Clinical and Morphological Correlations and Mechanisms of Myocardial Hypertrophy in Obstructive Hypertrophic Cardiomyopathy

The dissertation is devoted to the study of the clinical and morphological features and mechanisms of myocardial hypertrophy in patients with obstructive hypertrophic cardiomyopathy. The study covers children and adults, as well as blood relatives of probands, which allows the age-related and familial components of the disease to be taken into account. On the basis of clinical, echocardiographic, histological, immunohistochemical, and molecular genetic data, correlations have been made between the severity of hypertrophy, the state of cardiomyocytes, stromal cells, and the extracellular matrix, and the features of the clinical course, the risk of heart failure, and sudden cardiac death.

Particular attention is paid to the comparative analysis of obstructive hypertrophic cardiomyopathy and essential hypertension, as well as to the combined course of these diseases. Diagnostic algorithms and criteria for the prognosis of fatal outcomes have been developed on the basis of clinical and morpho-functional indices, which is of importance for risk stratification and for the choice of management strategy for patients.

Relevance of the problem. Cardiovascular diseases remain the focus of researchers in many specialties: cardiac surgeons and cardiologists, pathomorphologists, geneticists, and molecular biologists. This is due to their prevalence and the steady increase in morbidity and mortality. The highest mortality is observed in patients of working age with genetically determined myocardial pathology. According to B. Maron et al. (1995), the prevalence of hypertrophic cardiomyopathy is 2 cases per 1000 population. The mortality of patients with obstructive hypertrophic cardiomyopathy ranges from 3 to 8% per year. Sudden cardiac death occupies a special place in the mortality structure of hypertrophic cardiomyopathy (Paleev N.R. et al., 1992; Kaktursky L.V., 2000; Bockeria L.A. et al., 2001; Davies M., McKenna W., 1995; Wigle E., 2001; McKenna W., Behr E., 2002; Link M., Maron B., 2005). Hypertrophic cardiomyopathy is a frequent cause of sudden death in young patients with marked myocardial hypertrophy, including those with an asymptomatic course of the disease (Maron B., 1987; 2005; Maron B. et al., 1995; McKenna W., Behr E., 2002; Roberts W., Maron B., 2005).

The clinical manifestations and instrumental diagnostic methods of hypertrophic cardiomyopathy had previously been analysed in detail by well-known Russian clinicians N.M. Mukharlyamov (1990), N.R. Paleev et al. (1992), L.A. Bockeria et al. (1997, 2003, 2005), M.S. Kushakovsky (1998), E.P. Amosova (1999), and many others. The identification of genetic defects opened a new era in the understanding of the aetiology of hypertrophic cardiomyopathy but did not become the key to understanding the pathogenesis of the disease (Redwood S., 2006; Braunwald E., Bristow M., 2000; Wigle E., 2001; Poliac L. et al., 2006). To date, there is no answer to the question of why disease onset at a young age is more often accompanied by marked myocardial hypertrophy, a severe course, and a high risk of fatal outcomes, whereas in elderly patients, by contrast, a lesser degree of myocardial hypertrophy and a relatively "benign" course of the disease are observed (Nicol R. et al., 2000; Maron B., 2002; McKenna W., Behr E., 2002). The indices characterising the features of myocardial hypertrophy, primarily the state of cardiomyocytes and stromal cells in children with obstructive hypertrophic cardiomyopathy, that is, at the earliest stages of disease development, have not been sufficiently studied.

The modern understanding of the mechanisms of hypertrophy development was largely formulated in the 1980s and is reflected in the works of Russian and foreign researchers. The main achievements at this stage of scientific development are associated with the emergence of the concept of hypertrophy and intracellular regeneration, as well as with the recognition of the general biological significance of cellular polyploidy and the pathogenetic role of polyploidy in the process of cardiomyocyte hypertrophy. An important contribution to the understanding of this problem has been made by studies of myocardial hypertrophy devoted to the capacity of cardiomyocytes and stromal cells to synthesise proteins (Meerson F.Z., 1968; Brodsky V.Ya., Nechaeva N.V., 1988; Meerson F.Z., Didenko V.V., 1992; Brodsky V. et al., 1993, 1994; Neuburger M. et al., 1998; Hannan R. et al., 2003; Field L., 2004).

Since the early 1990s, the first reports have appeared on a genetically regulated form of cell death—apoptosis of cardiomyocytes in various diseases of the cardiovascular system (Bockeria L.A. et al., 1995; Olivetti G. et al., 1994). Subsequently, apoptosis began to be considered not only as a biological phenomenon but also as a possible therapeutic target (Anversa P., Kajstura J., 1998; Narula N. et al., 1999, 2001, 2005; Bamford M. et al., 2000; Bennett M., 2002; Haider N. et al., 2002; Kajstura J. et al., 2006). The dynamic balance between cell growth and cell death underlies tissue homeostasis, and disruption of this balance underlies many pathological processes. The relevance of studying such characteristics in primary and secondary myocardial hypertrophy is obvious. First and foremost, this concerns the assessment of the state of cardiomyocytes and stromal cells as direct participants in the pathological process, the mechanisms of cardiomyocyte death, and the state of the extracellular matrix.

Thus, advances in genetic research and the emergence of new approaches to studying structural changes of the myocardium at the macroscopic, cellular, and molecular genetic levels emphasise the need for clinical and morphological correlations and for the search for mechanisms underlying myocardial hypertrophy in patients with obstructive hypertrophic cardiomyopathy.

Aim of the study. To establish the features of the pathogenesis of obstructive hypertrophic cardiomyopathy and to develop diagnostic algorithms and prognostic criteria based on molecular genetic characteristics and correlations of the clinical course of the disease with the morpho-functional state of the myocardium.

Objectives of the study

1. To study the features of the clinical course, indices characterising myocardial hypertrophy and the state of intracardiac haemodynamics, the influence of sex and age, and the nature of concomitant pathology in children and adults with obstructive hypertrophic cardiomyopathy, as well as in blood relatives of probands. To develop prognostic criteria for the combination of obstructive hypertrophic cardiomyopathy with essential hypertension.

2. To evaluate the morphostructural changes of the myocardium and the state of cardiomyocytes in children and adults with obstructive hypertrophic cardiomyopathy and to compare them with the features of the clinical course of the disease.

3. To investigate the state of stromal cells and the extracellular matrix in children and adults with obstructive hypertrophic cardiomyopathy and to compare them with the features of the clinical course of the disease, as well as with indices characterising morphostructural changes of the myocardium and the state of cardiomyocytes.

4. To determine the similarities and differences of indices characterising the state of cardiomyocytes, stromal cells, and the extracellular matrix in adult patients with obstructive hypertrophic cardiomyopathy and in patients with essential hypertension. To develop diagnostic algorithms for hypertrophic cardiomyopathy.

Main statements defended

An important determinant of the severity of myocardial hypertrophy, the severity of the course, and the frequency of fatal outcomes in obstructive hypertrophic cardiomyopathy is the age of the patient at the time of clinical manifestation of the disease.

Disease onset in childhood is characterised by marked myocardial hypertrophy. Progression of myocardial hypertrophy in children with obstructive hypertrophic cardiomyopathy is accompanied by acceleration of cardiomyocyte polyploidisation, as well as a more pronounced imbalance in the expression of genes of collagenolysis factors compared with adult patients.

The course of obstructive hypertrophic cardiomyopathy in adults is distinguished by greater severity of ventricular arrhythmias, a higher functional class of heart failure, and more pronounced disturbances of intracardiac haemodynamics compared with paediatric patients. Progression of clinical symptoms of obstructive hypertrophic cardiomyopathy in adult patients is accompanied by an increase in myocardial stromal area.

The mechanisms underlying cardiomyocyte hypertrophy and myocardial stromal hyperplasia in adults with obstructive hypertrophic cardiomyopathy and in patients with essential hypertension share similarities and substantial differences. The similarity is determined by cellular polyploidy and the secondary nature of stromal changes in relation to cardiomyocyte death. The differences consist in increased activation of nucleoli and proliferating cell nuclear antigen in cardiomyocytes and stromal cells, an increase in DNA content in cardiomyocyte nuclei, increased expression of genes of the main structural components of the extracellular matrix, as well as a more pronounced imbalance in the expression of genes of collagenolysis factors in patients with obstructive hypertrophic cardiomyopathy.

Scientific novelty and theoretical significance New data have been obtained on the features of the pathogenesis of obstructive hypertrophic cardiomyopathy in children and adults.

It has been shown that progression of myocardial hypertrophy in children during the prepubertal and pubertal periods coincides with the genetically determined period of natural polyploidisation of cardiomyocytes and is accompanied by increased activation of nucleoli and proliferating cell nuclear antigen, an increase in DNA content, and an increase in the number of high-ploidy cardiomyocyte nuclei. It has been found that in children with obstructive hypertrophic cardiomyopathy, compared with adult patients, there is a more pronounced imbalance in the expression of genes of collagenolysis factors due to decreased expression of the matrix metalloproteinase-1 gene and increased expression of the tissue inhibitor of matrix metalloproteinase-1 gene.

It has been shown that progression of clinical symptoms in adult patients with obstructive hypertrophic cardiomyopathy is accompanied by an increase in myocardial stromal area, including through the development of transmural scars and aneurysms of the left ventricle in some patients in the absence of haemodynamically significant changes in the coronary arteries. It has been found that in adult patients, activation of proliferating cell nuclear antigen in stromal cells is accompanied by progression of fibrosis.

New data have been obtained on the features of the pathogenesis of genetically determined cardiomyocyte hypertrophy compared with cardiomyocyte hypertrophy in patients with essential hypertension. It has been established that the similarity of mechanisms underlying myocardial hypertrophy, regardless of its origin, is determined by cellular polyploidy, as well as by the secondary nature of stromal changes in relation to cardiomyocyte death. It has been found that the substantial differences consist in increased activation of nucleoli and proliferating cell nuclear antigen in cardiomyocytes and stromal cells, and in an increase in the number of high-ploidy cardiomyocytes in patients with obstructive hypertrophic cardiomyopathy. It has been shown that in patients with obstructive hypertrophic cardiomyopathy, compared with patients with essential hypertension, the state of the extracellular matrix is characterised by increased expression of type I and III collagen genes and a more pronounced imbalance in the expression of genes of collagenolysis factors due to increased expression of the tissue inhibitor of matrix metalloproteinase-1 gene.

Practical significance

The practical significance of the work is determined by the development of risk stratification based on the comparison of clinical and morphological characteristics of the disease between deceased and surviving patients with obstructive hypertrophic cardiomyopathy. Risk stratification is a primary task in the examination of patients with obstructive hypertrophic cardiomyopathy and includes the risk of heart failure development, the risk of death from all cardiac causes, and the risk of sudden cardiac death.

An association has been established between a high risk of death from all cardiac causes and the presence of heart failure of a high functional class, as well as an association between the severity of heart failure and disturbances of intracardiac haemodynamics in adults with obstructive hypertrophic cardiomyopathy.

Sudden cardiac death is the leading cause of fatal outcomes in patients with obstructive hypertrophic cardiomyopathy. An association has been found between a family history of sudden death, age under 45 years, an increase in the degree of disturbance of myocardial architectonics, an increase in stromal area in the right half of the interventricular septum, and an increased risk of sudden death. Risk stratification for death is aimed at the timely identification of patients who require minor interventional procedures and surgical methods of treatment in order to prevent a fatal outcome.

A decrease in survival has been established in patients with obstructive hypertrophic cardiomyopathy combined with essential hypertension. Prognostic criteria for fatal outcome have been developed on the basis of discriminant analysis using indices of the clinical course of the disease and the results of echocardiographic examination. The expediency of using these criteria for the prevention of fatal outcomes in patients with obstructive hypertrophic cardiomyopathy combined with essential hypertension has been substantiated.

Implementation

The data obtained on the features of the pathogenesis of myocardial hypertrophy, on cofactors of progression of the pathological process, and on risk stratification in patients with obstructive hypertrophic cardiomyopathy have been implemented in the research, teaching, and clinical processes of the V.A. Almazov Research Institute of Cardiology and the Department of Faculty Therapy named after G.F. Lang of the Academician I.P. Pavlov Saint Petersburg State Medical University. A teaching manual "Primary and Secondary Cardiomyopathies. Morpho-Functional and Clinical-Genetic Parallels" has been published for senior students, clinical residents, and cardiologists (St Petersburg: SPbSMU Publishing House, 2004).

A diagnostic algorithm for obstructive hypertrophic cardiomyopathy has been developed. Patent for invention No. 2206893. Priority dated 20-06-03. The diagnostic algorithms are used in the clinical and diagnostic process of the pathologicoanatomical departments of City Hospital No. 23, the Mariinsky Hospital, and the Clinical Hospital of the Main Directorate of Internal Affairs of St Petersburg and Leningrad Oblast.

Prognostic criteria for fatal outcomes in patients with obstructive hypertrophic cardiomyopathy combined with essential hypertension have been developed and implemented in the practice of family physicians, cardiologists, and internists of City Polyclinic No. 111, and in the clinical process of the cardiology and therapeutic departments of the Mariinsky Hospital.

Approbation of the work

The materials of the dissertation have been published in the proceedings of congresses, conventions, conferences, and scientific sessions and have been presented as oral reports at a meeting of the St Petersburg Society of Cardiologists (2002, 2005); the Russian National Congress of Cardiologists (Moscow, 2001; St Petersburg, 2002); the European Congress on Heart Failure (Strasbourg, 2003); the Third World Congress on Heart Diseases (Washington, 2003); the European Congress of Cardiology (Vienna, 2003); the Third and Fourth International Scientific Conferences "Treatment of Cardiomyopathies" (Moscow, 2005); the European Congress of Cardiology (Lisbon, 2005); and the European Congress on Heart Failure (Stockholm, 2005). A total of 57 scientific works have been published on the topic of the dissertation.

Volume of the dissertation

The dissertation is presented on 380 pages of typewritten text and consists of an introduction, a literature review, a chapter on material and methods, 5 chapters of original research, a discussion of the results obtained, conclusions, practical recommendations, a list of references, and appendices. The bibliography contains 143 Russian and 488 foreign sources. The dissertation is illustrated with 74 figures and 40 tables.