Studies in primary hypercholesterolaemia.
thesisposted on 19.11.2015, 08:50 by Harnovdeep Singh. Bharaj
Cholesterol is an integral part of the cell membrane and influences both its fluidity and activity. Furthermore membrane lipids are influenced by plasma lipid levels. In familial hypercholesterolaemia (FH) red cell rheology and platelet aggregation is abnormal. These effects could be due to changes in plasma lipids since they are improved by cholesterol reduction. Section A Fasting lipid profile, membrane cholesterol, red cell ghost and platelet fluidity [using diphenyl hexatriene (DPH) and trimethylamino-diphenyl hexatriene (TMA-DPH) fluorescence anisotropy] and Ca2+ -Mg2+ -ATPase activity (using [32P] ATP hydrolysis) in 30 patients with heterozygous FH and 19 controls were compared before and after treatment with colestipol (10g) , simvastatin (10mg) and maxepa (10g). The two groups were generally comparable with respect to age, sex, BMI and blood pressure. In FH plasma cholesterol, membrane cholesterol, TMA-DPH anisotropy and red cell Ca2+ -Mg2+ -ATPase were increased whilst platelet Ca2+ -Mg2+ -ATPase was reduced (p<0.05). Colestipol and simvastatin reversed these changes toward controls. Maxepa increased DPH anisotropy and reduced Ca2+-Mg2+ -ATPase. In FH membrane fluidity and activity is altered and normalised by cholesterol lowering. This may account for the abnormal cell function in this condition. Section B A double blind, randomized, placebo controlled trial in hypercholesterolaemia (cholesterol 6.5-10 mmol/l, triglycerides <3 mmol/l). After 8 weeks of an AHA step I diet, patients were randomized to A: placebo; B: 5g colestipol + 10mg simvastatin; or C: 10g colestipol + 10mg simvastatin for 8 weeks. Patients were assessed 4 weekly. 44 patients were screened, 32 completed the study. Groups were generally comparable (group C patients were older p<0.02). Active treatment resulted in a 38% reduction in LDL cholesterol (p0.8). Mild gastro-intestinal upset was the commonest adverse event. Low dose combinations are effective and well tolerated. There is no apparent advantage of 10g over 5g colestipol when combined with l0mg simvastatin. HDL cholesterol and triglycerides were unchanged.