Remodeling of the left and right ventricles in arterial hypertension and possibilities of its pharmacological correction (clinical and experimental study)

The dissertation is devoted to a comprehensive study of cardiac remodeling in patients with arterial hypertension, with an emphasis on comparing changes in the left and right ventricles. The work combines clinical observations, pathomorphological studies, and experimental modeling in male Wistar rats. It investigates the prevalence and variants of left ventricular hypertrophy, the state of diastolic function of both ventricles, and the influence of sex, age, reproductive status in women, psychoemotional background, autonomic regulation, and hemodynamic factors on remodeling processes. Special attention is paid to the possibility of reverse development of structural and functional changes of the heart during long-term antihypertensive therapy with drugs of different classes and to assessing the prognostic significance of the detected disorders with respect to the development of heart failure.

Arterial hypertension (AH) remains one of the most widespread diseases and a cause of premature death and disability of patients (Kabalava Zh.D., 2000; Oganov R.G. et al., 2000, 2002; Britov A.N., 2003).

The heart is one of the main target organs in AH. Considerable attention has been paid in recent years to the study of cardiac remodeling in AH, since left ventricular hypertrophy (LVH) has been shown to be an independent risk factor for cardiovascular complications and sudden death (Olbinskaya L.I. et al., 2002; Chazova I.E. et al., 2002; Shlyakhto E.V., 2002; Levy D. et al., 1990; Kannel W., 1991). Cardiac remodeling in AH and the possibility of its reverse development is one of the key issues of modern cardiology (Belenkov Yu.N., 2002; Preobrazhensky D.V. et al., 2004; Verdecchia P. et al., 2003).

AH is associated with a complex pattern of structural changes of the heart and vessels, which are multifaceted and include hypertrophy of the heart muscle, myocardial fibrosis, thickening of the walls of large elastic and muscular arteries, remodeling of small muscular arteries, reduction of the number of vessels in the microcirculatory system, and elongation of small arteries (Shlyakhto E.V. et al., 2004; Heagerty A.M. et al., 1997; Schiffrin E.L. et al., 2000).

In clinical cardiology, the extensive study of cardiac remodeling in AH became possible with the introduction of the echocardiographic method, which made it possible to distinguish three variants of left ventricular (LV) remodeling: concentric hypertrophy, eccentric hypertrophy, and concentric remodeling of the LV. A fourth variant considered is normal LV geometry (Ganau A. et al., 1992; Roszaniec M. et al., 1992; Devereux R.B. et al., 1999).

The concentric type of LVH is believed to be associated with a worse prognosis with respect to cardiovascular complications and mortality.

However, there is no consensus in the literature on the prevalence of LVH and various variants of LV remodeling in patients with AH depending on their sex and age, and on the reproductive status in women (Shinilova T. et al., 2004; Khozyaimova N.Yu. et al., 2005; Hoomon N. et al., 1986; Pines A. et al., 1993; Tingleff J. et al., 1996; Zabalgoitia M. et al., 1997; Schirmer H. et al., 1999). A number of studies have shown that anatomical changes of the LV in AH are not always accompanied by an increase in myocardial mass (Myasnikov A.L., 1965; Konradi A.O. et al., 2005; Korneev V.A. et al., 2006).

To date, there are no answers to the following questions: why do some patients with AH with a sufficiently pronounced pressure load not develop compensatory LV hypertrophy? Can such a variant of remodeling be considered adaptive, and what morphological changes underlie it? Is the cause of the rapid development of heart failure (HF) in these patients an impairment of cardiac relaxation in diastole associated with fibrosis? There is a need for a comparative study of the state of diastolic function of the left and right ventricles of the heart. To determine the diagnostic and prognostic significance of diastolic function disorders of both the left and right ventricles.

Studies on cardiac remodeling in AH mainly concern the investigation of LV changes, and all the obtained data are automatically interpolated to the right ventricle (RV). An analysis of many years of clinical experience allowed A.L. Myasnikov as early as 1965 to conclude that in some patients with AH the signs of right ventricular failure precede the development of left ventricular failure, and in some patients with AH hypertrophy develops not only of the left but also of the right ventricle. However, to date there are few studies on RV changes in AH, since its clinical investigation presents considerable methodological difficulties (Veselova T.E. et al., 2003; Guseva O.V., 2003; Vasyuk Yu.A. et al., 2005; Aristhabai D. et al., 1994). The question of the possibility of predicting the development of heart failure in men and women with different types of cardiac remodeling has not been studied.

Morphological changes in the myocardium in AH are also mainly studied in the LV. A number of experimental studies have shown the leading role of the RV in the regulation of cardiac activity in health and disease (Frolov V.A. et al., 1971; Frolov V.A., Drozdova G.A., 1984, 2003). It is of practical importance to know to what extent the parameters of LV and RV remodeling detected clinically by non-invasive instrumental methods correspond to morphological changes in the myocardium at the tissue, cellular, and subcellular levels? What changes occur during the reverse development of cardiac remodeling? The solution of these questions undoubtedly requires morphological and experimental studies and substantiates the need to study the processes of cardiac remodeling as a whole.

At present, it has been shown that elevated blood pressure is a significant but not the only factor leading to the development of LVH. Numerous clinical and experimental studies have noted the participation of the autonomic and hormonal regulatory systems in the development of cardiac remodeling in AH (Ryazanov A.S. et al., 2000; Belenkov Yu.N., 2003; Oganov R.G. et al., 2003; Shvalev V.N. et al., 1992, 2003; Shlyakhto E.V. et al., 2004; Cruickshank J.M. et al., 1992; Reid J.L., 2000; Braunwald E., 2001). A number of experimental works have shown the effect of noradrenaline administered in doses that do not increase blood pressure on the development of LVH (Laks M.N., 1976; Simpson P., 1983). The role of catecholamines in the development of fibrosis, one of the components in the development of diastolic dysfunction of the heart, is actively discussed (Sarkisov D.S. et al., 1966; Skvortsov A.A., Mareev V.Yu., 2001; Weber K.T. et al., 1991).

Such a significant influence of the sympathoadrenal system (SAS) on cardiac remodeling necessitates a comprehensive study of the features of autonomic regulation in patients with AH. The question remains open regarding the role of autonomic disorders in the formation of a particular variant of left and right ventricular remodeling of the heart and the development of diastolic dysfunction. The significance of these disorders in the features of cardiac remodeling in men and women, and in women with different reproductive status, has not been studied.

The question of changes in autonomic regulation of the circulatory apparatus in patients with AH with different psychoemotional background (subclinical depression and anxiety) and during stress tests (psychoemotional, cold, pharmacological), and the relationship between psychoemotional state and types of cardiac remodeling, remains open.

It is of interest to study changes in the influence of the autonomic nervous system on cardiac remodeling during long-term therapy with prolonged drugs of different classes.

Thus, at present it is relevant to study cardiac remodeling (left and right compartments) in patients with AH depending on sex, and in women also on reproductive status, and on the features of autonomic regulation, to investigate the influence of different variants of cardiac remodeling on the development of heart failure, and to study the question of reversibility of different variants of cardiac remodeling in patients with AH under the influence of pharmacological therapy.

Aim of the study

To investigate the clinical and experimental features of remodeling of the left and right ventricles of the heart in arterial hypertension and the possibilities of its pharmacological correction.

Objectives of the study

1. To study the features of structural and functional remodeling of the left and right ventricles of the heart in male and female patients with AH, and in women with different reproductive status. To investigate the pathomorphology of the right and left ventricles in AH.

2. To assess the features of the influence of left ventricular hypertrophy and diastolic dysfunction of the heart on the development of heart failure in men and women with AH.

3. To investigate variants of cardiac remodeling in patients with AH with different psychoemotional background and with different reactions of autonomic and hemodynamic parameters to stress tests. To identify features of the involvement of hemodynamic and autonomic factors in cardiac remodeling in men and women with AH.

4. To study experimentally the morphological changes in the myocardium of male Wistar rats induced by different doses of catecholamines and to assess the dynamics of reverse development of myocardial remodeling. To perform a clinical and experimental comparison of cardiac remodeling in AH.

5. To study the influence of antihypertensive drugs of different classes on cardiac remodeling, parameters of intracardiac and central hemodynamics, and autonomic regulation.

6. To develop recommendations for the examination and treatment of male and female patients with AH in order to achieve complete reverse development of cardiac remodeling.

Scientific novelty of the study

• For the first time, based on clinical, pathomorphological, and experimental studies, it has been shown that in AH remodeling occurs not only in the left but also in the right ventricle of the heart, and the morphological and functional changes proceed asynchronously. In some patients, impairment of diastolic function of the heart begins with isolated diastolic dysfunction of the right ventricle (RV). It has been revealed that transient disturbances of diastolic function during the cold test are more often observed in the RV than in the left, which confirms the greater sensitivity of the RV to extracardiac influences.

• Significant differences have been revealed in cardiac remodeling and the state of diastolic function in men and women with AH, as well as in women with different reproductive status. In male patients with AH, normal geometry of the left ventricle (LV) predominates, while in female patients with AH, concentric LVH predominates. It has been shown that the development of postmenopause in women leads to an increase in LV myocardial mass, the frequency of LVH development (2-fold), and an increase in the number of patients with the concentric form of LVH.

• For the first time, the possibility of predicting the development of heart failure (HF) in men and women with AH has been shown. It has been demonstrated that the presence of LVH and pronounced diastolic dysfunction significantly increases the risk of HF development in both men and women with AH. It has been shown that an excessively high E/A ratio (>1.5) of the LV has the most unfavorable prognostic significance for the development of heart failure in male patients with AH.

• The significance of hemodynamic and autonomic influences on cardiac remodeling in men and women with AH has been determined. Sex-related features of autonomic regulation make a significant contribution to the formation of the "hypertensive heart." For the first time, a relationship has been revealed between the psychoemotional background in patients with AH, cardiac remodeling, and sex-related features of autonomic regulation of the cardiovascular system at rest and during various functional tests.

• It has been shown that the sympathoadrenal system plays an important role in the development of various forms of cardiac remodeling, and the experiment has demonstrated that the character and degree of changes in the myocardium depend on the dose of catecholamines. For the first time, it has been shown that there is no reversibility of RV remodeling induced by catecholamines, in contrast to the LV, where positive dynamics are observed.

• It has been established that the influence of antihypertensive drugs of different classes on structural and functional changes of the heart differs in male and female patients with AH, as well as in women depending on reproductive status.

• The necessity of developing pathomorphological criteria for the variant of cardiac remodeling in AH without myocardial hypertrophy has been shown.

Practical significance of the study

It has been shown that normal LV geometry in male patients with AH, combined with pronounced diastolic dysfunction of the heart, is one of the most unfavorable variants of cardiac remodeling in terms of HF development, requires careful dynamic follow-up, and substantiates the need to develop pathomorphological criteria for the variant of cardiac remodeling in AH without myocardial hypertrophy. Particular attention should be paid to AH patients with an excessively high transmitral flow index, since it has been shown that this category of patients has the highest probability of developing HF.

The results obtained make it possible to sufficiently clearly individualize the prescription of antihypertensive drugs to patients with AH depending on the variant of cardiac remodeling, features of autonomic regulation, sex of the patients, and in women also on reproductive status.

The results of the study indicate that antihypertensive therapy, in addition to achieving the target blood pressure level, requires monitoring of LV myocardial mass, the state of diastolic function of both the left and right ventricles, and changes in autonomic and hemodynamic parameters during stress tests.

The unfavorable influence of subclinical depression on cardiac remodeling substantiates the necessity of mandatory use in clinical practice of screening methods for assessing the psychoemotional state of patients before the start of treatment and during antihypertensive therapy in order to correct psychoemotional disorders in patients with AH.

The use in practical cardiology of the method of assessing heart rate variability allows studying the baseline autonomic background in male and female patients with AH and predicting the possibility of developing pronounced autonomic imbalance during antihypertensive therapy with metoprolol and amlodipine, which may contribute to the progression of cardiac remodeling.

The expediency of using the cold test to identify the severity and direction of autonomic and hemodynamic stress response, diastolic dysfunction of the left and right ventricles, and the choice of optimal antihypertensive therapy depending on the autonomic profile of patients has been shown.

Practical implementation of the obtained results

The results of the work have been implemented in the educational process of the Department of Internal Diseases and the Department of Postgraduate Education and Outpatient Therapy of the Institute of Medical Education of Yaroslav-the-Wise Novgorod State University, in the work of the cardiology departments of the Novgorod Regional Clinical Hospital, City Clinical Hospital No. 2, the Central City Clinical Hospital of Veliky Novgorod, the Borovichi Central District Hospital of the Novgorod Region, the Ulyanovsk Regional Center for Arterial Hypertension of the Regional Clinical Hospital for War Veterans, and the Regional Cardiology Dispensary of Ulyanovsk. The materials of the work are used in lectures for students of the IV–VI courses of the medical faculty, intern doctors, and clinical residents of the Institute of Medical Education of NovSU.

Statements to be defended

1. Variants of cardiac remodeling in AH depend on the sex of the patients, the state of autonomic regulation, central hemodynamics, psychoemotional background, and in women also on reproductive status.

2. In AH, structural and functional changes occur not only in the left but also in the right ventricles, and these changes may proceed asynchronously, and in 1/4 of cases begin with the right ventricle. Left ventricular hypertrophy and pronounced disorders of left ventricular diastolic function in patients with AH develop independently of each other and increase the risk of heart failure.

3. Disorders of sympathetic regulation play an important role in the development of cardiac remodeling. In an experimental study, dopamine and adrenaline induce pronounced structural changes in both the left and right ventricles, and these changes are more pronounced in the right ventricle. Reversibility of remodeling induced by dopamine and adrenaline in the right ventricle is also less pronounced than in the left ventricle.

4. The influence of antihypertensive drugs of different classes on the reverse development of structural and functional changes of the heart in patients with AH depends on the variant of remodeling (presence of left ventricular hypertrophy, diastolic dysfunction of the heart), features of autonomic regulation, sex of the patients, and in women also on reproductive status.

5. Changes in blood pressure, left ventricular myocardial mass index, and diastolic function of the heart in patients with AH during effective antihypertensive therapy proceed independently of each other. Antihypertensive therapy, in addition to normalization of blood pressure, requires monitoring of left ventricular myocardial mass, the state of diastolic function of both the left and right ventricles, the state of the psychoemotional background, and changes in autonomic and hemodynamic parameters during stress tests.

Publications

The main provisions of the dissertation have been published in 53 works, including 2 monographs and 9 publications in central journals (Higher Attestation Commission of the Russian Federation).

Volume and structure of the dissertation

The dissertation is presented on 225 pages of typewritten text and consists of an introduction, 5 chapters including a review of the literature, material and methods of the study, results of original research and their discussion, a conclusion, findings, practical recommendations, and an appendix.

The dissertation contains 23 tables and 42 figures. The work uses 415 literature sources, of which 213 are domestic and 202 foreign.