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The consequences of atherosclerotic vascular disease are the leading cause of morbidity and mortality in the developed countries of the world and are rapidly approaching that status in the developing world. This chapter reviews the pathologic mechanisms of atherosclerotic disease development and progression, and details the interaction of these processes with the coagulation system. The earliest morphologically visible lesion of arterial atherosclerosis, the fatty streak, already is an advanced metabolic and immunologic locus that manifests as abnormalities of vascular tone, inflammation, cellular growth, and endothelial cell dysfunction. After years to decades, the lesions advance to form plaques that grow and eventually either impinge on the arterial lumen or rupture. Rupture of a vulnerable plaque is a catastrophic event that, through activation of both platelets and the coagulation cascade, triggers thrombosis, which leads to complete occlusion and tissue ischemia. Based on an increased understanding of the pathogenesis and consequences of atheromatous plaque development and progression, medical management of atherothrombotic syndromes has improved and is reviewed for the coronary, cerebrovascular, and peripheral arteries.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: ACC, American College of Cardiology; ACCP, American College of Chest Physicians; ACS, acute coronary syndrome; AHA, American Heart Association; apo, apolipoprotein; aPTT, activated partial thromboplastin time; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events; CK, creatine kinase; ECG, electrocardiogram; eNOS, endothelial nitric oxide synthase; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LDL, low-density lipoprotein; MCP, monocyte chemoattractant protein; MHC, major histocompatibility complex; MI, myocardial infarction; NO, nitric oxide; NSTEMI, non–ST-segment elevation myocardial infarction; PAD, peripheral arterial disease; PAI, plasminogen-activator inhibitor; PCI, percutaneous coronary intervention; TF, tissue factor; TGF, transforming growth factor; Th, T helper; VCAM, vascular cell adhesion molecule; VLDL, very-low-density lipoprotein.

Atherothrombosis describes a disease process that includes atherosclerosis and thrombosis in the artery. In the 1850s, Virchow1 described atherosclerosis as an inflammatory and prothrombotic process. Rokitansky, and later Duguid, posited that atherosclerotic lesions are initiated by incorporation of platelet lipids into the vessel wall (“encrustation”) following thrombosis. It was subsequently demonstrated that insudation of plasma lipoproteins is responsible for most of the lipid content of the atherosclerotic lesions. In 1913, Anitschkow, in Russia, noted atherosclerosis developing in rabbits fed a relatively high cholesterol diet. Although the involvement of inflammation in atherosclerosis has been known for more than 100 years, the molecular mechanisms of atherosclerotic disease initiation and progression have only become clearer over the past decade.2

Lipid accumulation in the arterial intima, a fatty streak (Table 135–1), can occur in adolescents and may progress in paroxysmal fashion to a hemodynamically significant lesion causing arterial insufficiency. Autopsy studies of young soldiers and young trauma victims indicated that occult coronary atherosclerotic plaques are commonly present in healthy individuals in their teens and twenties.3,4 In addition, intracoronary ultrasonograph studies demonstrated the presence of coronary ...

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