Atherosclerotic plaque rupture

A.C. Newby, Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol. Rev. 85 (2005) 1-31. 

Acute coronary syndromes (ACS) are a major cause of morbidity and mortality. They are characterized by intracoronary thrombus formation at the site of atherosclerotic plaques. Coronary thrombosis is the underlying mechanism in the transition from stable angina to the unstable angina (UA) syndrome, characterized by embolization of the developed thrombus and atherosclerotic plaque rupture. 

Fuster V Stein B, Ambrose JA, Badimon L, Badimon JJ, ChesebroJH. Atherosclerotic plaque rupture and thrombosis, Evolving concepts. Circulation 1990 82(suppl 3) 1147—1159. 

Rioufol G, Finet G, Ginon I, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome a three-vessel intravascular ultrasound study, Circulation 2002 106 ... 

Bennett MR. Apoptosis of yascular smooth muscle cells in yascular remodelling and atherosclerotic plaque rupture. Cardiovasc. Res. 1999 41(2) 361-368. 

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the entire epicardial coronary artery with subsequent acute myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. 

Lee K, Santibanez-Koref M, Polvikoski T, Birchall D, Mendelow AD, Keavney B (2013) Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis 226 74-81... 

Markers of systemic inflammation (e.g., C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be nontradi-tional risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future MI or UA. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk. The management of UA and NSTEMI is covered in detail in Chap. 16. 

R9. Rioufol, G., Finet, G., Ginon, I., Andre-Fouet, X., Rossi, R., Vialle, E., Desjoyaux, E., Convert, G., Huret, J. F., and Tabib, A., Multiple atherosclerotic plaque rupture in acute coronary syndrome A three-vessel intravascular ultrasound study. Circulation 106, 804-808 (2002). 

Fu, X., S. Y. Kassim, W. C. Parks, and J. W. Heinecke. 2001. Hypochlorons add oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 276(44) 41279-87. 

Botnar et al. (57) used EP-1873 to image thrombi in a rabbit model of atherosclerotic plaque rupture. These authors used a model known to produce atherosclerotic lesions in the aorta of the rabbit. Plaque rupture was then induced using Russell s viper venom and histamine. The ruptured plaque induces thrombus formation. One hour after plaque nqiture, EP-1873 was administered intravenously (2 pmol/kg). MR imaging post EP-1873 readily... 

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). 

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. 

O The cause of an acute coronary syndrome is the rupture of an atherosclerotic plaque with subsequent platelet adherence, activation, and aggregation, and the activation of the clotting cascade. Ultimately, a clot forms composed of fibrin and platelets. 

Endothelial dysfunction, inflammation, and the formation of fatty streaks contribute to the formation of atherosclerotic coronary artery plaques, the underlying cause of coronary artery disease (CAD). The predominant cause of ACS, in more than 90% of patients, is atheromatous plaque rupture, Assuring, or erosion of an unstable atherosclerotic plaque that occludes less than 50% of the coronary lumen prior to the event, rather than a more stable 70% to 90% stenosis of the coronary artery.3 Stable stenoses are characteristic of stable angina. 

Repeated injury and repair within an atherosclerotic plaque eventually lead to a fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells such as T lymphocytes. Maintenance of the fibrous plaque is critical to prevent plaque rupture and subsequent coronary thrombosis. 

Molecular imaging may potentially address not only the pathophysiology of ischemia but also vascular inflammation causing rupture of atherosclerotic plaques before major ischemic events. Initial approaches have used imaging of "indium radiolabeled monocytes [150], upregulated metallo-proteinases [151], and imaging of apoptosis in atherosclerotic lesions [152]. However, none have evolved into clinically useful tests. 

Atherosclerotic plaque also forms a target for imaging monoclonals. Most often, the antibodies employed display specificity for activated platelets, usually found in association with ruptured plaque. 

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 requires 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 rupture of an atherosclerotic plaque, be dissolved in a matter of hours. This rapid thrombolysis (dissolution of the clot) must be achieved without significant fibrinogenolysis elsewhere in the patient. 

Demrow et al. (1995) used the Folts model of unstable coronary stenosis, which closely mimics ruptured atherosclerotic plaque, causing unstable angina, to examine the effects of grape juice on platelet function in vivo. In this model,... 

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