Causes and pathogenesis of hypertrophic cardiomyopathy

Causes of hypertrophic cardiomyopathy

At the present stage of development of our knowledge, enough data has accumulated, suggesting that hypertrophic cardiomyopathy is a hereditary disease transmitted by an autosomal dominant type with various penetrance and expressiveness. Cases of the disease reveal in 54-67% of the parents and immediate relatives of the patient. The rest is the so-called sporadic form, in this case the patient does not have relatives who are ill with hypertrophic cardiomyopathy or who have hypertrophy of the myocardium. It is believed that the majority, if not all cases of sporadic hypertrophic cardiomyopathy also have a genetic cause, i.e. Are caused by random mutations.

Hypertrophic cardiomyopathy is a genetically heterogeneous disease, it is caused by more than 200 described mutations of several genes encoding the proteins of the myofibrillar apparatus. To date, 10 protein components of the heart sarcomere known to perform contractile, structural or regulatory function, whose defects are detected in hypertrophic cardiomyopathy. And in every gene, many mutations can be the cause of the disease (polygenic multiallelic disease).

The current level of development of medical genetics, development and introduction of high-precision DNA diagnostics methods using PCR in a wide clinical practice, determine significant progress in recognition of many pathological processes. The presence of a mutation associated with hypertrophic cardiomyopathy is recognized as the "gold standard" for diagnosis of the disease. At the same time described genetic defects are characterized by varying degrees of penetrance, severity of morphological and clinical manifestations. The severity of clinical manifestations depends on the presence and degree of hypertrophy. Mutations associated with high penetrance and poor prognosis are manifested by greater left ventricular hypertrophy and thickness of the interventricular septum. Than characterized by low penetrance and good prognosis. Thus, it has been shown that only individual mutations are associated with poor prognosis and a high rate of sudden death. These include the replacement of Arg403Gln, Arg453Cys, Arg719Trp, Arg719Gln, Arg249Gln in the b-myosin heavy chain gene, InsG791 in the myosin binding protein C and Aspl75Asn gene in the a-tropomyosin gene. For mutations in the gene troponin T is characterized by moderate hypertrophy of the myocardium, but the prognosis is quite unfavorable and the probability of sudden cardiac arrest is high. Other genetic abnormalities, as a rule, are accompanied by a benign course and a favorable prognosis or occupy an intermediate position according to the severity of the manifestations caused by them. It is believed that in 60-70% of families the genes responsible for this disease have not yet been identified.

Pathogenesis of hypertrophic cardiomyopathy

With hypertrophic cardiomyopathy, the genetic inferiority of contractile proteins causes the violation of metabolic and contractile processes in hypertrophied muscle. Morphological changes in the left ventricle determine the state of cardiohemodynamics.

The main pathogenetic factors of hypertrophic cardiomyopathy are as follows:

• decrease in elasticity and contractility of hypertrophied myocardium of the left ventricle with deterioration of its diastolic filling, as a result of which the myocardium work in recalculation per unit mass of the myocardium is significantly reduced;
• discrepancy of coronary blood flow in unchanged vessels of myocardial hypertrophy degree;
• compression of coronary vessels with hypertrophied myocardium;
• violation of the rate of excitation in the ventricles with asynchronous contraction of various parts of the myocardium;
• asynergism of contraction of individual parts of the myocardium with a decrease in the propulsive capacity of the left ventricle.

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