Causes and pathogenesis of hypertrophic cardiomyopathy

Causes of hypertrophic cardiomyopathy

At the present stage of development of our knowledge, sufficient data have been accumulated giving grounds to believe that hypertrophic cardiomyopathy is a hereditary disease transmitted by an autosomal dominant type with varying penetrance and expressivity. Cases of the disease are detected in 54-67% of parents and close relatives of the patient. The rest is the so-called sporadic form, in this case the patient has no relatives suffering from hypertrophic cardiomyopathy or having myocardial hypertrophy. It is believed that most, 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, its cause is more than 200 described mutations of several genes encoding proteins of the myofibrillar apparatus. At present, 10 protein components of the cardiac sarcomere are known, performing contractile, structural or regulatory function, defects of which are detected in hypertrophic cardiomyopathy. Moreover, in each gene, many mutations can be the cause of the disease (polygenic multiallelic disease).

The current level of development of medical genetics, development and introduction into wide clinical practice of high-precision DNA diagnostic methods using PCR determine significant progress in recognition of many pathological processes. The presence of one or another mutation associated with hypertrophic cardiomyopathy is recognized as the "gold standard" of disease diagnostics. At the same time, the described genetic defects are characterized by different 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 interventricular septum thickness. than those characterized by low penetrance and good prognosis. Thus, it was shown that only individual mutations are associated with poor prognosis and high incidence of sudden death. These include Arg403Gln, Arg453Cys, Arg719Trp, Arg719Gln, Arg249Gln substitutions in the b-myosin heavy chain gene, InsG791 in the myosin-binding protein C gene, and Aspl75Asn in the a-tropomyosin gene. Mutations in the troponin T gene are characterized by moderate myocardial hypertrophy, but the prognosis is quite unfavorable and there is a high probability of sudden cardiac arrest. Other genetic abnormalities, as a rule, are accompanied by a benign course and a favorable prognosis or occupy an intermediate position in the severity of the manifestations they cause. It is believed that in 60-70% of families, the genes responsible for this disease have not yet been identified.

Pathogenesis of hypertrophic cardiomyopathy

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

The main pathogenetic factors of hypertrophic cardiomyopathy are:

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

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