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Background-Homozygosity for a relatively common Cys282Tyr mutation of the human hemochromatosis-associated (HFE) gene was recently found to account for most cases of hereditary hemochromatosis. Because excess iron has been postulated to enhance risk of vascular disease, we studied whether occurrence of this mutation was associated with increased risk of first acute myocardial infarction in healthy middle-aged men in a prospective cohort study. Methods and Results-Study subjects were the 1150 participants in the population-based Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), aged 42, 48, 54, or 60 years at baseline, who had no coronary heart disease at baseline and for whom a DNA sample was available. Information about myocardial infarctions was collected prospectively by use of FINMONICA (FINnish MONItoring of trends and determinants in CArdiovascular disease study) and hospital data. Events were classified by MONICA (MONItoring of trends and determinants in CArdiovascular disease study) diagnostic criteria. The HFE Cys282Tyr mutation was assayed by a solid-phase minisequencing technique. One subject was homozygous and 76 individuals were heterozygous for the HFE Cys282Tyr mutation (6.7%). During a mean follow-up of 9 years, 8 (10.4%) of 77 carriers and 60 (5.6%) of 1073 noncarriers experienced an acute myocardial infarction. In a Cox proportional hazards model allowing for the other strongest risk factors, the carriers had a 2.3-fold (95% CI 1. 1 to 4.8; P=0.03) risk of acute myocardial infarction compared with noncarriers. Conclusions-Male carriers of the common hemochromatosis gene mutation are at 2-fold risk for first acute myocardial infarction compared with noncarriers.

Background: Epidemiological evidence concerning the role of iron, a lipid peroxidation catalyst, in coronary heart disease (CHD) is inconsistent. We investigated the association of the concentration ratio of serum transferrin receptor to serum ferritin (TfR/ferritin), a state-of-the-art measurement of body iron stores, with the risk of acute myocardial infarction (AMI) in a prospective nested case-control study in men from eastern Finland., Methods and Results: Transferrin receptor assays were carried out for 99 men who had an AMI during an average 6.4 years of follow-up and 98 control men. Both the cases and the controls were nested from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) cohort of 1931 men who had no clinical CHD at the baseline study. The controls were matched for age, examination year, and residence. AMIs were registered prospectively. Soluble transferrin receptors were measured by immunoenzymometric assay and ferritin concentration by radioimmunoassay from frozen baseline serum samples. The mean TfR/ferritin ratio was 15.1 (SE, 2.0) among cases and 21.3 (SE, 2.2) among controls (P=.035 for difference). In logistic regression models adjusting for other strongest risk factors for AMI and indicators of inflammation and alcohol intake, men in the lowest and second lowest thirds of the TfR/ferritin ratio had a 2.9-fold (95% CI, 1.3 to 6.6, P=.011) and 2.0-fold (0.9 to 4.2, P=.081) risk of AMI compared with men in the highest third (P=.010 for trend)., Conclusions: These data show an association between increased body iron stores and excess risk of AMI, confirming previous epidemiological findings.

Background: Exaggerated cardiovascular reactivity to mental stress is hypothesized to increase atherosclerotic risk. We examined this hypothesis using cross-sectional data from the Kuopio Ischemic Heart Disease study, a population-based epidemiological sample., Methods and Results: 901 Eastern Finnish men from four age cohorts (age, 42 to 60 years) were administered a standardized testing battery to assess cardiovascular reactivity to mental stress. Ultrasound measures of intima-medial thickness (IMT) and plaque height from the common carotid arteries were used as noninvasive markers of atherosclerosis. Diastolic blood pressure (DBP) responses to mental stress were significantly associated with mean IMT (b=.021, P=.006), maximum IMT (b=.026, P=.013), and mean plaque height (b=.017, P=.041). Significant associations were also shown between stress-related systolic blood pressure (SBP) reactivity and mean IMT (b=.0151, P=.042). When examined separately by age, associations with IMT were significant only in the youngest half of the sample (age, 46 and 52 years, n=433; for mean IMT, DBP b=.033, P=.0002, SBP b=.0266, P=.003; for maximum IMT, DBP b=.039, P=.002, SBP b=.032, P=.011). Results remained significant in the younger subjects after adjustment for smoking, lipid profiles, fasting glucose, and resting blood pressure (b=.024, P=.011); results also remained significant in a subgroup of unmedicated younger subjects without symptomatic cardiovascular disease (n=135; for SBP reactivity, b=.031, P=.036; for DBP, b=.037, P=.007)., Conclusions: The tendency to show exaggerated pressor responses to mental stress is a significant independent correlate of atherosclerosis in this population sample of Finnish men. The effect does not appear to be accounted for by the confounding influence of other risk factors or preexisting clinical disease.

Background: Characteristics of the work environment have been associated with cardiovascular morbidity and mortality, but it is unclear whether these factors are associated with preclinical manifestations of disease., Methods and Results: We investigated the association between job demands, economic reward, and the 4-year progression of carotid atherosclerosis in a population-based sample of 940 Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to estimate changes in plaque height, maximum and mean intima-media thicknesses across combinations of job demands, and income. Associations were examined in relation to atherosclerotic risk factors and were stratified by baseline levels of atherosclerosis and prevalent ischemic heart disease. Men who had jobs with high demands and low economic rewards had significantly greater 4-year progression of plaque height (0.33 mm, P = .008) and maximum intima-media thickness (0.32, P = .03) than men with low-demand, high-income jobs. The magnitude of these differences was not greatly attenuated by risk factor adjustment and did not differ when examined by the level of workplace resources, social support, or employment status. Larger differences were observed in a subsample of men who had more advanced atherosclerosis at baseline., Conclusions: These results show that men with demanding work that produces little economic reward have significantly greater progression of carotid atherosclerosis than more advantaged men. The relationship between job demands and health should be understood in a broad framework of interacting economic conditions, social circumstances, and behaviors that cascade over the life course and may ultimately contribute to socioeconomic inequalities in morbidity and mortality.

Background: Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland., Methods and Results: Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from > 400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7 beta-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution-mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid-reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7 beta-hydroxycholesterol (beta = 47, P = .0005), cigarette smoking (beta = .35, P = .0167), and LDL TBARS (beta = .23, P = .0862) and an increased oxidation susceptibility of VLDL + LDL (beta = .22 P = .1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% (P = .013) per unit (microgram/L) of 7 beta-hydroxycholesterol., Conclusions: The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.

Background: It has been documented that the HMG coenzyme A reductase inhibitors, or statins, can decrease cardiovascular events and mortality in patients with clinical coronary disease and moderately to severely elevated lipid levels. Additional data are required to demonstrate a reduction of vascular events in coronary patients with less than severely elevated lipid levels and in subgroups of this population., Methods and Results: Clinical data from four atherosclerosis regression trials that evaluated pravastatin were pooled for a predetermined analysis of the effect of that agent on the risk of coronary events. All trials were double-masked, placebo-controlled designs that used pravastatin as monotherapy for 2 to 3 years. The 1981 participants in the trials had evidence of atherosclerosis and mildly to moderately elevated lipid levels. For fatal or nonfatal myocardial infarction, there was a 62% reduction in events attributable to pravastatin (P = .001). This effect was evident in younger and older patients, men and women, and patients with and without histories of hypertension and prior infarction. There was a 46% reduction in all-cause mortality (P = .17), which, although not statistically significant, is consistent with the results of other statin trials. There also was a 62% reduction in the risk of fatal or nonfatal stroke (P = .054)., Conclusions: These pooled results provide strong evidence that pravastatin reduces the risk of cardiovascular events in patients with atherosclerotic disease and mildly to moderately elevated lipid levels. The benefit for reducing myocardial infarction is evident in older and younger patients, men and women, and patients with and without histories of hypertension and prior infarction.

Background: The atherosclerotic progression-reducing effect of LDL cholesterol (LDL-C) lowering has been established in subjects with severe atherosclerotic disease but not in persons with elevated LDL cholesterols without severe atherosclerosis. KAPS (Kuopio Atherosclerosis Prevention Study) is the first population-based trial in the primary prevention of carotid and femoral atherosclerosis., Methods and Results: The eligibility requirements were serum LDL-C > or = 4.0 mmol/L and total cholesterol < 7.5 mmol/L. Out of a geographically defined population, 447 men aged 44 to 65 years (mean, 57) were randomized to pravastatin (40 mg/d) or placebo for 3 years. Less than 10% of the subjects had prior myocardial infarction. Thirty-nine men discontinued study medication; however, efficacy data were available for 424 men. The primary outcome was the rate of carotid atherosclerotic progression, measured as the linear slope over annual ultrasound examinations in the average of the maximum carotid intima-media thickness (IMT) of the far wall of up to four arterial segments (the right and left distal common carotid artery and the right and left carotid bulb). For the carotid arteries, at the overall mean baseline IMT of 1.66 mm, the rate of progression of carotid atherosclerosis was 45% (95% CI, 16 to 69%) less in the pravastatin (0.017 mm/y) than the placebo (0.031 mm/y) group (P = .005). In the common carotid artery there was a treatment effect of 66% (95% CI, 30 to 95%; pravastatin 0.010 mm/y; placebo 0.029 mm/y; P < .002) at the overall mean baseline IMT of 1.35 mm. A treatment effect of 30% (95% CI, -1% to 54%) was found for the carotid bulb (pravastatin, 0.028; placebo, 0.040; P = .056) at the overall mean baseline IMT of 2.0 mm. The treatment effect was larger in subjects with higher baseline IMT values, in smokers and in those with low plasma vitamin E levels. There was no significant treatment effect on atherosclerotic progression in the femoral arteries., Conclusions: These data establish the antiatherogenic effect of LDL-C lowering by pravastatin in hypercholesterolemic men in a primary prevention setting and suggest a greater effect in smokers than in nonsmokers.

Background: There is a consistent body of evidence that socioeconomic status (SES) is importantly associated with cardiovascular morbidity and mortality. However, little information currently exists on the relationship between SES and early manifestations of atherosclerotic vascular disease., Methods and Results: We investigated the association between education, income, and occupation and intima-media thickness (IMT) in a population-based sample of eastern Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to estimate mean IMT across levels of SES in 1140 men. The association between SES and IMT was examined in relation to atherosclerotic risk factors and was also stratified by degree of atherosclerotic progression and was also stratified by degree of atherosclerotic progression and prevalent cardiovascular disease. There were significant, inverse, graded differences between levels of SES and IMT. For education, the age-adjusted mean IMTs for those with primary schooling or less, some high school, and completed high school or more were 0.96, 0.94, and 0.82 mm, respectively. The difference in mean IMT between the most extreme categories of education corresponds to a 15.4% increase in the risk of myocardial infarction. Similar patterns were found for each measure of SES, although the differences between the highest and lowest levels of SES were attenuated by adjustment for risk factors. In men who had no carotid stenosis or nonstenotic plaque and in men who had no indication of prevalent cardiovascular disease, a graded, inverse association between SES and IMT persisted, even after risk factor adjustment., Conclusions: These findings demonstrate a strong association between SES and atherosclerosis in an unselected population. The results show that this association was mediated by known atherosclerotic risk factors, was evident in the early stages of atherosclerosis, and was apparent in a healthy subgroup. Our findings suggest that the impact of SES is evident early in the natural history of atherosclerotic vascular disease.

Background: Even though previous studies have suggested an association between high fish intake and reduced coronary heart disease (CHD) mortality, men in Eastern Finland, who have a high fish intake, have an exceptionally high CHD mortality. We hypothesized that this paradox could be in part explained by high mercury content in fish., Methods and Results: We studied the relation of the dietary intake of fish and mercury, as well as hair content and urinary excretion of mercury, to the risk of acute myocardial infarction (AMI) and death from CHD, cardiovascular disease (CVD), and any cause in 1833 men aged 42 to 60 years who were free of clinical CHD, stroke, claudication, and cancer. Of these, 73 experienced an AMI in 2 to 7 years. Of the 78 decreased men, 18 died of CHD and 24 died of CVD. Men who had consumed local nonfatty fish species had elevated hair mercury contents. In Cox models with the major cardiovascular risk factors as covariates, dietary intakes of fish and mercury were associated with significantly increased risk of AMI and death from CHD, CVD, and any death. Men in the highest tertile (> or = 2.0 micrograms/g) of hair mercury content had a 2.0-fold (95% confidence interval, 1.2 to 3.1; P = .005) age- and CHD-adjusted risk of AMI and a 2.9-fold (95% CI, 1.2 to 6.6; P = .014) adjusted risk of cardiovascular death compared with those with a lower hair mercury content. In a nested case-control subsample, the 24-hour urinary mercury excretion had a significant (P = .042) independent association with the risk of AMI. Both the hair and urinary mercury associated significantly with titers of immune complexes containing oxidized LDL., Conclusions: These data suggest that a high intake of mercury from nonfatty freshwater fish and the consequent accumulation of mercury in the body are associated with an excess risk of AMI as well as death from CHD, CVD, and any cause in Eastern Finnish men and this increased risk may be due to the promotion of lipid peroxidation by mercury.

Background: Investigations of the progression of atherosclerosis in human arteries suggest that changes in the thickness of the arterial intima-media complex, observable with B-mode ultrasonography, may precede development of atherosclerotic lesions. For epidemiological studies and clinical trials, B-mode ultrasound has the advantage that it is noninvasive, can be used in nonsymptomatic subjects, and can be carried out repeatedly, thus reducing the necessary sample size. In the Kuopio Ischaemic Heart Disease Risk Factor Study, we have assessed the reliability of B-mode ultrasound through studying intraobserver and interobserver variability. We have also investigated its predictive value by associating ultrasound observations with clinical end points, risk factors for common carotid and femoral atherosclerosis, and predictors of progression of common carotid atherosclerosis., Methods and Results: The study of B-mode ultrasound reliability was conducted in 10 middle-aged men, with initial and two repeat scannings. The between-observer coefficient of variation was 10.5% for the first assessments by four observers. The intraobserver variability, described as the mean of the absolute difference between the first and third observations, was 0.087 mm, or 8.3% of the mean intimal-medial thickness (IMT). Ultrasonographic assessment of 1,257 men was compared with diagnostic information obtained from a prospective registry for acute myocardial infarction (AMI). The presence of any atherosclerotic findings was associated with a 3.0-fold risk of AMI. For each 0.1 mm of common carotid IMT, AMI risk increased by 11% (p < 0.001). Common carotid artery and femoral artery atherosclerosis, as assessed by mean maximal IMT, had different risk factor profiles. Age, serum low density lipoprotein cholesterol, smoking, platelet aggregability, serum copper, serum selenium (inversely), and blood hemoglobin were the strongest predictors of 2-year increase of common carotid IMT., Conclusions: On the basis of our experience and findings, the ultrasonographic assessment of common carotid atherosclerosis appears to be a feasible, reliable, valid, and cost-effective method for both population studies and clinical trials of atherosclerosis progression and regression.