Atherosclerosis is a chronic disease with a progressive course whose development practically starts from birth. The primary substrate of an atherosclerotic lesion is the deposition of lipids in the blood vessel intimacy, leading to gradual narrowing and impaired blood flow through the tissues. The clinical manifestations of the atherosclerotic process are numerous and, above all, depend on the degree of narrowing and the rate of stenosis. The most common clinical manifestations are due to rupture of atherosclerotic plaque which activates the process of thrombogenesis and leads to the development of obstruction of blood vessels. Removal of risk factors such as obesity, hyperlipidemia, hypertension leads to repair of endothelial dysfunction and slowing the pathogenesis of atherosclerotic plaque.
What is atherosclerosis?
Atherosclerosis is a diffuse disease of the arterial blood vessels that affects all the vascular troughs and is characterized by thickening and hardening of the arterial wall. It occurs primarily in the intima of the abdominal aorta, its large and wide branches, the arteries for the lower extremities, as well as the coronary and cerebral arteries. It is characterized by extracellular and intracellular lipid accumulation, monocytic / macrophage infiltration, foam cell formation, smooth muscle cell proliferation, and connective tissue protein accumulation.
Clinically, atherosclerosis can manifest as: coronary heart disease (angina, infarction, sudden cardiac death); cerebrovascular disease (stroke); peripheral vascular disease (intermittent claudication, gangrene).
Atherosclerosis is a complex disease with many predisposing factors called risk factors.
We divide all risk factors for atherosclerosis into variable and immutable.
Recent studies have shown that in addition to the classic risk factors, the most significant of which are dyslipidemia, hypertension, cigarette consumption and diabetes, there are also non-traditional risk factors, which include elevated oxidative stress, endothelial dysfunction and inflammation. Despite the large number of pathogenetic factors involved in the pathogenesis of atherosclerosis, the central role is still attributed to lipid disorders, which have been shown to be a major catalyst for the atherosclerotic process.
Dyslipidemia is a disorder of fat metabolism. It results in impaired concentration of individual lipids (hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia). Hyperlipidemia is the main one cause of atherosclerosis and associated diseases, cardiovascular disease, ischemic cerebrovascular disease and peripheral vascular disease.
The most important risk factors for atherosclerosis are elevated LDL, decreased HDL, cigarette consumption, hypertension, type II diabetes mellitus, age, family history for first-line relatives (men younger than 55 years, women younger than 65 years).
Numerous studies have shown the key role of lipids in atherogenesis, that is, the risk of cardiovascular disease is significantly lower if LDL is lower than 4.2 mmol / l, even in the presence of other risk factors. The combination of risk factors increases the possibility of endothelial dysfunction and the incidence of myocardial infarction.
Cholesterol is an integral part of the cell membrane and plays an important role in the production of steroid hormones. The body receives cholesterol in two ways: by cholesterol biosynthesis in the liver or by food intake. If more cholesterol is introduced into the body, decreased synthesis in the liver will occur. Other cells cannot synthesize cholesterol de novo but receive it from plasma. In body fluids, cholesterol is transported by lipoproteins – chylomicrons, low density lipoproteins (LDL) and high density lipoproteins (HDL). Chylomicrons transport triglycerides, cholesterol and other lipids from food to the liver and adipose tissue. Low-density lipoproteins carry cholesterol (which is oleate esterified) to peripheral tissue, and high-density lipoproteins transfer cholesterol from peripheral tissue to the liver. As peripheral cells cannot synthesize cholesterol, their main source of cholesterol is LDL particles. The mechanism of cholesterol uptake from LDL is performed by the LDL receptor located on the cell surface. LDL binds to a specific receptor and internalizes, ie. LDL is transferred to the cytosol by endocytosis in the form of an endocytic vesicle. It fuses with lysosomes, and lysosome enzymes break down LDL into constituent amino acids while cholesterol is released for cellular purposes. Released, unsterified cholesterol can be used for membrane biosynthesis or, if not currently required, can be re-esterified and deposited in the cell until needed. In homozygotes, the full function of LDL receptors occurs, and they die very quickly from the fulminant development of atherosclerosis, while in heterozygotes, one half are functional LDL receptors.
As LDL receptors have no normal function, they accumulate in the bloodstream, as does cholesterol, which is associated with their deposition in the vessel wall and the onset of atherosclerosis.
High density lipoproteins (HDL) have a proven protective effect. The basis of this action is the inverse transport of cholesterol – the transport of cholesterol from the peripheral tissues to the liver. HDL particles also carry antioxidant enzymes (PAF-acetylhydrolase and paraxinase) that break down oxidized LDL particles and counteract their pro-inflammatory effect. In addition, they prevent the expression of certain adhesive molecules.
Hypertriglyceridemia leads to alteration of cell membrane structure and activation of adenyl cyclase with the formation of oxidative stress in endothelial cells, monocytes and lymphocytes. It also stimulates platelet aggregation and adhesion as well as proliferation of smooth muscle cells.
An independent factor for the occurrence of atherosclerosis is the increased concentration of Lp (a) in the blood plasma as a result of increased oxidation and easy penetration of this small lipoprotein into the intimate blood vessel. Correction of hyperlipidemia is at the same time the prevention and treatment of atherosclerosis and its consequences. Hyperlipidemia therapy reduces cardiovascular mortality by 30-40% and reduces the incidence of non-fatal cardiovascular events.
In addition to hyperlipidemia, hypertension is another important risk factor for atherogenesis. In many hypertensive patients, there is activation of the renin-angiotensin (RAS) system. Activation of this system with the formation of angiotensin II (AT II) and subsequent activation of the AT II receptor, mainly of type AT I, is involved in the process of atherogenesis. Angiotensin II increases the expression of inflammatory factors such as P-selectin and the monocyte chemo-attractant protein-1 (MCP-1), which regulate adhesion of monocytes and other inflammatory cells. It also increases the uptake of oxidized low-density lipo-protein (ox-LDL) and cholesterol biosynthesis in macrophages, translating them into foam cells; increases the activity of the LOX-1 gene in the coronary endothelium culture, leads to an increase in apoptosis in human endothelial cells, the activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in macrophages, and NADPH oxidase increases oxidative stress. Mechanical stress of the vessel wall is a major feature of arterial hypertension that leads to activation of NADPH oxidase in smooth muscle cells and the consequent increase in oxidative stress.
Hypertension and hyperlipidemia, as the most significant risk factors for coronary artery disease, are often associated with a large number of patients. Studies have shown that AT II and ox-LDL do not act independently in the process of atherogenesis. Common properties are that both factors lead to the formation and release of free radicals, the degradation or reduction of endothelial nitric oxide synthetase expression, which in turn reduces the endothelium-dependent vasodilation. They also induce the activation of redox-sensitive nuclear factor kappa-B (NF-kB) transcription and exhibit pro-inflammatory properties (induce expression of adhesion molecules and cytokines, up-regulation of the monocyte chemoattractant protein-1 gene, and induce monocytic adhesion and apoptosis.
Experimental studies have shown that hyperlipidemia increases RAS activity. There is a linear correlation between plasma LDL cholesterol concentration and AT I receptor expression. Hyperglycemia in diabetes increases oxidative stress, which contributes to vascular dysfunction. It affects endothelial dysfunction by free radical production, sorbitol accumulation, non-enzymatic glycolysis of macromolecules; by direct activation of protein kinase C. Glycolysis of proteins and lipids takes place in every diabetic patient and this irreversibly leads to long-term vascular dysfunction. Initial glyoxidation of proteins produces early glycosylated products. Subsequently, reorganization of the molecules occurs, partly by oxidation, and glycosylation end products (AGEs) are formed, which react with surface receptors to produce free radicals, reduce the level of reduced glutathione and activate redox-sensitive transcription of the NF-κB nuclear factor. In diabetics, oxidative modification of LDL particles occurs in the circulation, unlike non-diabetics, which is usually a vessel wall because there are enough antioxidants in the circulation. Created AGE (advansed glycation end products) LDL particles lead to the expression of VCAM-1 and monocyte-endothelial interaction with the formation of atherosclerotic lesions.
The importance of the metabolic syndrome, as a set of risk factors for the onset of cardiovascular disease, is reflected, first of all, in its current prevalence. Based on WHO and NCEP ATP III Criteria, the prevalence of metabolic syndrome in the general US population is estimated to be 24%, while in the US population over 60 years it is 44%.
Atherogenesis is the formation of atheroma (a plaque composed of a lipid nucleus surrounded by connective tissue), which is also a major event in atherosclerosis. The primary inducer for the development of atheroma is damage to the endothelium of the blood vessels. Endothelial dysfunction triggers a series of successive reactions leading to an atherosclerotic lesion. There is a direct relationship between the risk factors for atherosclerosis (smoking, hyperlipidemia, hypertension, diabetes, inflammation, infection) and endothelial dysfunction. The immune system is early involved in the initiation of atherosclerosis, playing a dominant role in the development of inflammatory response in plaque. The development of atherosclerosis begins with morphologically invisible damage to the endothelium, which can be caused by physical, mechanical, chemical, toxic, infectious and immune factors.
A growing body of evidence indicates that some pathogenetic stimuli play a role in the production of reactive oxidative particles in the endothelial microenvironment and that oxidative stress plays a key role in the formation of endothelial dysfunction associated with atherosclerosis.
Oxidative stress is identified through an atherosclerosis process, whose early stage is endothelial dysfunction. With the advancement of the process of atherosclerosis, a large amount of free radicals is produced that further promotes atherogenesis. Increased production of free radicals further influences four fundamental mechanisms of atherogenesis: oxidation of LDL, dysfunction of endothelial cells and smooth muscle cells, growth and migration of monocytes.
Risk factors for atherosclerosis, such as hypertension and hyperlipidemia, are associated with increased production of oxidative particles. The same thing happens in diabetes and smokers. Numerous cytokines, such as tumor necrosis factor (TNF-), interferon (INF-9), interleukins (IL-1, IL-6) and angiotensin II, play significant roles in the intracellular production of free radicals. High concentrations of low density lipoprotein (LDL), especially the oxidative form (ox-LDL), induce the production of free radicals. Growth factors such as platelet-derived growth factor (PDGF), epidermal (EGF-epidermal growth factor) and vascular endothelial growth factor (VEGF) and hormones such as insulin have similar effects.
Atherogenic lesions primarily occur within the intima of the blood vessel, and in their development they start from fatty streaks and diffuse thickening of the intimacy, through fibrolipid plaque, to the developed lesions complicated by thrombosis, hemorrhage or calcification (“complicated lesions”). Oxidation of LDL particles, fatty streak formation and smooth muscle cell proliferation are the basis for the formation of atheromatous fibrolipid plaque. Several cellular forms from the arterial wall and blood are involved in the process of atherogenesis, namely endothelial cells, smooth muscle cells, macrophages, platelets, as well as numerous growth factors. The lipid theory hypothesis is based on the increased incorporation and accumulation of plasma LDL lipoproteins into the blood vessel wall and their transformation into a much more atherogenic form, called modified LDL. Oxidation of LDL particles is an initial process of the emergence of modified forms of LDL particles that are then recognized and ingested by macrophages.
The most studied was the oxidative modification of LDL (ox-LDL), which gave its name to the “peroxide theory of atherogenesis”. Predilection sites for endothelial damage (blood vessels) accumulate excess circulating LDL, leading to endothelial damage manifested by changes in permeability of the endothelial barrier, procoagulant properties, and the release of vasoactive substances. Oxidatively modified LDL particles exert a chemotaxic effect on circulating monocytes as well as on T-Ly. In addition to this effect, modified LDL leads to increased adhesion and aggregation of monocytes and T-Ly, forming two adhesive molecules on the surface of the endothelium, namely the vascular adhesive molecule-1 (VCAM-1) and the intercellular adhesive molecule-1 (ICAM-1); and leads to stimulation of release of monocytic chemotaxis protein from endothelial cells and additional mobilization of monocytes from the circulation. Monocytes and T-Ly chemotaxis pass through the endothelium and in the subendothelial space are converted to macrophages, taking up a large amount of modified LDL into foam cells, which form the lipid nucleus of the atheroma. Endothelial and smooth muscle cells are thought to be capable of modifying LDL by initiating a process of lipid peroxidation, after which macrophages recognize and ingest such modified LDL. LDL oxidation is accompanied by endothelial dysfunction and, consequently, loss of endothelium-dependent vasodilation, initiation of an inflammatory response and worsening of anticoagulant protection for thrombosis. Macrophages can secrete oxidized LDL and superoxide anion, which further damages the endothelium. Activated macrophages secrete numerous growth factors (PDGF, which stimulates the proliferation of fibroblasts and smooth muscle cells, TGF-R growth factor for smooth muscle cells).
The change of macrophages into foam cells enables the smooth muscle cells to be drawn by chemotaxis from the medium in the intimacy where their division, synthesis and secretion of the connective tissue matrix occurs, which enables the development of a fibromuscular proliferative lesion.
Complications of atherosclerosis
The first and most characteristic lesion of advanced atherosclerosis is atherosclerotic plaque; it consists of a lipid-rich marrow in the central part of the eccentrically thickened intima. The surface of the plaque facing the lumen is covered by a fibrous cap. The central part of the plaque is filled with a grain of mushy content, which is created by the enlargement and confluence of small collections of extracellular lipids. Lipids (predominantly LDL) enter the bloodstream directly, by plasma insertion or endocytosis by macrophages, via scavenger receptors after oxidative modification, and accumulate indirectly after necrosis of lipids packed with lipids. Over time, plaque content also increases in the plaque, consisting mainly of collagen and smooth muscle cells. The growing fibrolipid plaque is a substrate for the development of acute thrombotic complications. The relative ratio of core size and connective tissue is essential for plaque prognosis. A large, eccentric lipid nucleus, high macrophage density, and thin fibrous cap are at high risk for plaque rupture, thrombosis, and the development of acute coronary syndrome.
In mature plaques, two major components of the plaque are represented in different proportions: soft, lipid-rich atheromatous slurry and firm, collagen-rich sclerotic tissue. The sclerosing component is usually far more voluminous, stabilizing plaque and protecting it from disruption, while atheromatous pulp destabilizes plaque and makes it susceptible to rupture. The main determinants of plaque vulnerability are the size and composition of the atheromatous marrow, the thickness of the fibrous cap covering the plaque, acute inflammation within the cap, and the fatigue of the cap due to loading. The predilection site for plaque rupture is the marginal region, where the fibrous cap is the thinnest and infiltrated by macrophages. The disintegration of the fibrous cap is followed by the sudden exposure of highly thrombogenic pulp to blood flow.
On previously ruptured plaque or intact plaque, sudden thrombosis may occur due to changes in platelet function, coagulation and / or fibrinolysis, which is probably an important mechanism responsible for complete blood vessel occlusion and the onset of infarction. The deleterious role of macrophages after plaque rupture is reflected in stimulating the generation of thrombin and luminal thrombosis via a tissue factor. Tissue factor is an integral membrane protein, which binds to factor VII / VIIa and initiates a coagulation cascade. It is expressed on the surface of lipid-packed monocytes, macrophages and foam cells in human atherosclerotic lesions. Plaque rupture is also accompanied by the development of hematomas through cleft fibrosis, although some hematomas may occur within the lesion due to bleeding from newly formed blood vessels. Mature plaques, especially if they contain a large amount of fibrous connective tissue, can calcify, with mineral deposits replacing extinct cells and extracellular lipids. Advanced lesions are often associated with localized enlargement of the part of the blood vessel they occupy. Aneurysms that develop in this way may contain mural thrombi, and fragments of thrombus that can be discharged into the systemic circulation can lead to embolism. Even in the absence of complicated lesions, with the progression of atherosclerosis, the lumen of the blood vessel is increasingly narrowed, blood flow is impaired and the risk of further damage to endothelial cells is increased; this closes the vicious circle. The narrowing of the lumen of the blood vessel is accompanied by tissue hypoxia, and due to the decreased elasticity of the blood vessels, blood pressure increases. This increases the possibility of rupture of the altered wall of the blood vessel and the consequent leakage of blood into the surrounding tissue, especially in conditions of sudden and greater increase in blood pressure.
Atherosclerosis is a dynamic process characterized by significant changes in artery biology due to hemodynamic changes caused by plaque growth and its disruption. Impaired vascular biology associated with atherosclerosis and its risk factors include vasomotor dysfunction and plaque inflammation as well as prothrombin antifibrinolytic condition.