Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications.

We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P = 0.002), triglycerides by 15% [corrected] (P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% (P = 0.002); high-density lipoprotein cholesterol increased by 17% (P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[13C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a monoexponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007 mg kg-1 day-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0) mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration (P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study.

We have measured the hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B) in 6 patients with heterozygous familial hypercholesterolaemia (FH) (4 males, 2 females, age 47.0 +/- 2.7 years (mean +/- S.E.M.), weight 71.0 +/- 5.3 kg) and 6 normocholesterolaemic subjects matched for age, weight and sex (4 males, 2 females, age 47.5 +/- 3.1 years, weight 70.0 +/- 4.4 kg) using a stable isotope method. Each subject received a primed, constant infusion of [I-13C]leucine and isotopic enrichment of VLDL apo B was determined using gas-chromatography mass-spectrometry (GCMS). Mean plasma low-density-lipoprotein (LDL) cholesterol and apo B concentrations in the FH group were more than twice that in the control group (FH, 8.5 +/- 0.5 mmol/l vs. controls, 3.3 +/- 0.2 mmol/l, P < 0.001; and FH, 2.0 +/- 0.1 g/l vs. controls, 1.0 +/- 0.04 g/l, P < 0.0001, respectively). Plasma triglyceride (TG) and high-density-lipoprotein (HDL) cholesterol concentrations were not significantly different between the two groups. Although the fractional secretion rates of VLDL apo B were similar (FH, 14.3 +/- 3.6 pools/day vs. controls, 11.6 +/- 1.7 pools/day, P = 0.53), VLDL apo B pool size and VLDL apo B absolute secretion rates (ASR) were significantly higher in the FH group (FH, 234.2 +/- 27.8 mg vs. controls, 66.3 +/- 13.5 mg, P < 0.001; and FH, 51.4 +/- 17.9 mg/kg per day vs. controls, 9.4 +/- 1.1 mg/kg per day, P < 0.02, respectively). We conclude that FH is associated with increased hepatic secretion of VLDL apo B and that this may contribute to the elevated concentration of LDL-cholesterol. The findings are also consistent with the hypothesis that in FH increased hepatic cholesterol availability (due to increased uptake of LDL-cholesterol via the receptor-independent pathway) stimulates hepatic secretion of VLDL apo B.

Modified plasma-derived lipoproteins in human atherosclerotic plaques.

Low density lipoproteins extracted from surgical specimens of human atherosclerotic plaques (A-LDL) showed altered electrophoretic mobility indicating a greater negative charge than that of plasma LDL (P-LDL). A-LDL but not P-LDL showed high affinity binding/degradation by human monocyte-derived macrophages; this was inhibited by acetylated LDL but not by native P-LDL. Following injection of 125I-labelled autologous P-LDL prior to reconstructive arterial surgery, polyacrylamide and agarose gel electrophoresis of A-LDL extracted from arterial intima showed that the A-LDL and its apolipoprotein B moiety were derived from P-LDL; the electrophoretic mobility of the product A-LDL was greater than that of native P-LDL. The compositions of arterial intermediate density lipoprotein (A-IDL) and A-LDL differed from those obtained from human plasma intermediate density lipoprotein (P-IDL) and P-LDL. A-IDL showed a reduced triglyceride content and increased esterified and unesterified cholesterol. Although the total cholesterol content of A-LDL was similar to that of P-LDL, there was an increase in unesterified cholesterol and a decrease of cholesteryl ester. These studies indicate that LDL extracted from human atherosclerotic plaque is derived from and modified from P-LDL in vivo. Compared with native P-LDL, A-LDL showed differences in charge and composition, associated with its high affinity binding by the acetyl LDL receptor of human macrophages.

Maternal rubella at St. Thomas' Hospital: is there a need to change British vaccination policy?

During the 28 weeks starting April 3, 1978, 269 pregnant women were assessed serologically because of exposure to or development of rubella-like illnesses, this number being four times greater than that during either of the previous 2 years. Only 33 (12%) of these patients had previously been given rubella vaccine. Rubella was confirmed serologically in 17 patients; among patients attending antenatal clinics the overall risk of acquiring infection was about 1 in 155. The mean age of patients acquiring maternal rubella was 27.9 years, and all but 1 had left school before the rubella vaccination programme started. 55 (92%) of 60 household contacts were children, of whom 24 (40%) were of preschool age and 13 (21.7%) aged less than 2 years. The interval between contact and presentation for serological studies was often long and, because of this, 79 sera had to be tested for virus-specific IgM. No drastic change in rubella vaccination policy is required but there should be more emphasis on vaccination of women of childbearing age.