XII^th International Symposium on Atherosclerosis, Stockholm, Sweden. (June 25-29, 2000)
Plaque disruption with superimposed thrombosis is the main cause for the acute coronary syndrome of unstable angina, myocardial infarction, and sudden death. If we are able to detect a plaque that can rupture before this happens, we could prevent several of the deadly complications of atherosclerosis.

Stockholm, Sweden -- The issue of plaque instability and the development acute coronary syndromes has been the topic of one of the session of the Symposium. Plaque disruption with superimposed thrombosis is the main cause for the acute coronary syndrome of unstable angina, myocardial infarction, and sudden death. Composition and stability of the plaque, rather than its volume (i.e., severity of stenosis), are the most important determinants of atherosclerosis complications.

A lipid core covered by a fibrous cap, composed of smooth muscle cells (SMC) and extracellular matrix, characterizes advanced human atherosclerotic plaques. Plaque instability, manifesting as ulceration of the fibrous cap, plaque rupture, and intraplaque hemorrhage, is characteristic of plaques with a high content of lipid and an excess of macrophages and T lymphocytes in the cap. SMC are the only cell type in the atherosclerotic plaque capable of synthesizing a strong fibrous cap and disrupted aortic caps contain fewer SMC and less collagen than intact caps. Collagen is the main component of fibrous caps responsible for their tensile strength.

A wide range of proteases appears to be produced at focal sites in plaques. Macrophages are capable of degrading extracellular matrix by phagocytosis or by secreting proteolytic enzymes, in particular a family of metalloproteinases (MMPs) that may weaken the fibrous cap, predisposing its rupture. This is worsened with aging, as Dr E. Falk (Aarhus University, Denmark) pointed out. In fact, old vessels can no longer elongate and an increase of the stress on the vessel wall could lead to plaque rupture. If it were possible to detect a plaque that could rupture before happening, several deadly complications of atherosclerosis could be prevented. Three histological features of the vulnerable plaque have been reported: size of the atheroma, thickness of the fibrous cap, and inflammation. Dr G. Pasterkamp (Utrecht University, The Netherlands) described some of the imaging techniques that are currently deployed to visualize these characteristics of the vulnerable coronary plaques. However, unstable plaques do not cause narrowing of the vessels and the present imaging techniques have only a limited applicability. It is not expected that they will have prognostic properties for the development of acute clinical syndromes that often originate from non-haemodynamically significant lesions. On the contrary, 24% of lesions with limited narrowing stain positively for macrophages. Atherosclerotic plaques with signs of inflammation are vulnerable lesions and make up to 30-40% of all lesions, irrespective of lumenal narrowing. Therefore, systemic markers for inflammation may have more prognostic value for the identification of patients suffering from clinical events as a result of plaque rupture. Dr C. Packard (Glasgow University, UK) tested this hypothesis in middle-aged men enrolled in the primary prevention study WOSCOPS. The data showed that chronic inflammation is a strong determinant of risk in asymptomatic, moderately hypercholesterolemic men.

An animal model of plaque rupture would be of invaluable help for studying the devastating consequences of plaque rupture in order to elaborate preventive treatment. The apoE-deficient mice develop lesions that have characteristics similar to unstable plaques. Dr Falk and colleagues have challenged more than 200 of such middle-aged mice > 1 year old) with stressful stimuli (Chlamydia infection, swimming for long period of time, increase in blood pressure, etc.), with the intention of inducing the rupture of "vulnerable looking" aortic root plaques. The researchers found only one ruptured plaque, three cases of extravasation, and one thrombus. When the experiment was repeated in 18 older mice (1.5-2 years old), they discovered again only one ruptured plaque in the coronary artery and three thrombi. These results clearly indicate that vulnerable plaques in middle-aged mice do not easily rupture, concluded Dr Falk. However, in the same session, Dr C. Jackson (Bristol University, UK) described his experiments with apoE-deficient mice fed for 37-59 weeks with a high-fat diet. The animals were followed until their natural death and their carotid arteries and aorta were examined for signs of plaque ruptures. Lumenal thrombi associated with atherosclerotic plaque rupture were observed in most of the mice, and they were found almost exclusively in the brachiocephalic artery branches into the right carotid and right subclavian arteries. The ruptures were characterized by fragmentation and loss of elastin in the fibrous caps of relatively small and lipid-rich plaques overlying large complex lesion, with intraplaque hemorrhage. These data suggest that long-term fat-feeding of apoE-deficient mice could represent a useful and reproducible model of atherosclerotic plaque rupture. However, Dr Jackson noted that it is not clear why the mice died, since they should be able to survive through the left carotid artery perfusion. The occlusion could be a marker of thrombi originating from other area of the vascular bed. A key role is also played by the mouse strain, which was a mixed one (C57BL/SV129), since the pure C57BL background does not show these results.

The 92-kDa gelatinase B or metalloproteinase-9 (MMP-9) is the most prevalent form of MMPs secreted by activated macrophages, and has been shown to be more common in atherectomy materials from unstable angina and abdominal aortic aneurysm. Beside macrophages, SMC may release MMPs, an event relevant not only to atherogenesis, but especially to the process of restenosis after angioplasty. MMP-9 activity in microvessel beneath the lipid core can lead to intraplaque hemorrhage. Circulating MMP-9 and MMP-2 have been also identified. Dr S. Nikkari (Tampere University, Finland) measured the circulating levels of MMP-9 in 61 patients, with narrowing in one or more coronary arteries, and in 19 normal subjects. Serum MMP-9 concentrations tended to increase with the worsening of the disease. It did not predict the outcome, but there was a trend and it correlated with leukocyte count.

Finally, Dr V. Fuster (Mount Sinai Medical Center, New York, U.S.A.) presented some data on the pharmacological intervention directed toward the stabilization of the plaque. Several clinical studies demonstrated the ability of statins to reduce the incidence of coronary heart disease most probably by increasing the stability of the atherosclerotic plaque rather than by a reduction of the stenotic occlusion. However, new (not yet published) data show that the area of the lesion into the vessel wall start to decrease after a 12-month treatment with simvastatin. This effect may involve, in addition to cholesterol reduction, a direct activity of these drugs on the arterial wall. Statins have antithrombotic properties. The early effect (three weeks) is an anti-inflammatory one, then they act on the vessel wall. The inhibitory effect of statins on MMP-9 secretion, observed in a previously published in vitro study, suggests a potential mechanism for the stabilizing effect of these drugs on the atherosclerotic plaque.