Bonne G, Carrier L, Richard P, Hainque B, Schwartz K
From the INSERM Unit 153, the Service de Biochimie B, and the IFR de Physiologie et Génétique Cardiovasculaire, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Circ Res. 1998 Sep 21;83(6):580-93. doi: 10.1161/01.res.83.6.580.
Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ss-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, alpha-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.
肥厚型心肌病的特征是左心室和/或右心室肥厚，通常不对称且累及室间隔。典型的形态学改变包括心肌细胞肥大以及围绕疏松结缔组织增多区域的排列紊乱。心律失常和过早猝死很常见。在大多数情况下，肥厚型心肌病是家族性的，以常染色体显性性状遗传。分子遗传学研究结果表明，家族性肥厚型心肌病是一种肌节疾病，涉及7种不同基因的突变，这些基因编码肌原纤维装置的蛋白质：β-肌球蛋白重链、心室肌球蛋白必需轻链、心室肌球蛋白调节轻链、心肌肌钙蛋白T、心肌肌钙蛋白I、α-原肌球蛋白和心肌肌球蛋白结合蛋白C。除了这种位点异质性外，还存在广泛的等位基因异质性，因为在所有这些基因中都发现了大量突变。动物模型和体外分析的最新进展使人们对与家族性肥厚型心肌病相关的病理生理机制有了更好的理解。因此，可以初步得出以下一系列事件：突变导致一种有毒多肽，该多肽会被整合到肌节中。这将改变肌节功能，进而导致（1）心脏功能改变，然后（2）肌节和心肌细胞结构改变。一些突变会导致功能障碍，并支持“收缩功能减退”状态继以代偿性肥大的发病机制假说。其他突变会导致心脏功能亢进，并确定一种“收缩功能亢进”状态，直接诱发心脏肥大。开发其他动物模型以及开展将基因突变与功能缺陷联系起来的其他机制研究，现在是理解心肌细胞基本收缩单位的改变如何改变心脏表型和功能的关键问题。
