Riitta Salonen

Kuopio Atherosclerosis Prevention Study (KAPS) A Population-Based Primary Preventive Trial of the Effect of LDL Lowering on Atherosclerotic Progression in Carotid and Femoral Arteries

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.

Intake of Mercury From Fish, Lipid Peroxidation, and the Risk of Myocardial Infarction and Coronary, Cardiovascular, and Any Death in Eastern Finnish Men

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.

HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men.

BackgroundWe investigated the association of cholesterol concentrations in serum high density lipoprotein (HDL) and its subfractions HDL2 and HDL3 with the risk of acute myocardial infarction in 1,799 randomly selected men 42, 48, 54, or 60 years old. Methods and ResultsBaseline examinations in the Kuopio Ischaemic Heart Disease Risk Factor Study were done during 1984-1987. In Cox multivariate survival models adjusted for age and examination year, serum HDL cholesterol of less than 1.09 mmol/l (42 mg/dl) was associated with a 3.3-fold risk of acute myocardial infarction (95% confidence intervals [CI], 1.7-6.4), serum HDL2, cholesterol of less than 0.65 mmol/1 (25 mg/dl) was associated with a 4.0-fold risk of acute myocardial infarction (95% CI, 1.9-8.3), and serum HDL3 cholesterol of less than 0.40 mmol/l (15 mg/dl) was associated with a 2.0-fold (95% CI, 1.1-4.0) risk of acute myocardial infarction. Adjustments for obesity, ischemic heart disease, other cardiovascular disease, maximal oxygen uptake, systolic blood pressure, antihypertensive medication, serum low density lipoprotein cholesterol, and triglyceride concentrations reduced the excess risks associated with serum HDL, IIDL2, and HDL3 cholesterol in the lowest quartiles by 52%, 48%, and 41%, respectively. Additional adjustments for alcohol consumption, cigarettes smoked daily, smoking years, and leisure time energy expenditure reduced these excess risks associated with low HDL, HDL2, and HDL3 cholesterol levels by another 26%, 24% and 21%, respectively. ConclusionsOur data confirm that both total HDL and HDL2 levels have inverse associations with the risk of acute myocardial infarction and may thus be protective factors in ischemic heart disease, whereas the role of HDL3 remains equivocal. (Circulation 1991;84:129–139)

Prevalence of carotid atherosclerosis and serum cholesterol levels in eastern Finland.

We investigated the prevalence of carotid atherosclerosis and its association with serum lipoprotein cholesterol fractions in 412 Eastern Finnish men ages 42, 48, 54, or 60 years who were examined between February and December 1987 in the Kuopio Ischaemic Heart Disease Risk Factor Study. Carotid atherosclerosis was assessed with high-resolution B-mode ultrasonography. Of the participants, 37% had thickening of the intimal or medial layer of the arterial wall, 10% had plaques, 2% had stenosis in the right or left common carotid artery or in the carotid bifurcation, and only 51% were free of any detectable carotid atherosclerosis. The prevalence of atherosclerosis was 14.1%, 32.0%, 67.7%, and 81.9% in the four age groups, respectively. The mean age-adjusted serum low density lipoprotein (LDL) cholesterol concentration was 3.67 mmol/l (142 mg/dl) in men free of carotid atherosclerosis and 4.02 mmol/l (155 mg/dl) in those with at least intimal thickening (p = 0.003 for difference). The mean age-adjusted serum cholesterol concentration in the high density lipoprotein (HDL) fraction was 1.34 mmol/l (52 mg/dl) in the atherosclerosis-free and 1.27 mmol/l (49 mg/dl) in the atherosclerotic men (p = 0.029 for difference). There was a similar difference in both the serum HDL2 and the HDL3 cholesterol levels. Serum LDL and HDL (inverse) cholesterol were significant determinants of severity of carotid atherosclerosis in a multivariate regression model adjusting for age, obesity, plasma fibrinogen, cigarette-years, and duration of hypertension. Our data reveal the high prevalence of atherosclerosis in middle-aged Eastern Finnish men and provide further evidence of the roles of LDL and HDL cholesterol in atherosclerosis.

Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data.

The independent and joint associations of serum selenium and vitamin A (retinol) and E (alpha tocopherol) concentrations with the risk of death from cancer were studied in 51 case-control pairs--that is, 51 patients with cancer, each paired with a control matched for age, sex, and smoking. Case-control pairs came from a random sample of some 12000 people aged 30-64 years resident in two provinces of eastern Finland who were followed up for four years. Patients who died of cancer during the follow up period had a 12% lower mean serum selenium concentration (p = 0.015) than the controls. The difference persisted when deaths from cancer in the first follow up year were excluded. The adjusted risk of fatal cancer was 5.8-fold (95% confidence interval 1.2-29.0) among subjects in the lowest tertile of selenium concentrations compared with those with higher values. Subjects with both low selenium and low alpha tocopherol concentrations in serum had an 11.4-fold adjusted risk. Among smoking men with cancer serum retinol concentrations were 26% lower than in smoking controls (p = 0.002). These data suggest that dietary selenium deficiency is associated with an increased risk of fatal cancer, that low vitamin E intake may enhance this effect, and that decreased vitamin or provitamin A intake contributes to the risk of lung cancer among smoking men with a low selenium intake.

Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in eastern Finland

Basic research and our previous studies have suggested that mercury exposure enhances lipid peroxidation and the risk of myocardial infarction, but there are no studies concerning the association between mercury accumulation and atherosclerosis. We therefore investigated whether high hair mercury content is associated with accelerated progression of carotid atherosclerosis, determined by ultrasonographic assessment of common carotid intima-media thickness (IMT), in a prospective study among 1014 men aged 42-60 years. In a linear regression model adjusting for other atherosclerotic risk factors, high hair mercury content was one of the strongest predictors of the 4-year increase in the mean IMT (P2.81 microg/g (fifths) had an IMT increase of 0.105, 0.102, 0.113, 0.107 and 0.140 mm/4 years, respectively (P=0.041 for heterogeneity between groups). The IMT increase was 0.034 mm/4 years (31.9%) greater in the highest fifth than in the other fifths (P<0.05 for the difference). These findings suggest that mercury accumulation in the human body is associated with accelerated progression of carotid atherosclerosis.

Asymptomatic atherosclerosis and insulin resistance.

High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1- and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/l) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 +/- 2 versus 71 +/- 4 mumol/kg/min, p = 0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37 +/- 2 versus 50 +/- 4 mumol/kg/min, p = 0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis.

Exaggerated Blood Pressure Responses During Mental Stress Are Associated With Enhanced Carotid Atherosclerosis in Middle-Aged Finnish Men Findings From the Kuopio Ischemic Heart Disease Study

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.

Lipoprotein Oxidation and Progression of Carotid Atherosclerosis

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.

Increased risk of non-insulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men.

Abstract Objective: To investigate whether low vitamin E status is a risk factor for incident non-insulin dependent diabetes mellitus. Design: Population based follow up study with diabetes assessed at baseline and at four years. Setting: Eastern Finland. Subjects: Random sample of 944 men aged 42-60 who had no diabetes at the baseline examination. Intervention: Oral glucose tolerance test at four year follow up. Main outcome measures: A man was defined diabetic if he had either (a) a fasting blood glucose concentration >/=6.7 mmol/l, or (b) a blood glucose concentration >/=10.0 mmol/l two hours after a glucose load, or (c) a clinical diagnosis of diabetes with either dietary, oral, or insulin treatment. Results: 45 men developed diabetes during the follow up period. In a multivariate logistic regression model including the strongest predictors of diabetes, a low lipid standardised plasma vitamin E (below median) concentration was associated with a 3.9-fold (95% confidence interval 1.8-fold to 8.6-fold) risk of incident diabetes. A decrement of 1 µmol/l of uncategorised unstandardised vitamin E concentration was associated with an increment of 22% in the risk of diabetes when allowing for the strongest other risk factors as well as serum low density lipoprotein cholesterol and triglyceride concentrations. Conclusions: There was a strong independent association between low vitamin E status before follow up and an excess risk of diabetes at four years. This supports the theory that free radical stress has a role in the causation of non-insulin dependent diabetes mellitus.