cardiovascular disorders
Atherosclerosis
Pathophysiology of Atherosclerosis
Thefatty streakis the earliest visible lesion of atherosclerosis; it is an accumulation of lipid-laden foam cells in the intimal layer of the artery. Theatherosclerotic plaqueis the hallmark of atherosclerosis; it is an evolution of the fatty streak and has 3 major components: Lipids Inflammatory and smooth muscle cells A connective tissue matrix that may contain thrombi in various stages of organization and calcium deposits All stages of atherosclerosis—from initiation and growth to complication of the plaque (eg, myocardial infarction, stroke) —are considered an inflammatory response to injury mediated by specific cytokines. Endothelial injury is thought to have a primary initiating or inciting role. Nonlaminar or turbulent blood flow (eg, at branch points in the arterial tree) leads to endothelial dysfunction and inhibits endothelial production of nitric oxide, a potent vasodilator and anti-inflammatory molecule. Such blood flow also stimulates endothelial cells to produce adhesion molecules, which recruit and bind inflammatory cells. Risk factors for atherosclerosis (eg, Dyslipidemia , Monocytes in the subendothelium transform into macrophages. Lipids in the blood, particularly low-density lipoprotein (LDL) cholesterol and very-low-density lipoprotein (VLDL) cholesterol, also bind to endothelial cells and are oxidized in the subendothelium. Uptake of oxidized lipids and macrophage transformation into lipid-laden foam cells result in the typical early atherosclerotic lesions called fatty streaks. Degraded erythrocyte membranes that result from rupture of vasa vasorum and intraplaque hemorrhage may be an important additional source of lipids within plaques. Macrophages elaborate proinflammatory cytokines that recruit smooth muscle cell migration from the media and that further attract and stimulate growth of macrophages. Various factors promote smooth muscle cell replication and increase production of dense extracellular matrix. The result is a subendothelial fibrous plaque with a fibrous cap, made of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids. A process similar to bone formation causes calcification within the plaque. , cytomegalovirus) and Overview of Coronary Artery Disease (CAD). Putative mechanisms include indirect effects of chronic inflammation in the bloodstream, cross-reactive antibodies, and inflammatory effects of infectious pathogens on the arterial wall. However, evidence in favor of such a link is conflicting, and infection likely plays a minor role in atherosclerosis. Atherosclerotic plaques may be stable or unstable. Stable plaquesregress, remain static, or grow slowly over several decades until they may cause stenosis or occlusion. Unstable plaquesare vulnerable to spontaneous erosion, fissure, or rupture, causing acute thrombosis, occlusion, and infarction long before they cause hemodynamically significant stenosis. Most clinical events result from unstable plaques, which are often not hemodynamically significant on angiography; thus, plaque stabilization may be a way to reduce morbidity and mortality. The strength of the fibrous cap and its resistance to rupture depend on the relative balance of collagen deposition and degradation. Plaque rupture involves secretion of metalloproteinases, cathepsins, and collagenases by activated macrophages in the plaque. These enzymes digest the fibrous cap, particularly at the edges, causing the cap to thin and ultimately rupture. T cells in the plaque contribute by secreting cytokines. Cytokines inhibit smooth muscle cells from synthesizing and depositing collagen, which normally reinforces the plaque. Once the plaque ruptures, plaque contents are exposed to circulating blood, triggering thrombosis; macrophages also stimulate thrombosis because they contain tissue factor, which promotesthrombingeneration in vivo. One of 5 outcomes may occur: The resultant thrombus may organize and be incorporated into the plaque, changing the plaque’s shape and causing its rapid growth. The thrombus may rapidly occlude the vascular lumen and precipitate an acute ischemic event. The thrombus may embolize. The plaque may fill with blood, balloon out, and immediately occlude the artery. Plaque contents (rather than thrombus) may embolize, occluding vessels downstream. Plaque stability depends on multiple factors, including plaque composition (relative proportion of lipids, inflammatory cells, smooth muscle cells, connective tissue, and thrombus), wall stress (cap fatigue), size and location of the core, and configuration of the plaque in relation to blood flow. By contributing to rapid growth and lipid deposition, intraplaque hemorrhage may play an important role in transforming stable into unstable plaques. 50% and may produce predictable exercise-induced stable Angina Pectoris . Clinical consequences of plaque rupture in coronary arteries depend not only on that anatomical location of the plaque anatomy but also on relative balance of procoagulant and anticoagulant activity in the blood and on the vulnerability of the myocardium to arrhythmias. 