The pathogenic pathways of cardiovascular disease in perimenopausal women

Introduction

The problem of arterial hypertension is still of great significance. The human search for universal interventions to achieve longevity lies in the field of translational medicine. The fetal programming hypothesis explains the origin of metabolic syndrome, atherosclerosis, and cardiovascular disease [1]. No evident markers of disturbed vascular structure in women before the onset of menopause were found [2]. Thus, the decreased level of estrogens could be a trigger for endothelial malfunction and vasoconstriction.

The use of hormonal replacement therapy (HRT) is well known [3]. But some negative estrogen- or progesterone-dependent effects on women’s health were detected [4–6]. The increased level of coronary heart disease or brain stroke found in some studies stimulates investigations in the field [7]. Thus, the additional prescription of medicines for endothelial protection could be a prospect for women in their perimenopausal years.

Metabolic disorders of the transitional age are associated with obesity. Physical activity, a diet, and some pharmacological interventions could be appropriate options for the aging female population. The use of diet and L-arginine solutions were found to improve metabolic variables in obese patients [8–10]. Any diet could induce the feeling of hunger and psychological discomfort. The application of xylitol solutions is known to reduce this suffering and provide optimal carbohydrate metabolism [11]. The addition to HRT use of diet, L-arginine, and xylitol solutions could be a possible therapeutic strategy for life extension. This speculation was preliminarily tested in a 1-month program [12]. This research was designed to provide physicians with an efficient method to protect cardiovascular health and menopausal disorders in middle-aged women.

The study aimed to compare the effect of HRT and its combination with diet, L-arginine, and xylitol solutions on metabolic processes and cardiovascular health in perimenopausal women.

Material and methods

In total 106 women were enrolled in the prospective cross-sectional study. The reporting of the study was done according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [13]. The study protocol was approved by the Bioethics Committee of the Kharkiv Medical Academy of Postgraduate Education. Perimenopausal women who had visited the outpatient department each year for a preventive check were recruited to the study. The eligible participants were informed about the methodology of the study, its aims, objectives, indications, and possible complications before inclusion in the study. All patients who met the inclusion criteria gave written informed consent to participate in the investigation. They have not received any drugs including antihypertensives. The exclusion criteria were preexisting medical disorders such as diabetes mellitus type I, diabetes mellitus type II, thyrotoxicosis, rheumatic disease, malignancy, etc. The study was carried out among patients of the outpatient department of Kharkiv Municipal Perinatal Center between 1 June 2021 and 31 August 2021.

The 71 perimenopausal aged women were divided into two groups. The 36 patients of Group II received HRT. Sequential or continuous combined HRT was prescribed in patients with or without periods [5]. 35 women who had been prescribed additionally to HRT a diet, L-arginine infusions 200.0 ml once daily for a week, and 20 ml of oral L-arginine solution for 3 weeks, and also xylitol solution 200.0 ml once daily during the first 5 days of treatment were included in Group III. A low-carbohydrate and mild-fat diet (less than 26% carbohydrates or less than 130 gm/day) was used in the study [14–17]. The distribution of the nutrients was 20% of carbohydrates, 40% fat, and 40% protein. This diet featured a low glycemic index, slow ketogenesis, and anti-atherogenic effects [18]. The choice of such dosage and method of administration was made due to the bioavailability and fast therapeutic effect of L-arginine and xylitol [19, 20]. 35 healthy reproductive-aged women were included in Group I (control). They did not receive any diet or medications.

The variables body mass index (BMI), heart rate (HR), blood pressure (BP), and menopausal Cooperman’s score were determined before and after the 3-month program. Biochemical studies were performed in the Sinevo laboratory on a Cobas 6000 analyzer (Roche Diagnostics, Switzerland) before and after the 3-month interval. All the study population was tested for serum triglycerides (TG), total cholesterol (CHC), high-density lipoprotein cholesterol (HDL cholesterol), low-density lipoprotein cholesterol (LDL cholesterol), and very-low-density cholesterol (VLDL cholesterol). The concentrations of TG and CHC were studied by the colorimetric enzymatic method and HDL cholesterol was investigated by the colorimetric enzymatic method with pre-precipitation of LDL cholesterol and chylomicrons. The atherogenic index, which reflects the ratio of atherogenic (CHD and LDL cholesterol) and antiatherogenic (HDL cholesterol) fractions of cholesterol, was also calculated. The levels of glycemia and insulin on an empty stomach were detected with subsequent calculation of the HOMA index. C-reactive protein (C-RP) as a marker of chronic inflammation was investigated.

Statistical analysis was performed with the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) program. The results thus obtained were analyzed with Student’s t-test to compare data between groups. The significance was set at p-value < 0.05. For the statistical analysis of the relationship between X and Y, the correlation coefficients were estimated with Spearman’s test.

Results

The obtained results showed the homogeneity of average age, BMI, HR, BP, and Cooperman’s score in Group II and Group III before inclusion in the study (Table 1). But several variables changed significantly after a 3-month period. The BMI values did not show statistically significant differences except in Group I and Group III after 3 months of observation. The hemodynamic variables did not change significantly in Group II and Group III. But Cooperman’s score changed in Group III and showed similarity with Group I. Thus, the study showed the effect of the 3-month program on BMI and Cooperman’s score.

The results of the study revealed atherogenicity in Group II and Group III before the start of the program (Table 2). Increased levels of TG, TCH, LDL, VLDL, and decreased concentration of HDL were detected in perimenopausal women before inclusion in the study. Therefore, AI was elevated in Group II and Group III. The changes in the levels of TG, TCH, LDL, VLDL, HDL, and AI contributed to the restoration of the lipid profiles in Group III. These variables were not significantly different between Group I and Group III. Thus, the use of diet, xylitol, and L-arginine solutions could be an effective intervention contributing to vascular health in average-aged women.

Changes in carbohydrate metabolism in perimenopausal women were found (Table 3). The variables of glucose level and HOMA index did not show any statistically significant differences between all study groups. The insulin level was found to increase in Group II and Group III. But this parameter was similar in Group I and Group III without any statistically significant differences after 3 months. The level of CRP was elevated at inclusion in the study. But later on, this parameter was not different between Group I and Group III. Thus, the patients of perimenopausal age featured elevated levels of insulin and CRP. The restoration of these variables’ concentration occurred during the 3-month program.

The investigation of a possible relationship between BMI and other variables revealed certain regularities. The results of Spearman’s correlation indicated that there was a significant medium positive relationship between BMI and diastolic BP (r = 0.308, p = 0.018). A significant medium positive relationship between BMI and Cooperman’s score was found in Spearman’s test (r = 0.362, p = 0.022). The results of Spearman’s test showed that there was a significant medium positive relationship between BMI and glucose level (r = 0.451, p = 0.003). A significant large positive relationship in Spearmen’s test between BMI and CRP (r = 0.507, p = 0.001) was detected. Thus, the variable BMI was related to the regulation of hemodynamics, menopausal disorders, carbohydrate metabolism, and chronic inflammation. Spearman’s test showed a medium positive relationship between HOMA index and LDL cholesterol levels (r = 0.323, p = 030). Therefore, insulin resistance could be involved in atherogenesis. The found correlations showed a triggering role of obesity in metabolic disorders.

Discussion

This study showed additional opportunities in the prevention of metabolic disorders in perimenopausal women. The relationship found between BMI and diastolic BP supported the pathogenic role of metabolic disorders in chronic hypertension [21]. Systemic atherogenic vasculopathy could be related to insulin resistance and chronic inflammation [22]. The proposed method for the support of vascular health showed its efficiency in the restoration of lipid and carbohydrate metabolism. The observed decrease in C-RP level demonstrated a possible modulating influence of L-arginine [23]. The very sound finding was the fact of Cooperman’s score reduction in the process of diet, and the use of xylitol and L-arginine solutions. These interventions could enhance the effect of HRT.

Physical training is a popular intervention in anti- aging programs. A previous study revealed the role of additional physical activity in the reduction of insulin resistance in women with climacteric syndrome [24]. The diet is also known as a possible way to prevent metabolic disorders. The use of daily intake of vegetables was investigated in a study [25]. A diet including 400 g per day of vegetables contributed to a better lipid profile and provided a sufficient intake of energy. Weight loss is associated with the restoration of metabolites that are increased in obese and insulin-resistant women. The level of xylitol could be of use in the prediction of the response to diet. Lower baseline levels of xylitol were predictive of a greater decrease in BMI [26]. Deficiency of L-arginine was a marker of endothelial dysfunction during different stages of menopause [27]. The application of L-arginine solutions additionally to aerobic exercises in postmenopausal women decreased BP [8].

Since the effect of HRT on BP is multifactorial, the use of estrogens is not definitely understood [28]. Lower autonomic tone and increased arterial stiffness were found in postmenopausal women compared to male persons of a similar age [29]. The effects of estrogens depend on the peroxidation and endothelial function [30]. Thus, our findings emphasize the possible options for the prevention of atherogenicity. We found that the proposed 3-month program was a novel and efficient method for the protection of cardiovascular health in women. Weight gain was the main factor for insulin resistance, atherogenicity, and menopausal disorders. The use of diet, xylitol, and L-arginine improved metabolic processes and reduced menopausal disorders [12].

Conclusions

Body mass index in perimenopausal women was associated with BP, menopausal Cooperman’s score, carbohydrate metabolism, and inflammatory response. The use of a 3-month program including diet, xylitol, and L-arginine solutions contributed to the reduction of Cooperman’s score, chronic inflammation, and restoration of lipid and carbohydrate metabolism. We did not find any effect on hemodynamics.