The effects of hyperlipidaemia on the development of atherosclerosis and modification by pharmacological agents
The present study was designed to investigate the effect of lipid lowering therapy, using lovastatin or simvastatin (HMG-CoA reductase inhibitors), on coronary or aortic atherosclerotic lesion development in the St. Thomas' Hospital strain of genetically hyperlipidaemic rabbit. The primary aim of this study was to investigate the effects of lovastatin treatment on the development and regression of coronary atherosclerotic lesions in St Thomas' hospital rabbits (n=40). Light microscopic (LM) and scanning electron microscopic (SEM) examinations were carried out on the coronary arteries from lovastatin treated (12mg/Kg/day, for varying time periods) and control animals. No coronary lesions were found in lovastatin treated animals. However, coronary lesions were evident in a number of the untreated rabbits. Detailed histopathological examination demonstrated that the left septal (LSP) coronary arteries were most severely affected compared to the left circumflex LCX), left anterior descending (LAD) and right coronary arteries (RCA). There was no evidence of myocardial lesions present in either treated or control rabbits. To investigate the effect of simvastatin on established aortic atherosclerotic lesions, St. Thomas' rabbits (8 months old) (n=24) were treated with simvastatin (I0mg/Kg/day) for 12 months. Biochemical analysis of the treated animals revealed a 58% and 73% reduction in total plasma cholesterol and LDL cholesterol respectively. This decrease in LDL cholesterol led to a significant reduction of 82% (p<0.05) in the percentage area of fatty streaking and a reduction of 63% (p<0.05) in the intima to media ratio. A cholesterol exposure index was calculated based on plasma cholesterol levels and time. It was found that there was a highly significant linear relationship between cholesterol exposure index and fatty streaking (r[sup]2 =0.73) (p<0.001), and also between cholesterol exposure index and intima to media ratio (r[sup]2=0. 72) (p<0.001). The effect of lovastatin therapy on the macrophage foam cell population and the intercellular adhesion molecule-1 (ICAM-1) were studied in aortic atherosclerotic lesions of St Thomas' hospital rabbits using immunohistochemical techniques. Treatment with lovastatin led to a decrease in the number of macrophage foam cells in lesions. There was a 82% and 92% reduction after 6 and 10 months of treatment respectively. Moreover, there was significant increase in the ICAM-1 expression in the control animal group compared with the lovastatin treated group (p<0.001). It is concluded that in St. Thomas' rabbits development of coronary artery atherosclerotic lesions begins later than aortic lesions. However, early treatment with the lipid lowering 'statins ' can prevent the development of coronary atherosclerotic lesions. Later intervention may help to slow aortic lesion progression and may induce regression of established lesions. Interestingly, hypercholesterolemia and atherosclerosis were more pronounced in female than male St. Thomas' rabbits and the effect of 'statins ' were more prominent on the female rabbits. Lipid lowering therapy by 'statins' not only lowers total plasma cholesterol level, but may also aid to stabilise lesions and reduce the risk of plaque rupture through changes in plaque composition and adhesion molecule expression.