Discuss the risk factors for, the pathogenesis of, and the consequences of, coronary artery atherosclerosis. (<250 words)

Complications of atherosclerosis are the leading cause of death in the U.S., though the frequency is decreasing from lifestyle changes. Major risk factors for coronary atherosclerosis include hyperlipidemia, hypertension, and diabetes, all of which may be familial, and smoking. Increasing age and male sex also have predisposition to atherosclerosis. Other risk factors include increased dietary fat (particularly cholesterol), decreased exercise, obesity, oral contraceptive use, and stress.

Pathogenesis of atherosclerosis may be related to endothelial injury with increased permeability to lipids, increased intimal smooth muscle proliferation, and macrophage emigration and proliferation in the intima. Another theory holds that smooth muscle proliferation initiates plaque formation. Fatty lipid streaks, seen even in children, may not be precursors to atheromatous plaques in all cases. Resultant intimal plaques can increase in size, leading to increasing lumenal obstruction. Plaques can be complicated by ulceration, hemorrhage, thrombosis, and calcification.

The consequences of coronary atherosclerosis can be ischemia with angina, myocardial infarction with greater degrees of occlusion, and sudden death from severe occlusion or thrombosis.

Discuss the possible causes and the subsequent pathologic findings that could occur with a total serum cholesterol of 268 mg/dl. (<250 words)

A serum cholesterol of 268 mg/dl is well above the 200 mg/dl level that is associated with greater risk for serious complications of atherosclerosis. Though the level might be even higher, a risk for increased cholesterol could have a genetic basis in familial hypercholesterolemia. More commonly, diet plays a major role. An increased intake of dietary fat, particularly saturated fats, and increased dietary cholesterol will also increase total serum cholesterol. The type of cholesterol is important, because a higher HDL cholesterol is "good" while a higher LDL cholesterol is "bad" for risk of atherosclerosis. In diabetes mellitus, HDL cholesterol is degraded faster and LDL cholesterol attaches more readily to vessel walls, promoting atherogenesis. It is important to stress to patients the need to reduce cholesterol through diet and exercise to prevent complications of atherosclerosis.

A high cholesterol promotes atherogenesis by increasing deposition of lipid within areas of endothelial injury as well as promoting endothelial injury. Lipid accumulates in macrophages and proliferating smooth muscle cells to form plaques. As the plaques enlarge, the arterial lumen is narrowed. Complications depend upon the location of the plaques. Myocardial ischemia and infarction may result from coronary atherosclerosis. Mural thrombus could form over the site of such an infarction. A cerebral infarction (a "stroke") could result from cerebral arterial atherosclerosis or from embolization of thrombus from the heart. Renal arterial narrowing could lead to hypertension and chronic renal failure. Peripheral arterial occlusion could produce gangrene of an extremity.

Discuss how an atheroma is formed and the pathologic appearance that results. (<250 words)

Complications of atherosclerosis are a leading cause of death in the U.S., though mortality has been declining recently with lifestyle changes. Risk factors for atherosclerosis include: male sex, increasing age, genetic susceptibility (i.e., familial hypercholesterolemia or apoprotein dysfunction), hyperlipidemia, hypertension, smoking, and diabetes. "Soft" risk factors include obesity, lack of exercise, and stress.

Atheromas are thought to form when injury to the endothelium occurs; they tend to form in the proximal coronary arteries and at branch points where flow is most turbulent. The first stage in atheroma formation is the type I injury or "lipid lesion". Monocytes migrate in and become macrophages that accumulate lipid. There is no morphological change in the endothelium at this point. Grossly, a fatty streak may be seen. LDL receptors on arterial walls probably contribute to this type of lesion, as does a high serum LDL cholesterol.

The next stage in atheroma formation is the type II lesion, or "fibrointimal lesion" which appears when endothelial denudation occurs (but damage is limited to the intima). Macrophages produce growth factors that stimulate smooth muscle migration and proliferation as well as fibroblast production of collagen. Grossly, plaques appear on the arterial walls.

The type III stage occurs when both intima and media are damaged. The intima continues to thicken with increased smooth muscle and fibroblast activity, and the risk of thrombus formation increases. The lumen becomes progressively occluded, and ulceration, hemorrhage, and calcification, and recanalization afther thrombosis are additional complications that can be seen.

Discuss the causes and consequences of infarction. (<250 words)

An infarction usually occurs when there is loss of blood flow to the tissues in an organ. Loss of blood flow may occur from atherosclerotic narrowing of an artery, vascular thrombosis, or embolization. Thus, the causes of infarction often stem from causes for atherosclerosis, including increasing age, diet high in fat, hypercholesterolemia, hypertension, and smoking. If the artery becomes occluded slowly, the tissues may become ischemic but not infarcted. Atheromatous plaques can be complicated by thrombosis, with more sudden narrowing that leads to infarction. An embolus from a source such as the mural endocardium or valve of the heart can travel to a small peripheral artery and occlude it. Venous thrombosis leading to infarction is not common, but pulmonary embolism can sometimes produce pulmonary infarcts that are hemorrhagic.

Infarctions in most parenchymal organs such as the heart, spleen, or kidney exhibit coagulative necrosis. The infarcts are usually tan and wedge-shaped. They resolve with fibrosis to leave a scar. Cerebral infarctions have liquefactive necrosis because of the high lipid content of the brain and heal to leave a cystic space. If a small amount of tissue is infarcted, the organ function may not be severely affected. A larger infarct can produce serious disease, such as a myocardial infarction or a "stroke".