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.

One year experience in the treatment of familial hypercholesterolaemia with simvastatin.

Patients with heterozygous familial hypercholesterolaemia (FH) have a substantially increased risk of atherosclerosis due to very high plasma levels of cholesterol. Recent evidence has shown that coronary heart disease in these patients may regress with lipid-lowering therapy. In this study the efficacy and safety of simvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A, was investigated in 30 patients with FH over a period of one year. Substantial reductions in the plasma concentrations of total cholesterol (-28%), low-density lipoprotein (LDL) cholesterol (-32%), intermediate-density lipoprotein (IDL) cholesterol and apolipoprotein (apo) B (-33%) were achieved with 20 mg/day of simvastatin; there were no significant changes in triglycerides high-density lipoprotein cholesterol or apo A. In contrast to previous studies, 40 mg/day of simvastatin did not result in a further statistically significant fall in LDL cholesterol, IDL cholesterol or apo B in the group as a whole. The drug was well tolerated and no adverse clinical or laboratory events were recorded. In particular, no ophthalmological, hepatic or renal disorders were observed and there were no sleep disturbances. We conclude that simvastatin is an efficacious and safe drug to treat patients with heterozygous FH and that rarely will the dose need to be increased above 20 mg/day.

Quantitative studies of transfer in vivo of low density, Sf 12-60, and Sf 60-400 lipoproteins between plasma and arterial intima in humans.

To assess the potential of various plasma lipoprotein classes to contribute to the lipid content of the arterial intima, influx and efflux of these plasma lipoprotein fractions into and from the intima of human carotid arteries were measured in vivo. While low density lipoprotein (LDL) is known to transfer from plasma into the arterial wall, there is less information on the atherogenic potential of lipoproteins of intermediate density (Sf 12-60) or of very low density (Sf 60-400). Aliquots of the same lipoprotein (LDL, Sf 12-60 lipoprotein particles, or Sf 60-400 lipoprotein particles) iodinated with iodine-125 and iodine-131 were injected intravenously 18-29 hours and 3-6 hours, respectively, before elective surgical removal of atheromatous arterial tissue, and the intimal clearance of lipoproteins, lipoprotein influx, and fractional loss of newly entered lipoproteins were calculated. Intimal clearance of Sf 60-400 particles was not detectable (less than 0.3 microliter x hr-1 x cm-2), whereas the average value for both LDL and Sf 12-60 lipoprotein particles was 0.9 microliter x hr-1 x cm-2. Since the fractional loss of newly entered LDL and Sf 12-60 lipoprotein particles was also similar, the results suggest similar modes of entry and exit for these two particles. However, due to lower plasma concentrations of Sf 12-60 lipoproteins as compared with LDL, the mass influx of cholesterol in the Sf 12-60 particles was on the order of one 10th of that in LDL, and that of apolipoprotein B was about one 20th.(ABSTRACT TRUNCATED AT 250 WORDS)

Gemfibrozil in the treatment of resistant familial hypercholesterolaemia and type III hyperlipoproteinaemia.

The efficacy of gemfibrozil in the treatment of resistant familial hypercholesterolaemia and type III hyperlipoproteinaemia was evaluated in 26 individuals over a mean period of 16 months. In the untreated state both disorders are associated with a high frequency of coronary heart disease. In the former, gemfibrozil with a bile acid sequestrant reduced plasma cholesterol by 32%, an incremental decrease of 17% compared with sequestrant therapy alone. In type III, plasma cholesterol was reduced by 40% and plasma triglyceride by 70%, while high-density lipoprotein cholesterol increased by 45%. In none of the patients studied did clinical or biochemical side effects occur.

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.

Effective lipid lowering diets including lean meat.

The plasma lipid and lipoprotein responses to two modified isoenergetic diets including meat were studied in 15 free living men with hyperlipidaemia (mean plasma cholesterol and triglyceride concentrations 8.1 and 3.4 mmol/l). A reference diet (diet A, 42% energy from fat, ratio of polyunsaturated to saturated fatty acids (P:S ratio) 0.2) was compared with a fat reduced diet (diet B, 35% energy from fat, P:S ratio 0.5) and with a further fat modified diet supplemented with fibre (diet C, 27% energy from fat, P:S ratio 1.0). Daily intake of meat and meat products (180 g/day) was the same in each dietary period; that in diet A had a fat content typical of the average British diet, whereas that in diets B and C was based on very lean meat and meat products. During consumption of diet B the plasma cholesterol concentration fell by 8.6% and low density lipoprotein cholesterol by 11%. During consumption of diet C plasma cholesterol fell by 18.5% and low density lipoprotein cholesterol by 23.8%. Triglyceride and high density lipoprotein cholesterol concentrations and body weight did not change appreciably during the study. A modified diet including a moderate amount of lean meat and meat products is compatible with a reduced lipoprotein mediated risk of atherosclerotic heart disease.

A method for quantifying lipoprotein flux rates between plasma and arterial intima in vivo.

A new method is proposed for measuring in vivo the rates of transfer of plasma lipoprotein into and out of arterial intima in man. The technique requires the injection of a lipoprotein which can be labelled with two different tracers, followed by a single arterial sample during elective surgery. The feasibility of the method was tested by computer simulation and it was found that measurement uncertainties of the order of those likely in practice produced uncertainties of 7% SD in the calculated influx and 16% SD in the calculated efflux rates. The principal assumption, that lipoprotein in arterial intima can be modelled as a single compartment system, was tested in a preliminary study in an anaesthetised dog: reasonable evidence of monocompartmental behaviour was obtained. The new method was used in a preliminary study of three patients undergoing elective arterial surgery. Low density lipoprotein (LDL) labelled with 125I was injected about 24 h before surgery, followed by 131I-labelled LDL 4 to 6 h before surgery. The radioactivities of washed extracts of arterial intima were then measured in a gamma counter. LDL flux rates were higher in atherosclerotic specimens than in less seriously diseased or normal tissue, and were highest in the most hyperlipidaemic patient.

Hormonal and electrolyte responses during and after open heart surgery.

Maintenance of the balance of electrolytes and hormones within their normal range is necessary for normal myocardial metabolism. Open heart surgery involving cardiopulmonary bypass produces metabolic disturbances which affect normal metabolic homeostasis. Several studies have suggested that pulsatile cardiopulmonary bypass causes less severe metabolic disturbance than non-pulsatile bypass and that non-pulsatile bypass causes hypofunction of the anterior pituitary and adrenal glands. The present study, however, with non-pulsatile flow showed that there was no evidence of hypothalamo-pituitary-adrenal axis hypofunction when the hormonal values of corticotrophin (ACTH), cortisol and cortisone were corrected for the hemodilution involved in cardiac surgery. Electrolytes, particularly calcium, play an important role in myocardial contractility. The levels of ionized calcium are normally controlled by parathyroid hormone (PTH) with a negative feedback of calcium controlling the system. However, this study showed that significant increases in bioactive PTH during cardiopulmonary bypass were not related to the calcium concentration, but appeared to be influenced by low blood pH values and by the degree of hypothermia.

The effect of ionized calcium, pH, and temperature on bioactive parathyroid hormone during and after open-heart operations.

Normal myocardial function is dependent on the metabolic balance of a number of electrolytes and hormones. The calcium ion plays a major role in muscle contraction and is rigorously controlled within narrow limits. Open-heart surgery imposes metabolic disturbances on both electrolytes and hormones, especially ionized calcium. Normally, ionized calcium levels are controlled by parathyroid hormone with a negative feedback from the ionized calcium controlling the system, but the results from this study suggest that during open-heart procedures, ionized calcium does not impose its normal negative feedback on bioactive parathyroid hormone secretion. The low blood pH levels that occurred during the operative conditions of the patients studied and the level of hypothermia imposed on the circulating blood during cardiopulmonary bypass appeared to influence the control of parathyroid hormone secretion, causing high levels of hormone to be secreted during this period.

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.