Interrelationship and Mechanisms of the Formation of the Syndrome of Arterial Hypertension, Endothelial Dysfunction, and Psychoemotional Disorders in Women during Pregnancy

The dissertation is devoted to the study of the interrelationship and mechanisms of formation of the syndrome of arterial hypertension, endothelial dysfunction, and psychoemotional disorders in women during pregnancy. The work summarises data on the prevalence, classification, and diagnosis of arterial hypertension in pregnant women, examines current concepts of the role of endothelial dysfunction and disorders of nitric oxide metabolism in the pathogenesis of gestosis, as well as the psychophysiological characteristics of pregnant women.

The empirical part includes a comparative analysis of the indicators of twenty-four-hour ambulatory blood pressure monitoring, an assessment of endothelium-dependent vasodilation and the content of stable nitric oxide metabolites in blood plasma, as well as psychosocial testing in pregnant women with different forms of gestosis and with the physiological course of pregnancy. Correlations between the parameters of the twenty-four-hour blood pressure profile, markers of endothelial dysfunction, and psychoemotional indicators have been established; additional clinical criteria that can be used for the early diagnosis and assessment of the severity of gestosis have been identified.

Arterial hypertension (AH), according to the definition of the experts of the All-Russian Scientific Society for the Study of Arterial Hypertension, is the greatest non-infectious pandemic in the history of mankind, determining the structure of cardiovascular morbidity and mortality [20].

The beginning of the era of evidence-based medicine was marked by the development of clear approaches to the diagnosis and treatment of cardiovascular diseases (CVD). The majority of the first multicentre controlled studies in cardiology were conducted in the male population, taking into account the relatively earlier morbidity and mortality of this category of the population [51, 87, 135]. The underestimation of CVD risk in women has been replaced in recent decades by a rapid growth of interest in the problems of women's health [51, 87, 214]. At present, the close interrelationship between the functioning of the cardiovascular and reproductive systems in women is beyond doubt [87].

Women of reproductive age are characterised by a lower level of systolic and diastolic blood pressure (BP) compared with men [87]. Before the onset of menopause, AH in the female population occurs much less frequently than in men, which is explained by the multidirectional effects of testosterone and oestrogens on the tone of vascular smooth muscle [87].

A special stage in women of reproductive age is pregnancy, which is characterised by significant hormonal and haemodynamic changes [113]. One of the most frequent complications of pregnancy is gestosis — disorders of renal and cardiovascular function, leading to a sharp rise in BP and the development of the oedema syndrome [97].

According to current understanding, gestosis is regarded as an "adaptation disease" with all the stages inherent in the general adaptation syndrome [105, 117, 129, 144].

At present, many controversial issues remain in the pathogenesis of gestosis. However, increasing importance is attached to the vascular endothelium as a factor capable of unifying the principal mechanisms that maintain homeostasis at the microcirculation level [36, 107, 134, 192, 212, 225]. Moreover, the endothelium, being a unique monolayer of cells, is present in the principal target organs (liver, kidneys, central nervous system, uterus, placenta), changes in which in gestosis predetermine the outcome for the mother and the foetus [73, 107, 108, 153].

Among the numerous factors of endothelial origin, an unequivocal marker of endothelial dysfunction (ED) is nitric oxide (NO), which is capable of influencing vascular tone [11, 25, 84, 122]. Studies conducted in this direction in gestosis are quite few in number and highly contradictory [40, 118, 164, 192]. Furthermore, the most informative methods for diagnosing ED have not yet been determined.

AH belongs to the classical psychosomatic diseases. Psychological factors constitute one of the components of the complex set of pathogenetic mechanisms responsible for the development of AH. At the same time, the problem of psychosomatic interrelationships, in particular during pregnancy, is far from being resolved. There is an opinion that there is a mutual conditioning of psychophysiological and haemodynamic disorders in pregnant women [45, 75, 116].

Given the high frequency of gestosis in pregnant women with essential hypertension, as well as the commonality between these types of pathology of such a pathogenic link as ED, the study of psychovegetative disorders in parallel with clinical manifestations in patients with AH during pregnancy may make it possible to predict and, consequently, prevent the development of gestosis [115].

Thus, pregnancy may be called an indicator of cardiovascular risk in women in the older age group. Given that in young age the main problem in the prevention of CVD is the difficulty of assessing individual prognosis, data from the obstetric–gynaecological history may help to initiate preventive measures at an early stage [87]. The foregoing determines the need for further in-depth study of the mechanisms of formation and clarification of the possibilities of early diagnosis of arterial hypertension in pregnant women.

Aim of the study: to assess the role of endothelial dysfunction and psychoemotional disorders in the development of the syndrome of arterial hypertension in women during pregnancy.

Objectives of the study:

1. To carry out a comparative analysis of the indicators of twenty-four-hour ambulatory blood pressure monitoring in pregnant women with different forms of gestosis and with the physiological course of pregnancy.

2. To characterise the changes of disorders in the system of nitric oxide metabolism and endothelium-dependent vasodilation in women with gestosis and with the physiological course of pregnancy.

3. To compare the severity of psychoemotional disorders in women with gestosis and with the physiological course of pregnancy.

4. To ascertain the interrelationship of endothelial dysfunction, the severity of manifestations of arterial hypertension, and psychoemotional disorders in women with gestosis and with the physiological course of pregnancy.

The scientific novelty of the study lies in the fact that, for the first time, the interrelationship between disorders in the NO metabolism system and endothelium-dependent vasodilation (EDVD) in the formation of the AH syndrome and psychoemotional dysfunction in women with gestosis and with the physiological course of pregnancy has been assessed.

It has been shown that all patients with gestosis, compared with practically healthy women during pregnancy, are characterised both by an increase in the mean twenty-four-hour blood pressure values and by the formation of pathological daily BP rhythms of the non-dipper, night-peaker, and over-dipper types.

It has been demonstrated for the first time that, in pregnant women, changes in NO metabolism indicators (plasma levels of stable metabolites) and EDVD are not identical. The physiological course of pregnancy is associated with an increase in the levels of stable NO metabolites and EDVD indicators; the formation of gestosis is associated with a linear decrease in EDVD and a U-shaped dynamic of changes in the level of stable NO metabolites as gestosis advances. This fact indicates the contribution of different NO synthase isoforms to the content of stable NO metabolites in blood plasma.

It has been shown that all women with gestosis are characterised by disturbances of psychoemotional indicators. The presence of correlations between psychoemotional indicators, ED, and the parameters of twenty-four-hour ambulatory blood pressure monitoring (ABPM) makes it possible to regard endothelial dysfunction as one of the main pathogenetic mechanisms of the formation of gestosis in women during pregnancy.

The practical significance of the study lies in the fact that it demonstrates the clinical value of ABPM in pregnant women with all manifestations of gestosis.

Thus, even with normal office and mean twenty-four-hour BP values, in patients with oedema of pregnant women pathological twenty-four-hour BP indices have been revealed, as well as higher values of mean daytime systolic BP (SBP), diastolic BP (DBP), night-time SBP hypertension time index, night-time SBP and DBP hypertension area index, twenty-four-hour DBP hypertension area index, morning BP surge rate, and DBP variability, compared with practically healthy pregnant women.

The use of two methods for assessing ED in the present study made it possible to reveal their different clinical significance. Thus, a decrease in EDVD may serve as a criterion of gestosis severity, while the progression of gestosis is associated both with a decrease and an increase in the plasma levels of stable NO metabolites.

The detection of a high level of reactive and personal anxiety according to the Spielberger–Khanin test, anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), as well as high values of the scales of the Abbreviated Multifactor Personality Questionnaire (SMOOL), may serve as additional criteria for the presence of gestosis.

A particularly high-risk group according to ABPM data, detection of disorders in the nitric oxide metabolism system and EDVD, are women under 25 years of age with gestational hypertension, which indicates the imperfection of their adaptation processes.

Statements submitted for defence:

1. In all pregnant women, changes in the indicators of twenty-four-hour ambulatory blood pressure monitoring have been revealed. The least favourable twenty-four-hour blood pressure profile is observed in pregnant women with gestational hypertension.

2. The presence of gestosis is associated with endothelial dysfunction. The indicators of the content of stable nitric oxide metabolites and endothelium-dependent vasodilation change in this case unequally. An increase in gestosis severity is accompanied by a U-shaped change in the content of nitric oxide metabolites and a linear decrease in the indicators of endothelium-dependent vasodilation, assessed by ultrasound Doppler.

3. Women with gestosis are characterised by a high frequency of detection of personal and reactive anxiety, anxiety and depression, and changes in the SMOOL profile. Psychoemotional disorders in gestosis are interrelated with the indicators of endothelial dysfunction.

Approbation of the dissertation materials. The results of the work were reported and discussed at the interregional scientific and practical conference "Topical Issues of Clinical and Experimental Medicine, Medical Science and Education", dedicated to the 50th anniversary of the Kemerovo State Medical Academy (Kemerovo, 17 November 2005), the conference "Arterial Hypertension: Organ Lesions and Concomitant Pathology. Current State of the Problem" (Tomsk, 19–20 April 2006), the regional scientific and practical conference of young scientists and students with international participation "Problems of Medicine and Biology" (Kemerovo, 25–26 April 2006), the regional scientific and practical conference "Actual Problems of Cardiovascular Pathology" (Kemerovo, 24–25 September 2006), and at a joint meeting of the Departments of Faculty Therapy, Cardiology and Cardiovascular Surgery, Obstetrics and Gynaecology No. 1 and No. 2 of the Kemerovo State Medical Academy, the Therapeutic Clinic, and the maternity ward of the Regional Clinical Hospital of Kemerovo (Kemerovo, 9 June 2006).