Biomedical subjects
Publications and source records attributed to N E Miller.
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We investigated the metabolism of intermediate-density lipoproteins (IDL [1.006 to 1.019 g per milliliter]) and low-density lipoproteins (LDL [1.019 to 1.063 g per milliliter]) in two men with Type III hyperlipoproteinemia associated with myelomatosis. In vivo kinetic studies using radiolabeled autologous lipoproteins demonstrated a greatly reduced fractional catabolic rate of IDL, relative to control values (patients vs. normal, 0.006 and 0.025 per hour vs. 0.20 +/- 0.08 per hour [mean +/- S.E.M]) and a greatly prolonged IDL-to-LDL conversion time (45 and 17 hours vs. 5.4 +/- 1.6 hours). In studies in vitro, LDL from both patients failed to bind to the LDL receptor of normal blood lymphocytes, whereas LDL from subjects with familial Type III hyperlipoproteinemia bound normally to the receptor. In one patient immunoglobulin was shown to be associated with IDL and LDL. Thus, hyperlipoproteinemia reflected an impaired metabolism of IDL, probably secondary to the binding of immunoglobulin to the lipoproteins. A similar impairment of receptor-mediated LDL catabolism did not elevate the plasma LDL concentration because of the low IDL-to-LDL conversion rate.
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During treatment with probucol at the dose of 1 g per day, the mean reduction in low density lipoprotein (LDL) cholesterol concentration was 11.2% in polygenic hypercholesterolaemia (n = 9) and 9.4% in heterozygous familial hypercholesterolaemia (n = 6). However, there was marked heterogeneity of response: in seven of the patients with polygenic hypercholesterolaemia who had in common moderate elevation of LDL cholesterol (5.3-6.4 mmol/1), the reduction ranged from 13 to 40% (mean, 23%). In two of this group the change in LDL concentration was associated with a decrease in LDL apolipoprotein B synthetic rate. Of the patients with familial hypercholesterolaemia one showed a 33% reduction in LDL cholesterol, and one a 13% reduction. Total high density lipoprotein (HDL) cholesterol concentration tended to decrease during treatment. This reflected a reduction of the cholesterol concentration in the HDL3 subclass; HDL2 cholesterol remaining unchanged. Plasma triglyceride and very low density lipoprotein cholesterol were unaffected by probucol. The drug was well tolerated with only one patient complaining of severe diarrhoea, and two of mild and transient diarrhoea. No clinically significant changes occurred in serial resting electrocardiograms. Thus, probucol appears to be a useful drug for the treatment of most patients with polygenic hypercholesterolaemia, and of some patients with heterozygous familial hypercholesterolaemia.
A group of 12 young NZW rabbits of the same breeding strain were fed a diet enriched with 0.1% cholesterol by weight. The resulting modest hypercholesterolaemia resolved after 4-5 months. Two animals that died during this period showed no gross or microscopic atherosclerosis. After 6 months, the dietary cholesterol was increased to 0.2%. In some animals this resulted in moderate hypercholesterolaemia. One animal that died at this time showed no atherosclerosis with a mean serum cholesterol level of 224 mg/dl. Just after one year, dietary cholesterol was increased to 0.3%. This resulted in definite hypercholesterolaemia in some animals, but a few resisted the treatment with mean serum cholesterol levels around 40-60 mg/dl. In general, animals with established hypercholesterolaemia showed severe atherosclerosis, but often of a more fibrous and less cellular nature than is usual in the rabbit. Aortic wall cholesterol content (on a weight basis) correlated positively with serum cholesterol concentration (r = + 0.69, P approximately 0.05) and negatively with the ratio of HDL cholesterol to (LDL plus VLDL) cholesterol (double log plot: r = -0.79, P less than 0.025).
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1. The concordance of low density lipoprotein (LDL) receptor activity of blood mononuclear cells was examined in 26 pairs of monozygotic and 17 pairs of dizygotic normolipidaemic young adult male twins. 2. Receptor activity was quantified as the degradation of 125I-labelled LDL during a 6 h incubation, after derepression of the cells for 72 h in lipoprotein-deficient medium. 3. The total variance of receptor activity was similar in the two groups of twins. In contrast, within-pair variance was five times greater in dizygotic twins than in monozygotic twins (P less than 0.001). 4. Estimates of heritability, mostly based on the intra-class correlation coefficients (monozygotic, r = 0.83; dizygotic, r = 0.39), ranged from 0.72 to 1.05. 5. These results suggest that the maximal LDL receptor activity of peripheral cells in normolipidaemic subjects is largely genetically determined.
In order to gain further insight into the relationship between high-density lipoprotein (HDL) metabolism and plasma triglyceride transport, measurements were made of HDL cholesterol concentration, apoprotein (apo) AI and AII metabolism, very-low-density-lipoprotein (VLDL) apo B metabolism, and heparin-elutable adipose tissue lipoprotein lipase (LPL) activity in seventeen subjects with a wide range of plasma triglyceride concentrations (0.8-25 mmol/l). The fractional catabolic rate (FCR) of VLDL apo B was directly related to LPL activity (r = +0.80), providing evidence that the activity of the enzyme in adipose tissue is a determinant of the rate of lipolysis of VLDL in man. HDL cholesterol concentration was a positive function of both VLDL apo B FCR (r = +0.74) and LPL activity, a finding consistent with previous evidence for the origin of a proportion of HDL cholesterol from 'surface remnants' liberated during VLDL catabolism. THe FCRs of both apo AI and apo AII were inversely related to VLDL apo B FCR (AI, r = -0.52; AII, r = -0.69) and to LPL activity. The synthetic rate of ap AII, but not that of apo AI, was positively correlated with VLDL apo B synthesis (r = +0.7 1). Thus, the metabolism of the major proteins of HDl in man appears to be closely associated with VLDL metabolism.
A longitudinal study has been set up to examine the incidence of ischaemic heart disease and its associations with serum lipoproteins including high density lipoprotein cholesterol and its subfractions, certain haemostatic factors, and other "risk' factors. We report here on our pilot study findings. Cross-sectional data were available on 283 men and 68 women aged 45 to 64 representing 85% of the available population randomly selected from the lists of 16 general practitioners. Reproducibility of the measurements of total serum cholesterol, triglyceride, and low density lipoprotein cholesterol was acceptable. The reproducibility of some of the other serum lipid fractions, for example high density lipoprotein cholesterol, was less good, in part because of the small range of the values found for these components. Univariate associations of physical and behavioural characteristics and serum lipoproteins of men and women, with and without ischaemic heart disease, disclosed small and statistically nonsignificant differences except for levels of blood pressure. In particular, there was no significant difference in mean levels of serum high density lipoprotein cholesterol between men with ischaemic heart disease (0.91 mmol/l) and men without it (0.94 mmol/l). In examining our data for the determinants of serum high density lipoprotein cholesterol using a linear multiple regression model, sex, serum high density lipoprotein cholesterol, and very low density lipoprotein triglyceride were the major factors, each individually explaining about 7% of the variance of serum high density lipoprotein cholesterol levels. In addition, alcohol intake and obesity each explained a further 2% of the variance. The experience of the pilot study has led to modifications in the collection of blood samples and the subsequent estimation of lipid fractions.
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A variety of epidemiologic, biochemical, and experimental studies have established a direct relationship between low density lipoprotein (LDL) cholesterol concentration and the risk of developing ischemic heart disease. An even stronger inverse relationship has been demonstrated between high density lipoprotein (HDL) cholesterol and the risk of ischemic heart disease (IHD). Both of these associations reflect underlying relationships to atherogenesis. The mechanism by which elevated LDL levels lead to cholesterol ester deposition in arterial smooth muscle cells and/or macrophages is not clear. a causal relationship between low HDL levels and accelerated atherogenesis has not yet been established. Factors which increase plasma LDL concentration or reduce HDL concentration, with a consequent increase in the theoretical risk of coronary atherosclerosis, include obesity, physical inactivity, cigarette smoking, and progestin-containing oral contraceptives. Recent reports have added to this list widely used antihypertensive agents, such as thiazide diuretics and beta-blocking agents. The mechanisms and pathophysiologic significance of such drug-induced changes in lipoprotein levels are not clear. Until more information is available, however, it would seem prudent to avoid, whenever possible, any antihypertensive which in a given patient substantially lowers the HDL/LDL ratio.
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Seven patients with primary hypercholesterolaemia (baseline levels 7.5 to 13.1 mmol/l), and with no evidence of xanthomas, were treated with probucol 1 g daily. Plasma LDL-cholesterol decreased by 20% due to reduced LDL apo B synthetic rate. HDL-cholesterol also decreased; this fall was confined to the HDL3 subclass, while HDL2-cholesterol was unchanged.
To identify diets that are more effective than existing ones in reducing lipoprotein-mediated risk of atherosclerotic heart disease, the serum lipids and lipoprotein response to three modified diets was studied in twelve normal men living in an institution. The "Western" reference diet (40% energy from fat, P/S ratio 0.27) was compared in Latin square design with a fat-modified diet (diet B, 27% energy from fat, P/S 1.0, reduced cholesterol content); with a fat-modified diet supplemented with fruit, vegetable, and cereal fibre (diet C); and with a diet providing 40% energy from fat, having P/S ratio 1.0 and supplemented by fibre (diet D). The effects of fat modification and fibre-supplementation (diets C and D) were strongly additive-a fall serum cholesterol by 24-29%, in low-density-lipoprotein (LDL) cholesterol by 31-34%, and in serum triglyceride by 21-26%; and the reduction, by diet C, of the ratio of serum cholesterol to high-density-lipoprotein (HDL)-cholesterol by 21%, and that of LDL-cholesterol to HDL2-cholesterol by 26%. The additive effects of multiple changes in nutrient intake, each moderate in extent, permits the design of diets which are remarkably effective in reducing serum-cholesterol level.
In rats a graded series of stressors produced progressively greater suppression of lymphocyte function, as measured by the number of circulating lymphocytes and by phytohemagglutinin stimulation of lymphocytes in whole blood and isolated cultures. This evidence suggests that stress suppresses immunity in proportion to the intensity of the stressor.
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