心肌致密化不全的肌小节基因突变筛查及临床特征研究

【作者】 田涛；

【导师】 周宪梁；

【作者基本信息】 北京协和医学院 ， 内科学， 2014， 博士

【摘要】 研究背景：心肌致密化不全(NVM)是一种相对少见的遗传性心肌病,它以心室内形成过多异常粗大的肌小梁和交错的小梁间隐窝,使心室壁形成内层疏松、外层致密的两层结构为特点。因其常累及左室,故又被称为左室致密化不全(LVNC)。LVNC具有明显的遗传异质性,多种基因的突变都被证明与该疾病有关,包括TAZ、DTNA、 LDB3、MIB1和PRDM16。但以往的研究表明只有少数LVNC病例是由上述基因的突变所导致。肌小节基因突变通常被认为是肥厚性心肌病(HCM)的主要病因,也与遗传性扩张型心肌病(DCM)和遗传性限制型心肌病密切相关。近期的研究证实,肌小节基因突变同样也可导致LVNC而且在患者中的检出率较高。然而,因为现有研究纳入的对象都是白人而且样本量也较小,所以肌小节基因突变是否为LVNC的主要病因尚需进一步证实。研究目的：评估肌小节基因突变在中国LVNC人群中所占的比例及分布情况,初步探讨其基因型与临床表型的关系。研究方法：前瞻性入选2003至2010年在北京阜外心血管病医院明确诊断为LVNC的先证者。给予患者全面地临床评估,并采集外周血提取DNA。运用二代测序技术对10个肌小节相关基因(MYH7、MYBPC3.MYL2、MYL3、MYH6、TNNC1、TNNT2、 TNNI3、TPM1和ACTC1)进行DNA检测。研究结果：在纳入研究的57例LVNC患者中,仅有7例(12%)被检出携有肌小节基因突变。这些突变涉及4个基因(MYH7、ACTC1、TNNT2和TPM1),其中有4个突变位于4YH7(△Phe155、Arg249Gly、Arg369Gln和Glu929Lys),各有1个突变位于ACTC1(Ile329Thr)、TNNT2(Arg102Gln)和TPM1(A1a242Val)。所有这些突变均为杂合突变。除1个突变(MYH7基因上Arg369G1n突变)在以往的研究中报道过,其余均未见报道。在3位携带突变的先证者家庭成员中我们也检出了HCM或DCM患者。突变阳性患者的心肌病家族史检出率比突变阴性者要高(71%vs.8%,P=0.001),但两组患者在基线时的其余特征未见明显不同。经过3.5±1.7年的随访,我们发现突变阳性和突变阴性患者的生存率无明显的差异(P=0.90)。结论：肌小节基因突变不是中国汉族LVNC患者的主要病因。该类基因突变导致的心肌病在家族内部可能存在表型的变异。肌小节基因突变的检出提示患者很可能有心肌病家族史。LVNC表型的轻重似乎与该类基因突变无关。研究背景：心肌致密化不全(NVM),又称左室致密化不全(LVNC),它以心室内形成过多异常粗大的肌小梁和交错的小梁间隐窝,使心室壁形成内层疏松、外层致密的两层结构的为特点。早期有研究提示,LVNC患者心力衰竭、心律失常、系统栓塞的发生率较高,且预后较差,年死亡及心脏移植的发生率约13-24%。然而,由于以往研究纳入的患者通常较少且都是来源于白种人群,所以需要对亚裔LVNC人群的临床特点及预后进行进一步评估。研究目的：本研究旨在评估中国成人孤立性LVNC的临床特征及预后,并确定影响其预后的危险因素。研究方法：连续纳入2003至2012年在北京阜外心血管病医院明确诊断为孤立性LVNC的成人患者。详细收集患者的病史、心电图、心脏超声等临床资料。通过定期的复诊和/或及电话回访获得随访信息。研究结果：本研究共纳入106例患者。患者的平均年龄为46M7岁(年龄最小者16岁,最大者78岁)。在这些患者中,有60%(64/106)的患者心功能为III/IV级,有79%(84/106)的患者存在左室收缩功能异常(左室射血分数,LVEF<50%),左室扩大(左室舒张末期内径,LVEDD≥60mm)的患者有67%(71/106)。LVEF的降低与心功能分级增加(r=-0.72,P<0.001)、LVEED扩大(r=-0.65,P<0.001)、左房内径增加(r=-0.44,P<0.001)、肺动脉压升高(r=-0.38,P<0.001)和收缩压降低(r=0.20,P=0.04)有关。在58例接受了24小时动态心电图检查的患者中,分别有50%(29/58)和47%(26/58)的患者被检出有非持续性室速和频发室早。在平均2.9±2.1年的随访中,共有26%(28/106)的患者发生死亡和接受心脏移植,有4%(4/106)的患者发生了系统栓塞。患者年死亡及心脏移植的发生率为9.1%。多因素Cox回归分析表明,患者死亡及心脏移植的独立危险因素包括LVEF的降低(HR：0.96；95%CI：0.92-1.00；P=0.03)、合并右束支传导阻滞(HR：7.94；95%CI：2.36-26.72；P=0.001)和收缩压降低(HR：0.97；95%CI：0.94-1.00；P=0.02)。结论：中国成人LVNC患者主要的临床表现是心力衰竭和心律失常,而系统栓塞并不常见。尽管该疾病死亡和心脏移植发生率相对较高,但其预后比早期报道的要好。决定LVNC预后不良的因素主要为左心功能异常。合并右心功能异常可能也会影响患者的预后。更多还原

【Abstract】 Background:Non-compaction of ventricular myocardium (NVM) is an uncommon genetic cardiomyopathy, which is characterized by a two-layered myocardium with a thin compacted epicardial layer and a thick loosened endocardial layer composed of numerous prominent trabeculations and deep intertrabecular recesses. Because left ventricle is commonly involved, it is also called left ventricular non-compaction (LVNC). LVNC shows a remarkable genetic heterogeneity. Defects in several genes have been proved to be related to this disorder, including TAZ, DTNA, LDB3, MIB1and PRDM16. However, these genes were only responsible for a small number of LVNC cases. Sarcomeric gene mutations are generally considered to be the primary etiology of hypertrophic cardiomyopathy (HCM), and to be associated with inherited dilated cardiomyopathy (DCM) and restrictive cardiomyopathy. Recently, LVNC is also demonstrated to be caused by sarcomeric mutations. Some studies even reported that approximately30%of cases resulted from these mutations. However, these researches were conducted based on Caucasian cohorts with a small number of individuals. Thus, it remains unclear whether these gene mutations are the main cause of LVNC in Chinese populations.Aims:This study was aimed to investigate the prevalence of sarcomeric gene mutations in a Chinese population with LVNC, and to preliminarily explore the relationship between the genotype and phenotype of this disorder.Methods:Between2003to2010, patients diagnosed with LVNC were prospectively included at Fuwai Hospital, Beijing, China. Comprehensive clinical evaluation was provided to the probands and the available family members. DNA samples were isolated from the peripheral blood of the index cases. Ten sarcomeric genes were screened by next-generation sequencing technology, including MYH7, MYBPC3, MYL2, MYL3, MYH6, TNNC1, TNNT2, TNNI3, TPM1and ACTC1.Results:Of the57patients included, only7(12%) carried sarcomeric gene mutations. These heterozygous mutations were distributed among4genes,4mutations in MYH7(△Phe155, Arg249Gly, Arg369Gln and Glu929Lys),1each in ACTC1(Ile329Thr), TNNT2(Arg102Gln) and TPM1(Ala242Val). Of these mutations, one (Arg369Gln in MYH7) was previously reported in LVNC. HCM or DCM could be detected in family members of the3probands with sarcomeric gene mutations. A family history of cardiomyopathy occurred more frequently in mutation-positive patients than that in mutation-negative patients (71%vs.8%, P=0.001). No significant difference was observed in other clinical characteristics at baseline between the two group patients. Duding a follow-up of3.5±1.7years, the Kaplan-Meier analysis showed that survival free from death was comparable between mutation-positive and mutation-negative groups (P=0.90).Conclusions:Sarcomeric gene mutations are not the primary etiology of LVNC in Chinese Han populations. Phenotypic variation may occur in the family members of the probands with sarcomeric mutations. The mutation-positive index cases more likely have a family history of cardiomyopathy. The phenotypic severity of LVNC seems to be independent of presence or absence of sarcomeric mutations. Background:Non-compaction of ventricular myocardium (NVM), which is also called left ventricular non-compaction (LVNC), is an inherited cardiomyopathy characteristic of a two-layered myocardium with a thin compacted epicardial layer and a thick non-compacted endocardial layer composed of numerous prominent trabeculations and deep intertrabecular recesses. Initial studies showed that heart failure, arrhythmia and systemic embolism were common findings in LVNC, and that the patients had a poor prognosis with an annual mortality and heart transplantation rate of13-24%. However, previous studies only included small numbers of subjects and the great majority of them were conducted in Caucasian populations. So, its clinical profile and prognosis in Asians need to be further evaluated, and the predictors for poor prognosis also need to be identified.Aims:This study was undertaken to evaluate the clinical course of isolated LVNC, and to identify the predictors for adverse outcome in a Chinese population.Methods:Between2003and2012, adult patients diagnosed with isolated LVNC at Fuwai Hospital were consecutively included in this study. The medical history, electrocardiograms, and echocardiograms of these patients were analyzed by chart review. Follow-up data were collected by regular outpatient and/or telephone interviews with the patients or their family members.Results:A total of106subjects were included in this studies. Mean age of the patients was46±17(range:16±78years). Among these patients,64(60%) showed New York Heart Association (NYHA) functional class Ⅲ/Ⅳ,84(79%) had left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF),<50%) and71(67%) had dilated left ventricle (left ventricular end-diastolic diameter (LVEDD),≥60mm). Decreased LVEF was correlated to NYHA functional class Ⅲ/Ⅳ (r=-0.72, P<0.001), dilated LVEED (r=-0.65, P<0.001), enlarged left atrial diameter (r=-0.44, P<0.001), presence of pulmonary hypertension (r=-0.38, P<0.001) and low systolic blood pressure (r=0.20, P=0.04). Of the58patients receiving Holter monitoring, nonsustained ventricular tachycardia and frequent ventricular premature beats were detected in29(50%) and26(47%) of the patients, respectively. During a follow-up of2.9±2.1years,28(26%) patients died or underwent heart transplantation, and systemic embolism occurred in4(4%) patients. The annual incidence of mortality and transplantation was9.1%. Multivariate Cox analysis revealed that decreased LVEF (HR:0.96;95%CI:0.92-1.00; P=0.03), right bundle branch block (HR:7.94;95%CI;2.36-26.72; P=0.001) and low systolic blood pressure (HR:0.97;95%CI:0.94-1.00; P=0.02) were independent risk factors for death and heart transplantation.Conclusions:Heart failure and arrhythmia are common findings in Chinese isolated LVNC population, but systemic embolism is not. The prognosis of this disorder is better than that initially reported, although it is related to a relatively high incidence of death and heart transplantation. Left ventricular dysfunction predicts adverse outcome of isolated LVNC. Right ventricular dysfunction may also worsen the prognosis.更多还原