SupplementAcute coronary syndromes: biology
Introduction
The past few years have witnessed a remarkable advance in our understanding of the pathophysiology of coronary atherosclerosis.1, 2, 3, 4 Here we focus on the biological phenomena that lead to acute coronary syndromes (ACS).
Section snippets
Lesions
According to the criteria of the American Heart Association Committee on Vascular Lesions, plaque progression can be subdivided into the five phases and different lesion types shown in figure 1.5, 6 The so-called “vulnerable” type IV and type Va lesions (phase 2) and the so-called “complicated” type VI lesion (phase 4) are the most relevant to ACS.
Type IV and type Va lesions, although not necessarily stenotic at angiography, may be prone to disruption because of their softness due to a high
Early dynamic process of lipoprotein transport that leads to vulnerable lesions
Chronic minimal injury to the arterial endothelium is physiological and is often the result of a disturbance in the pattern of blood flow at bending points and near bifurcations of the arterial tree.1, 5 In addition to local shear forces that are probably enhanced in hypertension, chronic minimal endothelial injury or dysfunction, which leads to accumulation of lipids and monocytes (macrophages), is produced by hypercholesterolaemia, advanced glycation end-products in diabetes, chemical
Vulnerable lipid-rich plaque and its disruption
Type IV and type Va plaques are commonly composed of an abundant crescentic mass of lipids, separated from the vessel lumen by a discrete component of extracellular matrix (figure 1, figure 2).Fairly small coronary lesions by angiography may be associated with acute progression to severe stenosis or total occlusion and may eventually account for as many as two-thirds of the patients in whom unstable angina or other ACS develop.8, 9, 10 This unpredictable and episodic progression is most
Disruption of passive plaques
Related to physical forces, passive plaque disruption occurs most frequently where the fibrous cap is thinnest, most heavily infiltrated by foam cells, and therefore weakest. For eccentric plaques, this is often the shoulder or between the plaque and the adjacent vessel wall.11 Pathoanatomical examination of intact and disrupted plaques and in-vitro mechanical testing of isolated fibrous caps from aorta indicate that vulnerability to rupture depends on three factors: circumferential wall stress
Disruption of active plaques
The process of plaque disruption is not purely mechanical. Atherectomy specimens from patients with ACS reveal areas very rich in macrophages,12 and these cells are capable of degrading extracellular matrix by phagocytosis or secretion of proteolytic enzymes; thus, enzymes such as plasminogen activators and matrix metalloproteinases (MMPs, collagenases, gelatinases, and stromelysins) may weaken the fibrous cap and predispose it to rupture.13 Indeed, the MMPs and their co-secreted tissue
Acute thrombosis
Disruption of a vulnerable or unstable plaque with a subsequent change in plaque geometry and thrombosis results in a complicated lesion (figure 1 figure 2).Such a rapid change in atherosclerotic-plaque geometry may result in acute occlusion or subocclusion with clinical manifestations of unstable angina or other ACS. More frequently, however, the rapid changes seem to result in mural thrombus without evident clinical symptoms, which, by self-organisation, may be a main contributor to the
Substrate and TF-dependent thrombosis
There is striking heterogeneity in the composition of human atherosclerotic plaques, even in the same individual, and the disruption of plaques exposes different vessel-wall components to blood. Data on the thrombogenicity of disrupted atherosclerotic lesions are limited. In two different experiments, human aortic plaques were exposed to flowing blood at high shear rate and their thrombogenicity was assessed; the studied material included normal intima (free of disease), fatty streaks,
Hypercoagulable-dependent thrombosis
There is evolving evidence that circulating monocytes and white blood cells may be involved in TF expression and thrombogenicity;23 indeed, the predictive value for coronary events of high titres of C-reactive protein may be a manifestation of such systemic phenomena.24, 25, 26, 27 Hypercholesterolaemia, a high catacholamine drive such as in cigarette smoking, certain chemotactic determinants, and perhaps infections may be triggers of such hypercoagulable phenomena (panel).5, 7 Of interest, in
Vasoconstriction
Although many episodes of unstable angina and acute myocardial infarction are caused by the disruption or erosion of a plaque with superimposed thrombosis, other mechanisms that alter myocardial oxygen supply and demand must be considered. Original studies by Maseri and colleagues31 indicated that coronary vasoconstriction has an important role. In ACS, vasoconstriction may occur as a response, to a mildly dysfunctional endothelium near the culprit lesion or, more likely, may be a response to
Pathobiology
Stable angina (usually exertional) or stable silent ischaemia (exertional or not) commonly result from increases in myocardial oxygen demand that outstrip the ability of stenosed coronary arteries to increase oxygen delivery.
With regard to the pathobiology of ACS,34 in unstable angina, a fairly small fissuring of a lipid-rich plaque, and occasionally a superficial erosion of a fibrotic plaque, may lead to an acute change in plaque structure and a reduction in coronary blood flow, resulting in
Evolving biological directions
These directions can be divided into two areas: identification of vulnerable plaques and plaque stabilisation.
Identification of vulnerable plaques
Coronary angiography fails to give information about arterial wall pathology. Moreover, arteries accommodate plaque growth through outward displacement of the vessel wall thereby preserving lumen cross-sectional area. Intravascular ultrasound, electron-beam computed tomography, and angioscopy have all advanced our understanding by revealing atheromatous burden within coronary arteries. However, a most promising tool for non-invasive plaque characterisation appears to be magnetic resonance
Plaque stabilisation
Human atherosclerotic plaques can be stabilised by drugs or lifestyle modifications. Numerous lipid-lowering trials have independently shown significant clinical benefits without angiographic evidence of plaque regression.38 Because the decrease in serum cholesterol is not associated with a large decrease in the luminal narrowing of coronary arteries, these benefits are assiamed to be due to the stabilisation of vulnerable plaques rather than to plaque regression. Thus, experimentally, lipid
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