Serum cholesterol concentration and death from suicide in men: Paris prospective study I.

OBJECTIVE: To investigate whether low serum cholesterol concentration or changing serum cholesterol concentration is associated with risk of suicide in men. DESIGN: Cohort study with annual repeat measurements of serum cholesterol concentration (for up to four years). SETTING: Paris, France. SUBJECTS: 6393 working men, aged 43-52 in 1967-72, who had at least three measurements of serum cholesterol concentration. MAIN OUTCOME MEASURES: Individual change over time in serum cholesterol concentration (estimated using within person linear regression method); death from suicide during average of 17 years'' follow up after last examination. RESULTS: 32 men committed suicide during follow up. After adjustment for age and other factors, relative risk of suicide for men with low average serum cholesterol concentration (< 4.78 mmol/l) compared with those with average serum cholesterol concentration of 4.78-6.21 mmol/l was 3.16 (95% confidence interval 1.38 to 7.22, P = 0.007). Men whose serum cholesterol concentration decreased by more than 0.13 mmol/l a year had multivariate adjusted relative risk of 2.17 (0.97 to 4.84, P = 0.056) compared with those whose cholesterol remained stable (change of < or = 0.13 mmol/l a year). CONCLUSION: Both low serum cholesterol concentration and declining cholesterol concentration were associated with increased risk of death from suicide in men. Although there is some evidence in favour of a concomitant rather than a causal effect for interpreting these associations, long term surveillance of subjects included in trials of lipid lowering treatments seems warranted.     

Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study.

OBJECTIVE: To determine whether raised plasma glucose concentration independently influences outcome after acute stroke or is a stress response reflecting increased stroke severity. DESIGN: Long-term follow up study of patients admitted to an acute stroke unit. SETTING: Western Infirmary, Glasgow. SUBJECTS: 811 patients with acute stroke confirmed by computed tomography. Analysis was restricted to the 750 non-diabetic patients. MAIN OUTCOME MEASURES: Survival time and placement three months after stroke. RESULTS: 645 patients (86%) had ischaemic stroke and 105 patients (14%) haemorrhagic stroke. Cox''s proportional hazards modelling with stratification according to Oxfordshire Community Stroke Project categories identified increased age (relative hazard 1.36 per decade; 95% confidence interval 1.21 to 1.53), haemorrhagic stroke (relative hazard 1.67; 1.22 to 2.28), time to resolution of symptoms > 72 hours (relative hazard 2.15; 1.15 to 4.05), and hyperglycaemia (relative hazard 1.87; 1.43 to 2.45) as predictors of mortality. The effect of glucose concentration on survival was greatest in the first month. CONCLUSIONS: Plasma glucose concentration above 8 mmol/l after acute stroke predicts a poor prognosis after correcting for age, stroke severity, and stroke subtype. Raised plasma glucose concentration is therefore unlikely to be solely a stress response and should arguably be treated actively. A randomised trial is warranted.     

Assessing possible hazards of reducing serum cholesterol.

OBJECTIVE--To assess whether low serum cholesterol concentration increases mortality from any cause. DESIGN--Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary. MAIN OUTCOME MEASURES--Excess cause specific mortality associated with low or lowered serum cholesterol concentration. RESULTS--The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration. CONCLUSIONS--There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.     

Role of lipid-modifying therapy in the prevention of initial and recurrent stroke

PURPOSE OF REVIEW: To establish the role of cholesterol-modifying therapy in stroke prevention. RECENT FINDINGS: Population-based observational cohort studies show a variable weak positive relationship between increasing plasma total cholesterol concentrations and an increasing risk of ischaemic stroke, which is partly offset by a weaker negative association between decreasing total cholesterol concentrations and an increasing risk of with haemorrhagic stroke. However, randomized controlled trials show unequivocally that lowering plasma total cholesterol by approximately 1.2 mmol/l (and LDL-cholesterol by 1.0 mmol/l) is associated with a reduced relative risk of stroke and other serious vascular events by at least a quarter, and probably a third, without any increase in haemorrhagic stroke, in a wide range of men and women (including individuals with previous stroke). The proportional reduction in stroke risk is consistent, irrespective of the patient's age, baseline plasma cholesterol concentration, and absolute risk of stroke (although perhaps less in very low-risk individuals), but is increased with greater degrees of cholesterol lowering (15% or more), and thus with statin medications, which are more potent than non-statin interventions in lowering cholesterol levels. The absolute reduction in stroke risk achieved by statins is greatest among individuals at highest risk of stroke. Preliminary evidence suggests that lowering total cholesterol levels by diet may be an effective adjunctive therapy to statins, and raising plasma HDL-cholesterol concentrations among patients with coronary heart disease and low HDL-cholesterol levels ( 1 mmol/l) by means of gemfibrozil may also effectively prevent stroke. SUMMARY: Statin drugs are effective and safe in preventing initial and recurrent stroke. However, because they are costly, they should probably be restricted to individuals with an annual risk of stroke and other serious vascular events of 3% or greater, and possibly as low as 1.5%, because routine monitoring of plasma cholesterol, and liver and muscle enzyme concentrations is probably no longer necessary.     

Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study.

OBJECTIVE--To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease. DESIGN--Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21,515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion. SUBJECTS--Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982. MAIN OUTCOME MEASURE--The difference in mortality from ischaemic heart disease for a 0.6 mmol/l difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration. RESULTS--The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/l in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/l in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration. CONCLUSIONS--The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.     

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease,and stroke: systematic review and meta-analysis

Objectives To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment.Design Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke.Main outcome measures Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol.Results Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population.Conclusions Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.     

By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?

OBJECTIVE--To estimate by how much and how quickly a given reduction in serum cholesterol concentration will reduce the risk of ischaemic heart disease. DESIGN--Data on the incidence of ischaemic heart disease and serum cholesterol concentration were analysed from 10 prospective (cohort) studies, three international studies in different communities, and 28 randomised controlled trials (with mortality data analysed according to allocated treatment to ensure the avoidance of bias). MAIN OUTCOME MEASURE--Decrease in incidence of ischaemic heart disease or mortality for a 0.6 mmol/l (about 10%) decrease in serum cholesterol concentration. RESULTS--For men results from the cohort studies showed that a decrease of serum cholesterol concentration of 0.6 mmol/l (about 10%) was associated with a decrease in incidence of ischaemic heart disease of 54% at age 40 years, 39% at age 50, 27% at 60, 20% at 70, and 19% at 80. The combined estimate from the three international studies (for ages 55-64 years) was 38% (95% confidence interval 33% to 42%), somewhat greater than the cohort study estimate of 27%. The reductions in incidence of ischaemic heart disease in the randomised trials (for ages 55-64 years) were 7% (0 to 14%) in the first two years, 22% (15% to 28%) from 2.1-5 years, and 25% (15% to 35%) after five years, the last estimate being close to the estimate of 27% for the long term reduction from the cohort studies. The data for women are limited but indicate a similar effect. CONCLUSIONS--The results from the cohort studies, international comparisons, and clinical trials are remarkably consistent. The cohort studies, based on half a million men and 18,000 ischaemic heart disease events, estimate that a long term reduction in serum cholesterol concentration of 0.6 mmol/l (10%), which can be achieved by moderate dietary change, lowers the risk of ischaemic heart disease by 50% at age 40, falling to 20% at age 70. The randomised trials, based on 45,000 men and 4000 ischaemic heart disease events show that the full effect of the reduction in risk is achieved by five years.     

Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke

Statins reduce the risk of cardiovascular events by lowering the blood cholesterol. Many genes involved in the pharmacodynamic pathway of statins have been part of pharmacogenetic research in patients with hypercholesterolemia, with an emphasis on genes involved in the cholesterol pathway. The present study was carried out with an aim to evaluate the association between the genetic variants of lipoprotein lipase gene [HindIII (+/+)/HindIII (?/?)], multiple drug resistance gene (C3435T) and endothelial nitric oxide synthase gene (4a/4b) with clinical outcome including an increased risk of recurrent stroke or death in ischemic stroke patients on atorvastatin therapy. 525 stroke patients and 500 healthy controls were involved in the study. Follow-up telephone interviews were conducted with patients post-event to determine stroke outcome. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. A significant association of MDR1 and LPL gene variants with bad outcome in stroke patients on atorvastatin therapy was found. However, there was no significant association of 27?bp VNTR polymorphism of eNOS gene with outcome. MDR analysis was carried out to analyze gene–gene interaction involving these gene variants contributing to clinical outcome of patients on stratin therapy but no significant interaction between these variants was observed. In conclusion the individuals with HindIII (?/?) genotype of LPL and CC genotype of MDR1 gene would benefit more from atorvastatin therapy.     

Raised serum urate concentration as risk factor for premature mortality in middle aged men: relation to death from cancer.

Low serum cholesterol concentrations are associated with deaths from cancer. This association was found in a prospective study of middle aged men in Malmö and consideration of possible explanations for the lowering of serum cholesterol prompted an analysis of serum urate in relation to deaths from cancer. A total of 127 of the 7725 participants in the Malmö study had died since screening. A weakly positive but significant correlation between raised serum urate concentration and total mortality was found. This correlation was wholly explained by neoplastic deaths (p less than 0.01), while there were no associations with alcohol related deaths or with deaths from coronary heart disease. When the deaths from cancer were classified as "early" or "late"--that is, occurring less than or more than 2.5 years after the screening--the correlation between raised urate concentrations and cancer mortality was confined to the "early" deaths (p less than 0.001). Further studies are needed to substantiate the relation between raised serum urate concentrations and fatal neoplasia. Nevertheless, these findings weigh against recent suggestions that uric acid has an antioxidant protective effect against cancer.     

Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices

ObjectiveTo compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations.DesignCross sectional study.Setting17 practices within 17 primary care groups in Trent region, United Kingdom.ParticipantsPatients aged 35 years or over taking lipid lowering drugs and with at least two serum cholesterol concentrations recorded on computer.Results1353 of 2469 (54.8%) patients receiving lipid lowering treatment had a last recorded serum cholesterol concentration of ⩽5 mmol/l. Significantly more patients taking statins achieved the target value for serum cholesterol (5 mmol/l) than those taking fibrates (1307 (57%) v 46 (26%); P<0.0001). Atorvastatin and simvastatin were the most effective drugs in achieving the target. Significant differences were found between lipid lowering drugs for the pretreatment serum cholesterol concentration, the most recent cholesterol concentration, and the associated percentage reduction. Atorvastatin and simvastatin achieved the greatest percentage reduction in serum cholesterol concentrations (30.1%, 95% confidence interval 28.8% to 31.4%, and 28.0%, 26.7% to 29.3%, respectively). Although the mean serum cholesterol concentrations in this unselected population tended to be higher than those in clinical trials, the percentage reduction was consistent with the trials.ConclusionThe ability of individual statins to lower serum cholesterol concentration varied, with atorvastatin and simvastatin being the most effective. The percentage reductions agreed with those of randomised controlled trials indicating likely benefits in unselected patients in primary care. As the initial serum cholesterol concentrations were higher than those in randomised controlled trials, target serum cholesterol values of ⩽5 mmol/l may be unrealistic even for patients taking the most efficacious drugs. Also, the higher initial levels could mean that the absolute reduction in cardiovascular risk in primary care patients is greater than thought.

What is already known on this topic

Statins in patients with coronary heart disease help reduce further cardiovascular events and improve survivalThis seems to be a class effect of statins, although there may be important differences in effectiveness between themLess than half of patients in the community who take lipid lowering drugs achieve target serum cholesterol values

What this study adds

Statins vary in their ability to lower serum cholesterol concentration, with atorvastatin and simvastatin achieving the best resultsThe percentage reductions agreed with those found in randomised controlled trialsSince the initial serum cholesterol concentrations were higher than in trials, absolute risk reductions in primary care patients may be greater than thoughtTarget values of ⩽5 mmol/l may be unrealistic even for patients on the most efficacious drugs, because the initial mean cholesterol values of primary care patients are higher than those of patients in trials     

Non-fasting serum triglyceride concentration and mortality from coronary heart disease and any cause in middle aged Norwegian women.

OBJECTIVE--To study the association between non-fasting serum triglyceride concentrations and mortality in women from coronary and cardiovascular disease and all causes. DESIGN--Follow up by ambulatory teams of men and women who underwent cardiovascular screening for a mean of 14.6 years. SETTING--National health screening service in Norway. SUBJECTS--25,058 men and 24,535 women aged 35-49 years. MAIN OUTCOME MEASURE--Predictive value of non-fasting serum triglyceride concentrations. RESULTS--At initial screening total serum cholesterol concentration, serum triglyceride concentration, blood pressure, height, and weight were measured, and self reported information about smoking habits, physical activity, and time since last meal were recorded. During subsequent follow up 108 women died from coronary heart disease, 238 from cardiovascular diseases, and 931 from all causes. In women mortality increased steadily with increasing triglyceride concentration for all three causes of death. With the proportional hazards model and adjustment for age, systolic blood pressure, total cholesterol concentration, time since last meal, and number of cigarettes a day the relative risk between triglyceride concentration > or = 3.5 mmol/l and < 1.5 mmol/l was 4.7 (95% confidence interval 2.5 to 8.9) for deaths from coronary heart disease, 3.0 (1.9 to 4.8) for deaths from cardiovascular disease, 2.3 (1.8 to 2.9) for total deaths in all women. CONCLUSIONS--A raised non-fasting concentration of triglycerides is an independent risk factor for mortality from coronary heart disease, cardiovascular disease, and any cause mortality among middle aged Norwegian women in contrast to what is seen in men.     

Diabetes mellitus and raised serum triglyceride concentration in treated hypertension--are they of prognostic importance? Observational study.

OBJECTIVE: To analyse whether metabolic changes during long term treatment with antihypertensive drugs are associated with an increased risk of coronary heart disease. DESIGN: Observational study. SETTING: Gothenburg, Sweden. SUBJECTS: 686 middle aged hypertensive men, recruited after screening of a random population sample, and followed for 15 years during treatment with predominantly beta adrenoceptor blockers or thiazide diuretics, or both. Coronary heart disease and diabetes mellitus were registered at yearly patient examinations. Entry characteristics, as well as within study serum concentrations of cholesterol and triglycerides and the development of diabetes mellitus, were related to the incidence of coronary heart disease in a time dependent Cox''s regression analysis. MAIN OUTCOME VARIABLE: Coronary heart disease morbidity. RESULTS: Diabetes mellitus, raised serum cholesterol and triglyceride concentrations present at the beginning of the study were all significantly predictive of coronary heart disease in univariate analysis. The relative risk of diabetes mellitus and of a 1 mmol/l increase in the cholesterol and triglyceride concentrations was 2.12 (95% confidence interval 1.11 to 4.07), 1.21 (1.05 to 1.39), and 1.21 (1.03 to 1.43) respectively. However, when the within study metabolic variables were analysed, only the serum cholesterol concentration was significantly and independently associated with coronary heart disease (relative risk 1.07 (1.02 to 1.13)). Although the triglyceride concentrations increased slightly during the follow up, the within study serum triglyceride concentrations were not associated with the incidence of coronary heart disease (1.04 (0.96 to 1.10)). New diabetes mellitus-that is, onset during follow up-was not significantly associated with an increased risk for coronary heart disease (1.48 (0.37 to 6.00)). CONCLUSIONS: Metabolic disturbances such as diabetes mellitus and hyperlipidaemia presenting before the start of antihypertensive treatment have a prognostic impact in middle aged, treated hypertensive men. Moreover, while within study cholesterol concentration was an independent predictor of coronary heart disease, drug related diabetes mellitus and raised serum triglyceride concentrations that are associated with treatment do not seem to have any major impact on the coronary heart disease prognosis in this category of patients.     

Serum semaphorin 7A is associated with the risk of acute atherothrombotic stroke

Semaphorin 7A (Sema7A), a neural guidance cue, was recently identified to regulate atherosclerosis in mice. However, the clinical relevance of Sema7A with atherosclerotic diseases remains unknown. The aim of this study was to investigate the association between serum Sema7A and the risk of acute atherothrombotic stroke (AAS). We measured serum concentrations of Sema7A in 105 newly onset AAS cases and 105 age‐ and sex‐matched controls, showing that median Sema7A level in AAS cases was over three times of that in controls (5.86 vs 1.66 ng/mL). Adjusted for hypertension, body mass index, fasting blood glucose, total cholesterol, triglyceride, high‐density lipoprotein (HDL)‐cholesterol, low‐density lipoprotein (LDL)‐cholesterol, current smoking and alcohol consumption, multivariate logistic regression showed that higher Sema7A was independently associated with the odds of AAS (OR = 6.40, 95% CI: 2.88‐14.25). Each 1‐standard deviation increase in Sema7A was associated with a threefold higher odds of AAS (OR = 3.42, 95% CI: 1.84‐6.35). Importantly, adding Sema7A to a multivariate logistic model containing conventional cardiovascular risk factors improved the area under receiver operating characteristic curves from 0.831 to 0.891 for the association with AAS. In conclusion, elevated serum Sema7A is independently associated with the risk of AAS, suggesting that it may play a potential role in AAS.     

Survival in treated hypertension: follow up study after two decades

Objective: To compare survival and cause specific mortality in hypertensive men with non-hypertensive men derived from the same random population, and to study mortality and morbidity from cardiovascular diseases in the hypertensive men in relation to effects on cardiovascular risk factors during 22-23 years of follow up. Design: Prospective, population based observational study. Subjects and methods: 686 hypertensive men aged 47-55 at screening compared with 6810 non-hypertensive men. The hypertensive men were having stepped care treatment with either β adrenergic blocking drugs, thiazide diuretics, or combination treatment. Mortality, morbidity, and adverse effects were registered at yearly examinations and from death certificates. Main outcome measures: All cause mortality and cause specific mortality. Results: Treated hypertensive men had significantly impaired probability of total survival as well as survival from coronary heart disease and stroke. All cause mortality as well as coronary heart disease and stroke mortality were very similar in hypertensive men and normotensive men during the first decade, but increased steadily thereafter despite continuous good blood pressure control. Smoking, signs of target organ damage, and high serum cholesterol levels, but not blood pressure at screening, were significantly related to the incidence of coronary heart disease during follow up. In time dependent Cox’s regression analysis, the incidence of coronary heart disease was significantly related only to serum cholesterol concentrations in the study. Cancer mortality was almost similar in treated hypertensive men (61/686, 8.9%) and non-hypertensive men (732/6810, 10.8%). Conclusion: Treated hypertensive men had impaired survival and increased mortality from cardiovascular disease compared with non-hypertensive men of similar age. These differences were observed during the second decade of follow up. During an observation period of 22-23 years—about 15 000 patient years—hypertensive men receiving diuretics and β blockers had no increased risk of cancer or non-cardiovascular disease.

Key messages

• Hypertension is a prevalent (10-20%) and important risk factor for cardiovascular disease.
• In controlled trials over 3-5 years drug treatment for hypertension prevents these complications, but little is known about long term prognosis
• During 20-22 years treated hypertensive men had a significantly increased mortality, especially from coronary heart disease, compared with non-hypertensive men from the same population
• The high incidence of myocardial infarction was related to organ damage, smoking, and cholesterol at the time of entry to the study, and to achieved serum cholesterol concentrations during follow up
• The poor prognosis for mortality from coronary heart disease is dependent upon strict monitoring of serum cholesterol concentrations

     

Hypocholesterolaemia and non-cardiovascular disease: metabolic studies on subjects with low plasma cholesterol concentrations.

Some epidemiological studies have suggested an inverse relation between serum cholesterol concentration and mortality from cancer. Two hypotheses that might explain such a relation were investigated. To assay potentially deleterious effects of hypocholesterolaemia on cell membranes the lipid content and fluidity of blood mononuclear cells were measured in healthy male volunteers with a wide range of serum cholesterol concentration (3.2-10.0 mmol/l (124-387 mg/100 ml)). Fluidity, unesterified cholesterol content, and the ratio of cholesterol to phospholipid were unrelated to serum cholesterol and to low density lipoprotein cholesterol concentrations. Similar measurements were made on fibroblasts and mononuclear cells incubated with a range of concentrations of low density lipoprotein; fluidity was altered only at extremely low concentrations, suggesting that changes in cell membranes are unlikely to occur at serum cholesterol concentrations attainable by dietary or drug treatment of hyperlipidaemia. In the same population direct relations were confirmed between low density lipoprotein concentration and plasma concentrations of retinol and beta carotene. This is compatible with the suggestion that an association between low cholesterol concentration and cancer may be secondary to a relation between low retinoid concentrations and cancer.     

Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome.

OBJECTIVE--To see if the claim that lowering cholesterol values prevents coronary heart disease is true or if it is based on citation of supportive trials only. DESIGN--Comparison of frequency of citation with outcome of all controlled cholesterol lowering trials using coronary heart disease or death, or both, as end point. SUBJECTS--22 controlled cholesterol lowering trials. RESULTS--Trials considered by their directors as supportive of the contention were cited almost six times more often than others, according to Science Citation Index. Apart from trials discontinued because of alleged side effects of treatment, unsupportive trials were not cited after 1970, although their number almost equalled the number considered supportive. In three supportive reviews the outcome of the selected trials was more favourable than the outcome of the excluded and ignored trials. In the 22 controlled cholesterol lowering trials studied total and coronary heart disease mortality was not changed significantly either overall or in any subgroup. A statistically significant 0.32% reduction in non-fatal coronary heart disease seemed to be due to bias as event frequencies were unrelated to trial length and to mean net reduction in cholesterol value; individual changes in cholesterol values were unsystematically or not related to outcome; and after correction for a small but significant increase in non-medical deaths in the intervention groups total mortality remained unchanged (odds ratio 1.02). CONCLUSIONS--Lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. Claims of the opposite are based on preferential citation of supportive trials.     

Concentrations of high density lipoprotein cholesterol,triglycerides, and total cholesterol in ischaemic heart disease.

OBJECTIVE--To assess the roles of serum concentrations of total cholesterol, high density lipoprotein cholesterol, and triglycerides in predicting major ischaemic heart disease. DESIGN--Men recruited for the British regional heart study followed up for a mean of 7.5 years. SETTING--General practices in 24 British towns. PATIENTS--7735 Middle aged men. END POINT--Predictive value of serum concentrations of lipids. MEASUREMENTS AND MAIN RESULTS--At initial screening serum concentrations of total cholesterol, high density lipoprotein cholesterol, and triglycerides were determined from non-fasting blood samples. Altogether 443 major ischaemic heart disease events (fatal and non-fatal) occurred during the study. Men in the highest fifth of the distribution of total cholesterol concentration (greater than or equal to 7.2 mmol/l) had 3.5 times the risk of ischaemic heart disease than did men in the lowest fifth (less than 5.5 mmol/l) after adjustment for high density lipoprotein cholesterol concentration and other risk factors. Men in the lowest fifth of high density lipoprotein cholesterol concentration (less than 0.93 mmol/l) had 2.0 times the risk of men in the highest fifth (greater than or equal to 1.33 mmol/l) after adjustment for total cholesterol concentration and other risk factors. Men in the highest fifth of triglyceride concentration (greater than or equal to 2.8 mmol/l) had only 1.3 times the risk of those in the lowest fifth (less than 1.08 mmol/l) after adjustment for total cholesterol concentration and other risk factors; additional adjustment for high density lipoprotein cholesterol concentration made the association with ischaemic heart disease disappear. CONCLUSIONS--Serum concentration of total cholesterol is the most important single blood lipid risk factor for ischaemic heart disease in men. High density lipoprotein cholesterol concentration is less important, and triglyceride concentrations do not have predictive importance once other risk factors have been taken into account.     

Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

Mortality in two radom samples of women aged 55-64 followed up for 20 years.

Two random samples of women aged 55-64 living in the Vale of Glamorgan and the Rhondda Fach were followed up for 20 years. In each sample heights, weights, serum cholesterol concentrations, and specific causes of death were noted and the Quetelet index (weight/height2) calculated. The two samples were combined for analysis of total mortality. In the combined sample there was a strong positive association between Quetlet index and both total mortality and mortality from ischaemic heart disease. Multiple logistic regression analysis showed that both of these associations were significant, as was the strong positive association between Quetelet index and mortailty from ischaemic heart disease in the samples considered separately. There was no significant association between cholesterol concentration and mortality from ischaemic heart disease in each sample. There was a small negative association between cholesterol concentration and both total mortaility in the combined sample and ischaemic heart disease in the Rhondda Fach sample. These results suggest that the Quetelet index is important for prognosis, whereas the serum cholesterol concentration is not.