Inflammation in atherosclerosis: some thoughts about acute coronary syndromes.

The innate or natural immune response is the body’s rapid first line of defense for environmental threats (eg, trauma and infection), responding long before an immune defense is mounted.1,2 This response involves a series of reactions that have evolved to limit damage, isolate pathogens (noxious agents), and initiate repair processes. Cells distinguish between pathogen and self by using signals from patternrecognition receptors, scavenger receptors (CD-36, SR-A), and Toll-like receptors (TLRs) on macrophage and dendritic cells.2 These receptors recognize pathogen-associated patterns in nucleic acids, proteins, carbohydrates, and lipids. Flow-dependent regulation of TLR2 surface expression in endothelial cells and ligation of TLR1, TLR2, and TLR4 in plaque result in recruitment of adaptor protein myeloid differentiation factor 88, followed by activation of nuclear factorB and mitogen-activated protein kinases.1– 4 This results in a cascade of proinflammatory molecules such as interleukin (IL)-6 that drive C-reactive protein (CRP) production, chemokines that act as chemoattractants, and serine proteases that drive thrombosis, all of which contribute to inflammation and pathogen clearance. Accumulating evidence supports a central role for inflammation in preclinical atherosclerosis, with acute coronary syndrome (ACS) as a principle clinical expression.4 Indeed, ACS, ischemic brain syndrome (stroke/transient ischemic attack), and peripheral arterial occlusion1– 4 result from a chronic inflammatory process, as well as disorders of lipid metabolism, modified by genetic and environmental factors. Arterial wall function and structure are modulated by interactions between injurious agents, blood vessel wall elements and monocytes, T lymphocytes, and platelets. Invading mononuclear cells release enzymes (eg, matrix metalloproteinases [MMPs]) that degrade collagen and elastin, thereby allowing cells to invade by disrupting matrix layers that otherwise stabilize developing plaque (Figures 1 and 2). Clot forming and inflammatory pathways then work in tandem to accelerate local macrophage and T-cell activation, which contributes to plaque erosion or rupture, forming a surface on which activated platelets may initiate thrombosis and microembolism and perhaps lead to continuing inflammation. In vulnerable patients, atherosclerosis develops under the influence of conditions that traumatize the endothelium, eg, aging, elevated blood pressure, increased low-density lipoprotein (LDL) cholesterol, obesity, diabetes, smoking, and potentially infections. Inflammation is documented by increased temperature in unstable plaque and an increase in circulating leukocytes consistent with the rubor, calor, and tumor of classic description.3,4 Lesion susceptibility is greatest in vascular branches or curvatures with altered hemodynamics (Figure 1C and 1D) where endothelial proliferation, apoptosis, and permeability increase. Expression of adhesion molecules and chemokines facilitates recruitment of macrophages laden with oxidized lipid (foam cells) and weakening of the fibrous cap. Platelet and leukocyte microaggregates at sites of plaque erosion release cytokines and other factors (eg, CD40 ligand [CD40L] and receptor, CRP, local angiotensin II, tissue-type plasminogen activator and inhibitor, IL-1, IL-6, MMPs, chemokines, and cell adhesion molecules) are all important contributors to and/or