Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases. Clinical significance and correction of endothelial dysfunction Main supporting mechanisms

Chronic cerebral ischemia (CHI) is a disease with progressive multifocal diffuse brain damage, manifested by neurological disorders of varying degrees, caused by a reduction in cerebral blood flow, transient ischemic attacks or previous cerebral infarctions. The number of patients with symptoms of chronic cerebral ischemia in our country is steadily growing, amounting to at least 700 per 100,000 population.

Depending on the severity of clinical disorders, three stages of the disease are distinguished. Each stage in turn can be compensated, subcompensated and decompensated. In stage I, headaches, a feeling of heaviness in the head, dizziness, sleep disturbances, decreased memory and attention are observed, in the neurological status - scattered small-focal neurological symptoms, insufficient for diagnosing the delineated neurological syndrome. In stage II, the complaints are similar, but more intense - memory progressively deteriorates, unsteadiness when walking occurs, difficulties arise in professional activities; Clear symptoms of organic, neurological lesions of the brain appear. Stage III is characterized by a decrease in the number of complaints, which is associated with the progression of cognitive impairment and a decrease in criticism of one’s condition. In the neurological status, a combination of several neurological syndromes is observed, which indicates multifocal brain damage.

The role of endothelial dysfunction in the pathogenesis of atherosclerosis and arterial hypertension

The main factors leading to the development of chronic cerebral ischemia are atherosclerotic vascular damage and arterial hypertension (AH).

Risk factors for the development of cardiovascular diseases, such as hypercholesterolemia, arterial hypertension, diabetes mellitus, smoking, hyperhomocysteinemia, obesity, physical inactivity, are accompanied by impaired endothelium-dependent vasodilation.

Endothelium is a single-layer layer of flat cells of mesenchymal origin that lines the inner surface of blood and lymph vessels and cardiac cavities. To date, numerous experimental data have been accumulated that allow us to speak about the role of the endothelium in maintaining homeostasis by maintaining the dynamic balance of a number of multidirectional processes:

vascular tone (regulation of vasodilation/vasoconstriction processes through the release of vasodilator and vasoconstrictor factors, modulation of the contractile activity of smooth muscle cells);
hemostasis processes (synthesis and inhibition of platelet aggregation factors, pro- and anticoagulants, fibrinolysis factors);
local inflammation (production of pro- and anti-inflammatory factors, regulation of vascular permeability, leukocyte adhesion processes);
anatomical structure and vascular remodeling (synthesis/inhibition of proliferation factors, growth of smooth muscle cells, angiogenesis).

The endothelium also performs transport (carries out two-way transport of substances between the blood and other tissues) and receptor functions (endotheliocytes have receptors for various cytokines and adhesive proteins, express on the plasmalemma a number of compounds that ensure adhesion and transendothelial migration of leukocytes).

An increase in blood flow velocity leads to increased formation of vasodilators in the endothelium and is accompanied by an increase in the formation of endothelial NO synthase and other enzymes in the endothelium. Shear stress is of great importance in the autoregulation of blood flow. Thus, with an increase in arterial vascular tone, the linear velocity of blood flow increases, which is accompanied by an increase in the synthesis of endothelial vasodilators and a decrease in vascular tone.

Endothelium-dependent vasodilation (EDVD) is associated with the synthesis in the endothelium of mainly three main substances: nitrogen monoxide (NO), endothelial hyperpolarizing factor (EDHF) and prostacyclin. Basal NO secretion determines the maintenance of normal vascular tone at rest. A number of factors, such as acetylcholine, adenosine triphosphoric acid (ATP), bradykinin, as well as hypoxia, mechanical deformation and shear stress, cause the so-called stimulated secretion of NO, mediated by the second messenger system.

Normally, NO is a powerful vasodilator and also inhibits the processes of remodeling of the vascular wall, suppressing the proliferation of smooth muscle cells. It prevents platelet adhesion and aggregation, monocyte adhesion, protects the vascular wall from pathological changes and the subsequent development of atherosclerosis and atherothrombosis.

With prolonged exposure to damaging factors, a gradual disruption of the functioning of the endothelium occurs. The ability of endothelial cells to release relaxing factors decreases, while the formation of vasoconstrictor factors persists or increases, i.e., a condition defined as “endothelial dysfunction” is formed. Pathological changes occur in vascular tone (general vascular resistance and blood pressure), vascular structure (structural preservation of the layers of the vascular wall, manifestations of atherogenesis), immunological reactions, inflammation processes, thrombus formation, fibrinolysis.

A number of authors provide a more “narrow” definition of endothelial dysfunction - a condition of the endothelium in which there is insufficient production of NO, since NO is involved in the regulation of almost all endothelial functions and, in addition, is the factor most sensitive to damage.

There are 4 mechanisms through which endothelial dysfunction is mediated:

1) impaired bioavailability of NO due to:

reduction of NO synthesis when NO synthase is inactivated;
a decrease in the density of muscarinic and bradykinin receptors on the surface of endothelial cells, irritation of which normally leads to the formation of NO;
increased NO degradation—NO destruction occurs before the substance reaches its site of action (during oxidative stress);

2) increased activity of angiotensin-converting enzyme (ACE) on the surface of endothelial cells;

3) increased production of endothelin-1 and other vasoconstrictor substances by endothelial cells;

4) violation of the integrity of the endothelium (de-endothelialization of the intima), as a result of which circulating substances, directly interacting with smooth muscle cells, cause their contraction.

Endothelial dysfunction (ED) is a universal mechanism in the pathogenesis of arterial hypertension (AH), atherosclerosis, cerebrovascular diseases, diabetes mellitus, and coronary heart disease. Moreover, endothelial dysfunction both itself contributes to the formation and progression of the pathological process, and the underlying disease often aggravates endothelial damage.

With hypercholesterolemia, cholesterol and low-density lipoproteins (LDL) accumulate on the walls of blood vessels. Low density lipoproteins are oxidized; the consequence of this reaction is the release of oxygen radicals, which, in turn, interacting with already oxidized LDL, can further enhance the release of oxygen radicals. Such biochemical reactions create a kind of pathological vicious circle. Thus, the endothelium is constantly exposed to oxidative stress, which leads to increased decomposition of NO by oxygen radicals and weakened vasodilation. As a result, DE is realized in changes in the structure of the vascular wall or vascular remodeling in the form of thickening of the vessel media, a decrease in the lumen of the vessel and the extracellular matrix. In large vessels, the elasticity of the wall decreases, the thickness of which increases, leukocyte infiltration occurs, which, in turn, predisposes to the development and progression of atherosclerosis. Remodeling of blood vessels leads to disruption of their function and typical complications of hypertension and atherosclerosis - myocardial infarction, ischemic stroke, renal failure.

With the predominant development of atherosclerosis, NO deficiency accelerates the development of atherosclerotic plaque from a lipid spot to a crack in the atherosclerotic plaque and the development of atherothrombosis. Hyperplasia and hypertrophy of smooth muscle cells increases the degree of vasoconstrictor response to neurohumoral regulation, increases peripheral vascular resistance and is thus a factor stabilizing hypertension. An increase in systemic blood pressure is accompanied by an increase in intracapillary pressure. Increased intramural pressure stimulates the formation of free radicals, especially superoxide anion, which, by binding to nitric oxide produced by the endothelium, reduces its bioavailability and leads to the formation of peroxynitrite, which has a cytotoxic effect on the endothelial cell and activates the mitogenesis of smooth muscle cells, there is an increased formation of vasoconstrictors, especially endothelin-1, thromboxane A2 and prostaglandin H2, which stimulates the growth of smooth muscle cells.

Diagnosis of the functional state of the endothelium

There are a large number of different methods for assessing the functional state of the endothelium. They can be divided into 3 main groups:

1) assessment of biochemical markers;
2) invasive instrumental methods for assessing endothelial function;
3) non-invasive instrumental methods for assessing endothelial function.

Biochemical assessment methods

Reduced NO synthesis or bioavailability is central to the development of DE. However, the short lifetime of the molecule severely limits the use of measuring NO in serum or urine. The most selective markers of endothelial dysfunction include: von Willebrand factor (vWF), antithrombin III, desquamated endothelial cells, content of cellular and vascular adhesion molecules (E-selectin, ICAM-1, VCAM-1), thrombomodulin, protein C receptors, annexin -II, prostacyclin, tissue plasminogen activator t-PA, P-selectin, tissue coagulation pathway inhibitor (TFPI), protein S.

Invasive assessment methods

Invasive methods involve chemical stimulation of muscarinic endothelial receptors with endothelium-stimulating drugs (acetylcholine, methacholine, substance P) and some direct vasodilators (nitroglycerin, sodium nitroprusside), which are injected into the artery and cause endothelium-independent vasodilation (ENVD). One of the first such methods was radiocontrast angiography using intracoronary injection of acetylcholine.

Non-invasive diagnostic methods

Recently, there has been great interest in the use of photoplethysmography (PPG), i.e. recording a pulse wave using an optical sensor to assess the vasomotor effect that appears during the occlusion test of nitric oxide and the functional state of the endothelium. The most convenient place to place the PPG sensor is a finger. The formation of the PPG signal primarily involves the pulse dynamics of changes in the pulse volume of blood flow and, accordingly, the diameter of the digital arteries, which is accompanied by an increase in the optical density of the measured area. The increase in optical density is determined by pulse local changes in the amount of hemoglobin. The test results are comparable to those obtained from coronary angiography with the administration of acetylcholine. The described phenomenon underlies the functioning of the non-invasive diagnostic hardware and software complex “AngioScan-01”. The device allows you to identify the earliest signs of endothelial dysfunction. Registration technology and volumetric pulse wave contour analysis make it possible to obtain clinically significant information about the state of the stiffness of elastic arteries (the aorta and its main arteries) and the tone of small resistive arteries, as well as to assess the functional state of the endothelium of large muscular and small resistive vessels (the methodology is similar to ultrasound "cuff test")

Pharmacological methods for correcting endothelial dysfunction in patients with CCI

Methods for correcting DE in CCI can be divided into two groups:

1) elimination of factors aggressive to the endothelium (hyperlipidemia, hyperglycemia, insulin resistance, postmenopausal hormonal changes in women, high blood pressure, smoking, sedentary lifestyle, obesity) and, thus, modification and reduction of oxidative stress;
2) normalization of endothelial NO synthesis.

To solve these problems, various drugs are used in clinical practice.

Statins

Reducing the level of cholesterol in the blood plasma slows down the development of atherosclerosis and in some cases causes regression of atherosclerotic changes in the vessel wall. In addition, statins reduce lipoprotein oxidation and free radical damage to endothelial cells.

NO donors and NO synthase substrates

Nitrates (organic nitrates, inorganic nitro compounds, sodium nitroprusside) are a donor of NO, i.e., they exhibit their pharmacological effect by releasing NO from them. Their use is based on vasodilating properties that promote hemodynamic unloading of the heart muscle and stimulation of endothelium-independent vasodilation of the coronary arteries. Long-term administration of NO donors can lead to inhibition of its endogenous synthesis in the endothelium. It is with this mechanism that the possibility of accelerated atherogenesis and the development of hypertension is associated with their chronic use.

L-arginine is a substrate of endothelial NO synthase, leading to improved endothelial function. However, the experience of its use in patients with hypertension and hypercholesterolemia has only theoretical significance.

Dihydropyridine calcium antagonists improve EDVD by increasing NO (nifedipine, amlodipine, lacidipine, pranidipine, felodipine, etc.).

ACE inhibitors and AT-II antagonists

In experiments, EDVD could be improved with the help of angiotensin-converting enzyme inhibitors and angiotensin-2 antagonists. ACE inhibitors increase the bioavailability of NO by reducing the synthesis of angiotensin-2 and increasing plasma bradykinin levels.

Other antihypertensive drugs

Beta blockers have vasodilating properties due to stimulation of NO synthesis in the vascular endothelium and activation of the L-arginine/NO system, as well as the ability to stimulate NO synthase activity in endothelial cells.

Thiazide diuretics lead to increased NO synthase activity in endothelial cells. Indapamide has a direct vasodilating effect through putative antioxidant properties, increasing the bioavailability of NO and reducing its breakdown.

Antioxidants

Given the role of oxidative stress in the pathogenesis of endothelial dysfunction, it is expected that the administration of antioxidant therapy may become a leading strategy in its treatment. The reverse development of endothelial dysfunction in the coronary and peripheral arteries has been proven with the use of glutathione, N-acetyl cysteine, and vitamin C. Drugs with antioxidant and antihypoxic activity can improve endothelial function.

Thioctic acid (TA, alpha lipoic acid)

The protective role of MC in relation to endothelial cells from extra- and intracellular oxidative stress has been demonstrated in cell culture. In the ISLAND study in patients with metabolic syndrome, TC contributed to an increase in EDVD of the brachial artery, which was accompanied by a decrease in the plasma levels of interleukin-6 and plasminogen activator-1. TC affects energy metabolism, normalizes NO synthesis, reduces oxidative stress and increases the activity of the antioxidant system, which may also explain the decrease in the degree of brain damage during ischemia-reperfusion.

Vinpocetine

Numerous studies have shown an increase in volumetric cerebral blood flow with the use of this drug. It is assumed that vinpocetine is not a classic vasodilator, but relieves existing vasospasm. It enhances the utilization of oxygen by nerve cells, inhibits the entry and intracellular release of calcium ions.

Deproteinized hemoderivative of calf blood (Actovegin)

Actovegin is a highly purified hemoderivative of calf blood, consisting of more than 200 biologically active components, including amino acids, oligopeptides, biogenic amines and polyamines, sphingolipids, inositol phosphooligosaccharides, metabolic products of fats and carbohydrates, free fatty acids. Actovegin increases the consumption and use of oxygen, thereby activating energy metabolism, shifting cell energy metabolism towards aerobic glycolysis, inhibiting the oxidation of free fatty acids. At the same time, the drug also increases the content of high-energy phosphates (ATP and ADP) under conditions of ischemia, thereby replenishing the resulting energy deficit. In addition, Actovegin also prevents the formation of free radicals and blocks apoptosis processes, thereby protecting cells, especially neurons, from death under conditions of hypoxia and ischemia. There is also a significant improvement in cerebral and peripheral microcirculation against the background of improved aerobic energy exchange of vascular walls and the release of prostacyclin and nitric oxide. The resulting vasodilation and decrease in peripheral resistance are secondary to the activation of oxygen metabolism of the vascular walls.

The results obtained by A. A. Fedorovich convincingly prove that Actovegin not only has a pronounced metabolic effect, increasing the functional activity of the microvascular endothelium, but also affects the vasomotor function of microvessels. The vasomotor effect of the drug is most likely realized through an increase in the production of NO by the microvascular endothelium, which results in a significant improvement in the functional state of the microvascular smooth muscle apparatus. However, a direct myotropic positive effect cannot be excluded.

Recent work by a group of authors has studied the role of Actovegin as an endothelial protector in patients with CCI. When using it, patients recorded an improvement in blood flow in the carotid and vertebrobasilar systems, which correlated with an improvement in neurological symptoms and was confirmed by indicators of normalization of the functional state of the endothelium.

Despite the emergence of individual scientific studies, the problem of early diagnosis of endothelial dysfunction in CCI remains insufficiently studied. At the same time, timely diagnosis and subsequent pharmacological correction of DE will significantly reduce the number of patients with cerebrovascular diseases or achieve maximum regression of the clinical picture in patients with different stages of chronic cerebral ischemia.

Literature

Fedin A.I. Selected lectures on ambulatory neurology. M.: LLC "AST 345". 2014. 128 p.
Suslina Z. A., Rumyantseva S. A. Neurometabolic therapy of chronic cerebral ischemia. Toolkit. M.: VUNMC Ministry of Health of the Russian Federation, 2005. 30 p.
Schmidt E. V., Lunev D. K., Vereshchagin N. V. Vascular diseases of the brain and spinal cord. M.: Medicine, 1976. 284 p.
Bonetti P. O., Lerman L. O., Lerman A. et al. Endothelial dysfunction. A marker of atherosclerotic risk // Arterioscler. Thromb. Vasc. Biol. 2003. Vol. 23. P. 168-175.
Buvaltsev V.I. Endothelial dysfunction as a new concept for the prevention and treatment of cardiovascular diseases // International. honey. magazine 2001. No. 3. P. 202-208.
Storozhakov G. I., Vereshchagina G. S., Malysheva N. V. Endothelial dysfunction in arterial hypertension in elderly patients // Clinical gerontology. 2003. No. 1. P. 23-28.
Esper R. J., Nordaby R. A., Vilarino J. O. et al. Endothelial dysfunction: a comprehensive appraisal // Cardiovascular Diabetology. 2006. Vol. 5 (4). P. 1-18.
Mudau M., Genis A., Lochner A., Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis // Cardiovasc. J. Afr. 2012. Vol. 23(4). P. 222-231.
Chhabra N. Endothelial dysfunction is a predictor of atherosclerosis // Internet J. Med. Update. 2009. Vol. 4 (1). P. 33-41.
Buvaltsev V.I. Vasodilating function of the endothelium and possible ways of its correction in patients with arterial hypertension. dis. ...Dr. med. Sciences: 14.00.06. M., 2003. 222 p.
Novikova N. A. Endothelial dysfunction is a new target for drug therapy in cardiovascular diseases. Vrach. 2005. No. 8. P. 51-53.
Verma S., Buchanan M. R., Anderson T. J. Endothelial function testing as a biomarker of vascular disease // Circulation. 2003. Vol. 108. P. 2054-2059.
Landmesser U., Hornig B., Drexler H. Endothelial function. A critical determinant in atherosclerosis? // Circulation. 2004. Vol. 109 (suppl II). P. II27-II33.
Chazov E. I., Kukharchuk V. V., Boytsov S. A. Guide to atherosclerosis and coronary heart disease. M.: Media Medica, 2007. 736 p.
Soboleva G. N., Rogoza A. N., Shumilina M. V., Buziashvili Yu. I., Karpov Yu. A. Endothelial dysfunction in arterial hypertension: vasoprotective effects of new generation β-blockers // Ross. honey. magazine 2001. T. 9, No. 18. P. 754-758.
Vorobyova E. N., Schumacher G. I., Khoreva M. A., Osipova I. V. Endothelial dysfunction is a key link in the pathogenesis of atherosclerosis // Ros. cardiol. magazine 2010. No. 2. P. 84-91.
Madhu S. V., Kant S., Srivastava S., Kant R., Sharma S. B., Bhadoria D. P. Postprandial lipaemia in patients with impaired fasting glucose, impaired glucose tolerance and diabetes mellitus // Diabetes Res. Clin. Practice. 2008. Vol. 80. P. 380-385.
Petrishchev N. N. Endothelial dysfunction. Causes, mechanisms, pharmacological correction. St. Petersburg: Publishing house of St. Petersburg State Medical University, 2003. 181 p.
Voronkov A.V. Endothelial dysfunction and ways of its pharmacological correction. Diss. ...Dr. med. Sciences: 03.14.06. Volgograd, 2011. 237 p.
Gibbons G. H., Dzau V. J. The emerging concept of vascular remodeling // N. Engl. J. Med. 1994. Vol. 330. P. 1431-1438.
Lind L., Granstam S. O., Millgård J. Endothelium-dependent vasodilation in hypertension: a review // Blood Pressure. 2000. Vol. 9. P. 4-15.
Fegan P. G., Tooke J. E., Gooding K. M., Tullett J. M., MacLeod K. M., Shore A. C. Capillary pressure in subjects with type 2 diabetes and hypertension and the effect of antihypertensive therapy // Hypertension. 2003. Vol. 41(5). P. 1111-1117.
Parfenov A. S. Early diagnosis of cardiovascular diseases using the hardware-software complex “Angioscan-01” // Polyclinic. 2012. No. 2 (1). pp. 70-74.
Fonyakin A.V., Geraskina L.A. Statins in the prevention and treatment of ischemic stroke // Annals of Clinical and Experimental Neurology. 2014. No. 1. P. 49-55.
Hussein O., Schlezinger S., Rosenblat M., Keidar S., Aviram M. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL // Atherosclerosis. 1997. Vol. 128(1). P. 11-18.
Drexler H. Nitric oxide and coronary endothelial dysfunction in humans // Cardiovasc. Res. 1999. Vol. 43. P. 572-579.
Ikeda U., Maeda Y., Shimada K. Inducible nitric oxide synthase and atherosclerosis // Clin. Cardiol. 1998. Vol. 21. P. 473-476.
Creager M. A., Gallagher S. J., Girerd X. J., Coleman S. M., Dzau V. J., Cooke J. P. L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans // J. Clin. Invest. 1992. Vol. 90. P. 1242-1253.
Shilov A. M. Place of third generation calcium channel blockers in the metabolic syndrome continuum // Difficult patient. 2014. No. 12 (4). pp. 20-25.
Berkels R., Egink G., Marsen T. A., Bartels H., Roesen R., Klaus W. Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms // Hypertension. 2001. V. 37. No. 2. P. 240-245.
Wu C. C., Yen M. H. Nitric oxide synthase in spontaneously hypertensive rats/C.C. Wu // J. Biomed. Sci. 1997. Vol. 4 (5). P. 249-255.
Young R. H., Ding Y. A., Lee Y. M., Yen M. H. Cilazapril reverses endothelium-dependent vasodilator response to acetylcholine in mesenteric artery from spontaneously hypertensive rats // Am. J. Hypertens. 1995. Vol. 8 (9). P. 928-933.
Parenti A., Filippi S., Amerini S., Granger H. J., Fazzini A., Ledda F. Inositol phosphate metabolism and nitric-oxide synthase activity in endothelial cells are involved in the vasorelaxant activity of nebivolol // J. Pharmacol. Exp. Ther. 2000. Vol. 292(2). P. 698-703.
Murphy M.P. Nitric oxide and cell death // Biochim. Biophys. Acta. 1999. Vol. 1411. P. 401-414.
Perfilova V. N. Cardioprotective properties of structural analogues of GABA. Author's abstract. dis. ...Dr.Biol. Sci. Volgograd, 2009. 49 p.
Ishide T., Amer A., Maher T. J., Ally A. Nitric oxide within periaqueductal gray modulates glutamatergic neurotransmission and cardiovascular responses during mechanical and thermal stimuli // Neurosci Res. 2005. Vol. 51(1). P. 93-103.
Sabharwal A.K., May J.M. Alpha-Lipoic acid and ascorbate prevent LDL oxidation and oxidant stress in endothelial cells // Mol. Cell. Biochem. 2008. 309 (1-2). P. 125-132.
Kamchatnov P. R., Abusueva B. A., Kazakov A. Yu. The use of alpha-lipoic acid in diseases of the nervous system // Journal of Neurology and Psychiatry named after. S. S. Korsakova. 2014. T. 114., No. 10. P. 131-135.
Karneev A. N., Solovyova E. Yu., Fedin A. I., Azizova O. A. The use of α-lipoic acid preparations as neuroprotective therapy for chronic cerebral ischemia // Handbook of a polyclinic physician. 2006. No. 8. P. 76-79.
Burtsev E. M., Savkov V. S., Shprakh V. V., Burtsev M. E. 10 years of experience in using Cavinton for cerebrovascular disorders // Journal of Neurology and Psychiatry named after. S. S. Korsakova. 1992. No. 1. P. 56-61.
Suslina Z. A., Tanashyan M. M., Ionova V. G., Kistenev B. A., Maksimova M. Yu., Sharypova T. N.. Cavinton in the treatment of patients with ischemic disorders of cerebral circulation // Russian Medical Journal. 2002. No. 25. P. 1170-1174.
Molnar P., Erdö S. L. Vinpocetine is as potent as phenytoin to block voltage-gated Na+ channels in rat cortical neurons // Eur. J. Pharmacol. 1995. Vol. 273(5). P. 303-306.
Vaizova O. E. Pharmacological and extracorporeal correction of vascular endothelial dysfunction in cerebral atherosclerosis. dis. ...Dr. med. Sciences: 14.00.25. Tomsk, 2006. 352 p.
Machicao F., Muresanu D. F., Hundsberger H., Pflüger M., Guekht A. Pleiotropic neuroprotective and metabolic effects of Actovegin’s mode of action // J Neurol Sci. 2012; 322(1):222-227.
Elmlinger M. W., Kriebel M., Ziegler D. Neuroprotective and Anti-Oxidative Effects of the Hemodialysate Actovegin on Primary Rat Neurons in Vitro // Neuromolecular Med. 2011; 13 (4): 266-274.
Astashkin E. I., Glazer M. G. and others. Actovegin reduces the level of oxygen radicals in whole blood samples of patients with heart failure and suppresses the development of necrosis of transplanted human neurons of the SK-N-SH line. Reports of the Academy of Sciences. 2013: 448 (2); 232-235.
Fedorovich A. A., Rogoza A. N., Kanishcheva E. M., Boytsov S. A. Dynamics of the functional activity of the microvascular endothelium during an acute pharmacological test with the drug Actovegin // Consilium medicum. 2010. T. 12. No. 2. P. 36-45.
Uchkin I. G., Zudin A. M., Bagdasaryan A. G., Fedorovich A. A. The influence of pharmacotherapy of chronic obliterating diseases of the arteries of the lower extremities on the state of the microvasculature // Angiology and Vascular Surgery. 2014. T. 20, No. 2. P. 27-36.
Fedin A. I., Rumyantseva S. A. Selected issues of basic intensive therapy of cerebrovascular disorders. Methodical instructions. M.: Intermedica, 2002. 256 p.
Fedin A. I., Starykh E. P., Parfenov A. S., Mironova O. P., Abdrakhmanova E. K., Starykh E. V. Pharmacological correction of endothelial dysfunction in atherosclerotic chronic cerebral ischemia // Journal of Neurology and Psychiatry named after. S. S. Korsakova. 2013. T. 113. No. 10. P. 45-48.

A. I. Fedin,
E. P. Starykh 1
M. V. Putilina, Doctor of Medical Sciences, Professor
E. V. Starykh,Doctor of Medical Sciences, Professor
O. P. Mironova, Candidate of Medical Sciences
K. R. Badalyan

H What is the cause of the development of metabolic syndrome and insulin resistance (IR) of tissues? What is the relationship between IR and progression of atherosclerosis? These questions have not yet received a clear answer. It is believed that the primary defect underlying the development of IR is dysfunction of vascular endothelial cells.

Vascular endothelium is a hormonally active tissue, which is conventionally called the largest “endocrine gland” in humans. If all endothelial cells are isolated from the body, their weight will be approximately 2 kg, and their total length will be about 7 km. The unique position of endothelial cells at the border between circulating blood and tissues makes them most vulnerable to various pathogenic factors in the systemic and tissue circulation. It is these cells that are the first to encounter reactive free radicals, oxidized low-density lipoproteins, hypercholesterolemia, high hydrostatic pressure inside the vessels they line (with arterial hypertension), with hyperglycemia (with diabetes). All these factors lead to damage to the vascular endothelium, to dysfunction of the endothelium as an endocrine organ and to the accelerated development of angiopathy and atherosclerosis. A list of endothelial functions and their disorders are listed in Table 1.

Functional restructuring of the endothelium under the influence of pathological factors goes through several stages:

Stage I - increased synthetic activity of endothelial cells, the endothelium works as a “biosynthetic machine”.

Stage II - violation of the balanced secretion of factors regulating vascular tone, the hemostasis system, and processes of intercellular interaction. At this stage, the natural barrier function of the endothelium is disrupted and its permeability to various plasma components increases.

Stage III - depletion of the endothelium, accompanied by cell death and slow processes of endothelial regeneration.

Of all the factors synthesized by the endothelium, the role of “moderator” of the main functions of the endothelium belongs to endothelial relaxation factor or nitric oxide (NO). It is this compound that regulates the activity and sequence of “launching” of all other biologically active substances produced by the endothelium. Nitric oxide not only causes vasodilation, but also blocks the proliferation of smooth muscle cells, prevents the adhesion of blood cells and has antiplatelet properties. Thus, nitric oxide is a basic factor in antiatherogenesis.

Unfortunately, it is the NO-producing function of the endothelium that turns out to be the most vulnerable. The reason for this is the high instability of the NO molecule, which is by nature a free radical. As a result, the beneficial antiatherogenic effect of NO is leveled out and gives way to the toxic atherogenic effect of other factors of damaged endothelium.

Currently There are two points of view on the cause of endotheliopathy in metabolic syndrome . Proponents of the first hypothesis argue that endothelial dysfunction is secondary to existing IR, i.e. is a consequence of those factors that characterize the state of IR - hyperglycemia, arterial hypertension, dyslipidemia. During hyperglycemia, the enzyme protein kinase C is activated in endothelial cells, which increases the permeability of vascular cells to proteins and impairs endothelium-dependent vascular relaxation. In addition, hyperglycemia activates peroxidation processes, the products of which inhibit the vasodilatory function of the endothelium. In arterial hypertension, increased mechanical pressure on the walls of blood vessels leads to disruption of the architecture of endothelial cells, increased permeability to albumin, increased secretion of vasoconstrictor endothelin-1, and remodeling of vascular walls. Dyslipidemia increases the expression of adhesion molecules on the surface of endothelial cells, which gives rise to the formation of atheroma. Thus, all of the above conditions, increasing endothelial permeability, expression of adhesive molecules, reducing endothelium-dependent vascular relaxation, contribute to the progression of atherogenesis.

Proponents of another hypothesis believe that endothelial dysfunction is not a consequence, but a cause of the development of IR and related conditions (hyperglycemia, hypertension, dyslipidemia). Indeed, in order to connect with its receptors, insulin must cross the endothelium and enter the intercellular space. In the case of a primary defect in endothelial cells, transendothelial insulin transport is impaired. Consequently, an IR condition may develop. In this case, IR will be secondary to endotheliopathy (Fig. 1).

Rice. 1. Possible role of endothelial dysfunction in the development of insulin resistance syndrome

In order to prove this point of view, it is necessary to examine the state of the endothelium before the onset of IR symptoms, i.e. in individuals at high risk of developing metabolic syndrome. Presumably, children born with low birth weight (less than 2.5 kg) are at high risk of developing IR syndrome. It is these children who subsequently develop all the signs of metabolic syndrome in adulthood. This is associated with insufficient intrauterine capillarization of developing tissues and organs, including the pancreas, kidneys, and skeletal muscles. When examining children aged 9-11 years who were born with low birth weight, a significant decrease in endothelium-dependent vascular relaxation and a low level of the antiatherogenic fraction of high-density lipoproteins were found, despite the absence of other signs of IR. This study suggests that, indeed, endotheliopathy is primary to IR.

To date, there has been no sufficient evidence to support the primary or secondary role of endotheliopathy in the genesis of IR. At the same time, it is an indisputable fact that that endothelial dysfunction is the first link in the development of atherosclerosis associated with IR syndrome . Therefore, the search for therapeutic options for restoring impaired endothelial function remains the most promising in the prevention and treatment of atherosclerosis. All conditions included in the concept of metabolic syndrome (hyperglycemia, arterial hypertension, hypercholesterolemia) aggravate endothelial cell dysfunction. Therefore, eliminating (or correcting) these factors will certainly improve endothelial function. Antioxidants that eliminate the damaging effects of oxidative stress on vascular cells, as well as drugs that increase the production of endogenous nitric oxide (NO), such as L-arginine, remain promising drugs that can improve endothelial function.

Table 2 lists drugs that have been shown to have antiatherogenic effects by improving endothelial function. These include: statins ( simvastatin ), angiotensin-converting enzyme inhibitors (in particular, enalapril ), antioxidants, L-arginine, estrogens.

Experimental and clinical studies to identify the primary link in the development of IR are ongoing. At the same time, a search is underway for drugs that can normalize and balance endothelial functions in various manifestations of insulin resistance syndrome. It has now become quite obvious that a particular drug can only have an antiatherogenic effect and prevent the development of cardiovascular diseases if it directly or indirectly restores the normal function of endothelial cells.

Simvastatin -

Zokor (trade name)

(Merck Sharp & Dohme Idea)

Enalapril -

Vero-enalapril (trade name)

(Veropharm CJSC)

?■ .: ...

1. The development of atherosclerosis and its complications (ischemic heart disease, acute myocardial infarction, cerebral stroke, remodeling of the heart and blood vessels, heart failure, and, finally, death) is a sequential chain of events united by the concept of the cardiovascular continuum (CVC). The triggering point for SSC is a number of diseases and factors, such as arterial hypertension, lipid and carbohydrate metabolism disorders, smoking, etc. (so-called “risk factors”).

2. The influence of risk factors on the development of SSC can be carried out with the participation of various mechanisms. One of the most important among them is endothelial dysfunction (ED). ED is defined as the loss of endothelial barrier properties, the ability to regulate the tone and thickness of the vessel, control the processes of coagulation and fibrinolysis, and have an immune and anti-inflammatory effect. The underlying mechanisms of ED are associated with a decrease in the synthesis and increased breakdown of NO - a universal biological mediator that blocks vasoconstrictive, proliferative and aggregative effects provoked by risk factors. Hyperactivation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in NO metabolism disorders and the development of ED. Increased synthesis of angiotensin II on the surface of endothelial cells leads not only to a decrease in the expression of NO, but also to an acceleration of the proliferation of SMCs (the development of hypertrophy of the vascular wall - HSS and left ventricle LVH), to increased adhesiveness and permeability of the vessel and the development of microangiopathy, strengthening the inflammatory component of the vascular wall’s response to risk factors.

The loss of barrier qualities by the endothelium, increased permeability of the wall to cholesterol-rich lipoproteins and macrophages serves as the basis for the development of atherosclerotic changes (lipid spots, streaks, and then plaques) in the intima of the vessel. The gradual development of a chronic stenotic process in the coronary arteries of the coronary arteries and the subsequent hibernation of the myocardium themselves gradually lead to cardiac remodeling. This is also facilitated by the energy-intensive and hemodynamically (through an increase in peripheral vascular resistance) interconnected GSS and LVH.

A significant acceleration in the development of SSC occurs when an atherosclerotic plaque is destabilized and ruptured and a thrombus is formed at the site of rupture. The clinical expression of this situation is acute coronary syndrome (ACS) and AMI. (or stroke in relation to the brain). The main reason for the destabilization of the plaque and the development of ACS is ED: the development of inflammation on its surface, increasing the permeability of the endothelium to macrophages and blood cells, increasing the coagulating and weakening fibrinolytic properties of the blood.

Reducing the consequences of a vascular accident (AMI, stroke) and reducing the death of cardiomyocytes (CMC) is the main goal of the next stage of CVS. Achieving this goal became possible with the advent of drug and surgical methods for eliminating (preventing) stenosis. The most effective and affordable of them is angioplasty with stenting of target vessels. However, mechanical impact on the vessel and elimination of stenosis, especially in conditions of ED, after some time often provokes the development of restenosis, which can contribute to the formation of even more CMC and aggravate the course of the underlying disease. The same applies to reconstructive operations on the vessels of the heart (brain, etc.).

At the next stage of SSC - during post-infarction cardiac remodeling, the absence of the protective role of the vascular endothelium leads to the rapid development of clinically significant heart failure and, without appropriate treatment, to death. Proliferative processes in the myocardium with a predominance of fibrosis, a lack of reserve for dilatation of the microvascular bed as a consequence, a decrease in myocardial contractility, especially under load, is a direct result of ED. A manifestation of ED in the periphery in patients with CHF is a violation of microcirculation in the striated muscles and the associated decrease in stress tolerance, a tendency to edema, and the development of cachexia.

The central role of ED in the development of CVS is due to the fact that 90% of the RAAS components are located in tissues: in the heart, kidneys, adrenal glands, but mainly on the surface of vascular endothelial cells. Therefore, hyperactivation of the RAAS most often and quickly affects the vascular endothelium. Knowledge of the mechanisms and driving forces of the development of CVS arms us with the understanding that the optimal means of preventing and treating CVS diseases are, among others, measures to eliminate ED. Since hyperactivation in the tissue (endothelial) RAAS plays a key role in the development of ED, the most effective drugs will be ACE inhibitors. having the highest affinity for tissue components of the RAAS. The drug of choice among other ACE inhibitors is quinapril (Accupro), a drug with the best indicators of blocking activity of the tissue RAAS.

Tatyana Khmara, cardiologist, City Clinical Hospital named after I.V. Davydovsky about a non-invasive method for diagnosing atherosclerosis at an early stage and selecting an individual aerobic physical activity program for the recovery period of patients with myocardial infarction.

Today, the FMD test (assessment of endothelial function) is the “gold standard” for non-invasive assessment of endothelial condition.

ENDOTHELIAL DYSFUNCTION

The endothelium is a single layer of cells lining the inner surface of blood vessels. Endothelial cells perform many vascular functions, including vasoconstriction and dilation, to control blood pressure.

All cardiovascular risk factors (hypercholesterolemia, arterial hypertension, impaired glucose tolerance, smoking, age, excess weight, sedentary lifestyle, chronic inflammation and others) lead to dysfunction of endothelial cells.

Endothelial dysfunction is an important precursor and early marker of atherosclerosis, allows for a fairly informative assessment of the selection of treatment for arterial hypertension (if the selection of treatment is adequate, then the vessels respond correctly to therapy), and also often allows timely identification and correction of impotence in the early stages.

Assessment of the state of the endothelial system formed the basis of the FMD test, which allows identifying risk factors for the development of cardiovascular diseases.

HOW IT’S DONEFMD TEST:

The non-invasive FMD method involves a vessel stress test (analogous to a stress test). The sequence of the test consists of the following steps: measuring the initial diameter of the artery, clamping the brachial artery for 5-7 minutes and re-measuring the diameter of the artery after removing the clamp.

During compression, the blood volume in the vessel increases and the endothelium begins to produce nitric oxide (NO). When the clamp is removed, blood flow is restored and the vessel expands due to accumulated nitric oxide and a sharp increase in blood flow speed (300–800% of the original). After a few minutes, the dilation of the vessel reaches its peak. Thus, the main parameter monitored by this technique is the increase in the diameter of the brachial artery (%FMD is usually 5–15%).

Clinical statistics show that in people with an increased risk of developing cardiovascular diseases, the degree of vascular dilation (%FMD) is lower than in healthy people due to the fact that endothelial function and nitric oxide (NO) production are impaired.

WHEN TO DO A VASCULAR STRESS TEST

Assessing endothelial function is the starting point for understanding what is happening to the body's vascular system even during initial diagnosis (for example, a patient presenting with vague chest pain). Now it is customary to look at the initial state of the endothelial bed (there is a spasm or not) - this allows you to understand what is happening to the body, whether there is arterial hypertension, whether there is vasoconstriction, whether there is any pain associated with coronary heart disease.

Endothelial dysfunction is reversible. With the correction of risk factors that led to disorders, endothelial function is normalized, which makes it possible to monitor the effectiveness of the therapy used and, with regular measurement of endothelial function, to select an individual aerobic physical activity program.

SELECTION OF AN INDIVIDUAL PROGRAM OF AEROBIC PHYSICAL ACTIVITY

Not every load has a good effect on blood vessels. Too intense exercise can lead to endothelial dysfunction. It is especially important to understand the load limits for patients in the recovery period after heart surgery.

For such patients in the City Clinical Hospital named after. I.V. Davydovsky, under the leadership of the Head of the University Clinic of Cardiology, Professor A.V. Shpektra, developed a special method for selecting an individual physical activity program. In order to select the optimal physical activity for the patient, we measure %FMD readings at rest, with minimal physical activity and at the maximum load. Thus, both the lower and upper limits of the load are determined, and an individual load program is selected for the patient, the most physiological for each person.

It has been proven that endothelial cells of the vascular bed, carrying out the synthesis of locally acting mediators, are morphofunctionally oriented towards optimal regulation of organ blood flow. The total mass of the endothelium in humans ranges from 1600-1900 g, which is even greater than the mass of the liver. Since endothelial cells secrete a large number of different substances into the blood and surrounding tissues, their complex can therefore be considered the largest endocrine system.

In the pathogenesis and clinic of arterial hypertension, atherosclerosis, diabetes mellitus and their complications, one of the important aspects is considered to be disruption of the structure and function of the endothelium. In these diseases, it appears as the primary target organ, since the endothelial lining of blood vessels is involved in the regulation of vascular tone, hemostasis, immune response, migration of blood cells into the vascular wall, synthesis of inflammatory factors and their inhibitors, and performs barrier functions.

Currently, endothelial dysfunction is understood as an imbalance between mediators that normally ensure the optimal course of all endothelium-dependent processes.

Disturbances in the production, action, and destruction of endothelial vasoactive factors are observed simultaneously with abnormal vascular reactivity, changes in the structure and growth of blood vessels, which are accompanied by vascular diseases.

The pathogenetic role of endothelial dysfunction (EDF) has been proven in a number of the most common diseases and pathological conditions: atherosclerosis, arterial hypertension, pulmonary hypertension, heart failure, dilated cardiomyopathy, obesity, hyperlipidemia, diabetes mellitus, hyperhomocysteinemia. This is facilitated by such modifiable risk factors for cardiovascular diseases as smoking, hypokinesia, salt load, various intoxications, disorders of carbohydrate, lipid, protein metabolism, infection, etc.

Doctors, as a rule, encounter patients in whom the consequences of endothelial dysfunction have already become symptoms of cardiovascular diseases. Rational therapy should be aimed at eliminating these symptoms (clinical manifestations of endothelial dysfunction may include vasospasm and thrombosis).

Treatment of endothelial dysfunction is aimed at restoring the vascular dilator response.

Drugs that have the potential to affect endothelial function can be divided into 4 main categories:

1. replacing natural projective endothelial substances (stable analogues of PGI2, nitrovasodilators, r-tPA);

2. inhibitors or antagonists of endothelial constrictor factors (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, TxA2 synthetase inhibitors and TxP2 receptor antagonists);

3. cytoprotective substances: free radical scavengers superoxide dismutase and probucol, lazaroid inhibitor of free radical production;

4. lipid-lowering drugs.

ACE inhibitors.

The effect of ACE inhibitors on endothelial function has been most widely studied. The enormous importance of the endothelium in the development of cardiovascular diseases stems from the fact that the main part of ACE is located on the membrane of endothelial cells. 90% of the total volume of the renin-angiotensin-aldosterone system (RAAS) is in organs and tissues (10% in plasma), so hyperactivation of the RAAS is a prerequisite for endothelial dysfunction.

The participation of ACE in the regulation of vascular tone is realized through the synthesis of the powerful vasoconstrictor angiotensin II (AII), which exerts its influence through stimulation of AT1 receptors of vascular smooth muscle cells. In addition, ATII stimulates the release of endothelin-1. At the same time, oxidative stress processes are stimulated, numerous growth factors and mitogens are synthesized (bFGF - fibroblast growth factor, PDGF - platelet-derived growth factor, TGF-b1 - transforming growth factor beta, etc.), under the influence of which the structure of the vascular wall changes.

Another mechanism, more associated with endothelial dysfunction itself, is associated with the property of ACE to accelerate the degradation of bradykinin. Secondary messengers of bradykinin are NO, prostaglandins, prostacyclin, tissue plasminogen activator, endothelial hyperpolarizing factor. An increase in the activity of ACE, located on the surface of endothelial cells, catalyzes the breakdown of bradykinin with the development of its relative deficiency. The lack of adequate stimulation of bradykinin B2 receptors of endothelial cells leads to a decrease in the synthesis of endothelial relaxation factor (EGF) - NO and an increase in the tone of vascular smooth muscle cells.

Comparison of the effect of ACE inhibitors on the endothelium with other antihypertensive drugs shows that simple normalization of pressure is not enough to restore endothelial function. Many studies have shown that ACE inhibitors can attenuate the process of atherosclerosis even in conditions of stable blood pressure and lipid profile. The best “success” in this direction is achieved by ACE inhibitors, which have the greatest affinity for the tissue (endothelial) RAAS.

Among the known ACE inhibitors, quinaprilat (the active metabolite of quinapril) has the greatest affinity for the tissue RAAS, which in terms of tissue affinity is 2 times higher than perindoprilat, 3 times higher than ramiprilat and 15 times higher than enalaprilat. The mechanism of the positive effect of quinapril on endothelial dysfunction is associated not only with its modulating effect on bradykinin metabolism and improvement of the function of B2 receptors, but also with the ability of this drug to restore the normal activity of muscarinic (M) endothelial receptors, which leads to indirect dilatation of arteries due to receptor-dependent increase synthesis of EGF-NO. There is now evidence that quinapril has a direct modulating effect on EGF-NO synthesis.

The ability to improve endothelial function is also demonstrated by other ACE inhibitors that have a high affinity for the tissue RAAS, in particular perindopril, ramipril, and, less commonly, enalapril.

Thus, taking ACE inhibitors neutralizes the vasoconstrictor effects, prevents or slows down the remodeling of the walls of blood vessels and the heart. Noticeable morphofunctional changes in the endothelium should be expected after approximately 3-6 months of taking ACE inhibitors.

Lipid-lowering drugs.

Currently, the most popular theory is that atherosclerosis is considered as a reaction to damage to the vascular wall (primarily the endothelium). The most important damaging factor is hypercholesterolemia.

The richest lipoprotein (LP) particles are low-density lipoproteins (LDL), which carry about 70% of plasma cholesterol (CL).

On the surface of the endothelium there are specialized receptors for various macromolecules, in particular for LDL. It has been shown that with hypercholesterolemia, the structure of the endothelium changes: the cholesterol content and the ratio of cholesterol/phospholipids in the membrane of endothelial cells increases, which leads to a disruption of the barrier function of the endothelium and an increase in its permeability to LDL. The result is excessive intimal infiltration of LDL. During passage through the endothelium, LDL undergoes oxidation, and mainly oxidized forms of LDL penetrate into the intima, which themselves have a damaging effect on the structural elements of both the endothelium and the intima. As a result of modification (oxidation) of LDL with the help of “scavenger receptors”, massive uncontrolled accumulation of cholesterol occurs in the vascular wall with the formation of foam cells - monocytes, which penetrate the endothelium, accumulate in the subendothelial space and acquire the properties of macrophages that capture lipids. The role of macrophages is far from exhausted by this. They secrete biologically active compounds, including chemotaxins, mitogens and growth factors, which stimulate the migration from the media to the intima of smooth muscle cells and fibroblasts, their proliferation, replication and synthesis of connective tissue.

Peroxide-modified LDL is the most atherogenic. They have a direct cytotoxic effect, causing damage to the endothelium, stimulate the adhesion of monocytes on its surface, interact with blood clotting factors, activating the expression of thromboplastin and plasminogen activation inhibitor.

Peroxide-modified LDL plays a role directly in the development of endothelial dysfunction, inhibiting the production of endothelial relaxation factor - NO and causing increased production of endothelin - a potential vasoconstrictor.

In the early stages, atherosclerosis is represented by so-called lipid strips, which contain foam cells rich in cholesterol and its esters. Subsequently, connective tissue develops around the area of lipid accumulation and the formation of a fibrous atherosclerotic plaque occurs.

According to the currently accepted concept, the clinical and prognostic significance of coronary atherosclerosis is determined by the stage of development and morphological features of atherosclerotic plaques.

In the early stages of formation, they contain a large amount of lipids and have a thin connective tissue capsule. These are the so-called vulnerable, or yellow, plaques. The thin connective tissue membrane of yellow plaques can be damaged both due to the influence of hemodynamic factors (pressure changes in the vessel, compression and stretching of the wall), and as a result of the fact that macrophages and mast cells contained near the membrane produce proteinases that can destroy the protective interstitial matrix . Erosion or rupture of the connective tissue capsule of yellow plaques occurs at the edge of the plaque near the intact segment of the coronary artery. Violation of the integrity of the fibrous capsule leads to contact of the detritus and lipids contained in the plaque with platelets and to the immediate formation of a blood clot. The release of vasoactive substances by platelets can lead to coronary artery spasm. As a result, acute coronary syndrome develops - unstable angina or small-focal myocardial infarction (with parietal thrombosis of the coronary artery), large-focal myocardial infarction (with occlusive coronary artery). Another manifestation of atherosclerotic plaque rupture may be sudden death.

At later stages of development, fibrous plaques are dense, rigid formations that have a strong connective tissue capsule and contain relatively few lipids and a lot of fibrous tissue - white plaques. Such plaques are located concentrically, cause hemodynamically significant (75% or more) narrowing of the coronary artery and, thus, are the morphological substrate of stable angina pectoris.

The possibility of rupture of the dense fibrous capsule of a white plaque is not excluded, but is much less likely than a yellow plaque.

Due to the importance that is currently attached to vulnerable (yellow) plaques in the genesis of acute coronary syndrome, the prevention of their formation is considered as the main goal of lipid-lowering therapy in primary and especially in secondary prevention of coronary artery disease. Statin therapy can stabilize an atherosclerotic plaque, that is, strengthen its capsule and reduce the likelihood of rupture.

Experience with the use of various lipid-lowering drugs shows that in many cases the beneficial effect of treatment of patients is observed already in the first weeks, when there is no talk of regression of atherosclerotic lesions. The positive effect of lipid-lowering drugs in the early periods of their use is primarily due to the fact that a decrease in the level of LDL cholesterol in the blood leads to an improvement in endothelial function, a decrease in the number of adhesive molecules, normalization of the blood coagulation system and restoration of NO formation suppressed during hypercholesterolemia.

With hypercholesterolemia, the formation of NO is suppressed and the response of the arteries to the action of vasodilators such as acetylcholine is distorted. Reducing the level of cholesterol in the blood allows you to restore the ability of arteries to dilate when exposed to biologically active substances. Another reason for the beneficial effect of lipid-lowering therapy is the improvement of oxygen diffusion through the capillary wall with reduced levels of cholesterol and LDL.

Naturally, after 1.5-2 months of treatment with lipid-lowering drugs, atherosclerotic plaques cannot decrease in size. The functional class of angina pectoris primarily depends on the tendency of the arteries to spasm, on the initial vascular tone, which is primarily determined by the oxygenation of smooth muscle cells. The relationship between the concentration of blood lipids and oxygenation of the endothelium of the vascular wall has been proven by a number of studies.

In the presence of hyperlipidemia, a kind of dynamic barrier of lipoproteins is created between the blood and the endothelial covering of the vessel, which, located on the periphery of the blood flow, serve as an obstacle to the path of oxygen from red blood cells to the vascular endothelium and beyond. If this obstacle to oxygen diffusion turns out to be significant, vascular tone will increase, and the readiness for regional vascular spasm increases.

A particularly important result of lipid-lowering therapy is a reduction in mortality from cardiovascular diseases and overall mortality. This was established in many fundamental studies on the primary and secondary prevention of atherosclerosis and ischemic heart disease, in which cholesterol-lowering therapy for about 5 years led to a reduction in mortality from cardiovascular diseases by 30-42% and overall mortality by 22-30%. .

Antioxidants.

There is ample evidence that free radicals, lipid peroxidation and oxidative changes in LDL play a role in the initiation of the atherosclerotic process. Oxidized LDL is highly toxic to cells and may be responsible for damage to the endothelial layer and death of smooth muscle cells.

Peroxide-modified LDL delays the formation or inactivates NO. With hypercholesterolemia and developing atherosclerosis, when the production of superoxide radical by endothelial cells and macrophages is increased, conditions are created for the direct interaction of NO with the superoxide radical with the formation of peroxynitrate (ONNN-), which also has a strong oxidative potential. In this case, switching NO to the formation of peroxynitrate deprives it of the opportunity to exhibit a protective effect on the endothelium.

According to numerous experimental and clinical studies, it has been revealed that antioxidants inhibit the modification of LDL, reduce their entry into the arterial wall and, thus, prevent the development of atherosclerosis.

A decrease in the concentration of lipids in the blood also entails a decrease in lipid peroxidation products, which have a damaging effect on the endothelium. It is not surprising that the combined use of cholesterol-lowering drugs from the group of HMC-CoA reductase inhibitors and antioxidants (probucol) has a more pronounced protective effect on the endothelium than these drugs alone.

There is evidence that the precursors of foam cells, macrophages, do not phagocytose native, unchanged LDL; they ingest only modified LDL, after which they transform into foam cells. It is they, which have undergone LDL peroxidation and are captured by macrophages, that play a leading role in the development of endothelial dysfunction and the progression of atherosclerosis.

Antioxidants protect LDL from peroxidation, and therefore from intensive uptake of LDL by macrophages, thus reducing the formation of foam cells, endothelial damage and the possibility of intimal lipid infiltration.

Free peroxide radicals inactivate NO synthetase. This effect underlies the positive effect of antioxidants on the tone and regulating function of the endothelium.

One of the most well-known antioxidants is vitamin E - alpha-tocopherol. A number of studies have been conducted that have demonstrated that vitamin E at a dose of 400-800-1000 IU per day (100 IU corresponds to 100 mg of tocopherol) reduces the sensitivity of LDL to oxidation and protects against the development of endothelial dysfunction and the progression of atherosclerosis - IHD.

In large doses (1 g per day), ascorbic acid, vitamin C, also has an antioxidant effect, which also significantly reduces the sensitivity of LDL to oxidation.

Beta-carotene, provitamin A, has a similar effect on LDL, so beta-carotene, like vitamins C and E, inhibits the oxidation of LDL and can be considered as one of the means of preventing atherosclerosis.

Simultaneous long-term use of vitamins C and E for preventive purposes reduces the risk of death from coronary artery disease by 53%.

The antioxidant properties of probucol should be especially highlighted. Probucol is a weak lipid-lowering drug. The effect of probucol is not associated with a decrease in blood lipid levels. In the blood, it binds to lipoproteins, including LDL, protecting them from peroxide modification and thus exhibiting an antioxidant effect. Probucol is dosed at 0.5 2 times a day. After treatment for 4-6 months, it is necessary to take a break from taking it for several months.

Among the antioxidants, the well-known drug Preductal (trimetazidine, Servier, France) stands apart. The use of preductal is based on its ability to reduce cell damage caused by free radicals.

It is now obvious that atherosclerosis is a process characterized by fundamental patterns inherent in any inflammation: exposure to a damaging factor (oxidized LDL), cellular infiltration, phagocytosis and formation of connective tissue.

Trimetazidine is now known to significantly reduce the production of malondialdehyde and diene conjugates. In addition, it maximally prevents intracellular glutathione deficiency (a natural intracellular “scavenger” of free radicals) and increases the ratio of reduced/oxidized glutathione. These data indicate that against the background of trimetazidine, the increase in oxidative activity of cells occurs to a lesser extent.

The effect of trimetazidine also affects platelet aggregation. This effect is due to inhibition of the arachidonic acid cascade and thereby a decrease in the production of thromboxane A2. This further manifests itself in a decrease in platelet aggregation caused by collagen.

There is also evidence that trimetazidine prevents the activation of neutrophils.

Hormone replacement therapy in women (HRT).

HRT in women after menopause is currently considered as one of the important areas in the prevention and treatment of coronary artery disease and arterial hypertension.

Available data on the vasoprotective effect of estrogens indicate that under the influence of estrogens the synthesis of prostacyclin increases, the adhesive properties of platelets, macrophages and leukocytes, the content of cholesterol and LDL decrease.

According to the placebo-controlled HERZ study, HRT increases basal NO levels and thereby reduces blood pressure.

Promising directions in the treatment of endothelial dysfunction.

Great hopes are placed on the activation of the L-arginine/NO/guanylate cyclase system by exogenous factors. Nitrosothiol, sodium nitroprusside, L-arginine, protoporphyrin X, disulfide, etc. can be used as activators.

The use of the drug bosentan, which is an endothelin receptor blocker, is promising.

Encouraging results have also been obtained from experimental and clinical trials of recombinant genes encoding the synthesis of endothelial growth factors VEGF and bFGF. A single transendocardial injection of the DNA of these genes into the zone of hibernating myocardium in a number of patients with coronary artery disease caused, after 3-6 months, a significant increase in perfusion and left ventricular ejection fraction, reduced the frequency of angina attacks, and increased exercise tolerance. A noticeable clinical effect was obtained when these drugs were administered into ischemic tissues of patients with obliterating atherosclerosis of the arteries of the lower extremities.

Among medications, the drug nebivolol (Nebilet, Berlin-Chemie, Germany) deserves special attention - it is a representative of the third generation of highly selective beta-blockers. This agent has a modulating effect on the release of NO by the vascular endothelium with subsequent physiological vasodilation. This induces endothelium-dependent relaxation of the coronary arteries. Pre- and afterload, end-diastolic pressure in the left ventricle are gently reduced, and diastolic dysfunction of the heart is eliminated.

Normalization of endothelial function is achieved in a number of cases as a result of correction of risk factors and non-drug treatment methods (loss of body weight in case of initial obesity, salt load, smoking cessation, alcohol abuse, elimination of various intoxications, including infectious origin, increased physical activity, physiotherapeutic and balneological procedures, etc.).

LDL apheresis is used to treat patients with homozygous and heterozygous familial hypercholesterolemia resistant to dietary therapy and lipid-lowering drugs. The essence of the method is the extraction of apo-B-containing drugs from the blood using extracorporeal binding with immunosorbents or dextran cellulose. Immediately after this procedure, the level of LDL cholesterol decreases by 70-80%. The effect of the intervention is temporary, and therefore regular lifelong repeated sessions are required at intervals of 2 weeks to 1 month. Due to the complexity and high cost of this treatment method, it can be used in a very limited number of patients.

Thus, the available arsenal of drugs and non-drug treatment methods already today makes it possible to effectively correct endothelial dysfunction for a number of diseases.

Assessment and correction of endothelial dysfunction today is a new and most promising direction in the development of cardiology.