[Paranoid]

Atherosclerosis begins early in life but usually remains clinically silent until it has progressed to the point where it results in disease. The earliest lesions are fatty streaks, which are observed in young children as flat yellow intimal lesions. These consist of large numbers of lipid-laden foam cells, which are derived macrophages. Although fatty streaks may regress, they are considered precursor lesions which may progress into fibrofatty or atheromatous plaques. The plaque is the full blown lesion of atherosclerosis and it has two main components. The surface has a fibrous cap, comprised mainly of smooth muscle cells and collagen. Beneath this is the central necrotic core, comprised of cell debris, cholesterol and foam cells. A complicated plaque is one which has undergone calcification, ulceration, thrombosis, or hemorrhage. As explained later, these complications are very important precipitants to cardiac ischemic events.

The pathogenesis of a plaque is a complex process, not fully understood, and with many contributory factors. The most accepted hypothesis is the response to injury hypothesis, in which plaques can be viewed as the result of an excessive inflammatory - fibroproliferative response to various forms of insult to the arterial wall. Lesions are initiated as a response to some form of endothelial injury. Injury allows adherence of platelets and monocytes. These monocytes migrate into the vessel wall where they accumulate lipid and become foamy macrophages. Smooth muscle cells from the vessel wall migrate into the lesion where they proliferate and produce extracellular matrix such as collagen. Growth factors derived from these cellular components play a major role in pathogenesis (platelet derived growth factor, fibroblast growth factor, etc...). With this theory of pathogenesis, one can explain the contributory role of most of the risk factors in causing endothelial injury or providing plaque substrate.

Major Risk Factors
Because ischemic heart disease and its associated syndromes are the result of coronary atherosclerosis, the risk factors are basically the same for all.

hypercholesterolemia - Risk is proportional to serum level of LDL cholesterol.. Reduction achieved via decreased dietary fat or pharmacotherapy lessens risk. Hyperlipidemia may be familial, and thus may account for the fact that a strong family history of premature CAD is a significant risk factor. HDL cholesterol is protective.
hypertension - Although definitely a risk factor, HTN alone probably does not cause plaques. Rather, it may act synergistically with hypercholesterolemia by first causing mechanical wall stress and damage.
smoking - Causes endothelial damage and therefore promotes plaque thrombosis. Cessation greatly reduces risk of CAD.
diabetes mellitus - Strong independent risk factor. A hypothesis is that glycosylation products cause release of growth factors that stimulate smooth muscle proliferation.

Other Risk Factors
hyperhomocysteinemia - This is becoming an established independent risk factor but is still under evaluation. Reduction of levels by folate therapy may be beneficial.
advanced age, male sex, obesity, sedentary
lifestyle, type AA@ personality, psychological stress