Porth's Essentials of Pathophysiology, 4e

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Disorders of Blood Flow and Blood Pressure

C h a p t e r 1 8

Clinical Manifestations Atherosclerosis usually doesn’t cause signs and symp- toms until it severely narrows or totally blocks an artery. Many people don’t know they have the disease until they have a medical emergency, such as a heart attack or stroke. Signs and symptoms will depend on the vessels involved and the extent of vessel obstruction. Atherosclerotic lesions produce their effects through narrowing of the vessel and production of ischemia; sudden vessel obstruction due to plaque hemorrhage or rupture; thrombosis and formation of emboli resulting from damage to the vessel endothelium; and aneurysm formation due to weakening of the vessel wall. 1,2 In larger vessels, such as the aorta, the important compli- cations are those of thrombus formation and weakening of the vessel wall. In medium-sized arteries, such as the coronary and cerebral arteries, ischemia and infarction due to vessel occlusion are more common. Although atherosclerosis can affect any organ or tissue, the arter- ies supplying the heart, brain, kidneys, lower extremi- ties, and small intestine are most frequently involved (see Fig. 18-6). Vasculitis The vasculitides are a group of vascular disorders that cause inflammatory injury and necrosis of the blood ves- sel wall. 1,2,15,16 Vessels of any type in virtually any organ can be affected, resulting in a broad spectrum of signs and symptoms. Because they may affect veins and capil- laries, the terms vasculitis, angiitis, and arteritis often are used interchangeably. Besides the finding referable to the specific tissue or organ involved, the clinical manifes- tations typically include constitutional signs and symp- toms such as fever, myalgia, arthralgia, and malaise. The two most common pathogenic mechanisms of vasculitis are direct invasion of the vascular wall by an infectious agent and immune-mediated inflammation. 1 The most common mechanisms that initiate nonin- fectious vasculitis are pathological immune responses that result in endothelial activation, with subsequent vessel obstruction, and ischemia of the dependent tis- sue. In almost all forms of vasculitis, the triggering event initiating and driving the inflammatory process is unknown. 2,16 A number of persons with vasculitis have circulating antibodies called antineutrophil cytoplasmic antibodies (ANCAs) that react with antigens in the cytoplasm of neutrophils. 1 Although the precise pathologic mecha- nism is unknown, these antibodies may serve to initi- ate an inflammatory state that continually recruits and stimulates neutrophils to release reactive oxygen species and proteolytic enzymes. 1 Serum ANCA titers, which can correlate with disease activity, may serve as a use- ful quantitative diagnostic marker for ANCA-associated vasculitides. The vasculitides are commonly classified based on etiology, pathologic findings, and prognosis. One

the reduction in blood flow becomes increasingly greater as the disease progresses. Complicated atherosclerotic lesions develop when the fibrous plaque breaks open, producing hemorrhage, ulceration, and scar tissue deposits. Thrombosis is the most important complication of atherosclerosis. It is caused by slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque. Although the risk factors associated with atheroscle- rosis have been identified through epidemiologic studies, many unanswered questions remain regarding the mech- anisms that contribute to the development of athero- sclerotic lesions. The vascular endothelial layer, which consists of a single layer of cells with cell-to-cell attach- ments, normally serves as a selective barrier that protects the subendothelial layers by interacting with blood cells and other blood components. One hypothesis of plaque formation suggests that injury to the endothelial vessel layer is the initiating factor. 1,2 A number of factors are regarded as possible injurious agents, including prod- ucts associated with smoking, immune mechanisms, and mechanical stress such as that associated with hyperten- sion. The fact that atherosclerotic lesions tend to form where vessels branch or where there is turbulent flow suggests that hemodynamic factors may also play a role. Hyperlipidemia, particularly elevated LDL, is also believed to play an active role in the pathogenesis of the atherosclerotic lesion. Interactions between the endo- thelial layer of the vessel wall and white blood cells, particularly the monocytes (blood macrophages), nor- mally occur throughout life; these interactions increase when blood cholesterol levels are elevated. One of the earliest responses to elevated cholesterol levels is the attachment of monocytes to the endothelium. The monocytes have been observed to move through the cell-to-cell attachments of the endothelial layer into the subendothelial spaces, where they are transformed into macrophages. Activated macrophages release free radicals that oxi- dize LDL, which in turn is toxic to the endothelium, causing endothelial cell loss and exposure of the sub- endothelial tissue to blood components. This leads to platelet adhesion and aggregation and fibrin deposition. Platelets and activated macrophages release various fac- tors that are thought to modulate the proliferation of smooth muscle cells and the deposition of extracellular matrix in the lesions. 1,2,14 Activated macrophages also ingest the oxidized LDL to become foam cells, which are present in all stages of atherosclerotic plaque forma- tion. Some of these cells die in place, releasing their fat and cholesterol-laden membranes into the intercellular space. This attracts more macrophages. Lipids released from necrotic foam cells accumulate to form unstable plaques (also known as vulneral plaque). Unstable plaques typically are characterized histologically by a large central lipid core, an inflammatory infiltrate, and a thin fibrous cap. These vulnerable plaques are at risk of rupture, often at the shoulder of the plaque (see Fig. 18-7A) where the fibrous cap is thinnest and the mechanical stresses highest. 2,14

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