In an experimental animal model of carotid thrombosis, we have demonstrated the superiority of a fibrin-targeted MR contrast agent for in vivo detection of chronic or organized thrombus, compared with NCE MRI and Gd-DTPA injection.

Abstract-Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2 Ϫ/Ϫ mice showed a 61.4% reduction (PϽ0.01) in intimal area and a 62% reduction (PϽ0.05) in intima/media ratio when compared with CCR2 ϩ/ϩ littermates. The response of CCR2 ϩ/Ϫ mice was not significantly different from that of CCR2 ϩ/ϩ mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2 Ϫ/Ϫ mice when compared with CCR2 ϩ/ϩ littermates (PϽ0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2 Ϫ/Ϫ or CCR2 ϩ/ϩ mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury. . MCP-1 antigen is not detected in normal vascular endothelium, but is found on the luminal endothelium of early human atherosclerotic lesions. 2 MCP-1 expression is induced in medial SMCs during early atherosclerotic lesion development in carotid arteries of non-human primates fed a hypercholesterolemic diet. 3 In advanced human atherosclerotic plaques, MCP-1 is expressed in macrophages and SMCs. 2,4,5 MCP-1 antigen and mRNA are also induced in medial SMCs in animal models of arterial injury. 6 -8

Coronary angioplasty has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977. The primary success rate has improved despite the increase in procedure and case complexity. However, acute reocclusion and late restenosis, which constitute the most important problems after successful angioplasty, continue to occur in about 5% and 35% of patients within 3 to 6 months, respectively. Angioscopic and pathologic observations have suggested that a multifactorial pathophysiologic process accounts for acute reocclusion, involving marked thrombosis, intimal dissection, medial and subintimal hemorrhage, vascular recoil and vasocontriction. In contrast, chronic restenosis involves the development of fibrocellular intimal hyperplasia within a milieu created by vascular injury, platelet activation, thrombin generation and the release of mitogens. Although current pharmacologic approaches, which involve antithrombotic and anticoagulant therapy, have been largely ineffective in eliminating acute reocclusion and chronic restenosis, recent advances in the research in thrombosis, platelet receptors and smooth muscle growth regulation have allowed new therapeutic options to be tested in the experimental setting, with subsequent potential clinical applications in patients.

No abstract

Background Hypoxia is an important microenvironmental factor influencing atherosclerosis progression by inducing foam-cell formation, metabolic adaptation of infiltrated macrophages and plaque neovascularization. Therefore, imaging plaque hypoxia could serve as a marker of lesions at risk. Methods and Results Advanced aortic atherosclerosis was induced in 18 rabbits by atherogenic diet and double balloon endothelial denudation. Animals underwent 18F-FMISO PET and 18F-fluorodeoxyglucose (18F-FDG) PET imaging after 6–8 months (atherosclerosis induction) and 12–16 months (progression) of diet initiation. Four rabbits fed standard chow served as controls. Radiotracer uptake of the abdominal aorta was measured using standardized uptake values (SUV). Following imaging, plaque hypoxia (pimonidazole), macrophages (RAM-11), neovessels (CD31) and hypoxia-inducible factor-1α (HIF-1α) were assessed by immunohistochemistry. 18F-FMISO uptake increased with time on diet (SUVmean, 0.10±0.01 in non-atherosclerotic animals versus 0.20±0.03 (P=0.002) at induction and 0.25±0.03 (P<0.001) at progression). Ex vivo PET imaging corroborated the 18F-FMISO uptake by the aorta of atherosclerotic rabbits. 18F-FDG uptake also augmented in atherosclerotic animals, with a SUVmean of 0.43±0.02 at induction versus 0.35±0.02 in non-atherosclerotic animals (P=0.031), and no further increase at progression. By immunohistochemistry, hypoxia was mainly located in the macrophage-rich areas within the atheromatous core, whereas the macrophages close to the lumen were hypoxia-negative. Intraplaque neovessels were found predominantly in macrophage-rich hypoxic regions (pimonidazole+/HIF-1α+/RAM-11+). Conclusions Plaque hypoxia increases with disease progression and is present in macrophage-rich areas associated with neovascularization. 18F-FMISO PET imaging emerges as a new tool for detection of atherosclerotic lesions.

Platelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspirin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 production and adenosine diphosphate-induced platelet aggregation pathways, respectively. Aspirin has proven benefits in primary and secondary prevention of coronary artery disease. Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study demonstrates for the first time the benefit of adding clopidogrel to aspirin rather than using aspirin alone in patients having acute coronary syndromes without ST-segment elevation myocardial infarction. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events and may derive special benefit from the combination therapy. Aspirin resistance can be assessed through platelet aggregometry testing, measurement of urinary thromboxane metabolites, and, possibly, genomic testing in the future.

Abstract-There is a need for a rapid antithrombotic effect after the administration of antiplatelet drugs in the setting of acute coronary syndromes and percutaneous interventions. Clopidogrel, a new thienopyridine derivative, is an efficient antiplatelet agent. However, the standard regimen of clopidogrel (75 mg/d) requires 2 to 3 days before significant antithrombotic effects. Patients with stable arterial disease on chronic aspirin therapy (nϭ20) were treated with clopidogrel either with a front-loaded regimen, 300 mg the first day and 75 mg/d the next 7 days, or with a standard regimen, 75 mg/d for 8 days. Blood thrombogenicity was assessed by quantification of platelet-thrombus formation in an ex vivo perfusion chamber, by ADP-induced platelet aggregation, and by ADP-induced fibrinogen binding. At 2 hours, mean total thrombus area with the standard regimen was not significantly reduced. In contrast, at 2 hours, the mean total thrombus area with the front-loaded regimen was significantly decreased by 23.1Ϯ8.5% versus baseline (PϽ0.05). ADP-induced platelet aggregation (with 5 and 10 mol/L) was also significantly (PϽ0.05) reduced with the front-loaded regimen at 2 hours, with the mean platelet aggregation being 82.2Ϯ4.4% and 81.8Ϯ4.5%, respectively, versus baseline. Similarly, flow cytometry demonstrated a significant decrease (PϽ0.05) in the ADP-induced fibrinogen binding (with 0.12 and 0.6 mol/L) at 2 hours in this front-loaded regimen group (36.1Ϯ2.0% and 53.2Ϯ9.3%). With the standard regimen, platelet activity was not significantly reduced at 2 hours. Our data suggest that a front-loaded regimen of clopidogrel added to aspirin achieves a significant antithrombotic effect at 2 hours in patients with known atherosclerotic disease on chronic aspirin therapy. This provides a rationale for using front-loaded clopidogrel in combination with aspirin in percutaneous coronary interventions.

Our knowledge of the pathophysiology of coronary atherosclerosis has remarkably changed in the last few years. The types of atherosclerotic lesions, the mechanisms of progression of coronary atherosclerosis with plaque instability and disruption, and the subsequent thrombotic phenomenon leading to acute coronary syndromes are now better understood (1-3). Therapeutic strategies leading to atherosclerotic lesion stabilization and even regression, as well as new antithrombotic strategies to alleviate or prevent the thrombotic complications are being pursued. This review focuses on the coronary unstable atherosclerotic plaque and complicatin g thrombosis. Historical background of coronary unstable plaque and thrombosis As recently reviewed (3) Dr. V.P. Obrastzow, a Russian physician, first described the clinical presentation of acute myocardial infarction in 1910. In 1912, Dr. J.B. Herrick associated the clinical presentation of acute infarction with thrombotic coronary occlusion. In 1929, Dr. S. Levine pointed out the importance of risk factors, a finding later confirmed by the Framingham Heart Study. In 1959, Drs. A.P. Fletcher and S. Sherry pioneered ttre use intravenous thrombolytic therapy. That year, the development of selective coronary angiography by Dr. M. Sones showed the importance of coronary occlusion in myocardial infarction and eventually led to the first coronary artery bypass operation by Drs. Garrett, Dennis and DeBakey, its systematic application by Dr. R. Favaloro and to percutaneous transluminal coronary angioplasty by Dr. A. Gruntzig. The specific description of plaque disruption leading to an acute myocardial infarction was mainly contributed by Dr.