Jussi K. Huttunen

Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.

In a randomized, double-blind five-year trial, we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein (HDL) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg per deciliter [5.2 mmol per liter] in two consecutive pretreatment measurements). One group (2051 men) received 600 mg of gemfibrozil twice daily, and the other (2030 men) received placebo. Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total, low-density lipoprotein (LDL), and non-HDL cholesterol and triglycerides. There were minimal changes in serum lipid levels in the placebo group. The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group--a reduction of 34.0 percent in the incidence of coronary heart disease (95 percent confidence interval, 8.2 to 52.6; P less than 0.02; two-tailed test). The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study. There was no difference between the groups in the total death rate, nor did the treatment influence the cancer rates. The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia.

Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment.

BackgroundWe studied the joint effect of baseline triglyceride and lipoprotein cholesterol levels on the incidence of cardiac end points in the trial group (n = 4,081) of the Helsinki Heart Study, a 5-year randomized coronary primary prevention trial among dyslipidemic middle-aged men. The relative risks (RR) were calculated using Cox proportional hazards models with a dummy variable technique that allows simultaneous study of subgroup combinations from the placebo and treatment groups. Methods and ResultsIn the placebo group (n = 2,045), the low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio was the best single predictor of cardiac events. This ratio in combination with the serum triglyceride level revealed a high-risk subgroup: subjects with LDL-C/HDL-C ratio >5 and triglycerides >2.3 mmol/1 had a RR of 3.8 (95% CI, 2.2-6.6) compared with those with LDL-C/HI)L-C ratio ≤5 and triglyceride concentration ≤2.3 mmol/1. In subjects with triglyceride concentration >2.3 mmol/l and LDL-C/H1)L-C ratio ≤5, RR was close to unity (1.1), whereas in those with triglyceride level ≤2.3 mmoVIl and LDL-C/HDL-C ratio >5, RR was 1.2. The high-risk group with LDL-C/HDL-C ratio >5 and triglyceride level >2.3 mmol/1 profited most from treatment with gemfibrozil, with a 71% lower incidence of coronary heart disease events than the corresponding placebo subgroup. In all other subgroups, the reduction in CHD incidence was substantially smaller ConclusionsSerum triglyceride concentration has prognostic value, both for assessing coronary heart disease risk and in predicting the effect of gemfibrozil treatment, especially when used in combination with HDL-C and LDL-C.

Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants

To prospectively assess the role of lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease, the serum Lp(a) concentration was determined in 130 subjects without coronary events and in 138 patients in whom coronary events (i.e. fatal and non-fatal myocardial infarction and cardiac death) occurred during the 5-year Helsinki Heart Study. The participants of this study (n = 4081) were 40-55-year-old men who were devoid of coronary heart disease at the beginning of the trial; half were randomized to gemfibrozil and the other half to placebo treatment. In patients with coronary events blood pressure and total cholesterol were not significant predictors of the events but their LDL cholesterol was higher than compared to the control group in this cohort (P less than 0.05). The serum Lp(a) concentration was determined by immunoassay from samples obtained 3 months after the beginning of the trial and then stored at -20 degrees C until analysed. Studies on the effect of long term storage at -20 degrees C on serum Lp(a) levels did not reveal significant changes in Lp(a) concentration in sera stored for up to 8.5 years. The distribution of Lp(a) concentrations were similar in the men with coronary events and the controls. Nor did the mean or median levels of Lp(a) differ significantly between the two groups. Measurements of Lp(a) levels in fresh samples using 2 different immunoassays did not reveal any significant difference between the participants who had survived a myocardial infarction or participants without cardiac events. Thus, we conclude that in the Helsinki Heart Study cohort the serum Lp(a) level was not a predictor of future coronary events.

Antioxidants in adipose tissue and risk of myocardial infarction: the EURAMIC study

Laboratory and epidemiological studies suggest that the antioxidants, vitamin E and beta-carotene, protect against coronary heart disease. In a European multicentre case-control study alpha-tocopherol and beta-carotene concentrations were measured in adipose-tissue samples collected in 1991-92 from 683 people with acute myocardial infarction and 727 controls. Mean adipose-tissue beta-carotene concentration was 0.35 microgram/g in cases and 0.42 in controls, with age-adjusted and centre-adjusted mean difference 0.07 microgram/g (95% confidence interval [CI] 0.04-0.10). Mean alpha-tocopherol concentrations were 193 micrograms/g and 192 micrograms/g for cases and controls, respectively. The age-adjusted and centre-adjusted odds ratio for risk of myocardial infarction in the lowest quintile of beta-carotene as compared with the highest was 2.62 (95% CI 1.79-3.83). Additional control for body-mass index and smoking reduced the odds ratio to 1.78 (95% CI 1.17-2.71); other established risk factors did not substantially alter this ratio. The increased risk was mainly confined to current smokers: the multivariate odds ratio in the lowest beta-carotene quintile in smokers was 2.39 (95% CI 1.35-4.25), whereas it was 1.07 for people who had never smoked. A low alpha-tocopherol concentration was not associated with risk of myocardial infarction. Our results support the hypothesis that high beta-carotene concentrations within the normal range reduce the risk of a first myocardial infarction. The findings for alpha-tocopherol are compatible with previous observations of reduced risk among vitamin E supplement users only. The consumption of beta-carotene-rich foods such as carrots and green-leaf vegetables may reduce the risk of myocardial infarction.

Fatty-acid composition of serum lipids predicts myocardial infarction.

During a follow-up of five to seven years 33 out of 1222 middle-aged men initially free of coronary heart disease sustained fatal or non-fatal myocardial infarction or died suddenly. The fatty-acid composition of serum triglycerides, phospholipids, and cholesterol esters had been measured at the start of the surveillance in these men and in a control group of 64 men matched for age, serum cholesterol and triglyceride concentrations, blood pressure, obesity, smoking, and one-hour glucose tolerance. Palmitic and stearic acids of phospholipids were significantly higher and linoleic and most polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, of phospholipids were lower in the subjects who sustained coronary events compared with the controls. Linoleic acid tended to correlate negatively with blood pressure while other polyunsaturated fatty acids, especially eicosapentaenoic acid, exhibited a negative correlation with blood pressure and relative body weight in the controls but not in the subjects who sustained coronary events. These findings suggest that the fatty-acid pattern of serum phospholipids is an independent risk factor for coronary heart disease.

Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients

The role of preceding infection as a risk factor for ischaemic stroke was investigated in a case-control study of 54 consecutive patients under 50 years of age with brain infarction and 54 randomly selected controls from the community matched for sex and age. Information about previous illnesses, smoking, consumption of alcohol, and use of drugs was taken. A blood sample was analysed for standard biochemical variables and serum cholesterol, high density lipoprotein cholesterol, triglyceride, and fasting blood glucose concentrations determined. Titres of antimicrobial antibodies against various bacteria, including Staphylococcus, Streptococcus, Yersinia, and Salmonella and several viruses were determined. Febrile infection was found in patients during the month before the brain infarction significantly more often than in controls one month before their examination (19 patients v three controls; estimated relative risk 9·0 (95% confidence interval 2·2 to 80·0)). The most common preceding febrile infection was respiratory infection (80%). Infections preceding brain infarction were mostly of bacterial origin based on cultural, serological, and clinical data. In conditional logistic regression analysis for matched pairs the effect of preceding febrile infection remained significant (estimated relative risk 14·5 (95% confidence interval 1·9 to 112·3)) when tested with triglyceride concentration, hypertension, smoking, and preceding intoxication with alcohol. Although causality cannot be inferred from these data and plausible underlying mechanisms remain undetermined, preceding febrile infection may play an important part in the development of brain infarction in young and middle aged patients.

Adipose tissue isomeric trans fatty acids and risk of myocardial infarction in nine countries : the EURAMIC study

Dietary isomeric trans fatty acids-mainly produced by hydrogenation of oils-are suspected of increasing the risk of coronary heart disease. Dietary trans fatty acid intake is reflected in the fatty acid composition of adipose tissue. In an international multicentre study in eight European countries and Israel (EURAMIC), adipose tissue aspiration samples were obtained from 671 men with acute myocardial infarction (AMI), aged 70 years or less, and 717 men without a history of AMI (controls). The proportion of fatty acids, including isomeric trans monoenoic fatty acids with 18 carbon atoms (C18:1), was determined by gas chromatography. Although there were considerable differences between countries in mean (SD) proportion of adipose tissue C18:1 trans fatty acids, there was no overall difference between cases (1.61 [0.92]%) and the controls (1.57 [0.86]%). The risk of AMI did not differ significantly from 1.0 over quartiles of adipose C18:1 trans fatty acids: the multivariate odds ratio was 0.97 (95% CI 0.56-1.67) for the highest versus lowest quartile. After exclusion of subjects from Spanish centres because they had far lower proportions of adipose trans fatty acids than subjects from other countries, there was a tendency to increased risk of AMI in the upper quartiles of C18:1 trans; however, the trend was not statistically significant. Our results reflect considerable differences between countries in dietary intake of trans fatty acids but do not suggest a major overall effect of C18:1 trans fatty acids on risk of AMI. We cannot exclude the possibility that trans fatty acids have a significant impact on risk of AMI in populations with high intake.

Omega-3 Fatty Acids in Adipose Tissue and Risk of Myocardial Infarction The EURAMIC Study

Omega-3 fatty acids have potential antiatherogenic, antithrombotic, and antiarrhythmic properties, but their role in coronary heart disease remains controversial. To evaluate the association of omega-3 fatty acids in adipose tissue with the risk of myocardial infarction in men, a case-control study was conducted in eight European countries and Israel. Cases (n=639) included patients with a first myocardial infarction admitted to coronary care units within 24 hours from the onset of symptoms. Controls (n=700) were selected to represent the populations originating the cases. Adipose tissue levels of fatty acids were determined by capillary gas chromatography. The mean (+/-SD) proportion of alpha-linolenic acid was 0.77% (+/-0.19) of fatty acids in cases and 0.80% (+/-0.19) of fatty acids in controls (P=0.01). The relative risk for the highest quintile of alpha-linolenic acid compared with the lowest was 0.42 (95% confidence interval [CI] 0.22 to 0.81, P-trend=0.02). After adjusting for classical risk factors, the relative risk for the highest quintile was 0.68 (95% CI 0.31 to 1.49, P-trend=0.38). The mean proportion of docosahexaenoic acid was 0.24% (+/-0.13) of fatty acids in cases and 0.25% (+/-0.13) of fatty acids in controls (P=0. 14), with no evidence of association with risk of myocardial infarction. In this large case-control study we could not detect a protective effect of docosahexaenoic acid on the risk of myocardial infarction. The protective effect of alpha-linolenic acid was attenuated after adjusting for classical risk factors (mainly smoking), but it deserves further research.

DDT (dicophane) and postmenopausal breast cancer in Europe: case-control study.

Abstract Objective: To examine any possible links between exposure to DDE (1,1-dichloro-2,2-bis (p -chlorophenyl)ethylene), the persistent metabolite of the pesticide dicophane (DDT), and breast cancer. Design: Multicentre study of exposure to DDE by measurement of adipose tissue aspirated from the buttocks. Laboratory measurements were conducted in a single laboratory. Additional data on risk factors for breast cancer were obtained by standard questionnaires. Setting: Centres in Germany, the Netherlands, Northern Ireland, Switzerland, and Spain. Subjects: 265 postmenopausal women with breast cancer and 341 controls matched for age and centre. Main outcome measure: Adipose DDE concentrations. Results: Women with breast cancer had adipose DDE concentrations 9.2% lower than control women. No increased risk of breast cancer was found at higher concentrations. The odds ratio of breast cancer, adjusted for age and centre, for the highest versus the lowest fourth of DDE distribution was 0.73 (95% confidence interval 0.44 to 1.21) and decreased to 0.48 (0.25 to 0.95; P for trend=0.02) after adjustment for body mass index, age at first birth, and current alcohol drinking. Adjustment for other risk factors did not materially affect these estimates. Conclusions: The lower DDE concentrations observed among the women with breast cancer may be secondary to disease inception. This study does not support the hypothesis that DDE increases risk of breast cancer in postmenopausal women in Europe. Key messages Organochlorines such as polychlorinated biphenyls and DDT may increase the risk of breast cancer in women DDE concentrations among the women with cancer were lower than among the controls, and there was an inverse risk gradient with higher DDE concentrations which remained significant after adjustment for risk factors for breast cancer These results are clearly incompatible with an increased risk of breast cancer at increased concentrations of DDE, although associations with other organochlorines cannot be excluded

Effect of Diet on Serum Lipoproteins in a Population with a High Risk of Coronary Heart Disease

The population of North Karelia, a county in Finland, has a high rate of coronary heart disease. It also has a high prevalence of hypercholesterolemia, but whether this reflects a diet rich in animal fats or is a result of genetic factors is unclear. We studied the effect on serum lipoproteins of a low-fat diet with a high ratio of polyunsaturated to saturated fatty acids in 54 middle-aged volunteers in North Karelia. Total serum cholesterol decreased, from 263 +/- 8 mg per deciliter (mean +/- S.E.) to 201 +/- 5 mg in men (P less than 0.0001) and from 239 +/- 8 to 188 +/- 8 mg in women (P less than 0.0001), along with low-density-lipoprotein cholesterol and apoprotein B. High-density lipoprotein decreased from 54 +/- 2 mg per deciliter to 44 +/- 2 in men (P less than 0.0001) and from 56 +/- 3 to 47 +/- 2 mg in women (P less than 0.0001). A small but significant reduction occurred in serum apoprotein A-I, whereas apoprotein A-II increased slightly. The individual changes in low-density-lipoprotein cholesterol correlated with those in high-density-lipoprotein cholesterol. The changes in serum lipids and apoproteins were reversed when the participants returned to their original diets. Our results suggest that the hypercholesterolemia characteristic of this population is due at least in part to dietary factors.