Microcirculatory disorders in patients with hypertensive disease and type 2 diabetes mellitus, and the possibility of their correction

The dissertation is devoted to the study of microcirculatory disorders in patients with hypertensive disease combined with type 2 diabetes mellitus and to the possibility of their correction with hypolipidemic therapy using simvastatin. The work examines the pathogenesis of microcirculatory bed damage, methods of its assessment (in particular, laser Doppler flowmetry), as well as the influence of statins on the state of microvessels and endothelial function in this category of patients. The investigation is aimed at developing individual criteria for the effective correction of the identified disorders and an algorithm for the optimal use of simvastatin in the combined therapy of combined pathology.

Hypertensive disease (HD) and type 2 diabetes mellitus (DM) remain the most widespread diseases in the world, significantly influencing the rate of formation of atherosclerotic lesions of intracardiac and peripheral vessels and worsening the prognosis of patients' lives, the terms of disability, and the frequency of lethal outcomes. At present, the question concerning the features of vascular bed damage in patients with HD combined with type 2 DM is being actively debated, since the broad prevalence of both diseases with a chronic course and a geometrical increase in the number of patients leads to the cumulation of vascular lesions, the methods of treatment of which cannot yet be considered perfect (I.I. Dedov, 2004; Zh.K. Kobalava, 2005).

The leading role of early cardiovascular mortality in limiting life expectancy in the absolute majority of patients with type 2 diabetes mellitus allowed the American Heart Association to classify diabetes as a cardiovascular disease (A.S. Ametov, 2003).

Previous studies have demonstrated the effectiveness of including angiotensin-converting enzyme inhibitors and angioprotectors in the combined therapy of microvascular damage both in patients with HD and in patients with type 2 diabetes mellitus (Zh.D. Kobalava, Yu.V. Kotovskaya, 2007).

Great hopes in prolonging the lives of patients with type 2 diabetes mellitus are presently associated with the use of statins (D.M. Aronov, 2002; I.I. Dedov, A.A. Aleksandrov, 2004). The fact is indisputable that statins are unquestionably indicated for patients with HD and coronary artery disease (CAD) combined with diabetes mellitus for the purpose of primary and secondary prevention of cardiovascular lesions. Thus, in the classical 4S study (2000), the positive influence of simvastatin on morbidity and mortality of CAD patients with moderate hypercholesterolemia was demonstrated: a reduction in the relative risk of coronary complications by 34%, cardiovascular mortality by 35%, the risk of stroke and/or transient cerebral circulatory disorder by 28%, and the need for operative revascularization by 37% was revealed. Statins conditionally leveled the negative influence of diabetes mellitus on coronary death. In the Heart Protection Study (2002), a reduction in the terms of hospitalization due to CAD and HD was noted, the safety of simvastatin and the independence of its positive influence from body mass, baseline lipid values, blood pressure level, and patient age were studied. The antiatherogenic properties of simvastatin and its ability to arrest the progression of atherosclerosis in CAD patients and partially reduce it were convincingly demonstrated by the results of the multicenter randomized trials MASS (1994) and SKAT (1999).

It has been established that in patients receiving antihypertensive treatment, an additional hypotensive effect of simvastatin is registered, improving the control of blood pressure in patients with hypertensive disease (P. Ofner, 2001).

There are works confirming the possibility of a positive influence of simvastatin on endothelial dysfunction. Thus, F. Nakashima and co-authors in 1996 established a significant increase in nitric oxide concentration against the background of a 12-week administration of simvastatin in patients with hypercholesterolemia exceeding 220 mg/dL.

Thus, at present there are works confirming the pronounced hypocholesterolemic effect of simvastatin, its protective influence in relation to coronary pathology, overall cardiovascular mortality, and the correction of endothelial dysfunction, in particular. However, these studies did not investigate the direct influence of statins on the microcirculatory system in patients with HD with or without diabetes mellitus.

Despite the sufficient volume of data on the pathogenesis, diagnosis, methods of treatment, and prevention of late complications of diabetes mellitus, the statistics on the frequency and outcome of lower limb lesions still remain disquieting. According to the results of epidemiological studies conducted in various countries, in the structure of all non-traumatic lower limb amputations, patients with diabetes mellitus constitute more than half (International Working Group on the Diabetic Foot, 2000).

At present, particular attention is being paid to the study of microcirculatory bed damage in the lower limbs in patients suffering from type 2 diabetes mellitus and to the role of the microcirculatory bed in the pathogenesis of diabetic foot syndrome (I.I. Dedov, 2005). To this day, there remains a divergence of opinions on the presence and severity of micro-level vessel damage in this cohort of patients. Many authors (O.V. Udovichenko, G.R. Galstyan, 2005) believe that the development of severe trophic disorders in the lower limbs in patients with diabetes mellitus is associated only with macrovascular disorders. However, there are works that have demonstrated the presence of changes at the microcirculatory level in patients with type 2 diabetes mellitus. Thus, in 1998, a work of the "Diabetic Foot" Center was published, in which changes of the microcirculatory bed in diabetic foot syndrome were established, but the forms of this syndrome (ischemic, neuropathic, mixed), its severity (with or without amputation of the foot or part thereof), and the type of diabetes mellitus (type 1 or type 2) were not taken into account. A. Pokrovsky and A. Chuprin demonstrated the diagnostic and prognostic significance of the use of transcutaneous oximetry and laser Doppler flowmetry methods for reconstructive vascular surgery of the lower limbs in patients with moderate arterial insufficiency and critical ischemia; however, the causes of ischemia and the presence of diabetes mellitus in patients were not taken into account in their work (1994).

At present, the method of laser Doppler flowmetry is widely used in clinical practice, allowing investigation not only of the state of microvessels but also indirectly of the severity of endothelial dysfunction and the features of the response reaction of microvessels to external disturbing influences.

This method was used in the work of the Endocrinological Research Center of the Russian Academy of Medical Sciences (M.I. Balabolkin, G.G. Mamayeva, E.A. Troshina, 2004), in which blood flow in the microcirculatory bed at various parts of the body, including the shin, was studied, but it contains no information on the reaction of the microcirculatory bed to disturbing influences, nor on the presence or absence of HD in these patients, or the possibility of using statins to correct changes in the microcirculatory bed (MCB).

To date, the capacity of statins to influence vascular damage in patients with diabetes mellitus and HD has been established; however, the pathogenetic aspects of microcirculatory bed damage in patients with HD combined with type 2 diabetes mellitus, as well as many aspects of the action of simvastatin, including its protective effect in relation to the microcirculatory bed of the lower limbs in patients with diabetic foot syndrome, have not yet been fully revealed.

In particular:

- the features of endothelial damage in patients with HD combined with type 2 diabetes mellitus have not been studied;

- the features of the influence of simvastatin on the peripheral link of lower limb circulation in patients with HD combined with type 2 diabetes mellitus, depending on its initial state and the duration of these diseases, have not been fully revealed;

- the significance and possibility of correction of microcirculatory disorders in patients with HD and type 2 diabetes mellitus by the administration of statins have not been studied, which served as the basis for conducting our investigations.

Aim and objectives of the study

Aim: to develop individual criteria for the effective correction of microcirculatory disorders (including the vasoactive function of the endothelium) in patients with hypertensive disease combined with type 2 diabetes mellitus through the use of simvastatin in combined therapy.

Objectives:

1. To study the features of disorders of the microcirculatory system at the level of the lower limbs in patients with hypertensive disease both combined with and without type 2 diabetes mellitus.

2. To develop criteria for assessing the severity of lower limb microvessel damage in patients with hypertensive disease combined with type 2 diabetes mellitus.

3. To compare morphometric (according to laser Doppler flowmetry data) and plasma markers of endothelial function in patients with hypertensive disease both combined with and without type 2 diabetes mellitus, and to evaluate the possibility of their correction with simvastatin.

4. To develop an algorithm for the optimal use of simvastatin in the combined therapy of hypertensive disease combined with type 2 diabetes mellitus.

Novelty of the study

1. Through a comprehensive study of the microcirculatory system, heterogeneous changes in microcirculation in the upper and lower limbs were established in patients with type 2 diabetes mellitus, with more severe damage to the microcirculatory bed of the lower limbs.

2. For the first time, the possibility of correction with simvastatin of the state of the microcirculatory system of the lower limbs and endothelial function in patients with hypertensive disease combined with type 2 diabetes mellitus with normostasis and congestive-spastic types of microcirculatory bed was demonstrated.

Practical significance

1. The diagnostic significance of the noninvasive method of investigating the microcirculatory bed by laser Doppler flowmetry for assessing the structural and functional state of microvessels in patients with hypertensive disease both combined with and without diabetes mellitus was demonstrated.

2. It was shown that the inclusion of simvastatin in the combined therapy of patients with hypertensive disease combined with type 2 diabetes mellitus allows improvement of the state of the microcirculatory system in patients with normostasis and congestive-spastic types, both with preserved and impaired autoregulation. In patients with the congestive-stasis type, three-month therapy with simvastatin does not substantially change the state of the microcirculatory bed.

Information on the implementation of results into practice and recommendations for their further use

Based on the materials of the dissertation, 8 scientific works have been published, including in the peer-reviewed journals: "Modern Problems of Science and Education", "Advances in Modern Natural Sciences", "Russian Journal of Cardiology", "Journal of Scientific Publications of Postgraduates and Doctoral Candidates". The results were reported at the 61st and 62nd scientific-practical conferences of young scientists and students of KSMA, the International Symposium "Diabetic Foot" 2005, the Russian National Congress of Cardiologists 2006; they are used in the educational process at the Department of Faculty Therapy of KSMU and have been implemented into the clinical practice of the endocrinological and rheumatological departments of the State Healthcare Institution "Regional Clinical Hospital No. 1 named after Prof. S.V. Ochapovsky".

Main propositions submitted for defense

1. Microcirculatory disorders in patients with type 2 diabetes mellitus differ from the microcirculatory changes in patients with HD.

2. Simvastatin exerts a corrective influence on the microcirculatory system of the lower limbs, the magnitude of which depends on its initial state.