Atherosclerosis - Causes and risk factors

The hallmark of atherosclerosis 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 (such as collagen, glycosaminoglycans, elastic fibers), thrombi, and calcium deposits. All stages of atherosclerosis, from plaque formation and growth to complications, are considered an inflammatory response to injury. Endothelial damage is thought to play a primary role.

Atherosclerosis preferentially affects certain regions of the arteries. Nonlaminar, or turbulent, blood flow (eg, at branching points in the arterial tree) leads to endothelial dysfunction and inhibits endothelial production of nitric oxide, a potent vasodilator and anti-inflammatory factor. Such blood flow also stimulates endothelial cells to produce adhesion molecules, which attract and bind inflammatory cells. Risk factors for atherosclerosis (eg, dyslipidemia, diabetes mellitus, smoking, hypertension), oxidative stressors (eg, superoxide radicals), angiotensin II, and systemic infection also inhibit nitric oxide release and stimulate production of adhesion molecules, proinflammatory cytokines, hemotactic proteins, and vasoconstrictors; the precise mechanisms are unknown. As a result, monocytes and T cells become attached to the endothelium, migrate to the subendothelial space, and initiate and perpetuate the local vascular inflammatory response. Monocytes in the subendothelial space are transformed into macrophages. Blood lipids, especially low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), also bind to endothelial cells and are oxidized in the subendothelial space. Oxidized lipids and transformed macrophages are transformed into lipid-filled foam cells, which is a typical early atherosclerotic change (so-called fatty streaks). Degradation of red blood cell membranes, which occurs as a result of rupture of the vasa vasorum and hemorrhage into the plaque, may be an important additional source of lipids within the plaque.

Macrophages secrete proinflammatory cytokines that induce smooth muscle cell migration from the media, which then attracts and stimulates macrophage growth. Various factors stimulate smooth muscle cell proliferation and increase the formation of a dense extracellular matrix. The result is a subendothelial fibrous plaque with a fibrous cap consisting of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. A process similar to bone formation leads to calcification within the plaque.

Atherosclerotic plaques may be stable or unstable. Stable plaques regress, remain stable, or grow slowly over several decades until they cause stenosis or become an obstruction. Unstable plaques tend to erode, fracture, or rupture directly, causing acute thrombosis, occlusion, and infarction much earlier than stenosis. Most clinical events result from unstable plaques that do not produce significant changes on angiography; thus, stabilization of atherosclerotic plaques may be a way to reduce morbidity and mortality.

The elasticity of the fibrous cap and its resistance to injury depend on the balance between collagen formation and degradation. Plaque rupture occurs as a result of the secretion of metalloproteases, cathepsins, and collagenases by activated macrophages in the plaque. These enzymes lyse the fibrous cap, especially at the edges, causing thinning of the capsule and eventual rupture. T cells in the plaque contribute by secreting cytokines. The latter inhibit the synthesis and deposition of collagen in smooth muscle cells, which normally strengthens the plaque.

After plaque rupture, its contents enter the circulating blood and initiate the process of thrombus formation; macrophages also stimulate thrombus formation by producing tissue factor, which promotes thrombin formation in vivo. Subsequently, events can develop according to one of five scenarios:

• 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 a thrombus to complete occlusion of a blood vessel, which leads to acute ischemia of the corresponding organ;
• development of embolism by a thrombus or its parts;
• filling of the plaque with blood, its increase in size with rapid occlusion of the vessel;
• development of embolism by 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 lipids, inflammatory cells, smooth muscle cells, connective tissue, and thrombus), wall stress (cap stretch), size, core location, and plaque position relative to linear blood flow. Intraplaque hemorrhage may play an important role in converting a stable plaque into an unstable one. In the coronary arteries, unstable plaques have a high macrophage content, a large lipid core, and a thin fibrous cap; they narrow the vessel lumen by less than 50% and tend to rupture suddenly. Unstable plaques in the carotid arteries have the same composition but usually cause problems by developing severe stenosis and occlusion without rupture. Low-risk atherosclerotic plaques have a thicker cap and contain less lipids; They often narrow the lumen of the vessel by more than 50% and lead to the development of stable angina.

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

The infectious hypothesis of atherosclerosis has been proposed to explain the serologic association between infections (e.g., Chlamydia pneumoniae, cytomegalovirus) and coronary artery disease. Proposed mechanisms include indirect effects of chronic inflammation in the bloodstream, cross-antibody formation, and vascular wall inflammatory response to infectious pathogens.

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Risk factors for atherosclerosis

There are many risk factors. Certain factors often co-occur, as in the metabolic syndrome, which is becoming increasingly 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

Non-modifiable

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

Proven to be modifiable

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

Modifiable, under study.

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

Early atherosclerosis is the disease in first-degree relatives before the age of 55 for men and before the age of 65 for women. It is unclear to what extent these factors contribute independently of other, often associated risk factors (eg, diabetes mellitus, dyslipidemia).

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

In dyslipidemia, the subendothelial amount and oxidation of LDL increases. Oxidized lipids stimulate the synthesis of adhesion molecules and inflammatory cytokines, and may have antigenic properties, initiating a T-mediated immune response and inflammation of the arterial wall. HDL protects against the development of atherosclerosis by reverse cholesterol transport; they may 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 significance independent of other dyslipidemias is unclear.

Arterial hypertension may lead to vascular inflammation via a mechanism associated with angiotensin II. The latter stimulates endothelial cells, vascular smooth muscle cells, and macrophages to produce proatherogenic mediators, including proinflammatory cytokines, superoxide anions, prothrombotic factors, growth factors, and oxidized lectin-like LDL receptors.

Diabetes mellitus leads to the formation of glycolysis products that increase the synthesis of proinflammatory 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 that are toxic to the vascular endothelium. Smoking, including passive smoking, increases platelet reactivity (possibly promoting platelet thrombosis) and plasma fibrinogen and hematocrit (increasing blood viscosity). Smoking increases LDL and decreases HDL; it also causes vasoconstriction, which is especially dangerous in arteries already narrowed by atherosclerosis. HDL increases to approximately 6 to 8 mg/dL within 1 month of smoking cessation.

Hyperhomocysteinemia increases the risk of atherosclerosis, although not as much as the above risk factors. It may be due to folate deficiency or a genetic metabolic defect. The pathophysiological mechanism is unknown but may involve direct endothelial injury, stimulation of monocyte and T cell production, LDL uptake by macrophages, and smooth muscle cell proliferation.

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

The high LDL levels characteristic of diabetes are highly atherogenic. The mechanism may involve increased susceptibility to oxidation and nonspecific endothelial injury.

High CRP levels do not reliably predict the degree of atherosclerosis but may indicate the likelihood of ischemia. They may indicate an increased risk of plaque rupture, ongoing ulceration or thrombosis, or increased lymphocyte and macrophage activity. CRP may be involved in atherogenesis through a variety of mechanisms, including impaired nitric oxide synthesis and increased effects on angiotensin type 1 receptors, chemoattractant proteins, and adhesion molecules.

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

Renal failure promotes the development of atherosclerosis in several ways, including worsening hypertension and insulin resistance, decreased apolipoprotein A-1, and increased lipoprotein(a), homocysteine, fibrinogen, and CRP.

Prothrombotic conditions increase the likelihood of atherothrombosis.

5-lipoxygenase polymorphisms (deletion or addition of alleles) can potentiate atherosclerosis by increasing leukotriene synthesis within plaques, leading to vascular reaction and migration of macrophages and monocytes, thus increasing subendothelial inflammation and dysfunction.