Regression of atherosclerosis : the clinical and metabolic response to cholesterol-lowering

Abstract

A large number of studies have established that raised cholesterol levels increase the probability of the development of atherosclerotic vascular disease, and that reducing serum cholesterol will result in fewer cardiac events in the treated population, both in those with and without evidence of pre-existing coronary disease. More direct evidence that this is due to alteration of the progression of the atheromatous plaques has resulted from angiographic studies demonstrating the halting of progression or even regression of the stenotic lesions. Some workers have found a relationship between the extent of lowering of the serum lipoproteins and the likelihood of regression, although it has not been clear whether this continues to hold true at the lower extremes, nor whether there may be a threshold level which requires to be achieved before regression may take place. The principal purpose of these studies was to investigate the effects of applying very intensive lipid-lowering therapy, including LDL-apheresis, in a group of patients with coronary artery disease and moderately severe hypercholesterolaemia to achieve subnormal lipoprotein levels, and comparing the effects of such treatment with those achieved in another group of subjects treated with drug therapy to the currently recommended therapeutic targets for such patients. The studies involved the measurement of lipids and lipoproteins before and after apheresis and at regular intervals throughout the two-year study period. ApoB metabolism was assessed at baseline and following completion of the treatment period, and the data analysed using a multicompartmental mathematical model. The patients were assessed non-invasively by exercise electrocardiography at regular intervals, and by thallium scintigraphy at baseline and at annual intervals. The principal end-point was the proportion of arterial segments undergoing regression or progression in each group assessed by computer-assisted analysis of coronary angiograms performed at baseline and on completion of the intervention. The results from these studies demonstrated radical differences in lipoprotein concentration and composition during treatment. There was increased catabolism of LDL precursors with diminished flux of apoB which may reflect up-regulation of the LDL-receptor, but a rapid return to pre-treatment lipid levels indicated the effects on lipoprotein metabolism were transient. There was a reduction in the progression of coronary disease in the majority of lesions, with a small number in each group undergoing definite regression. There were significant differences in the changes in exercise tolerance with treatment, and the likely mechanisms for this are discussed. The thallium scans demonstrated no difference between the groups in the number of segments with improved perfusion, but were shown to have some value in the non-invasive assessment of predicting angiographic changes in the proximal segments, particularly in the right coronary artery. The findings are put into the context of the recent publications on cholesterol reduction in coronary disease; implications for clinical management are drawn, and areas of potential future research are highlighted.