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CHAPTER 134 ATHEROSCLEROSIS

ATHEROTHROMBOSIS: Atherothrombosis describes a disease process that begins with ath-
erosclerosis and predisposes to thrombosis in the artery. In the 1850s,
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DISEASE INITIATION, Virchow described atherosclerosis as an inflammatory and prothrom-
botic process. Rokitansky, and later Duguid, posited that atherosclerotic
lesions are initiated by incorporation of platelet lipids into the vessel
PROGRESSION, AND wall (“encrustation”) following thrombosis. It was subsequently demon-
strated that insudation of plasma lipoproteins is responsible for most
TREATMENT of the lipid content of the atherosclerotic lesions. In 1913, Anitschkow
noted atherosclerosis developing in rabbits fed a relatively high choles-
terol diet. Although the involvement of inflammation in atherosclerosis
has been known for more than 100 years, the molecular mechanisms
Emile R. Mohler III and Andrew I. Schafer of atherosclerotic disease initiation and progression have become
clearer only in the recent past. It is now understood that the classical
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disagreement between the “lipid” hypothesis and the “inflammation”
SUMMARY hypothesis of atherogenesis can be reconciled because there is direct
linkage between cholesterol deposition and arterial inflammation in the
process. 3,4
The consequences of atherosclerotic vascular disease are the leading cause Lipid accumulation in the arterial intima, termed a fatty streak,
of morbidity and mortality in the developed countries of the world and are can occur in adolescents and may progress in paroxysmal fashion to
rapidly approaching that status in the developing world. This chapter reviews a hemodynamically significant lesion causing arterial insufficiency.
the pathologic mechanisms of atherosclerotic disease development and pro- Autopsy studies of young soldiers and young trauma victims indi-
gression, and details the interaction of these processes with the coagulation cated that occult coronary atherosclerotic plaques are commonly
system. The earliest morphologically visible lesion of arterial atherosclerosis, present in healthy individuals in their teens and twenties. In
5,6
the fatty streak, already is an advanced metabolic and immunologic locus that addition, intracoronary ultrasonograph studies demonstrated the
manifests as abnormalities of vascular tone, inflammation, cellular growth, presence of coronary atherosclerosis in 37 percent of healthy heart
and endothelial cell dysfunction. After years to decades, the lesions advance donors age 20 to 29 years, 60 percent of those age 30 to 39 years,
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to form plaques that grow and eventually either impinge on the arterial lumen and 85 percent of those older than age 50 years. Several theories are
or rupture. Rupture of a vulnerable plaque is a catastrophic event that, through espoused for this propitious condition. One well-recognized theory
is the response to injury hypothesis whereby the inciting event that
activation of both platelets and the coagulation cascade, triggers thrombo- predisposes to atherosclerosis is injury to the endothelial lining of the
sis, which leads to complete occlusion, and unless collateral circulation has artery. This hypothesis was formulated in animal studies that showed
already been established, results in tissue ischemia. Based on an increased vessel narrowing and intimal thickening after endothelial denudation
understanding of the pathogenesis and consequences of atheromatous plaque with angioplasty. However, human pathologic studies of early ath-
8,9
development and progression, medical management of atherothrombotic erosclerotic plaques indicate that endothelium is structurally present
syndromes has improved and is reviewed for the coronary, cerebrovascular, but is dysfunctional. The dysfunctional state of endothelium induces
and peripheral arteries. abnormalities in vascular tone, inflammation, growth, and thrombo-
sis. Atherosclerotic risk factors contribute to endothelial dysfunction
and promote atherosclerosis. This section describes the mechanisms
responsible for endothelial dysfunction and the impact of atheroscle-
rotic risk factors.
Acronyms and Abbreviations: 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; CABG, ATHEROSCLEROTIC RISK FACTORS
coronary artery bypass graft; CAD, coronary artery disease; CAPRIE, Clopidogrel Versus Increasing age, male gender, and heredity are the major athero-
Aspirin in Patients at Risk of Ischaemic Events; CCL, CC chemokine ligand; CK, creatine sclerotic cardiovascular disease risk factors that cannot be modified
kinase; CVD, cardiovascular disease; ECG, electrocardiogram; eNOS, endothelial nitric (Table 134–1). Abnormal lipids, smoking, improperly controlled hyper-
oxide synthase; EPC, endothelial progenitor cell; EV, extracellular vesicle; HAART, tension, improperly controlled diabetes mellitus, abdominal obesity,
highly active antiretroviral therapy; HDL, high-density lipoprotein; hsCRP, high- physical inactivity, and psychosocial factors are established risk factors
sensitivity C-reactive protein; IFN, interferon; Ig, immunoglobulin; IL, interleukin; that can be modified, accounting for most of the risk of myocardial
LDL, low-density lipoprotein; Lp-PLA lipoprotein phospholipase A ; MCP, monocyte infarction worldwide in both sexes and at all ages. 10
2
2
chemoattractant protein; MHC, major histocompatibility complex; MI, myocardial In addition to these traditional risk factors, newer risk factors have
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infarction; NO, nitric oxide; NOX, nicotinamide adenine dinucleotide phosphate been recognized. With the use of highly active antiretroviral ther-
oxidase; NSTEMI, non–ST-segment elevation myocardial infarction; PAD, peripheral apy (HAART), HIV-infected patients have demonstrated a dramatic
12
arterial disease; PAI, plasminogen-activator inhibitor; PCI, percutaneous coronary overall increase in life expectancy. At the same time, HAART-treated
intervention; SLE, systemic lupus erythematosus; SNP, single nucleotide polymor- HIV patients also have an increased risk of developing premature car-
phisms; TF, tissue factor; TFPI, tissue factor pathway inhibitor; TGF, transforming diovascular disease over time. Both HIV viral proteins and the antiret-
growth factor; Th, T helper; t-PA, tissue-type plasminogen activator; VCAM, vascular roviral drugs themselves cause endothelial dysfunction. They activate
cell adhesion molecule; VLDL, very-low-density lipoprotein; VWF, von Willebrand cell signaling cascades, induce oxidative stress, disturb mitochondrial
factor. function, alter gene expression, and impair lipid metabolism in vascular
cells, macrophages, and adipocytes. 13,14

Kaushansky_chapter 134_p2281-2302.indd 2281 17/09/15 3:49 pm