Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lipid component of vulnerable atherosclerotic lesions strongly determines the propensity for plaque rupture. Oxidized low-density lipoprotein (OxLDL) is a major component of the plaque lipid pool and contributes significantly to the inflammatory milieu. Because oxidation-specific antibodies (Ox-AB) have been shown to selectively immunostain human atherosclerotic lesions, we hypothesized that tagged Ox-AB may be useful for noninvasive imaging of atherosclerosis. Indeed, intravenously injected (125)I-MDA2, a prototype murine monoclonal Ox-AB, has strong selectivity for and accurately identifies lipid-rich atherosclerotic lesions in their entirety. Plaque uptake of (125)I-MDA2 strongly correlates with extent of atherosclerosis, measured by percentage of surface area and aortic weight, and thus provides an accurate quantitative measure of atherosclerotic burden. Dietary regression studies in mice have shown that (125)I-MDA2 uptake is more sensitive to "regression," not measured by physical dimensions but by depletion of OxLDL, suggesting a novel mechanism of plaque stabilization. In vivo gamma-camera scintigraphy with (99m)Tc-MDA2 revealed that imaging of lipid and oxidation-rich atherosclerotic lesions is feasible with this technique. We have developed IK17, the first human Ox-AB, which recognizes a unique oxidation-specific epitope, and may have significant advantages over murine antibodies. Ox-AB may be tagged with appropriate labels for use in nuclear, magnetic resonance, or ultrasound imaging. Potential applications include early diagnosis of lipid-rich atherosclerotic lesions, screening, and serial follow-up of high-risk individuals, identifying vulnerable plaques, and evaluating novel drug therapies on progression and regression of atherosclerosis.
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PMID:Noninvasive imaging of oxidized low-density lipoprotein in atherosclerotic plaques with tagged oxidation-specific antibodies. 1245 23

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized world. The progression of atherosclerotic plaques in coronary circulation is modulated by several risk factors. It is now clear that plaque composition is a major determinant of plaque disruption and superimposed thrombosis. Plaque vulnerability, defined as the propensity of plaques to disrupt, is further determined by intrinsic and extrinsic triggering factors. After disruption, the fatty core of the plaque and its high content of tissue factor provide a powerful substrate for the activation of the coagulation cascade. Plaque disruption can be clinically silent or cause symptoms of ischemia depending on thrombus burden and the degree of vessel occlusion. In addition, plaque disruption and subsequent healing are recognized to play key roles in the rapid plaque progression. This review looks at the mechanisms underlying the development and progression of atherosclerotic plaques, factors leading to plaque rupture and subsequent thrombosis, and their clinical consequences as potential targets for future research.
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PMID:Biologic aspects of vulnerable plaque. 1246 4

More studies on the natural history of carotid artery plaques are needed to predict more reliably which plaque types or features are the most dangerous (see Table 2). Studies on carotid and coronary endarterectomy specimens indicate a dynamic process of rupture, thrombus formation, healing, and remodeling of the plaque. A plaque from a symptomatic patient may not show any signs of plaque rupture if the plaque has healed or evolved since the debut of symptoms. Selection of high-risk symptomatic patients with carotid atherosclerosis for medical or surgical treatment requires reliable, noninvasive, and cost-effective imaging methods. B-mode ultrasonography can be used for detection of early (IMT) as well as late (plaque morphology) atherosclerotic disease. Plaque morphology evaluation on spiral CT imaging is only for research and not yet for clinical use. Asymptomatic patients with carotid atherosclerosis hardly benefit from surgical treatment, as the minimal decrease in ischemic stroke risk is almost equal to the risk of perioperative stroke or death. A high degree of carotid stenosis measured using conventional angiography is an accepted risk factor for stroke but does not identify all vulnerable plaques. Echolucency on ultrasound B-mode imaging can be included as an important parameter in this risk stratification, as it appears to predict rupture-prone, lipid-rich plaques in the mild to severely stenotic carotid artery of a symptomatic patient. The subjective evaluation of plaque morphology on B-mode ultrasound should be complemented or substituted with objective evaluation such as videodensitometric analysis. This method is commercially available and is a relatively cheap and investigator-independent solution, but more studies are required to determine the exact contribution of echolucency to stroke risk. Furthermore, the evaluation of plaque morphology using ultrasound B-mode is still subject to large variations and observer-dependence, limiting its clinical use. In contrast, carotid IMT measurements are reliable to monitor progression and regression of early carotid disease as well as the impact of interventions. This method, however, suffers when used in severely diseased vessels where the boundaries of the IMT complex are hard to distinguish in all segments of the artery. Spiral CT imaging is a preliminary test for plaque characterization, as it primarily identifies calcification but not the more relevant lipid component. Moreover, it is time and resource demanding and involves use of both contrast and radiation, increasing the risk of allergic events and cancer. Standardization and continuous quality control are important, as are consensus agreements on how to quantify lesions (especially IMT), calibrate and standardize B-mode images and outline the plaque, and analyze data. The development of imaging methods for atherosclerotic research is currently fast and promising. This progress is most necessary, considering the very high demands for surrogate endpoints and risk markers in clinical intervention studies. Whether ultrasonic plaque characterization can be implemented in broad general clinical practice, for example, in screening of individuals at high risk of developing atherosclerosis and ischemic events, has to be based upon data from large prospective studies with long-term follow-up. IMT is already used in population screening, as in the ARIC study [9,101].
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PMID:B-mode ultrasound and spiral CT for the assessment of carotid atherosclerosis. 1248 30

Atherosclerosis is the most common disease in the industrialised world and by 2020 is predicted to be the number 1 cause of death worldwide. It is a disease of the intima and media of small to medium sized arteries that develop slowly over many years. A number of risk factors for atherosclerosis have been identified, some of these are reversible and some are not. Most prominent amongst these is an elevated level of plasma cholesterol. The lowering of cholesterol reduces the risk of heart attacks, strokes and all forms of atherosclerotic vascular disease. Nonetheless, 70% of patients go on to get symptomatic disease. The disease process sets off an inflammatory response involving the vascular endothelium and both T and B cells of the immune system. Adhesion molecules are induced and proinflammatory cytokines and growth factors are produced by cells that orchestrate the atherosclerotic process. Narrowing the lumen of the artery leads to ischaemic symptoms. Within lesions under the influence of proteolytic enzymes released from activated macrophages (or foam cells--the hallmark of atherosclerosis) the centre of the plaque becomes liquefied to take on it's characteristic "gruel" like appearance. The shoulders of such plaque weaken and it becomes prone to rupture. Plaque rupture may lead to catastrophic thrombosis of coronary or cerebral arteries. The large amounts of tissue factor produced by macrophages make this a particularly likely event. On ulcerated plaques adherent platelets and thrombus create showers of emboli leading to ischaemic attacks. Like the effective treatment of LDL and it's role in the prevention of ischaemic attacks there has been a move to develop new drugs that raise HDL. The discovery of the role of a new class of ABC transporter, defective in Tangiers disease, responsible for cholesterol efflux from peripheral cells including the macrophage has created great excitement around ABC1 as a drug target. New areas, new possible targets and new genetic and genomic approaches will be discussed.
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PMID:The pathogenesis of atherosclerosis and new opportunities for treatment and prevention. 1259 6

Acute coronary syndrome (ACS) is often associated with the rupture of vulnerable atherosclerotic plaque, coronary thrombus formation, and abrupt limitation of blood flow, leading to adverse outcomes. Passivation of vulnerable plaque represents a therapeutic concept that has the potential to prevent or limit the magnitude of a new rupture in order to reduce the recurrence or severity of events. Plaque passivation can be defined as a process by which the structure or content of the atherosclerotic plaque is changed to reduce the risk of subsequent rupture and thrombosis. This may be achieved by using strategies that address different components of the plaque or the endothelium. The following factors can affect the susceptibility of plaque to rupture: macrophage infiltration; accumulation of inflammatory cells; paracrine secretion of enzymes that may cause degradation of the fibrous cap of coronary plaque; shear stress; circadian rhythm variation in stress hormone release; and infectious agents. The use of pharmacologic agents to reduce plaque vulnerability by passivation has been explored. Clinical studies demonstrate that lipid-modifying agents (e.g., statins), antiplatelet agents (acetylsalicylic acid, thienopyridines, thianopyridines, glycoprotein IIb/IIIa inhibitors), and antithrombotic agents (unfractionated heparin and low-molecular-weight heparin) can reduce the occurrence of acute coronary events in ACS patients. In addition, angiographic studies suggest that statins may also promote regression of atherosclerosis. Angiotensin-converting enzyme inhibitors, niacin, and calcium antagonists may also contribute to plaque passivation. This article reviews atherosclerotic plaque development and vulnerability and discusses some clinical studies highlighting the role of plaque passivation in the management of ACS patients.
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PMID:Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes. 1264 37

Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo, the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.
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PMID:Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. 1268 94

Constrictive remodeling occurs in significant atherosclerotic lesions of the diabetic patient, but the impact of diabetes mellitus (DM) on the angiographically normal coronary artery is still unclear. Morphometric analysis using intravascular ultrasound (IVUS) prior to intervention evaluated 54 sites in 33 DM patients and 106 in 62 non-diabetic patients. Vessel area (VA) and lumen area (LA) were measured at angiographically normal sites in the vessel. Plaque area (PA) was calculated as VA - LA. Percentage plaque area (%PA) was calculated as PA VA. Even in the angiographically normal site, mild coronary atherosclerosis was detected by IVUS in both groups. In the patients with DM, VA and LA were significantly smaller than in the non-diabetic patient (15.5 vs 17.8 mm(2), p<0.01; and 10.1 vs 12.2 mm(2), p<0.01 respectively), whereas % PA was similar (34.5 vs 31.6%). At angiographically normal sites where mild coronary atherosclerosis is detected by IVUS, the coronary artery of diabetic patients is smaller than that of the non-diabetic. These results suggest impaired compensatory enlargement or some other constrictive mechanism has already occurred in the early stages of coronary atherosclerosis in patients with DM.
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PMID:Impact of diabetes mellitus on angiographically silent coronary atherosclerosis. 1273 81

Atherosclerotic lesions are infiltrated by macrophages and T lymphocytes, potentially reactive to pathogens. We studied in vivo activated T lymphocytes that infiltrate atherosclerotic plaques of Helicobacter pylori-infected patients with or without anti-Chlamydia pneumoniae antibodies. In all atherosclerotic lesions, T helper type 1 (Th1) cells were predominant. C. pneumoniae-specific T cells were detected only in the plaques of anti-C. pneumoniae seropositive patients, whereas H. pylori-specific T cells were found in the gastric mucosa but not in the plaques of the same patients. Plaque-derived Th1 cells expressed cytotoxicity, proapoptotic activity, and help for monocyte tissue factor production. Although multifactorial, atherosclerosis can be regarded as a Th1-driven immunopathological condition.
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PMID:T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. 1274 Apr 34

Atherosclerosis is a progressive and complex pathophysiological process occurring in large arteries. Although it is of multifactorial origin, the disease develops at preferential sites along the vasculature in regions experiencing specific hemodynamic conditions that are predisposed to endothelial dysfunction. The exact mechanisms allowing endothelial cells to discriminate between plaque-free and plaque-prone flows remain to be explored. To investigate such mechanisms, we performed a proteomic analysis on endothelial cells exposed in vitro to these two-flow patterns. A few spots on the two-dimensional gel had an intensity that was differentially regulated by plaque-free versus plaque-prone flows. One of them was further investigated and identified as macrophage-capping protein (Cap G), a member of the gelsolin protein superfamily. A 2-fold increase of Cap G protein and a 5-fold increase of Cap G mRNA were observed in cells exposed to a plaque-free flow as compared with static cultures. This increase was not observed in cells exposed to plaque-prone flow. Plaque-free flow induced a corresponding increase in nuclear and cytoskeletal-associated Cap G. Finally, overexpression of Cap G in transfection assays increased the motility potential of endothelial cells. These observations together with the known functions of Cap G suggest that Cap G may contribute to the protective effect exerted by plaque-free flow on endothelial cells. On the contrary, in cells exposed to a plaque-prone flow, no induction of Cap G expression could be observed.
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PMID:Cap G, a gelsolin family protein modulating protective effects of unidirectional shear stress. 1275 61

Accumulating data from studies in animals and humans indicate that beta-blockade has antiatherosclerotic effects. To date, 2 long-term ultrasound studies provide the strongest evidence. The Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS) trial reported favorable effects with beta-blockade on early stages of atherosclerosis in patients with carotid plaque but no symptoms of carotid artery disease. Compared with placebo, metoprolol controlled release/extended release (CR/XL) 25 mg once daily significantly reduced plaque thickness after 18 months of treatment (net difference -0.058 mm/year; p <0.001) and at 3 years' follow-up (net difference -0.023 mm/year; p = 0.018). The Effects of Long-Term Treatment of Metoprolol CR/XL on Surrogate Variables for Atherosclerotic Disease (ELVA) trial demonstrated that beta-blockers and statins affect different mechanisms in the atherosclerotic process and have additive beneficial effects. Patients with hypercholesterolemia were randomized to metoprolol CR/XL 100 mg once daily or placebo once daily and concomitant statin therapy. The metoprolol CR/XL group had a significantly lower rate of progression of the composite carotid bulb intima-media thickness (IMT) plus common carotid IMT than the placebo group, both at 1 year (-0.08 vs -0.01 mm; p = 0.004) and after 3 years' follow-up (-0.06 vs +0.03 mm; p = 0.011). Several factors may contribute to the mechanism of benefit in these trials, including reduced sympathetic activity, improved hemodynamic parameters, and direct effects on the vascular endothelium.
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PMID:Antiatherosclerotic effects of beta-blockers. 1281 32


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