Part I. Diseases of Blood Circulation Organs

Atherosclerosis is the process that alters the artery wall so that in some of its sections atherosclerotic plaques — local thickening caused by deposition of cholesterol (C), fat and some other blood components, are formed, resulting in reduction of the internal arterial lumen.

As atherosclerosis progresses, the reduction reaches such a degree that the blood, rich with oxygen and other nutrients, hardly reaches the organ supplied by this vessel such as the heart or brain. In severe cases, the artery lumen can be completely closed. Process of artery closing is called occlusion. It occurs due to overlap of the vessel lumen by growing deposits, as well as as a result of blocking of the narrowed lumen by a blood clot. The latter case is referred to as formation of the so-called complicated plaque (Fig. 1.1), the surface of which is damaged as a result of rupture or erosion caused by a combination of several factors (loose lipid core, weakened plaque cover — due to a small amount of collagen and calcium, inflammation, unfavorable hemodynamic conditions, and other causes). Due to the disruption of the continuous plaque surface (“cracked” endothelium and adjacent vascular wall structures), the blood begins to contact the internal contents of the plaque, which contains substances able to trigger the processes of blood clot formation. The result of plaque rupture is thrombosis of various severity (mural or occlusive, i.e. completely closing the vessel lumen). To describe the latter condition, the term “atherothrombosis” is used, which is the most dangerous complication of atherosclerosis.

Atherothrombosis is considered the main cause of death and disability associated with atherosclerosis. The clinical consequences of atherothrombosis are acute ischemia, necrosis of part of an organ or tissue (myocardium, brain, limb, kidney, abdominal organs, etc.) that receives blood through this artery, or death of the patient (if a significant part of a vital organ has been damaged by ischemia or necrosis). The most frequent clinical symptoms of atherothrombosis are acute coronary syndromes (ACS; myocardial infarction — MI) and ischemic acute cerebrovascular events (ACVE — strokes). If the process of atherothrombosis occurs in the blood vessels of other organs (kidneys, limbs, abdominal organs), this leads to similar severe impairments of their functions.

Pathogenesis

Atherosclerotic damage to the arteries starts with the accumulation of lipoprotein particles rich with cholesterol in the arteries’ intima. The possibility of lipoproteins ingress and retention in the intima structures is, on the one hand, a result of increased endothelial permeability, on the other hand, — of binding the lipoprotein particles by components of the extracellular matrix, primarily with proteoglycan molecules.

Fig. 1.1. Atherosclerosis development. Schematic representation of the cross-section of the artery at different stages of the atherosclerotic process

Currently, the most substantiated point of view is that the initial stages of atherosclerosis are considered as a result of endothelial damage. The term “damage” in this situation suggests rather not mechanical injury of the endothelium but an impairment of its function manifested by increased permeability and adhesion. Normally, the interendothelial spaces are quite narrow and impenetrable for lipoproteins. Under the influence of certain substances (for example, catecholamines, angiotensin II, serotonin, endothelin, etc.), as well as under the influence of hypercholesterolemia, the interendothelial spaces widen, and low-density lipoprotein (LDL) particles penetrate the arterial intima (Fig. 1.2, part 1). Increase in blood cholesterol-rich lipoproteins content, arterial hypertension (AH), local hemodynamic changes, smoking, inflammatory diseases are considered among the principal factors causing arterial endothelium damage. It is believed that these, and, possibly, other unknown factors lead to loosening and thinning of the protective glycocalyx on the surface of endothelial cells, expansion of interendothelial gaps, loosening of endothelial fibrous structures and edema of the subendothelial intima layer.

Fig. 1.2. Atherosclerotic plague formation

Changes in the artery intima lipids are the next stage in atherosclerosis development. Lipoprotein particles that have penetrated the extracellular space of intima, bound and retained there by proteoglycans, are modified. Modified lipoproteins include peroxide-modified and glycosylated lipoproteins, autoimmune “lipoprotein-antibody”complexes, products of limited lipoprotein proteolysis, desialized and aggregated lipoproteins, and the above-mentioned complexes of lipoproteins with glycosaminoglycans. Modification of lipoproteins occurs not only in artery intima but also in the blood. The greatest significance in the development of atherosclerosis is currently attached to the chemical modification of lipoproteins occurring in intima: peroxidation and glycosylation.

Intima infiltration by circulating white blood cells and monocytes, which then transform into macrophages and, capturing modified LDL, turn into foam cells (see Fig. 1.2, part 2) is the next stage in atherosclerosis development. Before the interaction of monocytes and T-lymphocytes with endothelial cells and their penetration into the subendothelial space occurs, these cells adhere to the endothelium. This process involves special adhesive molecules and certain cytokines. White blood cells migration to the subendothelial space occurs not only under the influence of chemoattractant cytokines (chemokines) but also with the participation of modified LDL. By loading with lipids, macrophages participate in the removal of lipoproteins accumulated in the focus of developing atherosclerotic lesion. But in case of hyperlipidemia and a significant lipid accumulation in the artery wall, this function of macrophages is disrupted. As a result, foam cells, i.e. macrophages overloaded with lipids, mostly remain in arteries intima and die, undergoing apoptosis. At this time cholesterol esters, non-esterified cholesterol and cholesterol monohydrate crystals that were accumulated in the foam cells are released. These processes lead to focal cholesterol accumulation in arteries intima and create preconditions for the development of lipid spots, then lipid strips, and subsequently — atherosclerotic plaques. Foam cells also serve as a source of a number of cytokines and effector molecules such as oxygen superoxide anion and matrix metalloproteinases involved in the development and progression of atherosclerotic lesions.