Estimation of vascular stiffness in patients with arterial hypertension and atherosclerosis of the lower limb arteries taking into account hypolipidemic therapy

Introduction

Cardiovascular diseases (CVDs) are among the main causes of death in the world [1]. Significant risk factors for the development of cardiovascular pathology include arterial hypertension (AH) and atherosclerosis.

It is widely known that hypertension and atherosclerotic lesions of vascular walls are often components of comorbid pathology [2]. Hypertension is one of the factors contributing to the development of atherosclerosis, while atherosclerosis contributes to the progression of hypertension [3]. The combination of hypertension and atherosclerosis of various vascular basins leads to more rapid development of such CVDs as coronary heart disease, cerebral circulatory disorders, and ischemia of the lower extremities.

The results of numerous studies indicate the effect of increased blood pressure on lipid metabolism [4, 5]. Therefore, the activation of the renin-angiotensin-aldosterone system occurs with an increase in blood pressure, which leads to an additional acceleration of the processes of atherogenesis due to the stimulating effect on angiotensin type 1 (AT-1) receptors [6–9].

An increase in the level of low-density lipoprotein (LDL) cholesterol is associated with an increase in the content of free radicals, which are important in the development of both hypertension and atherosclerosis [10]. As a rule, endothelial dysfunction associated with impaired nitric oxide synthesis, an increase in endothelin-1 production and vasoconstriction lead to an increase in vascular wall stiffness [11–13].

Recently, special attention has been paid to the assessment of vascular stiffness, which is considered an independent marker of arterial damage as a target organ [14]. In clinical practice, the determination of arterial wall stiffness parameters, especially in comorbid AH patients, allows the timely identification of patients with a high risk of cardiovascular events [15].

As is known, antihypertensive and hypolipidemic therapy has a significant effect on the parameters of arterial rigidity. In this regard, one of the criteria for the effectiveness of therapy in patients with hypertension and atherosclerosis of the arteries of various basins is to achieve the target values of blood pressure and LDL cholesterol. Unfortunately, in real practice, not all patients with hypertension and peripheral atherosclerosis receive lipid-lowering therapy, primarily statins, and in a smaller percentage of cases, the achievement of target values of LDL cholesterol is monitored.

The purpose of the study was to evaluate the parameters of vascular stiffness in patients with AH and atherosclerosis of the arteries of the lower extremities (AALE), taking into account statin therapy.

Materials and methods

The study included 120 patients suffering from hypertension; the average age was 62.1±3.12. The duration of hypertension and the degree of hypertension did not significantly differ in all patients of the study (p>0.05). The exclusion criteria from the study were acute coronary syndrome, transient ischemic attack or acute cerebrovascular accident during the last six months, secondary forms of hypertension, severe cardiac arrhythmias, congenital and acquired heart defects, and decompensation of renal or hepatic insufficiency. The study was conducted in the conditions of the Rostov Regional Clinical Hospital of Rostov-on-Don.

The work was carried out in accordance with the standards of the Helsinki Declaration, approved by the independent ethics Committee of the Federal State Budgetary Educational Institution of Higher Education “Rostov State Medical University” of the Ministry of Health of the Russian Federation, Protocol No. 20/14 dated December 25, 2014. All the people included in the study signed a written informed voluntary consent.

All patients were divided into three main groups depending on the presence and clinical manifestations of AALE. The first group included 46 patients with hypertension and clinically manifested AALE, the average age was 61.7±5.5 years, the second group included 39 patients with hypertension and asymptomatic AALE, the average age was 63.8±8.1 years, and the third group consisted of 35 patients with hypertension without AALE, the average age was 60.8±8 years.

Each group of patients was divided into two subgroups taking into account statin intake: in the 1^st subgroup, patients did not receive hypolipidemic therapy, and in the 2^nd subgroup they received statins, while there were no significant differences in the frequency of statin use between the groups (30%, 48%, and 37% in the 1^st, the 2^nd and the 3^rd groups, respectively, p = 0.22). Patients were assigned to the 2^nd subgroup in the cases when the duration of statin intake at the time of hospitalization was more than one year. The first group of patients received atorvastatin at an average dose of 17.7 ± 4.4 mg, rosuvastatin at a dose of 10 mg, in the second group the average dose of simvastatin was 15±7 mg, atorvastatin — 20±7.7 mg, rosuvastatin — 11.67 ±4 mg, and in the third group atorvastatin was prescribed at an average dose of 21 ± 7.4 mg, rosuvastatin — 6.67±2.9 mg.

The groups of patients did not differ statistically significantly in the degree of hypertension determined by the office measurement of blood pressure (p>0.05). In the first group, in 22% of patients, blood pressure corresponded to the 1^st degree of hypertension, in 39% – the 2^nd and in 39% — the 3^rd degree of hypertension. In the second group, 31% of patients had the 1^st degree of hypertension, 36% had the 2^nd degree, and 33% had the 3^rd degree of hypertension. In patients of the third group, the 1^st and 2^nd degrees of hypertension were established in 34% of cases, and the 3^rd degree of hypertension was established in 32% of patients. When determining the stage of essential hypertension (EH), it was revealed that among the patients of the first group, all the patients had stage III of EH (100%), and among the patients of the 2^nd group, stage III (90%) was established in 90% of cases and stage II of EH – in 10%. The third group consisted of 37% of patients with stage II and 63% with stage III of EH; the differences between the groups were statistically significant (p=0.007). Taking into account the anamnesis data and the results of the studies, 16.2% of the study patients were classified as having high cardiovascular risk, and 83.8% – very high.

All the patients with hypertension received antihypertensive therapy in accordance with clinical recommendations [16], while the frequency of prescribing different classes of drugs did not significantly differ. Despite the ongoing antihypertensive therapy, the target values of blood pressure were not achieved in all patients included in the study.

The severity of atherosclerotic lesions of the arteries of the lower extremities was assessed according to ultrasound triplex scanning. According to the generally accepted Fontaine-Pokrovsky classification [17], based on the clinical manifestations of the disease, almost half (45.9%) of patients with AALE were diagnosed with stage I of pelvic limbs chronic ischemia, which allowed them to be assigned to the second group — with hypertension and asymptomatic AALE. In the first group, stage II was registered in 27.1% of cases, stage III in 15.3% of cases, and stage IV in 11.7% of patients.

Among the patients with hypertension and concomitant AALE, there were significantly more men than women (p<0.001). In the group of patients with hypertension and severe AALE, smokers were more common (61%), which significantly differed from the indicators in the second (31%, p=0.006) and third (26%, p=0.002) groups.

The patients underwent standard laboratory and instrumental methods of research. When performing laboratory tests, lipid profile parameters were evaluated with an assessment of the values of total cholesterol (TCH), LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (TG).

Vascular stiffness parameters were determined during the 24-hour blood pressure monitoring on the BP Lab device (Peter Telegin, Moscow, Nizhny Novgorod) by means of using the Vasotens software. The following indicators were evaluated: reflected wave transit time (RWTT), pulse wave velocity in the aorta (PWVao), arterial stiffness index (ASI), augmentation index (AIx), the maximum rate of increase in blood pressure (dP/dtmax), and ambulatory arterial stiffness index (AASI).

Statistical processing of the results was carried out using Microsoft Office Excel 16 (2015, Microsoft, USA), Statistica 10.0 (StatSoft, USA), and IBM SPSS Statistica 26.0 (IBM, USA). To determine statistically significant differences in quantitative data, a comparative analysis was performed using parametric (Student's t-test, ANOVA method) and nonparametric (Mann-Whitney, Kruskal-Wallis) criteria. It was believed that at p>0.05, there were no statistically significant differences. In the intergroup comparison, a posteriori analysis was carried out with the Bonferroni correction. Statistically significant differences in values were recognized at the level of p<0.017 in the case of comparison of 3 groups. Correlation analysis was performed using Spearman's rank correlation coefficient.

Results

Comparative characteristics of lipid profile values in patients of the studied groups are shown in Figure 1.

The values of THC, LDL cholesterol, and TG did not differ statistically significantly when compared between the groups (p>0.05). The level of HDL cholesterol in patients with hypertension and severe AALE (1±0.3 mmol/l) was significantly lower than in patients of the second (1.19±0.3 mmol/l, p=0.009) and third (1.14±0.26 mmol/l, p=0.04) groups.

The comparative analysis of the intake of different classes of statins and their doses in the studied groups of patients is presented in Figure 2.

The assessment of lipid profile indicators in patients suffering from hypertension and AALE of varying severity is of particular interest, taking into account statin intake.

The comparative characteristics of the lipid profile indicators of the 1^st and 2^nd subgroups of the studied groups are shown in Figure 3.

The analysis of the obtained data indicates statistically significantly higher values of THC (mmol/l) in the 1^st subgroup in comparison with the indicators in the 2nd subgroup in patients of all the groups (p<0.05). The level of LDL cholesterol (mmol/l) was significantly lower in patients of the 2^nd subgroup compared with patients not taking statins, among patients of the second (3.84 mmol/l vs. 2.72 mmol/l, p=0.001) and the third (3.65 mmol/l vs. 2.75 mmol/l, p=0.004) groups. Statistically significant differences in HDL cholesterol values between the subgroups were found in patients with hypertension and severe AALE (0.94 mmol/l vs. 1.09 mmol/l, p=0.031). The significantly lower level of TG (mmol/l) while taking statins was determined in a group of patients with hypertension without peripheral atherosclerosis (1.43 mmol/l vs. 1.13 mmol/l, p =0.041).

Despite the ongoing therapy, the target values of LDL cholesterol for patients with high and very high cardiovascular risk (1.8 mmol/L and 1.4 mmol/L, respectively) were not achieved in all patients of the study, due to the appointment of low doses of statins, lack of control over the achievement of target values, as well as, possibly, low adherence to hypolipidemic therapy.

The comparative characteristics of vascular stiffness parameters in patients of the 1^st and 2^nd subgroups of the first group are presented in Table 1.

Analysis of the data obtained indicates statistically significantly lower values of ASI and Ip in patients of the 2^nd subgroup in comparison with patients not receiving statins (p<0.05). When comparing RWTT (ms) in patients of the 1^st and 2^nd subgroups, a distinct positive trend was revealed to register higher values in patients of the 2^nd subgroup (p=0.06). The revealed changes in PASI, AIx and RWTT indicators may indicate a positive effect of statin therapy on vascular stiffness. There were no statistically significant differences between the subgroups when comparing the values of PWVao, dP/dtmax, and AASI (p>0.05).

The comparative characteristics of vascular stiffness parameters in patients of the 1^st and 2^nd subgroups of the second group are presented in Table 2.

When evaluating the data obtained in patients with hypertension and concomitant asymptomatic AALE, there were no statistically significant differences in vascular stiffness between patients of the 1st and 2nd subgroups (p>0.05). However, after the analysis of the ASI (mmHg) values, a distinct tendency to a lower value of the indicator in patients receiving statins in comparison with patients of the 1^st subgroup (p=0.07) was revealed.

The comparative characteristics of vascular stiffness parameters in patients of the 1^st and 2^nd subgroups of the third group are presented in Table 3.

The presented data indicate that patients with hypertension without AALE who do not receive statins have higher vascular wall stiffness, as evidenced by statistically significantly lower values of RWTT (p=0.044) and higher values of PWVao (p=0.004) in comparison with patients receiving lipid-lowering therapy.

Discussion

Recently, great attention has been paid to the primary prevention of CVDs. In this regard, it is important to assess subclinical lesions of target organs, one of which is the vascular wall. An increase in vascular stiffness is a marker of a high risk of cardiovascular events. The analysis of such parameters of arterial rigidity as RWTT (ms), PWVao (m/s), ASI (mmHg), AIx (%), AASI, and dp/dtmax (mmHg/s) allows evaluating not only the state of the arterial bed but also the effectiveness of the therapy.

In recent years, some domestic and foreign studies have demonstrated the positive effect of statins on endothelial function and arterial stiffness [18–22]. The results of these studies indicate that there is a direct correlation between the degree of decrease in LDL cholesterol levels against the background of a high-intensity statin therapy regimen and the severity of slowing down of atherosclerotic processes in various vascular basins.

In the present study, the analysis of vascular stiffness parameters taking into account statin intake demonstrated that the highest values of ASI and AIx were recorded among patients of the first group with hypertension and clinically manifested AALE who were not taking statins. The results obtained suggest that, despite the lack of achievement of the target levels of LDL cholesterol and the preservation of dyslipidemia, the use of statins contributed to a decrease in vascular wall stiffness, and consequently, a decrease in cardiovascular risk in patients with hypertension and clinically manifested AALE. Discussing the positive effect of statins on the parameters of arterial rigidity in patients of the first group, it is necessary to take into account the pleiotropic effects of statins, which are associated with stabilization of atherosclerotic plaques, reduction of their tendency to rupture, improvement of endothelial function, suppression of inflammatory activity in the vascular wall, reduction of platelet aggregation and proliferative activity of smooth muscle cells in the artery wall [23, 24]. At the same time, there were no significant differences in arterial rigidity in patients with hypertension and asymptomatic AALE while taking statins.

In patients of the third group with hypertension without peripheral atherosclerosis, significantly lower values of PWVao and higher values of RWTT were revealed against the background of taking statins, which, apparently, is due not only to the effect on the stiffness of the vascular wall even in the absence of atherosclerotic lesion but also to their pleiotropic effect of statins.

It should be noted that the revealed differences in only some parameters of vascular stiffness against the background of statin therapy in patients included in the study are due to the appointment of low-intensity therapy with the failure to achieve the target values of LDL cholesterol, as well as, possibly, discrete intake of lipid-lowering drugs.

Thus, the results of the analysis indicate a low percentage of statin prescribing in patients with hypertension and AALE, the use of low doses of statins and the lack of control over the achievement of the target value of LDL cholesterol in real clinical practice. At the same time, against the background of even low-intensity statin therapy, there is a decrease in vascular stiffness, which is important for reducing the risk of cardiovascular events.

Conclusions

The use of statins as part of the complex therapy of patients with hypertension and concomitant AALE of varying severity helps to reduce the stiffness of the vascular wall, which is due to both the positive effect on the parameters of the lipid profile and the pleiotropic effects of statins.