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Hypercholesterolaemia has long been recognised as one of the major reversible risk factors for coronary artery disease. Among 356 222 men screened for the multiple risk factor intervention trial (MRFIT), there was a close linear relation between serum cholesterol and mortality during a six year follow up period.1 The relation extended right across the range of serum cholesterol measurements, indicating that even within the so called “normal” range, individuals who have a lower serum cholesterol have a lower risk of cardiovascular death. Nevertheless, it was not until the publication of the Scandinavian simvastatin survival study (4S) and the cholesterol and recurrent events (CARE) trial that treatment of hypercholesterolaemia in patients with coronary artery disease was shown to produce corresponding reductions in long term cardiovascular and all cause mortality.2 ,3 An important observation in these studies was that the survival curves separated within two years, indicating the benefits of treatment occurred very early. Any mechanistic theory accounting for these benefits must, therefore, be able to account for this early response to treatment. Three main mechanisms have been suggested: (a) modification of the progression of coronary atheroma; (b) stabilisation of the coronary plaque, reducing the risk of rupture; (c) correction of coronary endothelial function with restoration of normal vasomotor responses.
Modification of the progression of coronary artery disease
Current theories of atherogenesis consider oxidative modification of low density lipoprotein (LDL) as the central event that initiates and propagates coronary artery disease.4 ,5 Properties of oxidised LDL which contribute to its atherogenic potential are its chemotaxis for circulating monocytes, inhibition of tissue macrophage migration away from the arterial intima, enhanced macrophage uptake of LDL by scavenger receptors to form foam cells, and its cytotoxicity, causing endothelial cell injury.5 It was a logical expectation, therefore, that lowering LDL cholesterol with specific treatment would slow the progression of …