Die effek van besafibraat en 'n oplosbare nie-styselpolisakkariedsupplement op risikofaktore van koronêre hartvatsiekte in primate

Abstract

Coronary heart disease (CHO) accounts for most deaths in South Africa (Central Statistical Services) . Elevated total serum cholesterol (TC), hypertension and cigarette smoking are traditional well-known risk factors. Low levels of high density lipoprotein cholesterol (HOL-C), raised levels of low density lipoprotein cholesterol (LOL-C) and lipoprotein (a) [Lp(a)l, and more recently, elevated plasma fibrinogen have been identified as major risk factors for CHO in prospective, epidemiological surveys. Oyslipoproteinemia is often associated with glucose intolerance, hyperinsulinemia, obesity, hyperfibrinogenemia and increased plasminogen activator inhibitor-1-activity (PAl-1). This cluster of risk factors , when occurring together, is thought to be a coronary risk syndrome referred to as syndrome X or insulin-resistance syndrome (Kaplan, 1989). In human and in animal models, dietary supplements of soluble non-starch polysaccharides (NSP) have sign ificant hypocholesterolemic effects. The supplementation also improves glucose tolerance and lower plasma fibrinogen levels. A number of possible mechanisms for the lowering of risk of CHO has been proposed , but concensus has not been reached . Treatment with hypolipidemic drugs is frequently prescribed to patients who do not respond adequately to dietary recommendations. Among such drugs, fibrates have been widely used for many years. Bezafibrate (BF) , one of the newer derivates of clofibrate, is a well-tolerated drug with potent hypolipidemic properties as well as the ability to lower raised plasma fibrinogen . The mechanisms of action of BF on risk factors for CHO remains unclear. Because experimental examination of CHO in humans is confined by practical and ethical considerations, increasing numbers of investigators choose the nonhuman primate model due to similarities in lipid and lipoprotein metabolism . In the present study an obese, hypercholesterolemic model was developed and the effects of the soluble NSP, konjacglucomannan (KGM) and BF on risk factors of CHO were investigated. Ten male baboons (Papio ursinus) were fed a "Western" diet for 8 weeks supplemented with 15.6g KGM/day, and 10 male baboons the same diet with 4.2mg BF/day. Anthropometric measurements and ii biochemical variables were taken four times during the study period and liver samples at the end of the experiment. The results of the study showed that: • an obese, hypercholesterolemic baboon model at risk for CHO was successfully developed. • BF significantly decreased TC and apolipoprotein A. It also lowered LOL-C, apolipoprotein B, Lp(a) , fibrinogen and fasting glucose and insulin concentrations. A significant increase in triglycerides (TG) and % HOL-C of TC was found. The higher albumin levels and albumin-fibrinogen ratio after BF therapy showed a reduced risk to develop blood clots. An increase was found in PAl-1 . This should be investigated further since raised PAl-1 is a CHO-risk. • Supplementation of a Westernised diet with KGM lowered TC , Lp(a) , serum free fatty acids and PAl-1 significantly. A reduction was also found in LDL-C, Apo B, insulin sensitivity and fibrinogen . No change in TG and fasting glucose levels was observed . • Liver lipids and fatty acids were measured at the end of the study. Liver lipids and polyunsaturated fatty acids tended to be lower in the BF-group than in the KGM-group, indicating a different mechanism of action from that of KGM. The conclusion was reached that both interventions had beneficial effects on the CHD risk profile in the baboon model , whilst KGM had more pronounced effects. It seems as if the effects of BF were mediated through the liver. It is recommended that subjects at risk for developing CHD and patients with confirmed CHO (with the exception of familial hypercholesterolemia), should increase their intake of fermentable dietary fibre before medication is considered. No side effects were observed in the baboons fed KGM-supplements. On the contrary, their increase in body weight and daily energy intake from the diet were somewhat higher than the BF-group. The coronary risk profile of the KGM-group improved substantially. Reference values for baboons were gathered for various biochemical variables and anthropometric measurements. These normal ranges may be valuable for similar investigations in the future .