Other factors associated with difficult-to-quantify risks include lack of exercise and living a competitive, stressful lifestyle (“type A personality”).
The currently held view of pathogenesis is embodied in the response-to-injury hypothesis. This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression involves interaction of modified lipoproteins, monocytederived macrophages, T lymphocytes, and the cellular constituents of the arterial wall (Fig. 10.10 ). According to this model, atherosclerosis results from the following pathogenic events:
EC 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
Monocyte adhesion to the endothelium, migration into the intima, and differentiation into macrophages and foam cells
Lipid accumulation within macrophages, which respond by releasing inflammatory cytokines
SMC recruitment due to factors released from activated platelets, macrophages, and vascular wall cells
Some details of these steps are presented next.
EC injury is the cornerstone of the response to injury hypothesis. EC loss due to any kind of injury—induced experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals—results in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. However, early http://ebooksmedicine.net 1. Chronic endothelial “injury”:
Viruses Response to injury 2. Endothelial dysfunction (e.g., increased permeability, Platelet leukocyte adhesion), Monocyte monocyte adhesion, and migration 3. Macrophage activation,
Smoothsmooth muscle recruitment, muscle cell accumulation of lipids in vessel wall 4. Macrophages and smooth muscle cells engulf lipid human atherosclerotic lesions begin at sites of intact, but dysfunctional, endothelium. These dysfunctional ECs exhibit increased permeability, enhanced leukocyte adhesion, and altered gene expression, all of which may contribute to the development of atherosclerosis.
Suspected triggers of early atheromatous lesions include hypertension, hyperlipidemia, toxins from cigarette smoke, and homocysteinemia. Inflammatory cytokines (e.g., tumor necrosis factor [TNF]) also can stimulate proatherogenic patterns of EC gene expression. Nevertheless, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.
The importance of hemodynamic factors in atherogenesis is illustrated by the observation that plaques tend to occur at ostia of exiting vessels, at branch points, and along the posterior wall of the abdominal aorta, where there is turbulent blood flow. In vitro studies further demonstrate that nonturbulent laminar flow leads to the induction of endothelial genes whose products protect against atherosclerosis. Such “atheroprotective” genes may explain the nonrandom localization of early atherosclerotic  lesions.
Lipids typically are transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes). Dyslipoproteinemias can result from mutations in genes that encode apoproteins or lipoprotein receptors, or from disorders that derange lipid metabolism, e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus. Common lipoprotein abnormalities in the general population (and indeed, present in many myocardial infarction survivors) include (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol levels, and 3) increased levels of lipoprotein(a).
Several lines of evidence implicate hypercholesterolemia in atherogenesis: