Influence of the statin therapy on cardiovascular remodeling in arterial hypertension, combined with subclinical hypothyroidism

There is a proven relation between hypothyroidism and appearance of the pronounced structural and functional changes of the heart and blood vessels as well as atherosclerosis and its related diseases progress. At the same time, there is a lack of information regarding the influence of statins on indices of the structure and function of the heart and blood vessels in patients with arterial hypertension (AH) combined with subclinical hypothyroidism (SH).

Arterial hypertension (AH) is one of the most common chronic diseases. Its combination with other basic cardiovascular risk factors (age, high pulse pressure in elderly, smoking, dyslipidemia, increased levels of fasting glucose and impaired glucose tolerance, abdominal obesity and cardiovascular diseases in family anamnesis) significantly increases risks of fatal and non-fatal cardiovascular events [1]. Among additional unfavorable factors, hypothyroidism syndrome with its subclinical forms in particular deserves special attention. Subclinical hypothyroidism (SH) is the most common condition in thyroid pathology, which in the vast majority of cases is associated with autoimmune thyroiditis [2][3][4][5][6][7]. There is a proven connection between the manifest hypothyroidism and appearance of the pronounced changes in the structure and function of the heart, as well as with the progression of atherosclerosis and diseases related to it [8]. With the development of modern diagnostic methods, more and more data are Доказана связь гипотиреоза с появлением выраженных структурно-функциональных изменений сердца и сосудов, прогрессированием атеросклероза и связанных с ним болезней. В то же время, недостаточно информации о влиянии статинов на показатели структуры и функции сердца и сосудов у больных гипертонической болезнью (ГБ), сочетанной с субклиническим гипотиреозом (СГ).
Positive effect of the replacement therapy in various forms of the hypothyroidism has been proved, subclinical in particular. At the same time, there is a lack of information regarding the influence of statins on the indices of the structure and function of the heart and blood vessels due to their pleiotropic effects in patients with arterial hypertension combined with SH. The widespread use of statins in patients with arterial hypertension and various comorbid conditions dictates the necessity of the study of their effects in patients with AH combined with SH, and the study direction is, certainly, an issue of the current interest in modern internal medicine.

Aim
To study the effect of a long-term statin therapy on the cardiac structure and function, as well as on vascular remodeling in patients with arterial hypertension combined with subclinical hypothyroidism.

Material and methods
The studies were conducted at the clinical base of the Department of Propedeutics of Internal Medicine, Radiation Diagnostics and Radiation Therapy of ZSMU in the cardiology department of the CNI "City Hospital No. 6" of the Zaporizhzhia City Council.
After signing an informed consent, 31 patients (mean age 58 ± 10 years, 90 % women) with AH grade 1-3, stage II, of high and very high additional cardiovascular risks with the concomitant subclinical hypothyroidism were enrolled in the study. The diagnosis of AH was established in accordance with the recommendations of the Association of Cardiologists of Ukraine [1], and the diagnosis of subclinical hypothyroidism in accordance with the recommendations of the European Thyroid Association [33].
All patients received a combination of two or three first-line antihypertensive drugs at average therapeutic daily doses, and atorvastatin at a dose of 20-30 mg per day. Prior to treatment and after more than a year of follow-up, all patients underwent an echocardiographic examination and a carotid artery scan using My Lab Seven (Italy) device to study changes in the structural, geometric, and functional parameters of the heart and blood vessels. 24h-monitoring of blood pressure was performed before the initiation of therapy as well as a year later on a bifunctional device "Cardiotechnics-04" ("Incart", St. Petersburg, RF) with the simultaneous registration of blood pressure and ECG.
Statistical processing of the material was carried out using the software package Statistica 13.0 (StatSoft, USA), license number JPZ8041382130ARCN10-J. The normality of distribution of the quantitative signs was analyzed using the Shapiro-Wilk test. Parameters that had normal distribution are presented in the form of arithmetic mean and standard deviation (M ± SD).
For the indices that had a distribution that was different from normal, descriptive statistics data were provided in the form of median and lower and upper quartile -Me (Q25; Q75). Comparisons of the quantitative indices across the groups were carried out using the Student's and Mann-Whitney criteria, depending on the character of distribution. Qualitative indices were compared using Pearson's χ 2 . A difference of P < 0.05 was considered statistically significant. All tests were two-sided. However, under the influence of therapy, there was no significant change in the size of the cavities of the left atrium and both ventricles. The size of the left atrium before the treatment was 4.13 ± 0.48 cm, after 4.30 ± 0.78 cm (P = 0.617). The end-diastolic size of the left ventricle before treatment was 5.10 ± 0.60 cm, after a year of therapy 5.04 ± 0.57 cm, (P = 0.751). The end-systolic size of the left ventricle before treatment was 3.11 ± 0.38 cm, and after 3.06 ± 0.45 cm (P = 0.720). The diastolic size of the right ventricle before the treatment was 1.85 ± 0.60 cm, after a year of follow-up 2.01 ± 0.47 cm, the changes were statistically insignificant (P = 0.281).

Results
The absence of changes in the end diastolic and systolic sizes of the left ventricular cavity, as expected, didn't lead to statistically significant (P = 0.262) changes in its ejection fraction at the end of the annual follow-up period (before treatment 68.84 ± 5.43 %, after 67.13 ± 5.45 %).
No significant changes in thicknesses of the interventricular septum and the posterior wall of the left ventricle were observed. Before the beginning of treatment IVSd was 1.00 ± 0.19 cm, after it became 1.04 ± 0.20 cm, the difference is insignificant (P = 0.460). LVPWd before the treatment was 1.04 ± 0.19 cm, after 1.02 ± 0.70 cm, the difference is also insignificant (P = 0.632).
Due to the absence of the significant changes in the sizes of the left ventricular cavity and its walls, there were no significant changes in the relative thickness of the wall (before treatment 0.41 ± 0.07, after 0.41 ± 0.07, P = 0.871), as well as in the left ventricular mass index (before treatment 122.29 ± 37.36 g/m 2 , after 118.00 ± 31.00 g/m 2 , P = 0.849).

Analysis of the left ventricular diastolic function
indices revealed no significant effect of the antihypertensive therapy with statin supplementation in patients with AH and a concomitant subclinical hypo thyroidism on the end-diastolic pressure level; (E/e' before treatment 7.98 ± 2.7, after treatment 8.04 ± 2.46; P = 0.871), on the ratio of the early left ventricular filling velocity to the velocity of atrial systole (E/A before treatment 0.86 ± 0.32, after treatment 0.81 ± 0.28; P = 0.545), on the mean pulmonary artery pressure (before treatment 16.29 ± 5.08 mm Hg, after treatment 15.81 ± 4.98 mm Hg, P = 0.686).
The study of left ventricular diastolic filling types in dynamics revealed a tendency towards a decrease in the specific gravity of patients with "normal" type of filling of the left ventricle from 10 % (n = 3) to 6 % (n = 2) (P = 0.5638), with "pseudonormal" filling from 19 % (n = 6) to 16 % (n = 5) (P = 0.7570), and to an increase of the percentage of patients with the left ventricular filling type "impaired relaxation" from 71 % (n = 22) to 77 % (n = 24), (P = 0.5922). No patients with a restrictive left ventricular filling type were registered.
The influence of the statin therapy on vascular remodeling in patients of this group was characterized by a tendency towards a decrease in thickness of the intima-media complex of the right (0.769 ± 0.276 mm vs. 0.701 ± 0.222 mm, p = 0.512) and left (0.759 ± 0.185 mm vs. 0.745 ± 0.179 mm, P = 0.978) common carotid arteries.

Discussion
Data of literature sources and the results of our own studies regarding the dependence of indices of the heart structure and function in patients with arterial hypertension on the negative impact of subclinical hypothyroidism were described by us in the previous works [34], including the analysis of the effect of statins on the indices of 24h-blood pressure monitoring and their changes after a long-term intake by patients of this category [35,36].
In the study [37], researchers analyzed the effect of SH on the diastolic function of the left ventricle by studying changes in time intervals with the help of a pulsed-wave Doppler. A similar analysis is complemented by the data of pulsed-wave tissue Doppler imaging in the publication [38]. Analyzing the modifying effect of hypothyroidism on cardiovascular pathology, the authors of the last publication point to the important changes in the structure and function of the heart, particularly in the diastolic function, in patients with hypothyroidism, the severity of which depends, according to the researchers, on the severity and duration of the thyroid hormone deficit. Similar results were also obtained with the help of modern diagnostic methods -magnetic resonance imaging and radionuclide ventriculography [39], which coincide with the data obtained by us.
However, there is a lack of information regarding the influence of statin therapy on the heart and blood vessels in patients with arterial hypertension combined with SH. The results of our studies strongly suggest that the presence of a concomitant subclinical hypothyroidism in patients with AH significantly affects structural and geometric remodeling of the heart and blood vessels, which, along with the disorders of lipid metabolism, are a basis for prescription of statins to the patients in this category. In patients with AH and a concomitant SH, there was an inhibition of the processes of reverse pathological remodeling of the left ventricle observed on the background of antihypertensive therapy, even provided the addition of statins to the therapeutic regimens.
Achievement of the target level of blood pressure according to 24h-BPM in 75 % of patients with AH with subclinical hypothyroidism on the background of antihypertensive therapy with the addition of statins was not accompanied by a significant reduction in the cavity size, wall thicknesses, LV mass, improvement of the diastolic filling and systolic function, decrease in the thickness of intima-media complex [36,37]. The data obtained allow us to consider a concomitant subclinical hypothyroidism in patients with AH as a negative factor of additional cardiovascular risk, which should be taken into a consideration when prescribing therapy.

Conclusions
1. In patients with AH with a concomitant subclinical hypothyroidism, the antihypertensive therapy carried out during the year using first-line drugs with addition of atorvastatin is accompanied by an achievement of target level of SBP in the active period of the day in 75 %, in the passive period -in 65 % of patients (according to the 24h-BPM data).
2. Achievement of the target level of blood pressure in patients with AH with subclinical hypothyroidism on the background of antihypertensive therapy with addition of statins was not accompanied by a significant reduction in cavity sizes, wall thicknesses, LV mass, improvement in LV diastolic filling, and decrease in the thickness of intima-media complex.
Prospects for further studies are to investigate the effect of statin therapy as well as hormone replacement therapy on the structural-geometric and functional parameters of the heart and blood vessels in patients with AH with a concomitant subclinical hypothyroidism.