Arteriosclerosis

Introduction
Definition: Arteriosclerosis is a group of disorders characterized by
thickening and loss of elasticity of arteries that may or may not be associated with narrowing of lumen of the vessel. Three different patterns of arteriosclerosis are seen commonly:
Atherosclerosis: It is characterized initially by formation of intimal plaques (plate/patch like raised areas) that often have a central lipid core. Arteriosclerosis Monckebergs type (also called medial calcific sclerosis): This is characterized by deposition of calcium salts in media of blood vessels. Often do not produce luminal narrowing. Arteriolosclerosis: This is characterized by thickening of wall of small arteries and arterioles due to deposition of hyaline material (hyaline AS) or due to hyperplastic changes in the wall of arterioles (hyperplastic AS). Seen in conditions like hypertension and diabetes mellitus.

Atherosclerosis

Atherosclerosis
Atherosclerosis is characterized by presence of intimal plaques called atheroma. The name comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness)] Plaques may produce
Stenotic and/or occlusive lesions that may result in ischemic injury. Weaken the media of the involved vessel: This may result in aneurysm formation or rupture of the involved vessel Produce complications like thrombosis and thromboembolism.

Clinical Picture
The disease primarily affects elastic and large and medium sized muscular arteries like aorta, carotid, iliac, popliteal, renal and mesenteric vessels. The disease begins usually in childhood and remains asymptomatic, until it becomes advanced enough to produce symptoms, usually in late adulthood. Symptomatic disease is localized most often to:
Heart: Producing coronary artery disease, MI or sudden cardiac death. Aorta: Causing aneurysm formation. Brain: Manifests as strokes or TIA. Kidney: Produces renal failure. Lower extremities and intestines: Infarction and/or gangrene may occur.

Major Risk Factors for Atherosclerosis

Non-modifiable
Age: It is a slowly progressive disorder. Hence symptomatic manifestations and associated complications tend to appear with advancing age. Sex: It is more common amongst males as compared to premenopausal females, in whom greater estrogen levels offer some protection. Genetic profile: Many genes influence development of atherosclerosis, i.e. it is polygenic in nature. Family history of heart disease.

Modifiable
Hyperlipidemia Hypertension: Above 45 years of age hypertension is a major risk factor - even greater than hyperlipidemia. Cigarette smoking: An important risk factor, both in men and in women. Cigarette smoking also promotes thrombosis. Diabetes mellitus: It produces dyslipidemia. AGE products cause endothelial activation. In diabetes mellitus, PGA2 levels increase and PGI2 levels decrease. This accelerates thrombosis.

Minor Risk Factors for Atherosclerosis

Obesity: Compared to normal weight active women, the risk of heart disease is 54% higher in overweight active women and 87% higher in obese active women. The risk is greatest with visceral obesity. Women with waist measurements > 35 inches and men with waist measurements > 40 inches are at greater risk. Physical inactivity: Heart disease is 2.5 times more common in obese inactive women. Stress. Post menopausal estrogen deficiency. Factors that effect hemostasis and thrombosis. These are increased levels of homocysteine, C-reactive proteins, plasminogen activator inhibitor (PAI levels), and Lp (a). Chlamydia pneumoniae infection.

Multiple risk factors are more than additive. For example, with two factors, the risk is four folds. With three factors, the risk is seven folds.

Role of lipids in atherosclerosis

Epidemiological data indicate that the risk of CHD and other complications of atherosclerosis increase with rise in concentration of certain lipids. Contribution of different lipid molecules is as follows: Hypercholesterolemia is a major risk factor in causation of atherosclerosis. Role of hypertriglyceridemia has not been proven conclusively. Increased LDL level is a key contributory factor. Cholesterol forms major portion of a LDL molecule. And it is the LDL molecule which, tends to deposit cholesterol in intima. Risk of ischemic heart disease increases steeply when plasma cholesterol levels are in excess of 200 mg/dl. Normally, HDL particles mobilize cholesterol away from lipid laden cells. Hence high HDL concentrations prevent progression of atheromatous plaque. Regular physical activity and increased consumption of omega 3 fatty acids, raise HDL levels. Smoking and obesity decrease HDL levels.

LDL Molecule

Morphologic features of Atherosclerosis:

Key alteration is formation of an atheromatous plaque. This occurs due to accumulation of lipids in intima of blood vessels. Plaque is usually 0.5 to 1.5 cm in size, but can become larger due to coalescence. On sectioning, it appears whitish on the surface and yellowish and grummous towards the centre. OHE, an uncomplicated case shows an outer fibrous cap having some SMCs and T lymphocytes. Underneath the cap is collection of macrophages, T lymphocytes and SMCs. Deep core consists of lipid, foam cells and fibrin. At periphery of the lesion, new vessel formation may be seen. Plaque can undergo secondary changes (complicated plaque) like:
Calcification Rupture or erosion Hemorrhage within plaque. Superimposition of a thrombus. Weakening of media leading to aneurysm formation.

Schematic diagram of an Atheroma

Fibrous cap

Necrotic centre

Media

Diagrammatic structure of a fully evolved Atheroma

Pathogenesis
Current view about pathogenesis of atherosclerosis is that it is a chronic inflammatory response due to endothelial injury (Response to injury hypothesis). Endothelial injury can be due to several factors; some of them have been mentioned earlier. Apart from endothelial injury, activation of endothelial cells also play a role. Endothelial activation occurs when these cells get exposed to:
Cytokines and bacterial products: As occurs with infections Hemodynamic stress and excess of lipids: As occurs in HT and dyslipidemias. Exposure to AGE products: As seen in diabetes mellitus. Exposure to certain viruses, complement components and hypoxia.

Activated endothelial cells express adhesion molecules and other cytokines due to which:
inflammatory cells migrate into the intima. endothelial permeability increases, which allows ingress of excess lipoproteins into intima.

Pathogenesis (cont)
Oxidation of accumulated lipoproteins takes place; more so when larger concentration of inflammatory cytokines are present. Macrophages have receptors for oxidatively modified LP; hence these particles are readily ingested by macrophages (foam cells). Macrophages secrete GFs and cytokines like IL-1, MCP-1and TNF. These substances stimulate migration of SMCs from media into the intima. Migrating SMCs are functionally aberrant. They secrete collagen and ECM. This further increases the size of an atheroma. Above cytokines are chemotactic for leukocytes and cause accumulation of more and more T lymphocytes and macrophages. When accumulating inflammatory cells are stimulated by unknown microorganisms or other antigens, they start secreting fibrogenic cytokines. Concurrently, death of foam cells releases lipids. All these events contribute towards development of a stable atheroma.

Pathogenesis (cont)
If inflammatory activity is at a heightened level, the plaque becomes unstable. This is due to chemicals released by macrophages that digest SMCs and collagen. An unstable plaque - when exposed to increased shear stresses - is liable to rupture or erode. HT, lipid rich core, thin fibrous cap and presence of neovascularization favors rupture or erosion of the atheroma. Erosion exposes underlying thrombogenic molecules and this results in thrombus formation. When the thrombus is small, it is incorporated within an atheroma and contributes in increasing its size. When large, it may produce sudden occlusion of the vessel. Lipid lowering drugs, by removing lipids from an atheroma, tend to convert an unstable lesion into a stable plaque. Atheromas also induce complex changes in the medial layer, due to which localized constriction or dilatation are produced. Exact mechanism for these changes is unknown.

Sequence of Events in Development of Atheroma

Evolution of Atheroma and its Clinical Effects

Complications of Atherosclerosis

Some important complications of atherosclerosis are:

Coronary heart disease
Angina pectoris Myocardial infarction. Sudden death.

Cerebro-vascular disease
Transient ischemic attack Strokes.

Peripheral vascular disease

Intermittent claudication Critical limb ischemia that may culminate in gangrene. Ischemia of various other organs like GIT and kidney.

Aneurysm formation
Cardiac aneurysm following MI Aortic aneurysm

Monckeberg Medial Calcific Sclerosis

It is characterized by deposition of calcium in muscular arteries. It is usually seen in persons older than 50 years It does not encroach on lumen of the vessel

Arteriolosclerosis
It affects small arteries and arterioles. Two morphologic patterns are seen o Hyaline arteriolosclerosis. o Hyperplastic arteriolosclerosis Hyaline arteriolosclerosis o Usually associated with hypertension and DM. o The arteriolar walls are thickened and largely replaced by a homogeneous pink hyaline material. The lumina are narrowed. The hyaline material is probably derived from plasma proteins that have leaked across endothelial barriers and accumulated over the years.
Hyaline arteriolosclerosis

Hyperplastic Arteriolosclerosis
Seen in patients with malignant hypertension. Smooth muscle cells proliferate and undergo hypertrophy in an attempt to cope with rapidly rising blood pressure. Lesions appear as thickened concentric rings of media and intima surrounding narrowed vascular lumina. There is widespread ischemic injury in multiple organ systems. Renal failure and central nervous system hemorrhage can be rapidly fatal.