Atherosclerosis is a dynamic balance between the destructive influence of inflammatory cells and the reactive, stabilising effects of VSMCs. The balance is biased in favour of plaque rupture by factors such as high low density lipoprotein (LDL) cholesterol, lipid peroxidation and, probably, genetic variability in the inflammatory molecules involved. For example, there is a correlation between plaque progression and a polymorphism in the stromelysin-1 gene promoter. Also, it is entirely plausible that infective agents, in particular Chlamydia pneumoniae, which can be found in plaque macrophages, may exacerbate the inflammatory process and tip the balance in favour of plaque rupture; this hypothesis is currently being tested in clinical trials.
In contrast, the balance will be biased towards repair and stability by a reduction in plaque inflammation. Lipid lowering, by whatever means, is associated with a reduction in clinical events and animal studies have shown dramatic reductions in plaque inflammatory cell content during statin treatment, even in the absence of lipid lowering.19 These observations, coupled with a greater benefit from prav-astatin treatment than was predicted by the achieved reduction in LDL cholesterol in the West of Scotland coronary prevention study,16
• Atherosclerosis is not thought to represent an inflammatory reaction to the subendothelial accumulation of modified lipid
• Atherosclerosis is invariably associated with abnormal endothelial cell function. Vascular smooth muscle cells are the only cells capable of protecting against plaque rupture and its consequences
• The outcome of atherosclerosis is determined much more by plaque composition than plaque size
• Atherosclerotic lesions frequently enlarge as a consequence of repeated subclinical episodes of rupture and repair. The only logical conclusion to be drawn from the angiographic and outcome studies of statin treatment is that statin treatment stabilises atherosclerotic lesions
• Atherosclerosis is a dynamic process capable of being modified have led to the suggestion that some statins may exert effects on plaque stability which are additional to and independent of lipid lowering. Laboratory studies have shown that statins can exert direct effects on endothelial cell function, inflammatory cell activity, VSMC proliferation, platelet aggregation, and thrombus formation.20 21 Since the effects of different stains are not equivalent, it has been suggested that some may afford more or less protection than others for an equivalent lipid lowering effect. Such observations argue strongly for robust outcome studies to prove overall efficacy and safety.
Understanding of the non-lipid associated events in atherogenesis raises the prospect of developing drugs targeted at specific events in its pathogenesis which might act synergistically with lipid lowering drugs to enhance plaque stability. Possible targets include endothelial NO and adhesion molecule production, the matrix metalloproteinases, inflammatory cy-tokines and their receptors, and angiogenesis, since mice lacking specific angiogenic factors develop smaller atherosclerotic lesions than controls. If oxidised lipids are the major stimulus for atherogenesis, then antioxidants, such as vitamin E, might be expected to reduce the inflammatory drive in atherosclerosis and thereby promote plaque stability. However, despite early promise, recent large scale studies have cast doubt on the integrity of this hypothesis.
In addition to reducing inflammation, stimulation of the VSMC repair process should result in increased stability. For example, balloon angioplasty stimulates a vigorous VSMC repair response. This may contribute to restenosis and the re-emergence of angina, but the resulting lesion is always fibrotic and stable and rarely if ever precipitates an acute coronary event, even when the original target lesion was unstable. It is feasible therefore that better understanding of the molecular regulators of
VSMC behaviour may lead to drug treatments aimed at enhancing fibrous cap formation. Modulators of TGF ß activity may have a particularly important role to play in this context.
Atherosclerosis is a dynamic balance between lipid driven inflammatory cells and their cytokines within the substance of the plaque, and the natural stabilising properties of the surrounding VSMCs. That plaque composition is much more important than size is illustrated by clinical and laboratory studies with statins which have little effect on plaque size yet have a major influence on plaque composition and clinical outcome. In future, cardiologists will need to re-focus their attention away from angiographic appearances in symptomatic patients towards potential measures of inflammatory atherosclerotic activity in asymptomatic patients with subclinical disease. Our evolving knowledge of the cellular and molecular interactions that lead to plaque development and progression is likely to lead to novel imaging strategies and novel biochemical measures of disease progression, and potentially also to the development of drugs aimed specifically at stabilising atherosclerotic lesions. That this is achievable has already been demonstrated.
PLW is the British Heart Foundation Professor of Cardiovascular Medicine.
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• This was the first of a number of very influential reviews published by Ross on the pathogenesis of atherosclerosis. Although this review focuses very much on the role of platelets and smooth muscle cells in the development of an atherosclerotic lesion, subsequent reviews published in the same journal in 1986 and 1999 demonstrate the evolution of the field towards the recognition that atherosclerosis is fundamentally an inflammatory condition.
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• This article encapsulates the link between the cellular and molecular interactions thought to be taking place within atherosclerotic lesions and the clinical syndromes that result. In particular it emphasises the fundamental role of smooth muscle cells in protecting against plaque rupture.
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Additional references appear on the Heart website
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