Coronary heart disease, or atherosclerotic coronary artery disease, is the commonest cause of cardiovascular disability and death in the United States. Men are more often affected than women by an overall ratio of 4:1, but before age 40 the ratio is 8:1, and after age 70 it is 1:1. In men, the peak incidence of clinical manifestations is at age 50-60; in women, at age 60-70.

Risk Factors for Coronary Artery Disease
Epidemiologic studies have identified a number of important risk factors for premature coronary artery disease. These include a positive family history (particularly when onset is before age 50), age, male gender, blood lipid abnormalities, Diabetes mellitus, insulin resistance and the metabolic syndrome, hypertension, physical inactivity, cigarette smoking, elevated blood homocysteine levels, markers of inflammation such as C-reactive protein (CRP) and hyperfibrinogenemia, and hypoestrogenemia in women.

Interventions to lessen some of these risk factors, such as lipid abnormalities, hypertension, and smoking, reduce the risk for subsequent coronary events.

However, the benefit of reducing homocysteine levels is less clear, and hormone replacement therapy has been associated with an early increase in coronary risk. Patients with clinical manifestations of coronary disease before age 50 often have one or more of these predisposing risk factors, though many do not. The conventional risk factors are less closely linked to the onset of coronary disease in later years.

Overwhelming evidence indicates that abnormalities of lipid metabolism play a direct role in the pathophysiology of this condition. Risk increases progressively with higher levels of LDL cholesterol and declines with higher levels of HDL cholesterol. Therefore, the ratio of LDL to HDL cholesterol provides a composite marker of risk, with ratios below 3 indicating a lower risk and ratios above 5 indicating a higher risk. Other abnormalities of lipid metabolism also play a role in the pathogenesis of coronary artery disease, and these should be sought in individuals with otherwise unexplained premature disease. Among the patterns associated with increased atherosclerosis are elevated levels of apolipoprotein(a) and of small, dense LDL lipoprotein particles. These lipoproteins and their accompanying lipids appear more likely to pass into the vessel wall and may be more difficult to clear. Accumulating evidence suggests that hypertriglyceridemia is an independent risk factor for coronary artery disease as well. Elevated triglyceride levels often occur in association with other lipid abnormalities, including low levels of HDL cholesterol and elevated concentrations of lipoprotein(a) and small, dense LDL particles. Some experts advocate the use of non-HDL cholesterol, which accounts for several atherogenic lipids, as the preferred risk indicator.

It is now clear that markers of inflammation are another strong risk factor for coronary artery disease. CRP is the best-characterized inflammatory marker, but others include serum fibrinogen and the erythrocyte sedimentation rate and perhaps homocysteine as well. Although CRP levels > 10 ug/mL are often found in systemic inflammation, levels < 1, 1-3, and > 3 ug/mL, respectively, identify patients at low, intermediate, and high risk for future cardiovascular events. The prognostic value of CRP levels is independent and additive to lipid levels. CRP levels are often elevated in patients who have other conditions associated with accelerated Atherosclerosis, such as Diabetes, the metabolic syndrome, and Obesity. In patients presenting with acute coronary syndromes, these elevations identify a group that is at high risk for early recurrent events.

Pathophysiology
Knowledge concerning the pathophysiology of atherosclerosis and the clinical presentations of coronary artery disease is accumulating rapidly. Abnormal lipid metabolism or excessive intake of cholesterol and saturated fats- especially when superimposed on a genetic predisposition—initiates the atherosclerotic process. The initial step is the “fatty streak,” or subendothelial accumulation of lipids and lipid-laden monocytes (macrophages). Low-density lipoproteins (LDLs) are the major atherogenic lipid. High-density lipoproteins (HDLs), in contrast, are protective and probably assist in the mobilization of LDLs. The pathogenetic role of other lipids, including triglycerides, is less clear. LDLs undergo in situ oxidation, which makes them more difficult to mobilize as well as locally cytotoxic.

Macrophages migrate into the subendothelial space and take up lipids, giving them the appearance of “foam” cells. As the plaque progresses, smooth muscle cells also migrate into the lesion. At this stage, the lesion may be hemodynamically insignificant, but endothelial function is abnormal and its ability to limit the entry of lipoproteins into the vessel wall is impaired. If the plaque remains stable, a fibrous cap forms, the lesion becomes calcified, and the vessel lumen slowly becomes narrowed.

Although many atherosclerotic plaques remain stable or progress only gradually, others may rupture, with a resulting extrusion of lipids and tissue factors that result in a cascade of events culminating in intravascular thrombosis. The outcome of these events is determined by whether the vessel becomes occluded or whether thrombolysis occurs, either spontaneously or as the result of treatment, and whether the plaque subsequently becomes stabilized. The result may be partial or complete vessel occlusion (causing the symptoms of Unstable angina or myocardial infarction), or the plaque may become restabilized, often with more severe stenosis.

Several features are associated with enhanced plaque vulnerability, including a higher lipid content, a higher concentration of macrophages, and a very thin fibrous cap. Lesions with these characteristics are often the culprit lesions in young individuals, in whom acute myocardial infarction or sudden death is the first manifestation of coronary disease; this abrupt progression explains why most infarctions do not occur at the site of preexisting critical stenosis. Conversely, the relatively greater reduction in clinical events than in lesion severity in lipid-lowering treatment trials is probably explained by the regression or prevention of these early nonfibrotic lesions.

Recent observations have resurrected an old theory that Atherosclerosis progresses as the result of an inflammatory response in the vessel wall, perhaps initiated or worsened by an infectious agent. High levels of CRP may not only be a marker of inflammation and risk but may play a pathogenetic role in the atherosclerotic process. CRP is present in plaques and can activate endothelial cells to express adhesion molecules and chemotactic substances that attract macrophages as well as inhibit NO synthase, thus promoting lipid deposition and plaque instability. A number of infectious agents, including Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori, have been indirectly implicated in initiating or accelerating the inflammatory response, but confirmation thus far is lacking and randomized trials have not demonstrated benefit from antibiotic therapy.

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