THE LANCET Clinical trials have demonstrated that inhibitors of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) greatly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. 1,2 These drugs were designed to inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing hepatic production of low- density lipoprotein (LDL), and upregulating expression of hepatic LDL receptors, thus lowering concentrations of circulating LDL. With lower plasma LDL concentrations, plaque development should be retarded or should regress because of lipid loss, which would render the plaque less occlusive and less likely to disrupt or cause thrombosis. The use of simvastatin in the Scandinavian (4S) secondary intervention study 1 and the use of pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS) primary intervention trial 2 supported the hypothesis that drugs that lower plasma cholesterol concentration are of benefit to patients with coronary artery disease. However, the clinical benefit of the drugs used in these studies is manifest early in the course of lipid- lowering therapy before plaque regression could occur. Quantitative angiographic assessments of the impact of statin therapy on coronary atherosclerosis have demonstrated that improvement in arterial topographical morphology occurs slowly and only to a small extent. 3 In the Multicentre Anti-Atheroma Study (MAAS), 3 statistically significant improvement in arterial morphology occurred with simvastatin after 4 years and was not evident after 2 years. 3 However, it is difficult to attribute the time scale of less than 2 years, in which clinical benefit appeared in the 4S and WOSCOPS trials, solely to a decrease in LDL-cholesterol concentration. About 9 years elapsed before any real clinical benefit was found in the Program on the Surgical Control of the Hyperlipidaemias (POSCH) trial. 4 In the POSCH trial, plasma cholesterol was decreased by partial ilial bypass to a degree similar to that achieved in the statin trials and it may be that its clinical effects are attributable purely to changes in circulating lipoproteins. The activity of HMG-CoA reductase limits the rate of synthesis not only of cholesterol but also of a range of other molecules involved in functions such as cellular respiration and cell-cell recognition. Therefore it should not be surprising that the statins, as inhibitors of this enzyme, might modify constituents of the vascular milieu other than LDL cholesterol. Rudolph Virchow (1821–1902) originally proposed that vascular thrombosis was caused by a triad of changes: in the blood vessel wall, in blood flow, and in the constituents of the blood. We suggest that the clinical benefits of simvastatin and pravastatin therapy are best explained by their direct effects, in each component of the triad, on atherosclerotic and thrombotic mechanisms within arteries, as well as through the more conventionally accepted means of decreasing plasma LDL concentrations. Changes in the vessel wall The process of plaque fissuring, which results in thrombosis, triggers most acute coronary events. Most lesions prone to fissuring and rupture have a large core of lipid-laden macrophages and a thin fibrous cap underlying the endothelium. Although these vulnerable lesions account for 10–20% of all lesions, they are responsible for 80–90% of acute clinical events. 5 The reduction in clinical events secondary to lipid lowering has been conventionally attributed to the selective depletion of both the lipid and foam-cell content of this vulnerable subset of plaques by altering the balance between LDL accumulation and efflux in the plaque. This alteration of composition makes the plaque less likely to fissure, disrupt, or cause acute thrombosis. Whereas changes in plaque composition and development are likely to contribute significantly to the reduction in clinical endpoints in the long term, concurrent changes in other constituents or actions of the vessel wall, or both, may contribute to, and explain, the early benefit seen with statin treatment. Atherosclerosis is considered to be a chronic inflammatory disorder characterised by the presence of monocytes or macrophages and T lymphocytes in atherosclerotic lesions as well as the proliferation of smooth muscle cells, elaboration of extracellular matrix, and neovascularisation. Macrophages participate in the uptake and metabolism of lipids in the early stages of atherogenesis 6 and may accelerate atherogenesis by other mechanisms (figure 1) including secretion of mitogenic factors similar to platelet-derived growth factor (PDGF), which stimulate smooth-muscle proliferation and plaque neovascularisation. 7 Macrophages have been implicated in the pathophysiology of acute coronary syndromes as they produce enzymes which include members of the metalloproteinase family (interstitial collagenase, gelatinase, and stromelysin) that digest and weaken the plaque cap, making disruption more likely. 8 The site of plaque disruption, in addition to containing a large population of inflammatory cells, also expresses, in abundance, HLA-DR antigens, which indicates an active inflammatory response. Pravastatin has been shown to influence cholesterol metabolism in macrophages directly in vivo and in vitro, in a manner analogous to its effect in hepatocytes. 9 Single dose administration to normocholesterolaemic and hypercholesterolaemic individuals decreases cholesterol Vol 348 • October 19, 1996 1079 Lancet 1996; 348: 1079–82 Department of Pharmacology and Therapeutics, Clinical Sciences Unit, University College Cork, Ireland (C J Vaughan MB, M B Murphy MD, B M Buckley DPhil) Correspondence to: Dr Brendan M Buckley, The Cork Clinic, Bon Secours Hospital, College Road, Cork, Ireland Statins do more than just lower cholesterol Carl J Vaughan, Michael B Murphy, Brendan M Buckley Viewpoint