Hypolipidemic, Antiplatelet and Immunomodulatory Effects of Allicor in Patients with Coronary Heart Disease and Arterial Hypertension with Moderate Atherogenic Dyslipoproteinemias

The dissertation is devoted to the study of the hypolipidemic, antiplatelet, and immunomodulatory effects of the garlic-based preparation allicor in patients with coronary heart disease and arterial hypertension with moderate atherogenic dyslipoproteinemias. It examines the characteristics of the lipid spectrum, lipid peroxidation, platelet aggregation function, and immune status parameters in this category of patients depending on the presence of clinical manifestations of atherosclerosis. On the basis of the results obtained, tactics for the use of allicor have been developed with account taken of the individual ten-year risk of fatal cardiovascular complications according to the SCORE scale, and the possibility has been demonstrated of transferring patients into lower risk categories with long-term therapy combined with a hypolipidemic diet.

Relevance of the Problem

For several decades, cardiovascular diseases (CVD) have firmly held first place among all causes of mortality in economically developed countries. The etiological basis of the majority of CVD is atherosclerosis, which proceeds asymptomatically for many years and is sufficiently pronounced by the time clinical symptoms appear.

The most important result of recent discoveries in the field of the pathogenesis of atherosclerosis is the development of the concept of risk factors. From the standpoint of the possibility of preventing cardiovascular diseases caused by atherosclerosis, particular attention is drawn to modifiable risk factors for atherothrombosis: elevated blood pressure, cigarette smoking, abdominal obesity, low physical activity, dyslipoproteinemia, and hyperglycemia [37]; spontaneous platelet aggregation has recently been added to these [13, 285]. A proven fact is the participation of the immune system in the formation and progression of atherosclerotic lesions of the vascular wall [103].

The combination of several risk factors increases the frequency of development of cardiovascular complications (S.A. Shalnova, R.G. Oganov, A.D. Deev, 2006). In this regard, the question of the mutual influence of risk factors remains relevant. At present, there are few data on the interrelationships between the platelet component of hemostasis and the immune system in patients with atherogenic dyslipoproteinemias (including hyperlipoproteinemia (a)), especially depending on the presence of clinical manifestations of atherosclerosis in them.

Among the variety of agents used to correct risk factors for atherosclerosis (primarily hyperlipidemia), searches are underway for the most optimal, safe, and effective means possessing pleiotropic, multifactorial action, and indications for their use are being refined.

In marked hyperlipoproteinemia [207] in high and very high risk patients, the advisability of aggressive lipid-lowering therapy is beyond doubt, whereas in moderate hyperlipoproteinemia the use of modern powerful hypolipidemic agents provokes vigorous discussion, since it may prove clinically and economically irrational. Is the rule "the lower the LDL cholesterol, the better" always justified? What should be the tactics of hypolipidemic therapy in patients with moderately pronounced disorders of lipid metabolism and without clinical manifestations of atherosclerosis?

In this regard, the clinical use of agents (in particular, garlic-based preparations) possessing moderate hypolipidemic action and, preferably, pleiotropic effects and characterized by good tolerability appears relevant.

A number of researchers confirm the presence of a moderate hypocholesterolemic effect in garlic-based preparations [58, 100]. However, there are insufficient data on the effect of long-term administration of these agents on the lipoprotein spectrum and blood lipid peroxidation, especially in patients stratified into different risk groups according to the prognosis of cardiovascular complications. The role of lipoprotein (a) in the pathogenesis of atherothrombosis is widely discussed in the literature [5, 41], but there is no information on the specific effects of garlic components on its blood level. Reports on the effect of garlic preparations on platelet aggregation function are contradictory; moreover, most of them have been obtained experimentally [22, 289] or in patients with chronic cerebrovascular pathology [53]. The scarce data on the immunomodulatory effects of biologically active components of garlic have been obtained in the treatment of patients with immunodeficiencies of various origins — against the background of type 2 diabetes mellitus [96, 97] and severe infectious-destructive lung diseases [144], or experimentally [140]. There is no information in the literature on the effect of garlic preparations on the immune status of patients with atherogenic dyslipoproteinemias.

Aim of the study: to clarify the character of the effect of allicor on lipid metabolism, platelet hemostasis, and immune status in patients with coronary heart disease and arterial hypertension with moderate atherogenic dyslipoproteinemias, and to develop tactics for its use in this category of patients.

Tasks of the study:

1. To clarify the state of the lipid transport system, blood lipid peroxidation, platelet aggregation activity with various inducers (serotonin, ristocetin, adrenaline, ADP), and the immune system in patients with coronary heart disease and arterial hypertension with atherogenic dyslipoproteinemias, taking into account the presence of clinical manifestations of atherosclerosis.

2. To identify, in patients with atherogenic dyslipoproteinemias, interrelationships between the parameters of the platelet component of hemostasis, immune status, lipid profile, and free-radical lipid peroxidation in the blood.

3. To assess the character of the effect of allicor on the lipid transport and immune systems and on platelet aggregation activity in patients with coronary heart disease and arterial hypertension with atherogenic dyslipoproteinemias.

4. To develop tactics for the use of allicor in patients with atherogenic dyslipoproteinemias.

Scientific Novelty

It has been established that moderate hypercholesterolemia and hypertriglyceridemia cause modulation predominantly of the T-cell component of immunity (an increase in the relative content of T-helpers and a decrease in T-suppressors) and an increase in the activity of phagocytic cells (an increase in their oxidative potential).

It has been revealed that in patients with atherogenic dyslipoproteinemias the functional activity of platelets is influenced by the state of the oxidative potential of phagocytic cells, and in patients with clinical manifestations of atherosclerosis — also by the concentrations of CIC and IgG.

The moderate hypolipidemic, deaggregative, and immunomodulatory efficacy of long-term (6 months) administration of allicor in patients with atherogenic dyslipoproteinemias has been proved. Specific features of the deaggregative and immunomodulatory action of allicor in patients with atherogenic dyslipoproteinemias have been revealed, taking into account the presence of clinical manifestations of atherosclerosis.

Practical Significance of the Work

Tactics for the use of allicor in moderate atherogenic dyslipoproteinemias have been developed depending on the category of ten-year individual absolute risk of fatal cardiovascular complications (according to the SCORE scale): in patients with coronary heart disease, administration of allicor at a dose of 600 mg/day, and in patients without clinical manifestations of atherosclerosis, at a dose of 300 mg/day for 6 months makes it possible to achieve target values of lipid profile indices and blood lipid peroxidation, to reduce the degree and rate of aggregation and to increase the deaggregative capacity of platelets, to reduce the initial imbalance of immunological parameters, and to transfer patients with coronary heart disease from the category "very high individual ten-year risk of fatal cardiovascular complications" to the category "high risk," and patients without clinical manifestations of atherosclerosis from the category "high risk" to the category "moderate risk" (according to SCORE). The necessity has been proved of monitoring the blood lipid profile in conjunction with platelet aggregation function (qualitative and quantitative characteristics of the aggregatogram), as well as immune status, including the oxidative potential of phagocytic cells, the relative content of T-helpers and T-suppressors, and the levels of IgG and circulating immune complexes at baseline and during the therapy administered.

Implementation

Methods for studying platelet aggregation with various inducers and immune status parameters in patients with atherogenic dyslipoproteinemias against the background of hypolipidemic therapy, as well as the method of multifactorial prevention of cardiovascular complications in patients with moderate atherogenic dyslipoproteinemias using allicor, have been implemented in the practice of the therapeutic departments of the Municipal Healthcare Institution Emergency Hospital of the City of Kursk and Polyclinic No. 4 of the Municipal Healthcare Institution Botkin City Hospital of the City of Orel, as well as in the laboratory diagnostics department of Polyclinic No. 4 of the Municipal Healthcare Institution Botkin City Hospital of the City of Orel.

Main Statements Defended:

1. In patients with atherogenic dyslipoproteinemias suffering from CHD, in comparison with patients without clinical manifestations of atherosclerosis, activation of platelet aggregation ability induced by serotonin, ristocetin, adrenaline, and ADP is observed (an increase in its degree and rate), a decrease in deaggregative activity, and an increase in the frequency of irreversible aggregation.

2. In moderate hypercholesterolemia and hypertriglyceridemia, modulation of the T-cell component of immunity is observed (an increase in the relative content of T-helpers and a decrease in T-suppressors) and an increase in the activity of phagocytic cells (an increase in their oxidative potential). An increase in the oxidative potential of phagocytic cells in patients with atherogenic dyslipoproteinemias is accompanied by activation of platelet aggregation ability; in CHD patients, an increase in the functional activity of platelets is also facilitated by elevated levels of CIC and IgG.

3. The use of allicor in combination with a step I hypolipidemic diet for 6 months (against the background of basic drug therapy) in patients with atherogenic dyslipoproteinemias and CHD at a dose of 600 mg/day and in patients without clinical manifestations of atherosclerosis at a dose of 300 mg/day promotes the achievement of target values of lipid spectrum indices (according to the Recommendations of the All-Russian Scientific Society of Cardiologists (VNOK), 2004) and blood lipid peroxidation, favorable changes in platelet hemostasis and immune status, and a reduction in the ten-year individual risk of fatal cardiovascular complications (according to SCORE).

Approval of the Work

The main provisions of the dissertation were reported and discussed at the international scientific-practical conference "Saint Petersburg Scientific Readings 2004" (Saint Petersburg, February 4–7, 2004), the 69th Final Scientific Session of KSMU and the Department of Medical and Biological Sciences of the Central Chernozem Scientific Center of RAMS (Kursk, 2004), the Jubilee Scientific Conference of KSMU and the Session of the Central Chernozem Scientific Center of RAMS dedicated to the 70th anniversary of KSMU "University Science: A Look into the Future" (Kursk, 2005), and at meetings of the scientific-practical society of therapists and cardiologists of the Orel Region (2006–2007). The dissertation was approved on May 18, 2007, at the interdepartmental scientific-practical conference of the Departments of Internal Diseases No. 2, Propaedeutics of Internal Diseases, Endocrinology and Diabetology of the Kursk State Medical University, with the participation of therapists and cardiologists of the Municipal Healthcare Institution Emergency Hospital of the City of Kursk.

Publications

Fifteen scientific works have been published on the materials of the dissertation, of which 8 were in central press (including 3 with international participation and 1 in a peer-reviewed scientific publication recommended by the Higher Attestation Commission of the Ministry of Education and Science of the Russian Federation).

Scope and Structure of the Work

The dissertation is set out on 210 typewritten pages and consists of an introduction, a literature review, a description of materials and methods, results of the study, discussion, conclusions, practical recommendations, a list of references, and a 2-page appendix. The material presented is illustrated with 11 figures and 23 tables. The bibliography includes 298 sources, of which 177 are domestic and 121 are foreign.