Arterial Hypertension in Patients with Postmenopausal Metabolic Syndrome (Clinical and Instrumental Characteristics and Evaluation of Antihypertensive Treatment)

The dissertation is devoted to the study of the clinical features of arterial hypertension in women with postmenopausal metabolic syndrome and to a comparative evaluation of the effectiveness of two antihypertensive drugs with different mechanisms of action on the sympathetic nervous system. The research focuses on the analysis of the relationship between insulin resistance, abdominal obesity, dyslipidemia, and elevated blood pressure under conditions of estrogen deficiency. Particular attention is paid to the comparative influence of the I₁-imidazoline receptor agonist moxonidine and the selective β₁-adrenoblocker metoprolol on blood pressure levels, indicators of insulin resistance, glycemia, hemodynamic parameters during exercise tests, and heart rate variability. The data obtained are intended to substantiate a differentiated approach to the pathogenetic treatment of arterial hypertension in this category of patients.

The growing interest in the problem of metabolic syndrome in women during menopause is due to a large body of factual evidence indicating its substantial influence on the development of atherosclerosis, as well as to the fact that a significant increase in the prevalence of this pathology has recently been observed. It is known that individuals with metabolic syndrome present several risk factors, such as arterial hypertension (AH), insulin resistance, dyslipidemia, and abdominal obesity, which play an important role in atherogenesis.

With the development of menopause, the frequency of arterial hypertension increases substantially in women, and its pathogenesis has a number of specific features. It is known that, prior to the onset of menopause, blood pressure in women is lower than in men in the corresponding age groups [26, 85]. This suggests that female sex hormones exert a protective effect against the development of arterial hypertension. Several years after the onset of menopause and a reduction in blood estrogen levels, a tendency toward a BP increase is recorded that is unresponsive to replacement therapy with female sex hormones [19]. This suggests that hypoestrogenism is an important, but far from the only, factor in the pathogenesis of arterial hypertension in postmenopausal women.

Another factor contributing to the increased incidence of arterial hypertension in women during the menopausal period is weight gain and obesity. Over the past 20 years, an increase in the number of individuals with elevated body weight has been observed in all industrially developed countries. Obesity occurs 55–80% more frequently in women than in men, and the overwhelming majority among them are women in the menopausal period. Weight gain, in turn, is often accompanied by an increase in blood pressure, changes in the blood lipid profile, and the appearance of the insulin resistance syndrome.

Arterial hypertension and tissue resistance to insulin are the most important components of the metabolic syndrome. Insulin resistance contributes to an increase in blood pressure by influencing a number of pathogenetic mechanisms of arterial hypertension. One of them is the elimination of the vasodilatory effect of insulin. Hyperinsulinemia causes an increase in the activity of the sympathetic nervous system and a number of other hypertensive factors; however, in individuals with normal sensitivity to insulin, the hypertensive reaction is absent due to the vasodilatory effect of insulin. Activation of the sympathoadrenal and renin-angiotensin systems caused by hyperinsulinemia, under conditions of insulin resistance, is accompanied by an increase in cardiac output, total peripheral vascular resistance, and, accordingly, an increase in blood pressure.

Endothelial dysfunction probably also plays an important role in the development of arterial hypertension in insulin resistance. Against the background of hyperinsulinemia, the production of vasoconstrictor substances by the endothelium increases, in particular endothelin-1 and thromboxane A2, while the formation of nitric oxide and prostacyclin, which exert vasodilatory effects, decreases. [70, 174]

In addition, during the menopausal period, regardless of the presence of insulin resistance, an increase in the blood level of endothelin-1 is observed. This is explained by the fact that, during menopause, the production of estradiol, which blocks the synthesis of endothelin, decreases. Endothelin is a strong vasoconstrictor and, with a prolonged increase in its blood level, increases sodium reabsorption in the kidneys. In addition, endothelin enhances oxidative stress, which also contributes to an increase in BP. [18]

The combination of AH and insulin resistance in a single patient raises the requirements for pharmacological therapy, the corrective effect of which, with respect to one of the components of the metabolic syndrome, should not be accompanied by an aggravation of other risk factors for cardiovascular complications. The main requirements for the drug of choice for the treatment of AH in women with metabolic syndrome in postmenopause are that it should have a pronounced antihypertensive effect, the ability to improve glucose metabolism, should not worsen tissue insulin resistance, should limit the influence of neurohumoral factors on the cardiovascular system, reduce the activity of the sympathetic nervous system, decrease sodium and water retention, and should not worsen menopausal symptoms.

Among new-generation antihypertensive agents possessing the indicated effects, agonists of I₁-imidazoline receptors are of great interest. As demonstrated in a placebo-controlled study conducted by De Luca N. et al. (2000), treatment with the I₁-imidazoline receptor agonist moxonidine for 8 weeks produced a significant improvement in the sensitivity of peripheral tissues to insulin. The central mechanism of action of the drugs of the group under consideration is determined by agonism with respect to I₁-imidazoline receptors of neurons located in the ventrolateral nuclei of the medulla oblongata. Thereby, agonists of I₁-imidazoline receptors produce inhibitory effects on the hyperactivity of the sympathoadrenal system, leading to a decrease in blood pressure (BP) and a reduction in heart rate (HR).

The selective β₁-adrenoblocker metoprolol also exerts a pronounced hypotensive effect by reducing the activity of the sympathetic nervous system through blockade of neurohumoral influences, but it is distinguished by a peripheral mechanism of action. In addition, despite its sympatholytic effect, according to some researchers, metoprolol may not improve, and may even aggravate, the state of tissue resistance to insulin [75, 8].

A comparative study of drugs characterized by effects on different links in the regulation of sympathetic activity will ultimately allow a more differentiated approach to the organization of pathogenetic therapy for arterial hypertension in postmenopausal metabolic syndrome.

Aim of the study: To identify the clinical features of arterial hypertension in patients with postmenopausal metabolic syndrome and to comparatively assess the antihypertensive effectiveness of the I₁-imidazoline receptor agonist moxonidine and the β-adrenoblocker metoprolol.

OBJECTIVES OF THE STUDY

1. To study the clinical features of arterial hypertension in postmenopausal metabolic syndrome.

2. To determine the dynamics of glycemia levels during therapy with moxonidine and metoprolol in this category of patients.

3. To study the nature of the influence of these drugs on the level of insulin in blood plasma.

4. To evaluate the antihypertensive effect of the I₁-imidazoline receptor agonist moxonidine and the β-adrenoblocker metoprolol according to casual BP measurements, ambulatory BP monitoring, and dynamics under exercise tests in postmenopausal women with manifestations of metabolic syndrome.

5. To determine the influence of moxonidine and metoprolol on heart rate variability indicators in postmenopausal women with AH.

SCIENTIFIC NOVELTY

The conducted study made it possible to distinguish the clinical features of arterial hypertension in patients with postmenopausal metabolic syndrome: an increase in pulse pressure (PP) indicators, BP variability over 24 hours, an insufficient decrease in BP at night, and a hypertensive type of reaction under dynamic physical load.

The work presents a comprehensive evaluation of the influence of the I₁-imidazoline receptor agonist moxonidine and the β-adrenoblocker metoprolol on the state of insulin resistance, the level of blood pressure, and indicators of sympathovagal balance in patients with postmenopausal metabolic syndrome, which corresponds to the aims and objectives of this study.

For the first time, the features of the influence of I₁-imidazoline receptor agonists and β-adrenoblockers on the 24-hour BP profile, heart rate variability, and hemodynamic parameters under dynamic and static physical load tests have been demonstrated in this category of patients.

PRACTICAL SIGNIFICANCE OF THE WORK

The use of moxonidine as monotherapy for arterial hypertension in postmenopausal metabolic syndrome is justified by its high antihypertensive effectiveness and corrective influence on insulin resistance, as well as by its good safety profile and low frequency of adverse effects. At the same time, the β-adrenoblocker metoprolol possesses a more pronounced sympatholytic effect, which is especially important in the treatment of AH in this category of patients. Its use allows more effective control of BP levels during the nighttime period and of stress-induced hypertensive reactions.

The influence of the studied drugs on key links of the pathogenesis allows them to be considered as pathogenetic treatment for this pathology.

STATEMENTS PRESENTED FOR DEFENSE

1. Taking into account the key significance of insulin resistance in the pathogenesis of the metabolic syndrome, for the treatment of AH in patients with this pathology, the pathogenetically justified use is that of a drug of the I₁-imidazoline receptor group — moxonidine — which has demonstrated high antihypertensive effectiveness comparable to that of metoprolol and a positive influence on indicators of insulin resistance.

2. Despite the advantages of the I₁-imidazoline receptor agonist over the β-adrenoblocker with regard to the influence on tissue sensitivity to insulin, the data of ambulatory BP monitoring, VEM (bicycle ergometry) testing, as well as the results of the study of heart rate variability, indicate a higher hypotensive effectiveness of metoprolol during the nighttime period, as well as a more pronounced influence of metoprolol on sympathetic activity in women with postmenopausal metabolic syndrome.

APPROBATION OF THE STUDY RESULTS

The results of this study were reported at the XI Russian National Congress "Man and Drug," the All-Russian Scientific and Practical Conference of Young Scientists "Current Problems of Cardiology," and the Russian National Congress of Cardiologists in 2005.

The materials of the study have been implemented in the program of lectures and practical classes at the Department of Cardiology of the Faculty of Advanced Training of Physicians of the Russian State Medical University.