Atherosclerotic

The concentration of t-PA in human blood is 2—5 ng/mL, ie, 2—5 ppb. Plasminogen activation is accelerated in the presence of a clot, but the rate is slow. The dissolution of a clot requites a week or more during normal repair of vascular damage (17). Prevention of irreversible tissue damage during a heart attack requires that a clot, formed by mpture of an atherosclerotic plaque, be dissolved in a matter of hours. This rapid thrombolysis (dissolution of the clot) must be achieved without significant tibrinogenolysis elsewhere in the patient. 

General trends in radiopharmaceutical research emphasize the use of small peptides. These molecules, of which the agents mentioned for thrombosis localization are an example, exhibit rapid and specific binding, and rapid blood clearance, two important parameters for a successflil radiopharmaceutical. Peptides are readily labeled with Tc and lend themselves to formulation as lyophilized kits that can be rapidly and rehably reconstituted. Possible targets for these molecules are quite varied, ranging from atherosclerotic plaque to P-amyloid (for Alzheimer s disease), to a variety of somatic receptors the populations of which are increased or decreased in disease. 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Another study (84), which enrolled men and women between the ages of 21—55 who had mild hypertension and no recognizable cardiovascular risk factors, showed no significant differences in mortaUty between dmg- and placebo-treated patients. Significant reductions in hypertensive complications were noted, but atherosclerotic complications were not reduced. 

A reversible attack of chest discomfort, usually caused by an imbalance between the oxygen demand of the working heart muscle and the insufficient supply through narrow, atherosclerotic coronary arteries. 

In general, arterial thrombi are platelet-rich ( white clots ) and form at ruptured atherosclerotic plaques, leading to intraluminal occlusion of arteries that can result in end-organ injury (e.g., myocardial infarction, stroke). In contrast, venous thrombi consist mainly of fibrin and red blood cells ( red clots ), and usually form in low-flow veins of the limbs, producing deep vein thrombosis (DVT) the major threat to life results when lower extremity (and, occasionally, upper extremity) venous thrombi embolize via the right heart chambers into the pulmonary arteries, i.e., pulmonary embolism (PE). 

The calcification of atherosclerotic plaques may be induced by osteopontin expression, since osteopontin is a protein with a well-characterized role in bone formation and calcification. Vascular smooth muscle cell migration on osteopontin is dq endent on the integrin av 33 and antagonists of av 33 prevent both smooth muscle cell migration and restenosis in some animal model [8]. 

The atherosclerotic plaque overexpresses another chemoattractant, eotaxin, that may mediate mast cell... 

Mast Cell Regulation. Recent experiments have elucidated the deleterious role of mast cell activation in atherosclerotic mice. Atheromata from mast cell... 

Libby P, Aikawa M (2002) Stabilization of atherosclerotic plaques new mechanisms and clinical targets. Nat Med 8 1257-1262... 

Atherosclerotic plaques are lesions in the arterial vessels which arise during the process of atherogenesis. Most cases of acute heart attacks are caused by rupture of an atherosclerotic plaque. 

Human umbilical vein endothelial cells (HUVEC) express the isoforms ECE-la, -lb, -Id and ECE-2. In these cells, ET-1 is secreted via both a constitutive and a regulated pathway. The ratio of released ET-1 big-ET-1 is 4 1. About 80% of the ET-1 is secreted at the abluminal cell surface of endothelial cells. ECE-isoforms are abundantly expressed on the cell surface of endothelial cells and to a lower level also on vascular smooth muscle cells. In atherosclerotic lesions of vessels, however, ECE expression in smooth muscle cells is upregulated. ECE isoforms expressed in smooth muscle cells contribute significantly to the generation of mature ET in normal and in particular atherosclerotic vessels. 

In addition, ETB receptors are upregulated in vessels with atherosclerotic lesions and in pulmonary vessels of patients with severe pulmonary hypertension. The upregulation can be attributed to increased ETB receptor expression in smooth muscle cells and to ETB receptors expressed on infiltrating macrophages. 

Furthermore, there is some evidence for pleiotrophic effects (e.g., effects on hemostasis, vascular function, anti-inflammatory effects, and stabilizing effects on atherosclerotic plaques) of statins. The clinical relevance of this (and the potential difference between the various statins) is at present uncertain but subject to intense investigation. 

Cramping sensation in the leg or buttock precipitated reproducibly by walking or exercise that occurs as a result of decreased oxygen supply due to severe atherosclerotic disease of the peripheral vascular system. It typically subsides after a brief rest. 

The innermost layer of an artery, which consists of loose connective tissue covered by a monolayer of endothelium that resides on a basement membrane. In human arteries, the intima often contains resident smooth muscle cells even early in life. Atherosclerotic plaques form in the intima. 

An episode of acute regional ischemia in the brain leading to neuronal death. It is usually caused by thrombi or emboli from atherosclerotic plaques. 

An episode of acute cardiac ischemia that leads to death of cardiomyocytes. It is usually caused by a thrombotic atherosclerotic plaque. 

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

Atherosclerotic lesion l Monocyte recruitment l Progression of atherosclerosis... 

Macrophage/ atherosclerotic lesion Anti-inflammatory effects9 ... 

PPARa Liver, heart, skeletal muscle, atherosclerotic lesions TG- and LDL-C-lowering and HDL-C-raising re-directs excess cholesterol from the peripheral tissues to the liver for excretion into the bile via HDL-C slowed progression of atherosclerosis Fatty acids, eico-sanoids (fatty acids derived from FAS ) Fibrates fenofibrate (Tricor ), genfibrozil (Lopid ) Dyslipidemia... 

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