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Pathogenetic concepts of acute coronary syndromes

^* Zena and Michael A. Wiener Cardiovascular Institute, The Mount Sinai School of Medicine, New York, New York, USA

View larger version (59K): [in a new window]   Figure 1 Link between cardiovascular (CV) risk factors, endothelial dysfunction, inflammation, and acute coronary syndromes. Endothelial dysfunction can be caused by many pro-inflammatory atherogenic factors (i.e., oxidative stress, low shear stress, glycation end-products, smoking, probably infections). Initially, endothelial nitric oxide synthesis is decreased, leading to impairment of endothelial-dependent vasorelaxation; this represents one of the earliest changes of atherosclerosis. Endothelial cells thereafter increase expression of adhesion molecules (VCAM, ICAM-1, and so forth), which facilitate monocyte and platelet adherence to the vessel wall through their cell-surface integrin receptors. Inflammatory cells are responsible for the release of TF, the major trigger of the coagulation cascade. ACE = angiotensin converting enzyme; CNP = c-type natriuretic peptide; ICAM-1 = intercellular adhesion molecule; MCP-1 = monocyte chemoattractant protein-1; NFk = nuclear factor kappa; PDGF = platelet-derived growth factor; PGI2 = prostaglandin; TGF = transforming growth factor; VCAM = vascular cell adhesion molecule.

View larger version (44K): [in a new window]   Figure 2 Pathogenesis of plaque development. Endothelial dysfunction and inflammatory processes are crucial in the initiation and progression of atherosclerotic lesions. The major goal of endothelial activity is to maintain constant hemostatic and hemorheologic conditions through a balanced production of several vasoactive and thrombotic/antithrombotic substances. Arrow = promotion; dashed line = inhibition. CAM = cell adhesion molecules; CRP = C-reactive protein; ET = endothelin; FDP = fibrin degrading products; MCP-1 = monocyte chemoattractant protein-1; M-CSF = macrophage colony-stimulating factor; MMP = metalloproteinase; NO = nitric oxide; PAI-1 = plasminogen activator inhibitor-1; PGI2 = prostaglandin; SMC = smooth muscle cells; TF = tissue factor; tPA = tissue plasminogen activator; TXA2 = thromboxane A2; VEGF = vascular endothelial growth factor. Reproduced with permission from Lippincott, Williams and Wilkins.

View larger version (107K): [in a new window]   Figure 3 Acute coronary syndromes typically derive from atherosclerotic plaque disruption. Lipid-rich lesions (A) account for 70% of acute coronary occlusions. The shoulder regions of the plaque often have a thinner fibrous cap that is highly infiltrated with macrophages and are prone to rupture. Mural thrombi on disrupted or ulcerated plaques may progress to occlusive thrombi or be partially lysed and be replaced in the process of organization by the vascular repair response (B).

View larger version (118K): [in a new window]   Figure 4 Effect of the inhibition of vascular tissue factor activity by recombinant TF pathway inhibitor (rTFPI) on the thrombogenicity of human atherosclerotic lesions (30). (A) Representative immunophotograph of control. (B) rTFPI-treated human lipid-rich atherosclerotic lesions. rTFPI was associated with a significant reduction of acute thrombus formation, both platelet and fibrin(ogen) thrombus component, in human lipid-rich plaques. Reproduced with permission from Lippincott, Williams and Wilkins.

View larger version (138K): [in a new window]   Figure 5 Inhibition of tissue factor (TF) by TF pathway inhibitor (TFPI) reduces thrombus formation and intima hyperplasia after porcine coronary angioplasty (49). Administration of TFPI during coronary angioplasty prevented acute thrombus formation (B). Note the presence of mural thrombus (black arrow) and intramural hemorrhage (white arrow) in the control animal (A) despite similar vascular injury, as confirmed by the disruption of the internal elastic lamina and part of the media present in both A and B. Similarly, TFPI significantly reduced the proliferative response in porcine coronary arteries (D) 28 days after angioplasty as compared with control animals (C). Adapted from Roque M, et al. J Am Coll Cardiol 2000;36:2303–10 (31).