POSSIBILITIES OF PHARMACOLOGICAL CORRECTION OF STRUCTURAL AND FUNCTIONAL ALTERATIONS OF MICROCIRCULATION IN TERMS OF ENDOTHELIAL DYSFUNCTION IN COMORBID PATIENTS SUFFERED STROKE EVENT

Aim of the study – reveal clinical efficacy of naftidrofuryl in the aspect of correcting structural and functional changes of microcirculation (MC) in relation to the influence of the endothelial dysfunction (ED) parameters in comorbid patients suffered stroke event.

Materials and methods. The study included 95 patients suffered ischemic type of stroke in the carotid bassin. An average age of patients was 69.0 ± 5.3 years, stroke duration was 73.5 ± 8.4 days. Patients were randomized in 2 groups by using blind method of envelopes. The mentioned groups matched on the main clinical and demographic characteristics. Patients from the 1st group (primary group, n = 47) were treated with naftidrofuryl (Duzofarm) at the daily dose of 300 mg, 2 patients (comparison group, n = 48) received basic therapy only. 50 people without an acute cerebrovascular accident in history were allocated as a control group (group 3). The following blood biochemical parameters were assessed: glucose, creatinine, total cholesterol, high density lipoprotein; triglycerides; markers of endothelial dysfunction: von Willebrand factor (VWF), tissue plasminogen activator inhibitor-1 (PAI 1), antithrombin III (AT III) and plasminogen. MC was studied by the method of laser doppler flowmetry. The duration of the observation period was 6 months, and 4 visits were performed during this period.

Results. Initial task of group formation within the study protocol has been solved by us in a full range. Patients from Group 1 that received naftidrofuryl noted statistically significant differences after 3 and 6 months of follow-up observation. These differences reflected improvement in perfusion index, coefficient of variation, as well as endothelial, neurogenic and myogenic regulation of microvasculature, increase in perfusion oxygen saturation index in the microcirculation. We have found that an index of relative perfusion oxygen saturation in microvascular blood (Sm) being the main indicator that reflects oxygen saturation of microcirculation has significantly correlated with ejection fraction, PAI1, AT III, and plasminogen levels in group 1 patients in 3 and 6 months. We have also found significant correlation with ED when comparing parameters that express endothelial, neurogenic and myogenic regulation of microvessels. These data clearly demonstrated an association between improving of MC parameters and ED parameters in Group 1 patients.

Conclusion. Possibility of correction of MC alterations leading to the worsening of ischemia and ED progression is one of the most promising directions in the treatment of stroke patients. Aim of the drug therapy is to prevent ED progression, reduced vascular tone and restore an adequate level of tissue hemoperfusion.

1. Dzau V., Braunwald E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121(4 Pt 1):1244–63.

2. Крупаткин А.И. Колебания кровотока - новый диагностический язык в исследовании микроциркуляции. Регионарное кровообращение и микроциркуляция 2014;13(1):83–99. [Krupatkin A.I. Variations of blood flow – a new diagnostic language to the study of the microcirculation. Regionarnoe krovoobrashchenie i mikrotsirkulyatsiya = Regional Hemodynamics and Microcirculation 2014;13(1):83–99. (In Russ.)].

3. Malpas S.C. The rhythmicity of sympathetic nerve activity. Prog Neurobiol 1998;56(1): 65–96.

4. Guild S.J., Barrett C.J., McBryde F.D. et al. Quantifying sympathetic nerve activity: problems, pitfalls and the need for standardization. Exp Physiol 2010;95(1): 41–50.

5. Briant L.J., Burchell A.E., Ratcliffe L.E. et al. Quantifying sympathetic neurohaemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control. J Physiol 2016;594(17):4753–68.

6. Paparde A., Plakane L., Circenis K., Aivars J.I. Effect of acute systemic hypoxia on human cutaneous microcirculation and endothelial, sympathetic and myogenic activity. Microvasc Res 2015; 102:1–5.

7. Yokoyama T., Nakamuta N., Kusakabe T., Yamamoto Y. Sympathetic regulation of vascular tone via noradrenaline and serotonin in the rat carotid body as revealed by intracellular calcium imaging. Brain Res 2015;1596:126–35.

8. Roy T.K., Secomb T.W. Functional sympatholysis and sympathetic escape in a theoretical model for blood flow regulation. Front Physiol 2014;5:192.

9. Carda A.P., Marchi K.C., Rizzi E. et al. Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress. Stress 2015;18(2):233–43.

10. Zhang S., Cui N., Li S. et al. Interception of the endotoxin-induced arterial hyporeactivity to vasoconstrictors. Vascul Pharmacol 2014;62(1):15–23.

11. Mahoney F.I., Barthel D.W. Functional evaluation: the Barthel index. Md State Med J 1965;14:61–5.

12. Крупаткин А.И., Сидоров В.В. Лазерная допплеровская флоуметрия микроциркуляции крови. Руководство для врачей. М.: Медицина, 2005. [Krupatkin A.I., Sidorov V.V. Laser Doppler flowmetry blood microcirculation. Guidelines for doctors. Moscow: Meditsina, 2005. (In Russ.)].

13. Quan H., Sundararajan V., Halfon P. et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43(11):1130–9.

14. Feinstein A.R. Pre-therapeutic classification of co-morbidity in chronic disease. J Chronic Dis 1970;23(7):455–68.

15. Васильев А.П., Стрельцова Н.Н. Возрастные особенности микрогемоциркуляции. Регионарное кровообращение и микроциркуляция 2012;11(4):23–7. [Vasil’ev A.P., Strel’tsova N.N. Age peculiarities of the microcirculation. Regionarnoe krovoobrashchenie i mikrotsirkulyatsiya = Regional Hemodynamics and Microcirculation 2012;11(4):23–7. (In Russ.)].

16. Левичева Е.Н., Каменская О.В., Логинова И.Ю. и др. Резервные возможности микроциркуляторного кровотока периферических тканей при циркуляторной гипоксии. Регионарное кровообращение и микроциркуляция 2012;3(11):34–8. [Levicheva E.N., Kamenskaya O.V., Loginova I.Yu. et al. Back microcirculatory blood flow of peripheral tissues in circulatory hypoxia. Regionarnoe krovoobrashchenie i mikrotsirkulyatsiya = Regional Hemodynamics and Microcirculation 2012;3(11):34–8. (In Russ.)].

17. Александрова О.М. Состояние кровотока в сосудах микроциркуляторного русла у больных гипертонической болезнью. Вестник новых медицинских технологий 2008;15(1):147–50. [Aleksandrova O.M. The status of blood flow in the microcirculatory vessels in patients with hypertension. Vestnik novykh meditsinskikh tekhnolologiy = Bulletin of New Medical Technologies 2008;15(1):147–50. (In Russ.)].

18. Messner B., Bernhard D. Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol 2014;34(3):509–15.

19. Иванов А.Н., Гречихин А.А., Норкин И.А., Пучиньян Д.М. Методы диагностики эндотелиальной дисфункции. Регионарное кровообращение и микроциркуляция 2014;13(4):4–11. [Ivanov A.N., Grechikhin A.A., Norkin I.A., Puchin’yan D.M. Methods of endothelial dysfunction diagnosis. Regionarnoe krovoobrashchenie i mikrotsirkulyatsiya = Regional Hemodynamics and Microcirculation 2014;13(4):4–11. (In Russ.)].

20. Maupoint J., Besnier M., Gomez E. et al. Selective vascular endothelial protection reduces cardiac dysfunction in chronic heart failure. Circ Heart Fail 2016;9(4):e002895.

21. House S.L., Castro A.M., Lupu T.S. et al. Endothelial fibroblast growth factor receptor signaling is required for vascular remodeling following cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2016;310(5):H559–71.

22. Fang Y.C., Yeh C.H. Role of microRNAs in vascular remodeling. Curr Mol Med 2015;15(8):684–96.

23. Harvey A., Montezano A.C., Touyz R.M. Vascular biology of ageing – implications in hypertension. J Mol Cell Cardiol 2015;83:112–21.

24. Marconi A., Darquenne S., Boulmerka A. et al. Naftidrofuryl-driven regulation of endothelial ICAM-1 involves nitric oxide. Free Radic Biol Med 2003;34(5):616–25.

25. Hong H., Mackey W.C. The limits of evidence in drug approval and availability: a case study of cilostazol and naftidrofuryl for the treatment of intermittent claudication. Clin Ther 2014;36(8):1290–301.

26. Кузнецов М.Р., Косых И.В., Юмин С.М. и др. Применение нафтидрофурила в ангиологии. Ангиология и сосудистая хирургия 2014;20(4):27–35. [Kuznetsov M.R., Kosykh I.V., Yumin S.M. et al. Use of naftidrofuryl in angiology. Angiologiya i sosudistaya khirurgiya = Angiology and Vascular Surgery 2014;20(4):27–35. (In Russ.)].