Giordano C, D'Amati G
Dipartimento di Medicina Sperimentale e Patologia, Università di Roma La Sapienza.
Pathologica. 2005 Dec;97(6):361-8.
Cardiomyopathies are defined as diseases of the myocardium associated with cardiac dysfunction and are classified by morphological characteristics as hypertrophic (HCM), dilated (DCM) arrhithmogenic right ventricular (ARVC) and restrictive cardiomyopathy. These were once considered as specific diagnoses but there is now considerable evidence that many different gene mutations can cause these pathologies. In recent years, big emphasis has been given to the possibility that deregulation of cardiac metabolism may play a role in the mechanisms that lead to cardiac maladaptive remodelling. Cardiac energy metabolism is tightly controlled in mammalian organisms during development and in response to diverse dietary, physiologic, and pathologic conditions. The cardiac phenotype of many genetic diseases caused by mutations in proteins involved in mitochondrial energy production and/or homeostasis, underscores the importance of energetic pathway on cardiac function. For example, inborn errors in nuclear-encoded mitochondrial fatty acid oxidation (FAO) pathway enzymes and defects in fatty acid uptake are an important cause of childhood HCM and sudden death. Abnormalities in mitochondrial respiratory chain function, particularly those caused by mitochondrial DNA (mtDNA) mutations, are responsible for a heterogeneous group of clinical disorders, including isolated HCM. Mitochondrial cardiomyopathies (MCM) are characterized by an adverse clinical course with biventricular dilation and failure, even at a young age. Mutations in genes encoding the gamma2 subunit of AMP-activated protein kinase (PRKAG2), alpha-galactosidase A (GLA) and lysosome-associated membrane proteine-2 (LAMP2) can cause profound myocardial hypertrophy in association with electrophysiological defects. Unlike HCM due to sarcomere gene mutations, which is characterized by myofiber disarray and fibrosis, large cytosolic vacuoles characterize cardiomyopathy due to defect in energy metabolism. Ultrastructural analysis revealed massive mitochondrial proliferation in MCM and glycogen in complexes with protein and/or lipids in cardiomyopathy due to PRKAG2, GLA and LAMP2 mutations.
心肌病被定义为与心脏功能障碍相关的心肌疾病，根据形态学特征可分为肥厚型（HCM）、扩张型（DCM）、致心律失常性右心室心肌病（ARVC）和限制型心肌病。这些疾病曾经被视为特定诊断，但现在有大量证据表明，许多不同的基因突变可导致这些病理状况。近年来，人们非常重视心脏代谢失调可能在导致心脏适应性不良重塑的机制中发挥作用这一可能性。在哺乳动物机体发育过程中以及应对各种饮食、生理和病理状况时，心脏能量代谢受到严格控制。许多由参与线粒体能量产生和/或稳态的蛋白质突变引起的遗传疾病的心脏表型，突显了能量代谢途径对心脏功能的重要性。例如，核编码的线粒体脂肪酸氧化（FAO）途径酶的先天性缺陷以及脂肪酸摄取缺陷是儿童期HCM和猝死的重要原因。线粒体呼吸链功能异常，尤其是由线粒体DNA（mtDNA）突变引起的异常，是包括孤立性HCM在内的一组异质性临床疾病的病因。线粒体心肌病（MCM）的特征是临床病程不良，即使在年轻时也会出现双心室扩张和衰竭。编码AMP激活蛋白激酶（PRKAG2）γ2亚基、α-半乳糖苷酶A（GLA）和溶酶体相关膜蛋白2（LAMP2）的基因突变可导致严重的心肌肥厚并伴有电生理缺陷。与因肌节基因突变导致的HCM不同，后者的特征是肌纤维紊乱和纤维化，而能量代谢缺陷导致的心肌病则以大量胞质空泡为特征。超微结构分析显示，MCM中线粒体大量增殖，而因PRKAG2、GLA和LAMP2突变导致的心肌病中糖原与蛋白质和/或脂质形成复合物。
