IDL composition and angiographically determined progression of atherosclerotic lesions during simvastatin therapy.

Some patients with coronary artery disease experience continued progression of one or more coronary lesions despite treatment with drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and markedly lower plasma cholesterol levels. We examined relationships between the progression of coronary artery lesions and plasma lipoproteins, in particular intermediate density lipoprotein (IDL) and its composition, in 38 patients with coronary artery disease who had been treated with simvastatin for 2 years. Patients were given lipid-lowering dietary advice; 3 months later they were started on simvastatin therapy (10 mg/d) for 1 month, and after review of their plasma cholesterol levels, the dose was increased to 20 mg/d and later to 40 mg/d if the target level of plasma cholesterol had not been attained. Progression of lesions was determined by serial quantitative coronary angiography (variability of 5.5%) and was defined as an increase in percent diameter stenosis (%S)> or =10%; regression was defined as a decrease in %S > or =10%. The proportions of cholesteryl esters (CEs) and free cholesterol decreased significantly (P<.001), and proportions of protein and triglycerides increased significantly (P<.001) in IDL during simvastatin therapy. The CE content of IDL decreased significantly (-7.2 weight [wt]%, n=20, P<.001) in nonprogressors (patients who did not show progression of any lesions) and did not change significantly (-1.8 wt%, n=14, P=.36) in progressors (patients who showed progression of one or more lesions without regression of any lesion). This decrease in IDL CE content in nonprogressors was significantly (P=.01) different compared with the corresponding change in patients classified as progressors. Mean plasma cholesterol concentration tended to increase in progressors (0.47 mmol/L) and tended to decrease in nonprogressors (-0.39 mmol/L) during the initial 3-month diet period, and these changes were significantly different (P=.02). Furthermore, this change in plasma cholesterol level during the initial diet period was correlated significantly with the change in IDL CE content during the entire study (r=.348, n=38, P=.03). These data suggest that IDL CE content may be a determinant of progression of coronary lesions and may be influenced by compliance with or metabolic response to lipid-lowering dietary advice in patients with coronary artery disease during simvastatin treatment.

Urban/rural differences in red blood cell fatty acid composition, plasma lipids and diet in Melanesian Fijians.

OBJECTIVE: The aim of the study was to compare red blood cell (RBC) fatty acid composition, plasma lipids and lipoproteins and dietary intake between urban and rural Melanesian Fijians. DESIGN: A cross-sectional study was performed in a random subsample (n = 154) from a total survey population of 589 subjects. SETTING: Melanesian Fijians living in the relatively urban settlement of Nabua, Suva and On the remote island of Qamea (rural) were studied. RESULTS: The proportions of myristic acid (1.4% versus 0.3%, P < 0.001) and arachidonic acid (10.1% versus 11.4%, P < 0.01) were significantly higher and proportions of oleic acid (14.4% versus 13.2%, P < 0.05) and linoleic acid (11.9% versus 8.1%, P < 0.001) were significantly lower in RBC from rural compared with urban men, and a similar pattern was seen in women. Plasma cholesterol levels were significantly (P < 0.05) higher in the rural subjects. Urban/rural differences in plasma cholesterol levels were not significant when the proportion of RBC myristate was taken into account. CONCLUSIONS: The results suggest that consumption of myristic acid from coconut fat is greater and the intake of linoleic acid is less in Fijians living on a remote island and may contribute to their higher plasma cholesterol levels compared with their urban counterparts.

Plasma cholesterol ester transfer protein and distribution of cell cholesterol among plasma lipoproteins in vitro in distance runners and sedentary men.

Plasma cholesteryl ester transfer protein (CETP) activity and distribution of red blood cell (RBC) cholesterol among plasma lipoproteins during incubation of blood were determined in 14 distance runners and 10 sedentary men. Mean plasma CETP activity was similar in the runners (31% 10 microliters-1 18 h-1) and the sedentary men (32% 10 microliters-1 18 h-1). There was significantly (P < 0.05) greater accumulation of cell cholesterol in the HDL fraction (runners: 0.33 mmol l-1; sedentary men: 0.23 mmol l-1) which comprised a significantly (P < 0.05) larger proportion of the total amount of cell cholesterol lost to plasma (runners: 89%; sedentary men: 64%) in incubated blood from the runners. The results of this study suggest that in distance runners, high HDL concentrations are not accompanied by reduced plasma CETP levels but in conjunction with low triglyceride-rich lipoprotein levels in plasma, may promote preferential distribution of cell cholesterol into the 'antiatherogenic' HDL fraction.

Cholesterol metabolism in distance runners.

Faecal steroid excretion, including betasitosterol excretion, whole-body cholesterol synthesis, plasma lipids, and lipoprotein concentrations and habitual diet, were determined in 14 male distance runners and 14 sedentary men. The proportion of cholesterol-derived steroids excreted as bile acids, and the quantity of betasitosterol excreted in the faeces were significantly (P less than 0.05) higher in the runners compared with the sedentary men. Faecal betasitosterol excretion and the proportion of cholesterol-derived steroids excreted as bile acids were correlated significantly in the distance runners and the sedentary men (r = 0.774, n = 28, P less than 0.001). These results suggest that greater dietary intake of plant sterols may contribute to the higher proportion of cholesterol-derived steroids excreted as bile acids in distance runners.

Blood pressure in a random sample of the New Zealand population.

Blood pressures were measured as part of a health check in a randomly selected sample of the New Zealand population. One thousand, four hundred and ten men and 1605 women over 15 years were studied. Measurements were made by trained observers using the Hawksley Random Zero instrument. Systolic and diastolic pressures increased with age in men and women. There were 29% of men and 24% of women over the age of 45 with pressures over 160/95 mmHg of whom 24% of men and 33% of women were on treatment for hypertension. Of all subjects 9% of men and 12% of women were on treatment for hypertension. Systolic and diastolic pressures correlated significantly with body mass index, waist/hip ratio and skinfold measurements in men and women. The most significant correlation was with the body mass index. No regional or urban/rural differences were seen in systolic or diastolic pressures. A history of hypertension in the fathers of respondents related to blood pressures in the highest tertile of diastolic blood pressures in males, and systolic pressure of females. The association was not seen between mothers of respondents in respect of diastolic pressure.

Fecal bile acid concentration in distance runners.

Fecal bile acid concentration, fecal characteristics, bowel habits and habitual food intake were measured in male distance runners (n = 14) and sedentary men (n = 14). Fecal bile acid concentration was significantly (p less than 0.05) lower and stool weight, frequency of defecation and daily intake of fibre, carbohydrate, and protein were significantly (p less than 0.01) higher in the runners. After adjustment for differences in dietary fibre intake, fecal bile acid concentration was no longer significantly different between the distance runners and the sedentary men, but frequency of defecation remained significantly (p less than 0.05) higher in the runners. This study has identified lower fecal bile acid concentration in distance runners, which was probably due mainly to dilution of colon contents by higher consumption of dietary fibre. These findings may be relevant to the reduced incidence of colon cancer in physically active subjects.

Treatment of primary hypercholesterolaemia with simvastatin. New Zealand multicentre evaluation.

OBJECTIVE: To assess the efficacy of simvastatin in a large patient cohort. DESIGN: In an open multicentre study, after a four week placebo phase, patients were treated with simvastatin for 24 weeks; a subgroup continued therapy for a further 24 weeks. Efficacy of simvastatin (a) with prolonged use over three years, and (b) in combination with bezafibrate was assessed in an open single site study. SETTING: Lipid or cardiology specialist hospital outpatient clinics. PATIENTS: For the open multicentre study, 228 patients with primary hypercholesterolaemia (total cholesterol level greater than 6.5 mmol/L) were recruited, of whom 224 met entry criteria and completed the study. Forty-seven of these patients continued therapy for one year. In the open single site study, 22 patients (with low density lipoprotein [LDL] cholesterol levels greater than 4.3 mmol/L) participated in studies of long term use (n = 9) or of combined therapy (n = 13). INTERVENTION: Therapy in the open multicentre study began with 10 mg of simvastatin per day, doubling to 20 mg after six weeks and then 40 mg after 12 weeks of therapy if total cholesterol levels persisted above 5.2 mmol/L. In the study of long term use, simvastatin (40 mg daily) was taken continuously over three years. In the study of combination therapy, bezafibrate (600 mg daily) was taken in addition to simvastatin (40 mg daily) for 10 months. MAIN OUTCOME MEASURES: Plasma lipid and lipoprotein concentrations. RESULTS: In the multicentre study, total plasma cholesterol levels were reduced by 32.8% from 9.11 +/- 1.84 (in mmol/L, mean +/- SD) to 6.12 +/- 1.25 (P less than 0.001), and LDL cholesterol levels by 41.4% from 6.90 +/- 1.92 to 4.04 +/- 0.31 (P less than 0.001). The effect of therapy was sustained in those patients continuing therapy to 48 weeks. The study of long term use found no significant attenuation of effect over three years of monotherapy. Combined simvastatin/bezafibrate therapy reduced the LDL cholesterol concentration by a further 19.9% (P less than 0.001) from levels achieved on simvastatin alone. CONCLUSIONS: Simvastatin is an effective, well tolerated lipid lowering drug, without significant attenuation of effect with prolonged use. Simvastatin plus bezafibrate appears to be a potentially useful drug combination.

Risk factors for coronary heart disease in New Zealand and Sweden: Dunedin and Uppsala compared.

OBJECTS: to compare men and women over the age of 35 years in Dunedin (New Zealand) and Uppsala (Sweden) in respect of anthropometric values, dietary habits and certain coronary heart disease risk factors in view of known differences in coronary mortality between the two countries. METHODS: one hundred and ninety-five Dunedin and 94 Uppsala residents were chosen randomly from the respective populations, in the former city by electoral roll, in the latter by use of unique personal number. Measurements of height, weight, waist/hip ratio, blood pressure, blood lipids were made and dietary and smoking habits assessed. RESULTS: the Swedes were taller and leaner than the New Zealanders. Blood pressure and smoking habits were not significantly different but total blood cholesterol levels were lower in Uppsala men and women. Blood triglycerides were higher in Dunedin women but high density lipoprotein cholesterol levels tended to be lower in men and women in Uppsala. CONCLUSIONS: it was found by analysis of variance that the blood lipid level differences between the two populations could be explained by body mass index. Correction of lipid values for the waist/hip ratio partly explained the higher cholesterol values in Dunedin but diet differences may also have been contributory. The differences in coronary mortality between the population of New Zealand and Sweden are compatible with the view that our blood cholesterol findings reflect the different levels of risk.

Plasma noncholesterol sterols in male distance runners and sedentary men.

Plasma lathosterol concentration is taken to be an index of the rate of cholesterol synthesis and plasma concentrations of plant sterols just as campesterol and betasitosterol are taken to be indeces of cholesterol absorption efficiency. These noncholesterol sterols were measured in plasma from 14 male distance runners and 10 sedentary men. Plasma lathosterol concentration was 30% lower (P less than 0.02) and plasma betasitosterol concentration was 33% higher (P less than 0.02) in the runners compared to the sedentary men. Plasma concentrations of lathosterol and plant sterols were inversely and significantly (P less than 0.05) correlated in both the runners and the sedentary men. Plasma plant sterol concentrations were correlated positively and significantly (P less than 0.01) with plasma high density lipoprotein cholesterol (HDL-C) concentrations in the runners and sedentary men combined. These findings suggest that more efficient cholesterol absorption may lead to higher plasma plant sterol concentrations and may contribute to lower cholesterol synthesis rates, reduced concentrations of plasma lathosterol and higher plasma HDL-C concentration in distance runners.

Effect of eicosapentaenoic acid on restenosis rate, clinical course and blood lipids in patients after percutaneous transluminal coronary angioplasty.

In order to study the effects of eicosapentaenoic acid (Maxepa), Maxepa placebo and aspirin/dipyridamole combination on the clinical course and restenosis rate of atherosclerotic lesions after percutaneous transluminal coronary angioplasty 79 men and 29 women were randomly divided into three treatment groups and restudied angiographically within one year of the procedure. Angina recurred less in the Maxepa group than in the other groups, although not statistically so. Restenosis rate was significantly reduced in the Maxepa group (11%) compared to the placebo group (30%) but, while less, was not significantly lower than in the aspirin/dipyridamole group (17%). Maxepa treatment appears to reduce restenosis rate of coronary artery lesions after percutaneous transluminal coronary angioplasty and may be an acceptable and equally effective alternative therapy to aspirin/dipyridamole.

Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity.

Homozygosity for the apolipoprotein (apo) E variant apoE2(158 Arg----Cys) invariably gives rise to dysbetalipoproteinemia, and when associated with obesity or a gene for hyperlipidemia, results in type III hyperlipoproteinemia. The association of the E2/2 phenotype with type IV/V hyperlipoproteinemia rather than type III hyperlipoproteinemia in identical twin brothers led us to investigate the primary structure of their apoE. Lipoprotein electrophoresis on agarose gels confirmed the presence of increased very low density lipoproteins (VLDL) and chylomicrons but little, if any, beta-VLDL, indicating that these subjects did not have dysbetalipoproteinemia. When the apoE from these twins was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis on a system that can distinguish apoE2(158 Arg----Cys) from all other known apoE variants, it gave rise to two components. One had the unique mobility of apoE2(158 Arg----Cys), and one migrated in the position of the other variants of apoE (and normal apoE3), indicating that the brothers were heterozygous for apoE2(158 Arg----Cys) and a second apoE2 isoform. Cysteamine modification and isoelectric focusing showed that, like apoE2(158 Arg----Cys), the second apoE2 isoform also contained two cysteine residues. The structural mutation in the second apoE2 isoform was determined by peptide sequencing. Like normal apoE3, this variant had arginine at position 158, but differed from apoE3 by the substitution of cysteine for arginine at position 228. Total apoE isolated from the brothers had the same receptor-binding activity in a competitive binding assay as a 1:1 mixture of normal apoE3 and apoE2(158 Arg----Cys).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressures in a random sample of the New Zealand population: preliminary data from the life in New Zealand survey.

Blood pressures (BPs) were measured as part of a health check in a randomly selected sample of the New Zealand population in the Life in New Zealand survey. A total of 1,410 men and 1,605 women over 15 years of age were studied. Measurements were made by trained observers using the Hawksley random zero instrument. Systolic BP (SBP) and diastolic BP (DBP) increased with age in men and women. There were 29% of men and 24% of women over the age of 45 years with BPs over 160/95 mm Hg, of whom 24% of men and 33% of women indicated they were on treatment for hypertension. No regional or urban/rural differences were seen in either SBPs or DBPs. A history of hypertension in the fathers of respondents related to BPs in the highest tertile of SBPs in males, and SBPs in females. The association was not seen between mothers of respondents, except for DBP in women respondents.

Simvastatin (MK 733): an effective treatment for hypercholesterolemia.

This study describes the efficacy of the drug simvastatin. It is likely to be the first HMG CoA reductase inhibitor in Australia and New Zealand available for the treatment of hyperlipidemia. Twenty-four patients, 12 men and 12 women with primary hypercholesterolemia were randomly allocated to treatment by cholestyramine (eight patients) or to simvastatin (16 patients) for a 12-week period. With simvastatin, total cholesterol levels decreased by 37.5% from a baseline mean of 10.33 mmol/L to 6.4 mmol/L after 12 weeks. Low density lipoprotein (LDL) cholesterol concentration decreased by 48.2% from 8.40 mmol/L to 4.39 mmol/L. These effects were better than observed for cholestyramine alone where cholesterol and LDL-cholesterol reductions were 24.9% and 33.1% respectively. Thirteen patients, however, did not achieve target LDL levels of 3.62 mmol/L, or below, and therefore were treated with a combination of cholestyramine and simvastatin, resulting in a decrease of total cholesterol and LDL-cholesterol by 45.5% and 53.5% of baseline values studied over an eight-week period. No major clinical side-effects were encountered. One patient appeared to have had a change in colour vision at the end of the study at 20 weeks, without loss of visual acuity.

Physical training plasma lipoproteins and faecal steroid excretion in sedentary men.

Thirty sedentary men aged 25-52 participated in a 4-month randomized and controlled study of the effects of exercise on plasma lipoproteins and faecal steroid excretion. After 4 months the aerobic training group showed a significant (P = 0.047) increase in physical work capacity (+38 watts) and a significant (P = 0.025) decrease in faecal total steroid excretion (-257 mg/day) compared to corresponding changes in the control group. The drop in faecal total steroid excretion in the men who trained was mainly due to a significant (P less than 0.05) fall in faecal neutral sterol excretion (-240 mg/day). Plasma lipoprotein lipid concentrations did not change significantly during the study although plasma levels of very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol tended to fall in the men who trained. In the aerobic training group individual changes in plasma LDL cholesterol levels were significantly correlated with decreases in faecal total steroid excretion (p = 0.615, P less than 0.05) and faecal neutral sterol excretion (p = 0.627, P less than 0.05). The results of this study show that regular exercise is associated with a drop in faecal neutral sterol excretion which, if sufficiently large, may be associated with a decrease in plasma LDL cholesterol concentration.

Sitosterolaemia and heterozygous familial hypercholesterolaemia in a three year old girl: case report.

A case of a 3 1/2 year old female child is described in which symptomless cutaneous xanthomatosis led to the diagnosis of sitosterolaemia in the presence of a defect of low-density lipoprotein uptake by cultured fibroblasts. The condition responded to treatment by cholestyramine with normalisation of the blood lipid levels. Normal growth and development continued for three years of observation.