Susceptibility of low density lipoprotein to oxidation in familial hypercholesterolaemia

There is increasing evidence that oxidative modification of low density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Subjects with familial hypercholesterolaemia (FH) have elevated concentrations of LDL and develop premature atherosclerosis. The aim of the study was to determine whether the susceptibility of LDL to in vitro oxidation is increased in FH subjects. LDL was isolated from 15 FH homozygotes (mean age +/- SD, 19 +/- 10 years; mean LDL-cholesterol 16.86 +/- 3.55 mmol/l), 15 FH heterozygotes (38 +/- 13 years; LDL-cholesterol 5.58 +/- 1.78 mmol/l) and 15 normocholesterolaemic subjects (31 +/- 8 years; LDL-cholesterol 3.07 +/- 0.77 mmol/l). Susceptibility of LDL to in vitro copper-mediated oxidation was assessed by measuring conjugated diene production at 234 nm, the lag phase being a measure of the resistance of LDL to oxidation. Unexpectedly, the mean duration of the lag phase was 2.2 fold longer in the FH homozygotes (123.8 +/- 45.0 min) and 1.75-fold longer in the FH heterozygotes (99.9 +/- 40.6 min) than in the controls (57.1 +/- 27.9 min; P < 0.0001). Serum and LDL vitamin E levels were higher in the FH patient, but not when expressed relative to LDL-cholesterol concentration. There was also no correlation between LDL vitamin E concentration and duration of the lag phase. LDL bulk rather than the susceptibility of LDL to oxidation is probably the more important factor for the initiation and progression of atherosclerosis in FH patients.