control patients (28+/-3%) (P<0.01). The HCM subjects with coronary spasm had lower H/M ratios and higher WRs than HCM subjects without coronary spasm (P<0.05, respectively). In conclusion, impaired sympathetic nerve function may be associated with coronary vasospasm and diminished coronary blood flow reserve in HCM.     

Evaluation of a polymorphism in MYBPC3 in patients with anthracycline induced cardiotoxicity

Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3–5% in the Indian population. Polymorphism in intron 32 (deletion of 25 bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3–8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467 bp fragment while in the presence of the 25 bp deletion only a 442 bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25 bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442 bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401 bp and 66 bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity.     

Sudden cardiac death in hypertrophic cardiomyopathy

Background: Recent identification of mutations in the ß-myosinheavy chain gene (MYH7), a major responsible gene for HCM, hasprovided the opportunity to characterize genotype-phenotypecorrelation in HCM families. In this study we analysed the phenotypicexpression of two ß-myosin heavy chain (ßMHC)mutations in three unrelated HCM families. Methods: Living individuals from three unrelated HCM families(Families 1, 2, and 3) were screened by history, physical examination,electrocardiography, and two-dimensional echocardiography. Bloodwas collected from all individuals for DNA extraction. Polymerasechain reaction (PCR), restriction endonuclease digestion andchemical cleavage were utilized for detection of mutations.All mutations were confirmed by sequence analysis. Results:Identification of mutations: A missense mutation in exon 13of the ßMHC gene (Arg⁴⁰³Gln) was detected in HCM patientsfrom Families 1 and 2. PCR amplification of the exon 13 DNA,followed by Ddel digestion of the PCR product and gel electrophoresis,showed two fragments of 84 and 70 bp in normal individuals andfour fragments of 84, 70, 52 and 32 bp in HCM patients. Sequenceanalysis showed substitution of an adenine for guanine at codingposition 1208. In Family 3, a missense mutation in exon 16 ofthe ßMHC gene (Val⁶⁰⁶Met) was detected in HCM patients.Chemical cleavage of the PCR products showed an uncleaved productof 337 bp in the normal individuals, while in the affected individuals,in addition to the uncleaved product, a 90 bp cleaved productwas also detected, indicating the presence of a mismatch inone allele. Sequence analysis showed substitution of an adeninefor guanine in coding position 1817. Clinical Characteristics: Seven members of Family 1 had HCM,of whom five are alive. One patient died from sudden cardiacdeath (SCD) and another from recurrent cerebral embolL In Family2, 15 individuals had HCM of whom nine have died, seven fromSCD. The mean age at the time of SCD was 33 years. The thirdfamily is comprised of 11 affected individuals and one obligatecarrier, of whom one patient died at age 17 from progressiveheart failure. Two additional individuals in this family havealso succumbed to SCD to age 60. A variety of clinical and echocardiographicmanifestations of HCM were present in each family. Logrank test of Kaplan-Meier survival curves indicates thatArg⁴⁰³Gln mutation was associated with a poor prognosis in HCMfamilies as compared to Val⁶⁰⁶Met (P=0.034). Conclusions: ßMHC mutations despite showing variableclinical and echocardiographic manifestations of HCM are predictorsof survival in HCM families.     

Verapamil-induced ventricular tachycardia in hypertrophic cardiomyopathy

A 17-year old boy with hypertrophic obstructive cardiomyopathy(HOCM) developed repeated short runs of self terminating ventriculartachycardia 12 hours after starting oral verapamil, which wassubstituted for propranolol therapy. It is suggested that alterationsin sympathetic tone induced by changing from a beta-blockerto a calcium antagonist might have increased myocardial irritabilitythus favouring genesis of severe ventricular arrhythmias. Verapamilis often considered to be more effective than propranolol inthe treatment of HOCM. However, if propranolol is replaced byverapamil one has to take account of the possibility of seriousarrhythmias as demonstrated by our case.     

合并高血压的肥厚型梗阻性心肌病患者的临床特点分析

目的：探讨合并高血压的肥厚型梗阻性心肌病（hypertrophic obstructive cardiomyopathy,HOCM）患者的临床表现、超声心动图及预后特点. 方法：入选HOCM患者80例,根据是否合并高血压将患者分为2组：合并高血压的HOCM恶者为H-HOCM组（n=43）,无高血压的HOCM患者为N-HOCM组（n=37）.随访并对比分析两组患者的临床资料. 结果：与N-HOCM组患者相比,H-HOCM组患者年龄较大,合并糖尿病者较多,左室舒张末期内径和收缩末期内径增大,室间隔厚度降低（P＜0.05）.药物治疗方面,两组患者β受体阻滞剂应用率均较高（＞80％）,H-HOCM组患者血管紧张素受体阻断剂（ARB）和血管紧张素转换酶抑制剂（ACEI）应用率明显高于N-HOCM组（P＜0.05）.随访期间两组患者临床相关事件发生率无统计学差异. 结论：合并高血压的HOCM患者呈高龄趋势,多合并糖尿病,左室呈离心性肥厚,其预后特征有待深入观察.     

Arrhythmogenic left ventricular apical aneurysm in hypertrophic cardiomyopathy

A 70-year old lady with prior myectomy for hypertrophic obstructive cardiomyopathy presented with sustained ventricular tachycardia. She was found to have a large left ventricular (LV) apical aneurysm. Surgical intervention was not advised, due to the risk of creating a small LV cavity after surgery and ICD was not advised based on the risk of injuring a very thin walled aneurysm. The patient's arrhythmia settled on medical therapy, but unfortunately she suffered an unwitnessed death three months later.This case represents a rare complication to a rare disease with limited management options. In such patients evidence based medicine is of little help, if any.