Prospective association of lipoprotein(a) concentrations and apo(a) size with coronary heart disease among men in the Multiple Risk Factor Intervention Trial.

In this nested case-control study, lipoprotein (a) [Lp(a)] concentrations and apo(a) isoform size were measured in serum samples obtained from men participating in the prospective Multiple Risk Factor Intervention Trial (MRFIT). Serum from men aged 35 to 57 years and stored for up to 20 years were analyzed for Lp(a) levels (n=736) and isoform size (n=487), respectively. Cases involved nonfatal myocardial infarctions (MI; n=98), documented during the active phase of the study that ended on February 28, 1982 and coronary heart disease (CHD) deaths (n=148) monitored through 1990. Median Lp(a) levels did not differ between cases and controls and mean apo(a) size did not vary between cases and controls in the entire study population. When adjusted for age and Lp(a) concentration, logistic regression analysis indicated that small apo(a) isoforms were associated with CHD deaths among smokers (OR 3.31; 95% CI 1.07-10.28).

Homocyst(e)ine and risk of cardiovascular disease in the multiple risk factor intervention trial.

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for upto 20 years, were analysed for homocyst(e)ine. Cases involved non-fatal myocardial infractions, identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease, monitored through 1990. The non-fatal myocardial infarction occurred within 7 years of sample collection, whereas the majority of coronary heart disease deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: myocardial infarction cases, 12.6 micromol/L; myocardial infarction controls, 13.1 micromol/L; coronary heart disease death cases, 12.8 micromol/L; and coronary heart disease controls, 12.7 micromol/L. Odds ratios versus quartile 1 for coronary heart disease deaths and myocardial infarctions combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase (C-reactive) protein. These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.

Prospective association between lipid soluble antioxidants and coronary heart disease in men. The Multiple Risk Factor Intervention Trial.

A nested case-control study was performed using participants enrolled in the Multiple Risk Factor Intervention Trial (MRFIT). The cases involved nonfatal myocardial infarction or death from coronary heart disease. Serum samples (n = 734) obtained at baseline and frozen for approximately 20 years were analyzed for the antioxidants, carotenoids, retinol, and alpha-, gamma-, and total tocopherol. The concentrations of antioxidants were in the expected range and their association with low density lipoprotein (LDL) cholesterol reflected their absorption and transport mechanisms. Among nonsmokers, the odds ratios (95% confidence intervals (CI)) for quartile IV versus quartile I were 1.40 (0.40-4.89), 0.77 (0.20-2.96), 1.45 (0.38-5.56), 2.34 (0.56-9.81), and 2.40 (0.52-11.07) for retinol, total carotenoids, and alpha-, gamma-, and total tocopherol, respectively. The equivalent odds ratios (95% CI) for smokers were 0.90 (0.34-2.41), 0.66 (0.23-1.84), 0.67 (0.21-2.13), 2.04 (0.88-4.73), and 0.52 (0.16-1.67), respectively. This analysis of antioxidant concentrations by quartiles indicated no significant association of antioxidant levels with the risk of coronary disease death or nonfatal myocardial infarction.

Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial.

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for up to 20 years, were analyzed for homocyst(e)ine. Cases involved nonfatal myocardial infarctions (MIs), identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease (CHD), monitored through 1990. The nonfatal MIs occurred within 7 years of sample collection, whereas the majority of CHD deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: MI cases, 12.6 mumol/L; MI controls, 13.1 mumol/L; CHD death cases, 12.8 mumol/L; and CHD controls, 12.7 mumol/L. Odds ratios versus quartile 1 for CHD deaths and MIs combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase protein (C-reactive protein). These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.

Lung cancer mortality after 16 years in MRFIT participants in intervention and usual-care groups. Multiple Risk Factor Intervention Trial.

PURPOSE: The Multiple Risk Factor Intervention Trial (MRFIT), a randomized clinical trial for the primary prevention of coronary heart disease, enrolled 12,866 men (including 8194 cigarette smokers) aged 35-57 years at 22 clinical centers across the United States. Participants were randomized either to special intervention (SI), which included an intensive smoking cessation program, or to usual care (UC). After 16 years of follow-up, lung cancer mortality rates were higher in the SI than in the UC group. Since rates of smoking cessation in SI were higher than those for UC for the 6 years of the trial, and since risk of lung cancer mortality is known to decline with smoking cessation, these results were unexpected. The purpose of the present study was to investigate hypotheses that could explain the higher observed lung cancer mortality rates in the SI as compared with the UC group. METHODS: Analytic methods were employed to determine whether SI and UC participants differed either in baseline characteristics or in characteristics that changed during the trial and to determine whether these differences could explain the higher rates of lung cancer mortality among SI as compared to UC participants. Rates of mortality from coronary heart (CHD) were examined to explore the possibility that prevention of CHD death may have contributed to greater mortality due to lung cancer in the SI group. RESULTS: From randomization through December 1990, 135 SI and 117 UC participants died from lung cancer. The relative difference between the SI and U groups adjusted for age and number of cigarettes smoked per day, was 1.17 (95% CI:0.92-1.51). The greatest difference between the SI and UC groups in lung cancer mortality rates occurred among the heaviest smokers at baseline who did not achieve sustained smoking cessation by year 2. In this group the rates of death from CHD were approximately the same among the SI and UC subjects. No differences in baseline characteristics were found between SI and UC smokers who did not achieve sustained cessation by year 2, and there were no differences in follow-up characteristics between the two study groups that could explain the difference in lung cancer mortality. CONCLUSIONS: None of the hypotheses proposed to explain the unexpected higher rates of lung cancer mortality among SI as compared with UC subjects were sustained by the data. Thus we conclude that the difference observed is due to chance, and that a longer period of sustained smoking cessation plus follow-up is necessary to detect a reduction in lung cancer mortality as a result of smoking cessation intervention in a randomized clinical trial.

Antibodies to glutamic acid decarboxylase and diabetes mellitus in the Multiple Risk Factor Intervention Trial.

Diabetes mellitus is a heterogeneous disease. The better classification of types of diabetes mellitus among adults will improve epidemiologic studies of determinants of risk factors and genetic host susceptibility. Recently, an antibody to a specific enzyme, glutamic acid decarboxylase, has been closely linked to insulin-dependent diabetes mellitus. Sera were collected at baseline between 1972 and 1974 from initially nondiabetic participants in the Multiple Risk Factor Intervention Trial. After approximately 18 years of frozen storage, the serum samples were tested for antibodies to glutamic acid decarboxylase (anti-GAD) in 175 men who developed diabetes and 352 matched controls who did not develop diabetes during the 6-year follow-up. Nine of the 527 samples tested had elevated (19 or more units) titers of anti-GAD. Six of the nine men with elevated anti-GAD subsequently developed diabetes, and three of these six were ultimately placed on insulin therapy. These data suggest that elevated levels of anti-GAD may be a prospective marker for the subsequent development of insulin-dependent diabetes mellitus. The measurement of anti-GAD is relatively easy, can be performed in stored serum specimens, and may be used in epidemiologic studies to enhance the understanding of the determinants of diabetes mellitus.

Risk factors for the development of type II diabetes among men enrolled in the usual care group of the Multiple Risk Factor Intervention Trial.

OBJECTIVE: To study the association between selected risk factors and the subsequent incidence of type II diabetes over a 5-yr period. RESEARCH DESIGN AND METHODS: Between 1973 and 1976, a cohort of men from 22 clinical centers throughout the U.S. enrolled in the Usual Care group of the Multiple Risk Factor Intervention Trial. The men (5420 white, 428 black, 56 Asian, 70 Hispanic, and 26 other) were nondiabetic at baseline, were in the upper 15% of risk for coronary heart disease, and had at least two annual follow-up visits for fasting glucose measurements. The average age was 46 yr and average body mass index was 27.6 kg/m2. Incidence of diabetes was defined as use of insulin or hypoglycemic agents, fasting glucose > or = 140 mg/dl on two consecutive annual visits, or fasting glucose > or = 140 mg/dl followed the next year by insulin or hypoglycemic use. Observations were taken annually over a 5-yr period. RESULTS: Cumulative incidence of diabetes over 5 yr was 4.1%, with 247 incident cases. Development of diabetes was directly associated with race (blacks higher than non-blacks), reported parental history of diabetes, and with baseline levels of body mass index, fasting glucose, and glucose 1 h after a 75-g oral glucose load. These associations were statistically significant in both univariate and multivariate models. A significant interaction was observed between race and reported parental history of diabetes in development of diabetes, particularly within black men who reported a parental history. These individuals had higher than expected rates of diabetes development. CONCLUSIONS: The data from men in the Usual Care group enrolled in the Multiple Risk Factor Intervention Trial confirm previous findings regarding the associations between the development of diabetes and baseline glucose levels, obesity, race, and parental history of diabetes. The identification of these risk factors provides very powerful tools to identify individuals at high risk of diabetes mellitus who may be amenable to intervention, thereby reducing their risk of developing the disease and its complications.

Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. The Multiple Risk Factor Intervention Trial Research Group.

OBJECTIVE: To study the association between alcohol consumption and death from coronary heart disease and to determine the extent to which the association can be explained by the high-density lipoprotein (HDL) cholesterol level. DESIGN: A cohort study involving men enrolled in the Multiple Risk Factor Intervention Trial (MRFIT). SETTING: Community-based study. PARTICIPANTS: Men (n = 11,688) at high risk for developing coronary heart disease but without clinical evidence of it. More than 90% of the men were white, and the average age was 46 years. Five percent of the men abstained from alcohol during the trial, 81% consumed fewer than 21 alcoholic drinks per week, and 14% consumed more than 21 alcoholic drinks per week. MEASUREMENTS: Average alcohol intake over 7 years was calculated for MRFIT participants who were alive at the end of the trial and who had at least three follow-up records of alcohol consumption. Post-trial mortality during a 3.8-year period was assessed. RESULTS: The adjusted relative risk for death from coronary heart disease for each increase of 7 drinks per week was 0.89 (95% CI, 0.80 to 1.00), with an apparent dose-response relationship. The average HDL level was associated with the average alcohol intake in a least-squares regression model (beta = -0.0074; P less than 0.01). When the average HDL level was included in the proportional hazards model for mortality from coronary heart disease, the absolute value of the coefficient for average drinks per week declined 45%, yielding an adjusted relative risk for each additional 7 drinks per week of 0.94 (CI, 0.84 to 1.05). CONCLUSION: In middle-aged men who are light to moderate drinkers, the inverse association between alcohol consumption and death from coronary heart disease can be explained, in large part, by the HDL cholesterol level, which increases with alcohol consumption. However, alcohol consumption cannot be recommended because of the known adverse effects of excess alcohol use.

Comparison of smoking behavior change for SI and UC study groups. MRFIT Research Group.

BACKGROUND: The results of MRFIT smoking intervention program are presented for the 4,103 special intervention and 4,091 usual care men who reported smoking cigarettes at the first screening visit. RESULTS: Among the special intervention men, the reported cessation rate increased from 43.1% at 12 months to 48.9% at 72 months. The reported cessation rate among the usual care men increased from 13.5% at 12 months to 28.8% at 72 months. Among smokers who reported cessation at 72 months, 51.3% of special intervention men and 22.7% of usual care men had quit smoking within the first year and remained abstinent thereafter. Average thiocyanate and expired-air carbon monoxide served as objective measures of smoking and were significantly lower among the special intervention men than among the usual care men over the entire follow-up period. The reported cessation rates at 72 months varied according to initial levels of smoking. Smokers reporting 1-19 cigarettes per day at entry were more likely to quit than heavier smokers. For each category of smoking at entry (1-19, 20-39, and 40 or more cigarettes per day) significantly more special intervention than usual care smokers reported cessation. CONCLUSION: These results indicate that the MRFIT smoking intervention program was successful in promoting early cigarette smoking cessation and maintaining cessation over the entire trial for a large percentage of cigarette smokers.

Association between baseline risk factors, cigarette smoking, and CHD mortality after 10.5 years. MRFIT Research Group.

METHODS: The association between baseline risk factors and death from coronary heart disease (CHD) after 10.5 years was investigated for cigarette smokers and nonsmokers who entered the Multiple Risk Factor Intervention Trial (MRFIT). RESULTS: Rates per thousand person-years of CHD mortality were higher for smokers than for nonsmokers at every level of baseline risk factors examined. There were significant associations between CHD mortality and plasma low-density lipoprotein and high-density lipoprotein cholesterol for smokers and nonsmokers. The inverse association between CHD mortality and high-density lipoprotein cholesterol was significantly stronger among nonsmokers compared with that among smokers and was attributable to a very strong association for former smokers. An inverse relationship between CHD and body mass index was evident for smokers and nonsmokers. Rates of CHD death rose sharply when levels of fasting glucose exceeded 140 mg/dl, and there was a significant association between CHD mortality and blood sugar levels for nonsmokers but not for smokers. For both smokers and nonsmokers, an inverse univariate association between alcohol consumption and CHD mortality was evident. This association, however, did not persist after adjustment for plasma high-density lipoprotein cholesterol. CONCLUSION: Intervention on blood pressure and blood lipids is particularly important among cigarette smokers because of their increased risk of CHD death. The different associations between high-density lipoprotein cholesterol, fasting serum glucose, and CHD mortality for smokers and nonsmokers requires further investigation.