Atherosclerosis: Causes and Risk Factors

The atherosclerosis feature is an atherosclerotic plaque that contains lipids (intracellular and extracellular cholesterol and phospholipids), inflammatory cells (such as macrophages, T cells), smooth muscle cells, connective tissue (eg, collagen, glycosaminoglycans, elastic fibers), thrombi and calcium deposits . All stages of atherosclerosis - from the formation and growth of plaques to complications - are considered an inflammatory response to damage. It is believed that the primary role is played by endothelial damage.

Atherosclerosis mainly affects certain areas of the arteries. Non-laminar, or turbulent, blood flow (for example, in arterial tree branches) leads to endothelial dysfunction and suppresses endothelial formation of nitric oxide, a potent vasodilator and an anti-inflammatory factor. This blood flow also stimulates endothelial cells to produce adhesion molecules that attract and bind inflammatory cells. Risk factors for atherosclerosis (such as dyslipidemia, diabetes mellitus, smoking, hypertension), oxidative stress factors (eg, superoxide radicals), angiotensin II and systemic infection also inhibit the release of nitric oxide and stimulate the formation of adhesion molecules, pro-inflammatory cytokines, hemotaxis proteins and vasoconstrictors substances; more precise mechanisms are unknown. As a result, monocytes and T-cells are fixed in the endothelium, these cells move to the subendothelial space, initiation and fixation of the local vascular inflammatory response. Monocytes in the subendothelium are transformed into macrophages. Blood lipids, especially low-density lipoproteins (LDL) and very low density (VLDL), also bind to endothelial cells and are oxidized in the subendothelial space. Oxidized lipids and transformed macrophages are converted into lipid filled foam cells, which is a typical early atherosclerotic change (the so-called fatty strips). Degradation of erythrocyte membranes, which occurs due to rupture of vasa vasorum and hemorrhage into the plaque, may be an important additional source of lipids within the plaques.

Macrophages produce pro-inflammatory cytokines that cause the migration of smooth muscle cells from the middle vascular membrane, which further attracts and stimulates the growth of macrophages. Various factors stimulate the proliferation of smooth muscle cells and increase the formation of a dense extracellular matrix. As a result, a subendothelial fibrous plaque is formed with a fibrous cover consisting of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. A process similar to the formation of bone tissue leads to calcification of the vagina of the plaque.

Atherosclerotic plaques can be stable or unstable. Stable plaques regress, remain stable, or grow slowly over several decades until they cause stenosis or become an obstacle. Unstable plaques are prone to direct erosion, cracking or rupture, causing acute thrombosis, occlusion and infarction much earlier than stenosis. Most clinical events are the result of unstable plaques that do not give significant changes on the angiogram; Thus, the stabilization of atherosclerotic plaques can be a way to reduce morbidity and mortality.

The elasticity of the fibrous cap and its resistance to damage depend on the balance of the processes of collagen formation and its cleavage. Plaque rupture occurs as a result of secretion of metalloproteases, cathepsins and collagenases by activated macrophages in a plaque. These enzymes lyse the fibrous lid, especially around the edges, causing the capsule to thin out and eventually rupture. T cells in the plaque contribute to the secretion of cytokines. The latter inhibit in smooth muscle cells the synthesis and deposition of collagen, which usually strengthens the plaque.

After rupture of the plaque, its contents enter circulating blood and trigger the formation of a thrombus; macrophages also stimulate thrombus formation due to the production of a tissue factor that promotes the formation of thrombin in vivo. Eventually, events can develop according to one of five scenarios:

• the organization of a thrombus and its incorporation into a plaque, which leads to a change in the structure of its surface and rapid growth;
• rapid growth of the thrombus before complete occlusion of the blood vessel, leading to acute ischemia of the corresponding organ;
• the development of embolism by a thrombus or parts thereof;
• filling the plaque with blood, increasing it in size with rapid occlusion of the vessel;
• development of embolism with plaque contents (other than thrombotic masses), leading to occlusion of more distal vessels.

Plaque stability depends on many factors, including its composition (the ratio of lipid content, inflammatory cells, smooth muscle cells, connective tissue and thrombus), wall tension (tire extension), magnitude, location of the nucleus and the location of the plaque with respect to the linear blood flow. Hemorrhages within the plaque can play an important role in the transformation of a stable plaque into an unstable one. In the coronary arteries, unstable plaques have a high content of macrophages, a large lipid core and a thin fibrous capsule; they narrow the lumen of the vessel by less than 50% and tend to burst suddenly. Unstable plaques in the carotid arteries have the same composition, but usually cause problems due to the development of severe stenosis and occlusion, without rupture. Atherosclerotic plaques of low risk have a thicker capsule and contain fewer lipids; they often narrow the lumen of the vessel by more than 50% and lead to the development of stable angina of tension.

In addition to the anatomical features of the plaque itself, the clinical consequences of its rupture depend on the balance of procoagulant and anticoagulant blood activity, as well as the probability of arrhythmia.

An infectious hypothesis of the development of atherosclerosis was proposed to explain the serological relationship between infections (for example, caused by Chlamydia pneumoniae, cytomegalovirus) and ischemic heart disease. Prospective mechanisms include the indirect effects of chronic inflammation in the bloodstream system, the formation of cross-antibody and the inflammatory response of the vascular wall in response to infectious pathogens.

[1], [2], [3], [4], [5], [6], [7], [8]

Risk factors for atherosclerosis

There are a large number of risk factors. Certain factors often occur simultaneously, as in the metabolic syndrome, which is becoming more common. This syndrome includes obesity, atherogenic dyslipidemia, hypertension, insulin resistance, a predisposition to thrombosis and general inflammatory reactions. Insulin resistance is not a synonym for metabolic syndrome, but a possible key link in its etiology.

Risk factors for atherosclerosis

Unmodified

• Age.
• Family history of early atherosclerosis.
• Male.

Proven Modified

• Proven dyslipidemia (high total cholesterol, LDL, low HDL).
• Diabetes.
• Smoking.
• Arterial hypertension.

Modifiable, being at the stage of study.

• Infection caused by Chlamydia pneumoniae.
• High content of C-reactive protein.
• High concentration of LDL.
• High HDL content (LP put the sign "alpha").
• Hyperhomocysteinemia.
• Hyperinsulinemia.
• Hypertriglyceridemia.
• Polymorphism of 5-lipoxygenase genes.
• Obesity.
• Prothrombotic conditions (eg, hyperfibrinogenemia, high content of plasminogen activator inhibitor).
• Renal failure.
• Sedentary lifestyle

Early atherosclerosis is a disease in relatives of the first degree of kinship at the age of 55 years for men and up to 65 years for women. It is unclear how these factors contribute, independently of other, often associated risk factors (eg, diabetes, dyslipidemia).

Dyslipidemia (high total cholesterol, LDL cholesterol or low HDL cholesterol), AH and diabetes mellitus contribute to the progression of atherosclerosis, enhancing endothelial dysfunction and inflammation in the vascular endothelium.

With dyslipidemia, the subendothelial amount and LDL oxidation increase. Oxidized lipids stimulate the synthesis of adhesion molecules and inflammatory cytokines, can have antigenic properties, initiating a T-mediated immune response and inflammation of the arterial wall. HDL protect against the development of atherosclerosis by reverse cholesterol transport; they can also protect by transporting enzymes of the antioxidant system that can neutralize oxidized lipids. The role of hypertriglyceridemia in atherogenesis is complex, and whether it has an independent, independent of other dyslipidemia value, is unclear.

Arterial hypertension can lead to vascular inflammation through the mechanism associated with angiotensin II. The latter stimulates endothelial cells, vascular smooth muscle cells and macrophages to form proatherogenic mediators, including pro-inflammatory cytokines, superoxide anions, prothrombotic factors, growth factors, and oxidized lectin-like LDL receptors.

Diabetes leads to the formation of glycolysis products, which increase the synthesis of pro-inflammatory cytokines in endothelial cells. Oxidative stress and oxygen radicals formed in diabetes mellitus directly damage the endothelium and promote atherogenesis.

Cigarette smoke contains nicotine and other chemicals toxic to the vascular endothelium. Smoking, including passive, increases the reactivity of platelets (possibly, promoting platelet thrombosis) and the content of fibrinogen in the blood plasma and hematocrit (which increases the viscosity of the blood). Smoking increases the amount of LDL and decreases HDL; it also leads to vasoconstriction, which is especially dangerous for arteries already narrowed due to atherosclerosis. The amount of HDL is increased to approximately 6-8 mg / dl for 1 month after cessation of smoking.

Hyperhomocysteinemia increases the risk of atherosclerosis, although not as much as the aforementioned risk factors. This may be a consequence of a deficiency of folic acid or a genetic metabolic defect. The pathophysiological mechanism is unknown, but can concern direct damage to the endothelium, stimulation of the production of monocytes and T cells, the capture of LDL by macrophages, and the proliferation of smooth muscle cells.

Lipoprotein (a) is a modified version of LDL that has a cysteine-enriched zone homologous to plasminogen. High content may predispose to atherothrombosis, but the mechanism is unclear.

A large number of LDL, characteristic of diabetes mellitus, is very atherogenic. The mechanism may include increased susceptibility to oxidation and nonspecific damage to the endothelium.

The high content of SRV does not reliably predict the degree of atherosclerosis, but may indicate the probability of ischemia development. It may indicate an increased risk of rupture of the capsule of atherosclerotic plaque, continued ulceration or thrombosis, or increased activity of lymphocytes and macrophages. SRV can participate in atherogenesis through a variety of mechanisms, including abnormal synthesis of nitric oxide and increased effects on angiotensin type 1 receptors, chemoattractant proteins, and adhesion molecules.

Infection caused by C. Pneumoniae or other pathogens (eg, viruses, including HIV, or Helicobacter pylori), can damage the endothelium by direct exposure, endotoxin, stimulation of systemic or subendothelial inflammation.

Renal failure contributes to the development of atherosclerosis in several ways, including weight gain hypertension and insulin resistance, a decrease in the number of apolipoprotein A-1, and an increase in lipoprotein (a), homocysteine, fibrinogen, and SRV.

Prothrombotic conditions increase the likelihood of atherothrombosis.

Polymorphism of 5-lipoxygenase (removal or addition of alleles) can potentiate atherosclerosis, increasing the synthesis of leukotrienes within plaques, leading to vascular reaction and migration of macrophages and monocytes, thus increasing subendothelial inflammation and dysfunction.