Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.

OBJECTIVE--To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials. DESIGN--Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years). PATIENTS--24,847 Male participants; mean age 47.5 years. MAIN OUTCOME MEASURES--Total and cause specific mortalities. RESULTS--Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04). CONCLUSIONS--The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.     

Elevated membrane cholesterol concentrations inhibit glucagon-stimulated adenylate cyclase.

A method was devised which increases the cholesterol concentration of rat liver plasma membranes by exchange from cholesterol-rich liposomes at low temperature (4 degrees C). When the cholesterol concentration of liver plasma membranes is increased, there is an increase in lipid order as detected by a decrease in mobility of an incorporated fatty acid spin probe. This is accompanied by an inhibition of adenylate cyclase activity. The various ligand-stimulated adenylate cyclase activities exhibit different sensitivities to inhibition by cholesterol, with inhibition of glucagon-stimulated greater than fluoride-stimulated greater than basal activity. The bilayer-fluidizing agent benzyl alcohol is able to reverse the inhibitory effect of cholesterol on adenylate cyclase activity in full. The thermostability of fluoride-stimulated cyclase is increased in the cholesterol-rich membranes. Elevated cholesterol concentrations abolish the lipid-phase separation occurring at 28 degrees C in native membranes as detected by an incorporated fatty acid spin probe. This causes Arrhenius plots of glucagon-stimulated adenylate cyclase activity to become linear, rather than exhibiting a break at 28 degrees C. It is suggested that the cholesterol contents of both halves of the bilayer are increased by the method used and that inhibition of adenylate cyclase ensues, owing to the increase in lipid order and promotion of protein-protein and specific cholesterol-phospholipid interactions.     

Low cholesterol concentrations and severe depressive symptoms in elderly people.

OBJECTIVE--To investigate the reported association between low serum cholesterol concentration and severe depressive symptoms in an elderly population. DESIGN--Cross sectional analysis of pooled data from three communities of the established populations for epidemiologic studies of the elderly. Participants who completed their interview, including the Centers for Epidemiologic Studies'' depression scale and consented to measurement of their cholesterol concentration were included in the study. SUBJECTS--3939 men and women aged > or = 71. METHODS--chi 2 analysis, t tests, and multivariate regression analysis of the association between low cholesterol concentration and severe depressive symptoms. All analyses were stratified by sex, and multivariate analyses were adjusted for age, self reported health, physical function, number of drugs used, and weight loss. MAIN OUTCOME MEASURE--Score of depressive symptoms on the Centers for Epidemiologic Studies'' depression scale. RESULTS--Depressive symptoms, cholesterol concentration, weight, and use of drugs were all associated with age in men and women. The relative odds of severe depressive symptoms (score > or = 16) for those with low cholesterol concentrations (< 4.14 mmol/l) were 1.9 (95% confidence interval, 1.1 to 3.3) for the older group of men and 1.8 (1.1 to 2.9) for the older group of women. This association was also observed when depressive symptoms were analysed as a continuous rather than a categorical variable. In multivariate models that adjusted for age, self reported health, physical function, number of drugs used, and weight loss, the association was substantially weakened. CONCLUSIONS--After several factors relating to health had been controlled for, no significant association between low cholesterol concentration and severe depressive symptoms was found.     

Growth in utero and serum cholesterol concentrations in adult life.

OBJECTIVE--To see whether reduced rates of fetal growth are related to raised serum cholesterol concentrations in adult life. DESIGN--Follow up study of men and women whose size at birth had been recorded. SETTING--Jessop and Northern General Hospitals, Sheffield. SUBJECTS--219 men and women born in the Jessop Hospital during 1939-40. MAIN OUTCOME MEASURES--Serum concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B. RESULTS--Men and women who had had a small abdominal circumference at birth had raised serum concentrations of total and low density lipoprotein cholesterol and apolipoprotein B. This was independent of the duration of gestation. Serum concentrations of total cholesterol fell by 0.25 mmol/l (95% confidence interval 0.09 to 0.42) with each 1 in (2.54 cm) increase in abdominal circumference. The corresponding figure for serum low density lipoprotein cholesterol was 0.26 mmol/l (0.11 to 0.42) and for serum apolipoprotein B 0.04 g/l (0.02 to 0.07). Small head and chest circumferences at birth and short length were each associated with raised serum low density lipoprotein cholesterol concentrations but the trends disappeared in a simultaneous regression with abdominal circumference at birth. The association between abdominal circumference at birth and low density lipoprotein cholesterol concentration was independent of social class, current body weight, cigarette smoking, and alcohol consumption. CONCLUSION--Raised serum cholesterol concentrations in adult life are associated with impaired growth during late gestation, when fetal undernutrition has a disproportionate effect on liver growth. Impaired liver growth may permanently alter low density lipoprotein cholesterol metabolism.     

Structure of dipalmitoylphosphatidylcholine/cholesterol bilayer at low and high cholesterol concentrations: molecular dynamics simulation.

By using molecular dynamics simulation technique we studied the changes occurring in membranes constructed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol at 8:1 and 1:1 ratios. We tested two different initial arrangements of cholesterol molecules for a 1:1 ratio. The main difference between two initial structures is the average number of nearest-neighbor DPPC molecules around the cholesterol molecule. Our simulations were performed at constant temperature (T = 50 degrees C) and pressure (P = 0 atm). Durations of the runs were 2 ns. The structure of the DPPC/cholesterol membrane was characterized by calculating the order parameter profiles for the hydrocarbon chains, atom distributions, average number of gauche defects, and membrane dipole potentials. We found that adding cholesterol to membranes results in a condensing effect: the average area of membrane becomes smaller, hydrocarbon chains of DPPC have higher order, and the probability of gauche defects in DPPC tails is lower. Our results are in agreement with the data available from experiments.     

Effects of cimetidine and ranitidine on high density lipoprotein cholesterol concentrations.

To assess the effect of cimetidine and ranitidine on high density lipoprotein (HDL) cholesterol concentration two groups of eight patients with duodenal ulcer or oesophagitis matched for age, sex, and cigarette consumption were given either cimetidine 1 g daily or ranitidine 300 mg daily for one month. There was no significant change in the cholesterol content of HDL and its subfraction HDL3 after treatment with ranitidine or cimetidine, or in the cholesterol content of the subfraction HDL2 after treatment with ranitidine; the HDL2 cholesterol concentration was, however, significantly increased after treatment with cimetidine. Further studies are being undertaken to establish the mechanism of this effect.     

Abrupt modifications of phospholipid bilayer properties at critical cholesterol concentrations.

The fluorescence generalized polarization (GP) of 2-dimethylamino-6-lauroylnaphthalene (Laurdan) reveals different effects of cholesterol on the phase behavior of phospholipid bilayers. Phospholipid vesicles composed of gel, liquid-crystalline, and coexisting domains of the two phases have been studied at temperatures from 1 to 65 degrees C, without cholesterol and with cholesterol concentrations of 3-50 mol %. Laurdan GP measurements show the general effect of cholesterol of increasing the molecular dynamics of the gel and of decreasing the molecular dynamics of the liquid-crystalline phase. In the liquid-crystalline phase, the increased order yields Laurdan GP values close to those obtained in the gel phase. At cholesterol concentrations > 15 mol % a phase transition cannot be detected. Using the wavelength dependence of the excitation and emission GP spectra we determine that differences between the two phospholipid phases cannot be detected. In particular, in vesicles composed of coexisting gel and liquid-crystalline phases the GP wavelength dependence characteristic of coexisting domains cannot be observed at cholesterol concentrations > or = 15 mol %. Cholesterol causes the decrease in both the polarity and the dipolar relaxation effects on the neighborhood of the fluorescent naphthalene moiety of Laurdan. Probably because of a cholesterol-induced increase in the bilayer packing, these effects do not occur continuously with the increase of cholesterol concentration in the bilayer. Cholesterol concentrations inducing higher Laurdan GP values have been determined at about 5, 10, 15, 30, and 45 mol % with respect to phospholipids. We propose that the formation of ordered molecular microdomains at critical cholesterol concentrations can explain the occurrence of the observed discontinuities.     

Heritability of plasma cholesterol and triglyceride concentrations in swine

Three-hundred and eighteen female swine representing contemporary commercial swine breeds (34 Chester White, 43 Large White, 42 Landrace, 40 Yorkshire, and 159 four-breed crossbreeds) were used to evaluate genetic variation between and within breeds for levels of plasma cholesterol and plasma triglycerides. Blood was sampled from all pigs after a 16-hr fast at 154 days of age. Plasma cholesterol was measured in all pigs and triglycerides were measured in 232 pigs. Paternal half-sib heritabilities (h2) for plasma cholesterol and plasma triglycerides were 0.45 +/- 0.23 and 1.04 +/- 0.32, respectively. Breed differences were not apparent for either trait. Phenotypic and paternal half-sib genetic correlations between the two traits were 0.16 and 0.66, respectively. Neither body weight nor backfat depth were important in affecting the estimate of h2 for either trait. The relatively high h2 of total plasma cholesterol and of total triglycerides offers the possibility of developing, through selection, populations of hypercholesterolemic or hypertriglyceridemic swine useful as models for studies directed toward further understanding of human cardiovascular disease.     

Plasma lipids and lipoprotein cholesterol concentrations in people with different diets in Britain.

Concentrations of total cholesterol and cholesterol in the various lipoprotein fractions were measured in vegans, vegetarians, fish eaters (who did not eat meat), and meat eaters. Total and low density lipoprotein cholesterol concentrations were higher in meat eaters than vegans, with vegetarians and fish eaters having intermediate and similar values. High density lipoprotein cholesterol concentration was highest in the fish eaters but did not differ among the other groups. There were striking trends with age in total and low density lipoprotein cholesterol concentrations, which differed between men and women: women showed a steady increase in concentration with age, whereas concentrations in men did not increase appreciably after the age of 40, which may partly explain sex differences in the prevalence of coronary heart disease. The differences in total cholesterol concentration suggest that the incidence of coronary heart disease may be 24% lower in lifelong British vegetarians and 57% lower in lifelong vegans than in meat eaters.     

Normative standards of plasma cholesterol and triglyceride concentrations in Canadians of working age.

Fasting plasma cholesterol and triglyceride concentrations were determined for 6407 working Canadian adults aged 20 to 69 years in Toronto and Hamilton. Means, medians and 5th and 95th percentiles were ascertained from the data for men, women taking oral contraceptives or estrogen preparations, and women not taking such medication. Mean plasma cholesterol values (mg/dL) ranged in men from 168.3 at ages 20 to 24 years to 211.5 at ages 45 to 49 years, and in women using hormone preparations from 180.3 at ages 20 to 24 years to 224.2 at ages 50 to 54 years; corresponding values in women not using these preparations were 164.9 and 220.6. Plasma triglyceride means (mg/dL) ranged in men from 108.7 at ages 20 to 24 years to 166.7 at ages 40 to 44 years, in women using hormone preparations from 115.4 at ages 20 to 24 years to 145.3 at ages 45 to 59 years, and in women not using these preparations from 77.5 at ages 20 to 24 years to 112.4 at ages 50 to 54 years.     

Low serum cholesterol concentration and short term mortality from injuries in men and women.

OBJECTIVE--To determine whether total serum cholesterol concentration predicts mortality from injuries including suicide. DESIGN--Cohort study of men and women who had their serum cholesterol concentration measured as part of a general health survey in Värmland, Sweden in 1964 or 1965 and were followed up for an average of 20.5 years. SUBJECTS--Adults participating in health screening in 1964-5 (26,693 men and 27,692 women). The study sample was restricted to subjects aged 45-74 years during any of the 20.5 years of follow-up. MAIN OUTCOME MEASURES--Serum cholesterol concentration. Deaths from all injuries and suicides during three periods of follow up (0-6 years, 7-13 years, and 14-21 years) according to the Swedish mortality register in subjects aged 45-74. Adjustment was made for prevalent cancer (identified from the Swedish cancer register) at the time of a suicide. RESULTS--A strong negative relation between cholesterol concentration and mortality from injuries was found in men during the first seven years of follow up. The relative risk in the lowest 25% of the cholesterol distribution was 2.8 (95% confidence interval 1.52 to 4.96) compared with the top 25%. Most of the excess risk was caused by suicide with a corresponding relative risk of 4.2 (p for trend = 0.001). Correction for prevalent cancer did not change the results. Events occurring during the latter two thirds of the 20.5 years of follow up were not predicted. In women no relation between cholesterol concentration and mortality from injuries was found. CONCLUSIONS--Together with observations from intervention trials the findings support the existence of a relation between serum cholesterol concentration and suicide. The causality of such a relation is, however, not resolved.     

Serum cholesterol concentration and mortality from accidents,suicide, and other violent causes.

OBJECTIVE--To study the association of mortality from accidents, suicides, and other violent deaths with serum cholesterol concentration. DESIGN--Baseline measurements in two randomly chosen independent cohorts were carried out in 1972 and 1977. Mortality was monitored over 10-15 years through the national death registry. SETTING--Eastern Finland. SUBJECTS--The two cohorts comprised men (n = 10,898) and women (n = 11,534) born between 1913 and 1947. There were 193 deaths due to accidents, suicides, and violence among men and 43 among women. MAIN OUTCOME MEASURE--Mortality from accidents, suicides, and other violent deaths was used as the end point. Deaths from these causes were pooled together in the analyses. RESULTS--Serum cholesterol concentration was not associated with mortality from accidents, suicides, and other violent deaths in the univariate analyses or in the proportional hazards regression analyses including smoking, systolic blood pressure, alcohol drinking, and education. In both genders smoking was more prevalent among those who died from accidents, suicides, and other violent causes than from other causes. Frequent use of alcohol increased mortality from these causes. CONCLUSION--The risk of accidents, suicides, and other violent deaths was not related to serum cholesterol concentration, whereas such deaths were more prevalent in smokers and alcohol drinkers.     

Vincristine and vinblastine lower plasma cholesterol concentrations in rhesus monkeys

3-4 days after a single clinical dose of vincristine or vinblastine in rhesus monkeys there was a marked decrease in plasma low-density lipoprotein cholesterol concentrations. There was also a concomitant increase in plasma triacylglycerol concentrations. Plasma lipid levels returned to normal concentrations within 7-10 days after injection. Plasma high-density lipoprotein cholesterol concentrations were unaltered by the drugs. Electron micrographs of the hepatocytes from monkeys treated with vincristine or vinblastine showed an accumulation of glycogen particles and proliferation of smooth endoplasmic reticulum, which was accompanied by an increase in the number of lipoprotein-containing vesicles. These results indicate that vincristine and vinblastine alter plasma cholesterol and triacylglycerol concentrations in part by interfering with hepatic lipid and lipoprotein metabolism. These studies further suggest the possibility that other less cytotoxic alkaloids from Catharanthus species with clinically useful hypocholesterolemic activity may be discovered.     

Serum high density lipoprotein cholesterol,alcohol, and coronary mortality in male smokers.

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake. DESIGN--Cohort study. SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland. PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s. MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups. RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward. CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also.