The balance of atherosclerosis

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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.

1. Sorensen KE, Celermajer DS, Georgakopoulos D, et al. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 1994;93:50-5.

2. Ross R, Glomset J. The pathogenesis of atherosclerosis. Part 1. N Engl J Med 1976;295:369-77.

• 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.

3. Shanahan C, Weissberg P. Smooth muscle cell heterogeneity—patterns of gene expression in vascular smooth muscle cells in vitro and in vivo. Arterioscler Thromb Vasc Biol 1998;18:333-8.

4. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844-50.

• 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.

5. Glagov S, Weisenberg E, Zarius C, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:371-5.

6. Davies MJ. Stability and instability—2 faces of coronary atherosclerosis. The Paul-Dudley-White lecture 1995. Circulation 1996;94:2013-20.

• In this paper Davies elegantly sets out the fundamental pathological observations on which our current understanding of the pathogenesis and progression of atherosclerosis is founded. By quantifying the contribution of inflammatory cells to plaque rupture, Davies changed the whole approach to atherosclerosis research and treatment.

7. Ross R, Wight TN, Strandness E, et al. Human atherosclerosis. I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol 1984;114:79-93.

Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. CircRes 1998;82:704-12.

9. Davies MJ. Acute coronary thrombosis—the role of plaque disruption and its initiation and prevention. Eur Heart J 1995;16(suppl L):3-7.

10. McNamara CA, Sarembock IJ, Bachhuber BG, et al.

Thrombin and vascular smooth muscle cell proliferation: implications for atherosclerosis and restenosis. Semin Thromb Hemost 1996;22:139-44.

11. Falk E, Shah P, Fuster V. Coronary plaque disruption. Circulation 1995;92:657-71.

• This important publication demonstrates quite clearly that plaques that rupture and cause an acute myocardial infarction are most commonly those which do not cause the most significant stenoses when viewed angiographically. These observations confirm that the size of atherosclerotic lesions is less important than their content in determining outcome.

12. Callister TQ, Raggi P, Cooil B, et al. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography [see comments]. N Engl J Med 1998;339:1972-8.

13. Toussaint JF, LaMuraglia GM, Southern JF, et al.

Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation 1996;94:932-8.

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9.

• This paper firmly establishes the link between measurements of a circulating inflammatory marker, in this case a C reactive protein, and risk of a clinical event caused by atherosclerosis. Importantly, it shows that patients with the highest levels of CRP gain most benefit from aspirin treatment.

15. MAAS Investigators. Effect of simvastatin on coronary atheroma: the multicentre anti-atheroma study (MAAS). Lancet 1994;334:633-8.

16. Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.

17. LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The long-term intervention with pravastatin in ischaemic disease (LIPID) study. N Engl J Med 1998;339:1349-57.

• This is the largest and most recent of the secondary prevention studies with a statin, in this case pravastatin. The results prove beyond any reasonable doubt that statins prevent heart attacks and strokes in patients with established coronary artery disease, but effectively "normal" cholesterol concentrations.

18. Scandinavian Simvastatin Survival Study Group.

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994;344:1383-9.

19. Williams JK, Sukhova GK, Herrington DM, et al.

Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. JAm Coll Cardiol 1998;31:684-91.

20. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease [see comments]. N Engl J Med 1995;332:481-7.

21. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction [see comments]. JAMA 1998;279:1643-50.

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