Cholesterol and Atherogenesis

Introduction

Over a century of epidemiologic studies and randomized trials have definitively established the causal role of cholesterol in the development of atherosclerosis. Total cholesterol, and later low-density lipoprotein cholesterol (LDL-C), were shown to be necessary for atherogenesis, a process that is accelerated in the presence of other cardiovascular risk factors. Conversely, atherosclerotic plaque stabilization and regression can occur when LDL-C levels are lowered, resulting in the reduction of clinical atherosclerotic cardiovascular disease (ASCVD) events.

The lipid hypothesis was first proposed over 150 years ago by Virchow and colleagues, who described cholesterol accumulation as the hallmark of atherosclerotic plaque. Ignatoski, Anitschkow and colleagues described atherosclerosis in rabbits fed a diet high in animal products 50 years later.

Pathophysiology

LDL is a critical factor in all stages of athero­genesis, although very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) play a role as well. Cardiovascular risk factors, such as smoking, hypertension and insulin resistance/hyperglycemia, influence endothelial function. A dysfunctional endothelium facilitates the entry of atherogenic lipoproteins into the intima, either via the LDL-receptor or through direct infiltration through the endothelium.

LDL can be oxidized in the blood or as it passes through the proteoglycan matrix of the endothelium. Oxidation promotes atherogenesis through a number of mechanisms. Increased retention of oxidized LDL in the intima stimulates uptake by macrophages. Accumulating cholesterol transforms the macrophage into a lipid-laden foam cell. Figure 3-1 provides an overview of plaque initiation and progression.

Oxidized LDL also triggers secretion of chemoattractant factors that recruit inflammatory leukocytes and lymphocytes, in addition to promoting transcription of proatherogenic genes, production of matrix metalloproteinases and tissue factors, smooth muscle cell apoptosis and suppression of nitric oxide production. Endothelial dysfunction due to decreased nitric oxide synthesis is one of the earliest physiologic manifestations of atherosclerosis.

Macrophage foam cells produce cytokines that stimulate smooth muscle cell infiltration, which in turn promotes extracellular matrix production and fibrosis. This contributes to plaque progression and arterial remodeling. Continued exposure to the pro-atherogenic milieu accelerates the recruitment of inflammatory cells and macrophages, continued lipid accumulation, neovascularization, necrosis of the lipid core and fibrous cap formation.

Proteolytic enzymes released by the inflammatory cells can degrade the extracellular matrix, leading to destabilization of overlying thin fibrous cap and plaque rupture.

Complex advanced atherosclerotic lesions are characterized by compensatory vascular remodeling to preserve lumen diameter. Enlargement of the lesion beyond the effective diffusion distance for oxygen from the lumen leads to neovascularization, which in turn facilitates lipid core expansion, intraplaque hemor­rhage and calcification.

Lipid-rich plaques are extremely thrombogenic. When ruptured, they release intracellular membrane proteins and tissue factor into the lumen. Sufficient accumulation of thrombus occludes the artery, precipitating an acute ASCVD event such as myocardial infarction (MI) or stroke.

Cholesterol, inflammation, and thrombosis are important causal factors of atherosclerosis (Figure 3-2). This lethal triad is ultimately expressed clinically as acute ASCVD events sometime during the lifespan the majority of adults in the United States.

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Atherosclerosis Through the Lifespan

Atherosclerotic plaque progresses through several pathologically distinct phases (Figure 3-3), with the rate of progression depending on the diet and level of other cardiovascular (CV) risk factors.

In countries with habitual atherogenic diets, cholesterol-laden macrophages begin to accumulate as fatty streaks by age 2. Fibrous plaques develop in the teens, and are characterized by a thin fibrous cap overlying a lipid-rich core with smooth muscle cell infiltration and extracellular matrix accumulation. By the mid-30s, fibrous plaques constitute about 50% of coronary lesions in men and 30% in women. As atherosclerosis progresses, advanced plaques with large extracellular lipid accumulation develop and fibrous plaques become confluent. Advanced plaque is prone to rupture due to the high lipid content, increased inflammatory cell infiltration and the overlying thin fibrous cap. By age 50, advanced plaque occurs in the majority of individuals in Western populations. In low-risk populations, half of individuals will have advanced plaque by age 65.

Complicated lesions arise as advanced plaques erode or rupture with overlying thrombosis. Thrombosis is usually nonocclusive and clinically silent. Occlusive thrombosis most often occurs in a nonstenotic lesion. As the ruptured plaque heals, with further infiltration by smooth muscle and inflammatory cells and accumulation of extracellular matrix, calcification and some degree of stenosis often occur at this stage.

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Cholesterol-Lowering and Plaque Stabilization and Regression

Lowering LDL-C has been shown to stabilize atherosclerotic plaques by shrinking the lipid core, reducing inflammatory cell infiltration and microvessels and thickening the overlying fibrous cap. More aggressive LDL-C lowering with high intensity statins has a greater impact on plaque stabilization and can result in plaque regression. Microvessels are thought to serve as a potential pathway for reverse cholesterol transport. Microvessels regress once the cholesterol-rich core has been depleted.