Human Idiopathic Cardiomyopathy Research Articles

Involvement of human monogenic cardiomyopathy genes in experimental polygenic cardiac hypertrophy.

Hypertrophic cardiomyopathy thickens heart muscles, reducing functionality and increasing risk of cardiac disease and morbidity. Genetic factors are involved, but their contribution is poorly understood. We used the hypertrophic heart rat (HHR), a unique normotensive polygenic model of cardiac hypertrophy and heart failure, to investigate the role of genes associated with monogenic human cardiomyopathy. We selected 42 genes involved in monogenic human cardiomyopathies to study: 1) DNA variants, by sequencing the whole genome of 13-wk-old HHR and age-matched normal heart rat (NHR), its genetic control strain; 2) mRNA expression, by targeted RNA-sequencing in left ventricles of HHR and NHR at 5 ages (2 days old and 4, 13, 33, and 50 wk old) compared with human idiopathic dilated cardiomyopathy data; and 3) microRNA expression, with rat microRNA microarrays in left ventricles of 2-day-old HHR and age-matched NHR. We also investigated experimentally validated microRNA-mRNA interactions. Whole-genome sequencing revealed unique variants mostly located in noncoding regions of HHR and NHR. We found 29 genes differentially expressed in at least 1 age. Genes encoding desmoglein 2 ( Dsg2) and transthyretin ( Ttr) were significantly differentially expressed at all ages in the HHR, but only Ttr was also differentially expressed in human idiopathic cardiomyopathy. Lastly, only two microRNAs differentially expressed in the HHR were present in our comparison of validated microRNA-mRNA interactions. These two microRNAs interact with five of the genes studied. Our study shows that genes involved in monogenic forms of human cardiomyopathies may also influence polygenic forms of the disease.

Electron microscopic study of cardiac lesions induced in rats by isoproterenol and by repeated stress. With suggestion that idiopathic cardiomyopathy may be a "disease of adaptation".

An electron microscopic study of cardiac lesions induced in rats by isoproterenol and by repeated stress is described, and a possible pathogenetic mechanism of idiopathic cardiomyopathy is proposed. Three types of cardiac cells could be roughly differentiated according to the structure and arrangement of myofibrils: 1) normo-type with normal structure and normal arrangement of myofibrils, 2) nondestroyed-degenerated-type in which myofibrils show normal structure and abnormal arrangement, and 3) destroyed-degenerated-type with destroyed myofibrils. Various degrees and frequency of mitochondrial changes (accumulation, variation of size, swelling, loss of cristae and myelin figure), increase of glycogen granules, dilation of sarcoplasmic reticulum or T-tubules and nuclear changes were seen in every type. These 3 types seemed to correlate well with the degree of myocardial beta-adrenergic stimulation by isoproterenol or repeated stress. Normo-types were extensively observed in hearts exposed to mild myocardial beta-adrenergic stimulation. Nondestroyed-degenerated-types and destroyed-degenerated-types were frequently observed in hearts exposed to excessive myocardial beta-adrenergic stimulation. These results show a similarity between cardiac lesions induced in rats by isoproterenol or repeated stress and those seen in human idiopathic cardiomyopathy, and suggest the possibility that idiopathic cardiomyopathy is a "Disease of Adaptation."