The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters.
Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by 20 years of age.
Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.
Epidemiologic analyses (e.g., the Framingham study) demonstrate a significant correlation between the levels of total plasma cholesterol or LDL and the severity of atherosclerosis.
Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk for cardiovascular events.
The mechanisms by which dyslipidemia contributes to atherogenesis include the following:
Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair EC function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.
With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives, oxidized LDL and cholesterol crystals. LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or ECs and ingested by macrophages through the scavenger receptor, resulting in foam cell formation. Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to ECs and SMCs. More recently, it has been shown that minute extracellular cholesterol crystals found in early atherosclerotic lesions serve as “danger” signals that can activate innate immune cells such as monocytes and macrophages to produce IL-1 and other pro-inflammatory mediators.
Inflammation contributes to the initiation, progression, and complications of atherosclerotic lesions. Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional ECs express adhesion molecules that promote leukocyte adhesion, in particular, monocytes and T cells which migrate into the intima under the influence of locally produced chemokines.
Monocytes differentiate into macrophages and avidly engulf lipoproteins, including oxidized LDL and small cholesterol crystals. Cholesterol crystals appear to be particularly important instigators of inflammation through activation of the inflammasome and subsequent release of IL-1 (Chapter 5). Activated macrophages also produce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate SMC proliferation.
T lymphocytes recruited to the intima interact with the macrophages and also contribute to chronic inflammation. It is not clear whether the T cells are responding to specific antigens (e.g., bacterial or viral antigens, heat-shock proteins [see later], or modified arterial wall constituents and lipoproteins) or are nonspecifically activated by the local inflammatory milieu. Nevertheless, activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, ECs, and SMCs.
As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and matrix synthesis.
Intimal SMC proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions (see