Atherosclerosis

Ajeng Diantini

ENDOTHELIAL CELLS
Semipermeable membrane, controlling the transfer of small and large molecules into the arterial wall and through the walls of capillaries and venules. Maintain the non-thrombogenic blood-tissue interface by regulating thrombosis, thrombolysis and platelet adherence. Modulate vascular tone and blood flow Regulate immune and inflammatory reactions Modify lipoproteins in the artery wall Regulate the growth of other cell type. e.g: smooth muscle cells

ENDOTHELIAL DYSFUNCTION AND ACTIVATION Endothelial dysfunction: reversible changes in the functional state of E.C that occur in environmental stimuli. ex: endothelial cell changes induced by histamine, serotonin that cause: - increased vascular permeability - inhibition the release of NO - redistribution of P-selectin on stimulation of thrombine or histamine. Endothelial activation: a critical process in the pathogenesis of vascular disease

VASCULAR SMOOTH MUSCLE CELLS

Vasoconstriction and dilation Synthesis of collagen, elastin and proteoglycans Elaboration of growth factors and cytokines Migration to intima Proliferation Migration and proliferation regulated by: Growth promoters: platelete-derived growth factor (PDGF), bFGF, IL-1 Inhibitors: heparan sulfat, NO/EDRF, IFN-, TGF-

Arteriosclerosis
is a chronic disease of the arterial system characterized by abnormal thickening and hardening of the vessel walls. The tunica intima undergoes a series of changes that decrease the arterys ability to change lumen size. Smooth muscle cells and collagen fibers migrate into the tunica intima, causing it to stiffen and thicken. gradually narrows the arterial lumen.

Atherosclerosis
Is a form of arteriosclerosis in which the thickening and hardening of the vessel is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called a plaque. Is not a single disease

Is the leading contributor to coronary artery and cerebrovascular disease

Pathophysiology
Atherosclerosis is an inflammatory disease The lesions progress from - endothelial injury and dysfunction - fatty streak - fibrotic plaque - complicated lesions

Common risk factors: Smoking Hypertension DM Increased levels of LDL Decreased levels of HDL Hyperhomocystinemia

POSSIBLE CAUSES OF ENDOTHELIAL INJURY

Other causes are called the novel factors: Elevated C-reactive proteins Increased serum fibrinogen Insulin resistance Oxidative stress Infection Peridontal disease

HYPERHOMOCYSTEINEMIA Because of a genetic lack of the enzyme that breaks down homocysteine or because of a nutritional deficiency of folate, cobalamin (vitamin B12), pyridoxine (B6).

Mechanism by which it contributes to coronary disease: - incrases LDL - decreases vasodilator endogen - increases tendency for thrombosis

PATHOPHYSIOLOGIC EVENTS:
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Injured endothelial cells become inflamed and can not make normal amounts of antithrombotic and vasodilating cytokines. Inflammatory cytokines are released, including: TNF-, interferon, IL-1, toxic oxygen radicals, heat shock proteins (HSP). Growth factors are also released: angiotensin II, fibroblast growth factor(fGF), platelet-derived growth factor (PDGF), which stimulate smooth muscle cells proliferation in the affected cells. Macropages adhere to injured endothelium by way of adhesion molecules, such as vascular cell adhesion molecule (VCAM). These macropages then release enzymes and toxic oxygen radicals that create oxidative stress, oxidize LDL, and further injure the vessel wall.

Accumulation of foam cells in significant amount form a lession called a fatty streak. Fatty streaks produce more toxic oxygen radicals and cause immnunologic and inflammatory changes, resulting in progressive damage to the vessel wall. Decreasing levels of LDL can cause regression of atherosclerotic lessions and can improve endothelial function. At this point, smooth muscle cells proliferate, produce collagen, and migrate over the fatty streak forming a fibrous plaque. This process is mediated by many inflammatory cytokines, including growth factors (TGF-). Fibrous plaque may calcify, protrude into the vessel lumen, and obstruct blood flow to distal tissue, which may cause symptoms (angina)

Plaque rupture occurs because of the inflammatory activation of proteinase (MMP, cathepsins), and can be accelerated by bleeding within the lession (plaque hemorrhage) Plaque that have ruptured are called complicated plaques. Once rupture, exposure of underlying tiddue results in platelet adhesion, initiation of the clotting cascade, and rapid thrombus formation. The thrombus may suddenly occlude the affected vessel resulting in ischemia and infarction. Aspirin or other antithrombotic agents are used to prevent this complication of atherosclerotic disease.

Progression of Atherosclerosis

Fatty streak

Fibrous plaque

Complicated lesions

INTRAVASCULAR CELLS AND CONNECTIVE TISSUE MATRIX AND CELLS INVOLVED IN THE INFLAMMATORY RESPONSE

SEQUENCE OF LEUCOCYTES EVENTS IN INFLAMMATIONS

INFLAMMATORY MARKERS
Excellent predictor: hs-CRP Others: - fibrinogen - von Willebrand Factor - IL-6 - IL-1 - TNF- - adhesion molecules (selectins, ICAMs, serum amyloid A)

NEUTROPHILS EXTRAVASATION IN ENDOTHELIALNETROPHIL INTERACTIONS

LDL- Oxidation

CHEMICAL MEDIATORS OF INFLAMMATION.

TWO TYPES OF NO SYNTHESIS IN ENDOTHELIUM

Endothelium regulation of vasomotion

Factors causing endothelium-dependent vasodilation

Once injury has occurred , endothelial dysfunction and inflammation lead to the following pathophysiologic events
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2.

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4.

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Injured endothelial cells become inflamed and can not make normal amounts of antithrombotic and vasodilating cytokines. Inflammatory cytokines are released : TNF-, interferon-, interleukin-1, toxic oxygen radicals, heat shock proteins. Growth factors are released: angiotensin II, fibroblast growth factors, platelet-derived growth factor, which stimulate smooth muscle cell proliferation in the affected vessel Macrophage adhere to injured endothelium by way of adhesion molecules, such as VCAM-1. These macrophage then release enzymes and toxic oxygen radicals that create oxidative stress, oxidized LDL, and further injure the vessel wall.

Oxidized-LDL
Oxidized LDL is an important step in atherogenesis Oxidized-LDL is toxic to endothelial cells, causes smooth muscle proliferation, and activate further immune and inflammatory responses. Oxidized-LDL penetrates into the intima of the arterial wall and is engulfed by macrophages. Macrophages filled with oxidized-LDL are called foam cells. Accumulation of foam cells form a lesions called fatty streak.

Once formed, fatty streaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes progressive damage to vessel wall. Smooth muscle cells proliferate, produce collagen, and migrate over the fatty streak forming a fibrous plaque. This process is mediated by many inflammatory cytokines, including growth factors (TGF-). Fibrous plaque may calcify, protrude into the vessel lumen, and obstruct blood flow, especially during exercise, which may cause symptoms (e.g angina).

Many plaques are unstable and clinically silent until they rupture. Plaque rupture because of the inflammatory activation of proteinases, such as MMP and cathepsin and can be accelerated by bleeding within the lesion (paque haemorrhage) Atherosclerotic plaque can be classified according to their structure, which give insight into their stability and proneness to rupture. Plaque that have ruptured are called complicated plaque. Once rupture occurs, exposure of underlying tissue results in platelet adhesion, initiation of the clotting cascade, and rapid thrombus formation. Thrombus may suddenly occlude the affected vessel resulting in ischaemia and infarction.

CLINICAL MANIFESTATIONS
Partial vessel obstruction may lead to transient ischemic events, often associated with exercise or stress. Onced the lessions becomes complicated, increasing obstruction with superimposed thrombosis may result in tissue infarction. CAD caused by atherosclerosis is the major cause of myocardial ischemia.

Prevention of Coronary Heart Disease

3 dietary strategies are effective in preventing CHD: - substitute unsaturated fats- especially PUF for saturated fats. - increase consumption of omega-3 fatty acids from fish oil or plant sources. - eat a diet high in vegetables, fruits, nuts, and whole grains and low in refined grains. These diets together with no smoking, regular physical activity, maintaining a healthy weight may prevent the majority of CHD.

Evaluation and treatment

Health history (risk factors and symptoms) Physical examination Risk indicators in serum : lipid profile, hs-CRP, If coronary disease suspected, evauation of the plaque by ECG, USG, CT, MRI, nuclear scanning, and angiography. Treatment with drugs aimed at stabilizing plaque before they rupture. Risk reduction : smoking cessation, weight loss, control of hypertension, diabetes, and dyslipidemia through diet, exercise, and medication.