Dyslipidemia is a risk factor for atherosclerosis and PAD. This chapter will address (1) the significance of dyslipidemia in the pathogenesis of PAD, (2) the evidence for dyslipidemia as a risk factor for existence and progression of PAD, and (3) the evidence regarding lipid-modifying therapy in PAD.
Dyslipidemia is a key pathogenic factor predisposing to atherosclerosis. Lipoproteins are instrumental in the initiation of atherosclerotic plaques and their progression to hemodynamically significant lesions that cause arterial insufficiency.
Low-density lipoprotein cholesterol (LDL) is a key driver of the atherosclerotic process. Fatty streaks, the earliest visible sign of atherosclerosis, consist mainly of macrophage-containing foam cells that are full of oxidized LDL.1 Multiple factors including increased endothelial permeability, retention of lipoproteins in the intima, and sluggish removal of lipoproteins result in accumulation of LDL in the vessel wall.2,3,4 Oxidized LDL and its products cause a vigorous inflammatory and proatherogenic response through chemotactic signaling for monocytes, smooth muscle cells, and T lymphocytes.5,6 Oxidized LDL leads to increased expression of a host of inflammatory factors including vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and macrophage colony stimulating factor.7,8,9,10,11,12,13,14,15 The net effect of this is to attract, trap, and tether leukocytes to the endothelium, initiate transformation of monocytes into macrophage foam cells, and enhance smooth muscle cell proliferation in the intima to form an atheroma. Oxidized modification of LDL may also contribute to so-called plaque vulnerability through induction of type 1 metalloproteinase expression and an increase in tissue factor activity.5 The oxidation of LDL, then, is an initial insult that leads to a cascade of immunologic and vascular events that cause endothelial dysfunction as well as initiation and progression of atherosclerotic plaques (Figure 3-1).
Oxidized low-density lipoprotein (OxLDL) stimulates induction of inflammatory mediators and cellular adhesion molecules including selectins, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), and macrophage colony stimulating factor (M-CSF). Selectins trap leukocytes while VCAM-1 and ICAM-1 promote firm attachment of these leukocytes to the endothelium. MCP-1 further attracts monocytes and also allows cellular flow into the intimal layer. M-CSF is integral in the transformation of monocytes to macrophage foam cells that internalize oxLDL. The early atheromatous lesion becomes a fibrous atheroma through smooth muscle migration into the intimal layer.
Further supporting the pivotal role of LDL in atherosclerosis, atherosclerotic lesion formation in mice has been inhibited through immunization with products of oxidized LDL.16,17,18,19 Not surprisingly, in numerous human trials, lowering LDL through pharmacological means has been shown to reduce progression of atherosclerosis as well as the incidence of cardiovascular events.20,21,22...