Atherosclerosis
Diseases

PATHOGENESIS OF ATHEROSCLEROSIS

Arterial stenosis is caused predominantly by atherosclerosis.
Atherosclerosis derives its name from the Greek words "sclerosis" meaning hardening and "athere" meaning gruel (accumulation of lipid). The phenomenon is characterized by accumulation of cholesterol, infiltration of macrophages, proliferation of smooth muscle cells (SMC), accumulation of connective tissue components and formation of thrombus.
Atherosclerosis starts early in life, and some studies have shown that maternal hypercholesterolemia during pregnancy is associated with a marked increase in the formation of fatty streaks in the human fetus.
The disease appears earliest in the aorta (during fetal life), while it appears in the coronary arteries in the second decade and in the cerebral arteries in the third decade. Some lesions regress while others become complicated.

One of the earliest events in atherosclerosis is the entry of monocytes into the arterial intima. These monocytes differentiate into macrophages and start to accumulate large amounts of lipid through the uptake of modified lipoproteins which results in foam cell formation.
Macrophage-derived foam cells in turn stimulate smooth muscle cell (SMC) migration from the media into the intima, and in this way contribute to the progression of atherosclerosis. At this point, the atherosclerotic lesion is considered stable. It consists of a small necrotic core, if present at all, separated from the blood flow by a firm fibrous cap of SMCs and extracellular matrix. However, the release of matrix metalloproteinases by macrophages in the plaque leads to progressive collagen breakdown and thinning of the fibrous cap. They also produce pro-inflammatory cytokines with pro-apoptotic potential which may contribute to cell death of surrounding cells. Accordingly, stable atherosclerotic lesions slowly progress over a period of decades to advanced and unstable lesions. These lesions are characterized by a thin fibrous cap containing few SMCs overlying a large necrotic core composed of dead cells, lipid deposits and cellular debris. In contrast to stable lesions, advanced human atherosclerotic plaques also show intraplaque neovascularization.
These newly formed vessels are fragile and often reveal signs of leakage, thereby introducing platelets and red blood cells into the plaque.
Phagocyte have several receptors on their membrane that are involved in the phagocytic process such as receptors for lipoproteins (LDL), apoptotic cells (AC), red blood cells (RBC) and platelets (PLT). They interact either directly with their ligands or via bridging molecules.
The most important involved receptors are: CD14, lipopolysaccharide receptor; CD36, thrombospondin receptor; SRA, scavenger receptor class A; FcR, Fc fragment of immunoglobulin G receptor; LRP, LDL receptor-related protein; SREC, scavenger receptor of endothelial cells; CD91; β2-GPI, beta 2-glycoprotein 2; ABC-1, ATP-binding cassette-1; TSP, thrombospondin; PS, phosphatidylserine; PSR, PS receptor; αvβ3, vitronectin receptor.

RISK FACTORS

There are many risk factors associated with arterial stenosis, and it is possible divide them into two categories:

NON MODIFIABLE RISK FACTORS

• Genetic factors: hereditary hypercholesterolemia and hyperlipidemia
• Age: 50-65
• Men: before age 55, men are more at risk than women old

MODIFIABLE RISK FACTORS

• Diabetes: AGE
• Hypertension (high blood pressure)
• Smoking
• Metabolic syndrome
• ROS: they are generated by a variety of extracellular and intra-cellular mechanisms and are responsible for the oxidation of LDL
• Diet high in saturated fats
• Obesity
• Homocystinuria: it is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites in blood and urine
• Sedentary lifestyle
• Abnormal lipids or high cholesterol: retention of LDL in the vessel wall with subsequent oxidation is considered to be the most important event in the early stages of an atherosclerotic lesion. OxLDL promotes the recruitment and retention of monocytes and lymphocytes (and conversion to macrophages) and increases the production of various growth factors and cytokines. In the subendothelial space, the uptake of oxLDL by monocyte-derived macrophages reduces macrophage migration and leads to the formation of foam cells, the hallmark of atherosclerotic lesions. OxLDL is chemotactic for monocytes and T-cells.

One of the most common location of atherosclerotic plaque buildup is the carotid bifurcation, where the common carotid divides into the internal and external carotid arteries.

REFERENCES

IgG against CMV, Parvovirus, Chlamidia?

Reazioni immunitarie potrebbero essere in parte responsabili del processo aterosclerotico alla base di eventi coronarici acuti. L'evidenza arriva da uno studio italiano realizzato nei laboratori dell'Università Vita-Salute San Raffaele di Milano in collaborazione con la Bracco Imaging di Milano. L'indagine dimostra, per la prima volta, all'interno di placche coronariche di pazienti con sindrome coronarica acuta, una specifica attivazione di linfociti B con overespessione di geni codificanti alcune classi di IgG. Tuttavia, la natura della risposta immunitaria deve essere ancora definita. "Anche se non si è ancora scoperta la natura dell'antigene che stimola il sistema immunitario all'interno delle arterie coronarie quando un paziente è colpito da infarto, siamo ora in grado di cercarlo, visto che abbiamo a disposizione la traccia specifica che ha lasciato" ha dichiarato Roberto Burioni, uno dei coordinatori dello studio. "Una volta chiarita la natura dell'antigene, si può immaginare la messa a punto di test in grado di individuare i pazienti che, pur non presentando fattori di rischio, corrono tuttavia il pericolo di essere colpiti da infarto". (L.A.)

The Journal of Immunology, 2009, 183, 2537 -2544