Marian A J, Roberts R
Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
J Mol Cell Cardiol. 2001 Apr;33(4):655-70. doi: 10.1006/jmcc.2001.1340.
Hypertrophic cardiomyopathy (HCM), a relatively common disease, is diagnosed clinically by unexplained cardiac hypertrophy and pathologically by myocyte hypertrophy, disarray, and interstitial fibrosis. HCM is the most common cause of sudden cardiac death (SCD) in the young and a major cause of morbidity and mortality in elderly. Hypertrophy and fibrosis are the major determinants of morbidity and SCD. More than 100 mutations in nine genes, all encoding sarcomeric proteins have been identified in patients with HCM, which had led to the notion that HCM is a disease of contractile sarcomeric proteins. The beta -myosin heavy chain (MyHC), cardiac troponin T (cTnT) and myosin binding protein-C (MyBP-C) are the most common genes accounting for approximately 2/3 of all HCM cases. Genotype-phenotype correlation studies suggest that mutations in the beta -MyHC gene are associated with more extensive hypertrophy and a higher risk of SCD as compared to mutations in genes coding for other sarcomeric proteins, such as MyBP-C and cTnT. The prognostic significance of mutations is related to their hypertrophic expressivity and penetrance, with the exception of those in the cTnT, which are associated with mild hypertrophic response and a high incidence of SCD. However, there is a significant variability and factors, such as modifier genes and probably the environmental factors affect the phenotypic expression of HCM. The molecular pathogenesis of HCM is not completely understood. In vitro and in vivo studies suggest that mutations impart a diverse array of functional defects including reduced ATPase activity of myosin, acto-myosin interaction, cross-bridging kinetics, myocyte contractility, and altered Ca2+ sensitivity. Hypertrophy and other clinical and pathological phenotypes are considered compensatory phenotypes secondary to functional defects. In summary, the molecular genetic basis of HCM has been identified, which affords the opportunity to delineate its pathogenesis. Understanding the pathogenesis of HCM could provide for genetic based diagnosis, risk stratification, treatment and prevention of cardiac phenotypes.
肥厚型心肌病（HCM）是一种相对常见的疾病，临床诊断依据为无法解释的心脏肥大，病理诊断依据为心肌细胞肥大、排列紊乱和间质纤维化。HCM是年轻人心脏性猝死（SCD）的最常见原因，也是老年人发病和死亡的主要原因。肥大和纤维化是发病和SCD的主要决定因素。在HCM患者中已鉴定出九个基因中的100多个突变，所有这些基因均编码肌节蛋白，这导致人们认为HCM是一种收缩性肌节蛋白疾病。β-肌球蛋白重链（MyHC）、心肌肌钙蛋白T（cTnT）和肌球蛋白结合蛋白C（MyBP-C）是最常见的基因，约占所有HCM病例的2/3。基因型-表型相关性研究表明，与编码其他肌节蛋白（如MyBP-C和cTnT）的基因突变相比，β-MyHC基因突变与更广泛的肥大和更高的SCD风险相关。突变的预后意义与其肥大表达性和外显率有关，但cTnT中的突变除外，这些突变与轻度肥大反应和高SCD发生率相关。然而，存在显著的变异性，修饰基因等因素以及可能的环境因素会影响HCM的表型表达。HCM的分子发病机制尚未完全了解。体外和体内研究表明，突变会导致多种功能缺陷，包括肌球蛋白ATP酶活性降低、肌动蛋白-肌球蛋白相互作用、交叉桥接动力学、心肌细胞收缩力以及钙敏感性改变。肥大和其他临床及病理表型被认为是继发于功能缺陷的代偿性表型。总之，HCM的分子遗传基础已被确定，这为阐明其发病机制提供了机会。了解HCM的发病机制可为基于基因的心脏表型诊断、风险分层、治疗和预防提供依据。
