Atherosclerotic plaque development, atherosclerotic disease, pre-clinical and clinical stages, cigarette smoking

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Colorado State University
Biomedical Science
BMS 460
D.Rao Veeramachaneni

1 November Fatty streaks are a collection of foamy macrophages in the intima Sequence of atherosclerotic plaque development over decades – its “natural” history Injury to EC from a variety of insults causes loss of normal anithrombotic and vasodilator cytokines Inflammatory cytokines (TNF-α; interferon and interleukin-1) plus other factors such as oxygen radicals Growth factors are released in inflammation: angiotensin II, FGF, PDGF which stimulate VSMC proliferation Macrophages adhere to injured EC’s via adhesion molecules such as VCAM and invade wall (foam cells) Macrophages release enzymes and oxygen radicals oxidize the LDL and further injure vessel wall Evolution of a plaque from injury by Ox-LDL all the way to complicated plaque with calcifications LDL in intima Local cytokine activity stimulated by oxidative stress of oxidized LDL Chemoattractant activity Macrophage migration across wall (M-CSF) and expression of scavenger receptors Foam cells originate from VSMC/macrophages VSMCs divide and migrate in intima VSMC elaborate extracellular matrix (fatty streak to fibrous plaque) Calcification Oxidation of LDL LDL enters intima through intact endothelium Intimal LDL is oxidized into proinflammatory lipid Oxidized LDL causes adhesion and entry of monocytes and T lymphocytes across endothelium Monocytes differentiate into macrophages and then consume large amounts of LDL, transforming into foam cells Foam cells release growth factors (cytokines) that encourage atherosclerosis Summary of sequence of cellular interactions in atherosclerosis Risk factors Injury of EC Adhesion of platelets and monocytes Release of cytokines – growth factors and chemoattractants (Ox-LDL) incorporated into plaque EC matrix – lipid, collagen and degenerating foam cells Atherosclerotic Disease Affects large and medium sized elastic arteries – aorta, carotid and iliac arteries, coronary and popliteal arteries in particular Major consequences: myocardial infarction, cerebral infarctions, aortic aneurysms, peripheral arterial disease Atherosclerotic lesions cause stenosis gradually due to remodeling of vessel so that vessel diameter is preserved in early years. The “critical stenosis” is the point at which flow is curtailed to organ (70% fixed occlusion) and thus consequences develop – angina on exertion (stable angina), ischemic encephalopathy, bowel ischemia, intermittent claudication. Acute plaque change such as erosion/ulceration, rupturing/fissuring or hemorrhage into the plaque is followed by prompt partial or complete vascular thrombosis producing myocardial or cerebral infarction. Vasospasms round out the events which culminate in the classical manifestations of atherosclerotic disease: circulating adrenergic agonists, locally release platelet contents (thromboxane), impaired EC function (low “NO”) or high ET, vasoconstrictors from local inflammatory cells A person who develops a myocardial infarction does not necessarily have a several stenotic and hemodynamically significant lesion before the acute change. It is hard to predict who will develop myocardial infarctions and many asymptomatic people will have a sudden MI becau
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