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Modifiable Major Risk Factors
Hyperlipidemia—and, more specifically, hypercholesterolemia—is a major risk factor for development of atherosclerosis and is sufficient to induce lesions in the absence of other risk factors. The main cholesterol component associated with increased risk is low-density lipoprotein (LDL) cholesterol (“bad cholesterol”); LDL distributes cholesterol to peripheral tissues. By contrast, high-density lipoprotein (HDL) (“good cholesterol”) mobilizes cholesterol from developing and exis ting vascular plaques and transports it to the liver for biliary excretion. Consequently, higher levels of HDL correlate with reduced risk.
Recognition of these relationships has spurred the development of dietary and pharmacologic interventions that lower total serum cholesterol or LDL, and/or raise serum HDL, as follows:
High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol, and/or containing higher ratios of polyunsaturated fats, lower plasma cholesterol levels.
Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas
(trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them.
Statins are a widely used class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the
rate-limiting enzyme in hepatic cholesterol biosynthesis.
Called the response-to-injury hypothesis, the model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression involves interaction of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the cellular constituents of the arterial wall (Fig. 9–10). According to this model, atherosclerosis results from the following pathogenic events:
•Endothelial injury—and resultant endothelial dysfunction—leading to increased permeability, leukocyte adhesion, and thrombosis
•Accumulation of lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall
•Pl atelet adhesion
•Monocyte adhesion to the endothelium, migration into the intima, and differentiation into macrophages and foam cells
•Lipid accumulation within macrophages, which release inflammatory cytokines •Smooth muscle cell recruitment due to fac tors released from activated platelets, macrophages, and vascular wall cells
•Smooth muscle cell proliferation and ECM production。
