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Clinical and epidemiological studies have provided circumstantial evidence that oxidized low-density lipoprotein (LDL) and antioxidants are involved in the pathogenesis of atherosclerosis. Superoxide dismutases (SODs) have been shown in vitro to protect LDL from deleterious effects of superoxide anions. In the present study, we have used adenoviral gene transfer to determine effect of extracellular SOD (EC-SOD) on atherogenesis in LDL receptor -/- mice. Intravenous administration of EC-SOD adenovirus (2 x 10(9) plaque forming units) into tail vein targeted transgene mainly to liver and induced a 3.5- to sevenfold increase in plasma total SOD activity. EC-SOD was secreted into circulation for 2-3 weeks mostly in a truncated B-form, suggesting that endogenous proteolytic mechanisms control the level and distribution of the enzyme. Therapeutic potential was determined by measuring plasma resistance against copper oxidation and analyzing atherosclerotic lesion areas in aortas of LDL receptor -/- mice. Mice were kept on a cholesterol diet for 10 weeks before gene transfer and 3 or 6 weeks after the gene transfer. Results showed a tendency for a reduction in the overall lesion area after EC-SOD gene transfer as compared with LacZ transduced control mice, but the difference did not reach statistical significance. It is concluded that short-term overexpression of EC-SOD in vivo does not affect atherogenesis in LDL receptor -/- mice.

Background: Good cardiorespiratory fitness has been associated with reduced risk for clinical events of atherosclerotic vascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear., Objective: To study the association between cardiorespiratory fitness and the progression of early carotid atherosclerosis., Design: 4-year follow-up study., Setting: Eastem Finland., Participants: Population-based sample of 854 men 42 to 60 years of age., Measurements: Maximal oxygen uptake (VO2max [mL/kg per minute]) was measured directly by using respiratory gas exchange in a cycle ergometer exercise test. Carotid atherosclerosis was assessed by using B-mode ultrasonography., Results: After adjustments for age, technical covariates, and cigarette smoking, VO2max had strong, inverse, and graded associations with 4-year increases in maximal intima-media thickness (IMT) (standardized regression coefficient beta = -0.120; P = 0.002), plaque height (beta = -0.140; P < 0.001), surface roughness (beta = -0.147; P < 0.001), and mean IMT (beta = -0.080; P = 0.035). These associations weakened but remained statistically significant after additional adjustment for systolic blood pressure, serum levels of apolipoprotein B, diabetes, and plasma fibrinogen levels. The increases in maximal IMT, surface roughness, and mean IMT (23%, 31%, and 100%, respectively) were larger among men in the lowest quartile of VO2max (<26.1 mL/kg per minute) than among those in the highest quartile (>36.2 mL/kg per minute)., Conclusions: Good cardiorespiratory fitness is associated with slower progression of early atherosclerosis in middle-aged men. These findings are important because they emphasize that middle-aged men can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases. Additional research is warranted to investigate a possible causal relationship between cardiorespiratory fitness and atherosclerosis.

Although a number of epidemiological studies have evaluated the association between ss-carotene and the risk of cardiovascular diseases, there has been little research on the role of lycopene, an acyclic form of ss-carotene, with regard to the risk of cardiovascular disease. We investigated the relationship between plasma concentrations of lycopene and intima-media thickness of the common carotid artery wall (CCA-IMT) in 520 middle-aged men and women (aged 45 to 69 years) in eastern Finland. They were examined from 1994 to 1995 at the baseline of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized trial concerning the effect of vitamin E and C supplementation on atherosclerotic progression. The subjects were classified into 2 categories according to the median concentration of plasma lycopene (0.12 micromol/L in men and 0.15 micromol/L in women). Mean CCA-IMT of the right and left common carotid arteries was 1.18 mm in men and 0.95 mm in women with plasma lycopene levels lower than the median and 0.97 mm in men (P:<0.001 for difference) and 0.89 mm in women (P:=0.027 for difference) with higher levels of plasma lycopene. In ANCOVA adjusting for cardiovascular risk factors and intake of nutrients, in men, low levels of plasma lycopene were associated with a 17.8% increment in CCA-IMT (P:=0.003 for difference). In women, the difference did not remain significant after the adjustments. We conclude that low plasma lycopene concentrations are associated with early atherosclerosis, manifested as increased CCA-IMT, in middle-aged men living in eastern Finland.

Objectives: To study the efficacy of vitamin E and C supplementation on the progression of carotid atherosclerosis, hypothesizing an enhanced preventive effect in men and in smokers and synergism between vitamins., Design and Subjects: Double-masked two-by-two factorial trial, randomization in four strata (by gender and smoking status) to receive twice daily either 91 mg (136 IU) of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these or placebo for three years. A randomized sample of 520 smoking and nonsmoking men and postmenopausal women aged 45-69 years with serum cholesterol >/= 5.0 mmol L-1 were studied., Setting: The population of the city of Kuopio in Eastern Finland., Intervention: Twice daily either a special formulation of 91 mg of d-alpha-tocopherol, 250 mg of slow-release vitamin C, a combination of these (CellaVie(R)) or placebo for three years., Measurements: Atherosclerotic progression, defined as the linear regression slope of ultrasonographically assessed common carotid artery mean intima-media thickness (IMT), was calculated over semi-annual assessments., Results: The average increase of the mean IMT was 0.020 mm year-1 amongst men randomized to placebo and 0.018 mm year-1 in vitamin E, 0.017 mm year-1 in vitamin C and 0.011 mm year-1 in the vitamin combination group (P = 0.008 for E + C vs. placebo). The respective means in women were 0.016, 0.015, 0.017 and 0.016 mm year-1. The proportion of men with progression was reduced by 74% (95% CI 36-89%, P = 0.003) by supplementation with the formulation containing both vitamins, as compared with placebo., Conclusions: Our study shows that a combined supplementation with reasonable doses of both vitamin E and slow-release vitamin C can retard the progression of common carotid atherosclerosis in men. This may imply benefits with regard to other atherosclerosis-based events.

Most studies that examine the role of alcohol consumption in atherosclerosis and cardiovascular disease have overlooked the possible effect of drinking pattern. We investigated the association between the habit of heavy acute intake of beer and spirits (binging) and the 4-year progression of carotid atherosclerosis in a population-based sample of middle-aged Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD) were used to estimate changes in maximum and mean intima-media thickness (IMT) and the maximum plaque height in 764 KIHD participants who reported using beer and in 871 participants who used spirits. After adjustment for age, baseline carotid atherosclerosis, and average weekly alcohol consumption level, we observed the highest atherosclerosis progression in men who usually consumed a whole bottle of vodka or more in 1 session. For beer binging (>6 beers at a time), the magnitude of IMT progression was even higher, although this association was only marginally significant (P<0.1) because of smaller numbers. The associations were largely unaffected by adjustments for blood pressure, lipids, smoking, BMI, and medication. The magnitude of the difference was generally higher in a subgroup that was free of IHD at baseline. We conclude that the pattern of drinking associates with the progression of carotid atherosclerosis independently of the total level of alcohol consumption and risk factors.

Elevated blood pressure has consistently been associated with increased prevalence of preclinical atherosclerosis and with increased risk of clinical atherosclerotic cardiovascular disease (CVD). However, there is no prospective evidence of the association between blood pressure and the progression of preclinical atherosclerosis. We therefore investigated the relationships of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure to the 4-year increase in the measures of early carotid atherosclerosis, the mean and maximal common carotid intima-media thickness (IMT), assessed by B-mode ultrasonography, in 1026 men aged 42 to 60 years. Men with the SBP of <120, 120 to 126, 127 to 134, 135 to 143, and >143 mm Hg (fifths) had an increase in the mean IMT of 0.074, 0.090, 0.110, 0.136, and 0.158 mm per 4 years (P<0.001 for difference between groups, P<0.001 for linear trend) and in the maximal IMT of 0.212, 0.221, 0.279, 0.286, and 0.315 mm per 4 years, (P<0.001, P<0.001), respectively, adjusting for other atherosclerotic risk factors, including DBP. Also, pulse pressure, when adjusted for other risk factors including mean arterial pressure, was directly associated with the IMT increase. DBP was not independently related to the IMT increase. This is the first documentation to show that mildly elevated SBP and pulse pressure accelerate the progression of preclinical atherosclerosis. This study provides further evidence for the finding that systolic hypertension is a more important risk factor for atherosclerosis and consequent CVD than diastolic hypertension. Therefore, more attention should be paid to the level of SBP in the evaluation of CVD risk and in the treatment of hypertension.

Objective: To study the association of ultrasonographic manifestations of common carotid atherosclerosis with glucose intolerance in survivors of the cohort of men born in 1900-1919 in eastern Finland., Research Design and Methods: Carotid ultrasonography was carried out for 182 men in 1989. Glucose tolerance status classified based on an oral glucose tolerance test in 1984 and 1989 surveys was used in both prospective and cross-sectional analyses., Results: Carotid atherosclerosis was common in men aged 70-89 years. There was no significant difference in the maximal carotid intimal-medial thickness between diabetic and nondiabetic men and over different age-groups; it was 1.28, 1.33, and 1.36 mm in subjects with diabetes, impaired glucose tolerance, and normal glucose tolerance, respectively (P = 0.69). No association between the presence of a nonmineralized or a mineralized atherosclerotic lesion with diabetes was found. Fasting plasma insulin did not relate to ultrasonographically detectable atherosclerotic lesions., Conclusions: Hyperglycemia and hyperinsulinemia may not be main contributors to atherosclerosis in elderly men, partly because smoking is less common and total and LDL cholesterol concentrations are lower in diabetic men than in men with normal glucose tolerance.

Homocysteine is increasingly recognized as a risk factor for atherothrombotic arterial diseases. We investigated the relation between plasma concentrations of total homocysteine (tHcy) and common carotid artery intima-media wall thickness, measured by B-mode ultrasonography, in 513 asymptomatic men and women from eastern Finland aged 45-69 years. The subjects were examined in 1994-95 at the baseline of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, a randomized double-blind placebo-controlled two by two factorial trial on the effect of vitamin E and C supplementation in the prevention of atherosclerotic progression. The subjects were assigned into two categories according to the plasma tHcy concentration; concentration over 11.5 micromol/L (highest quartile) or concentration below 11.5 micromol/L. In this study population the mean plasma tHcy concentration was 10.0 micromol/L, and the prevalence of plasma tHcy concentration exceeding 11.5 micromol/L was 33% in men and 18% in women. The adjusted mean intima-media thickness of the right and left common carotid arteries was 1.12 mm in men with elevated plasma tHcy concentration and 1.02 mm in men with a plasma tHcy concentration below 11.5 micromol/L (P = 0.029). In women there was no significant difference. We conclude that elevated plasma tHcy concentrations are associated with early atherosclerosis, as manifested by increased common carotid artery intima-media wall thickness, in middle-aged eastern Finnish men.

Objectives: This study examined whether heightened cardiovascular reactivity and low socioeconomic status had synergistic effects on the progression of carotid atherosclerosis in a population of eastern Finnish men., Methods: Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to measure 4-year progression of intima-media thickness in 882 men according to cardiovascular reactivity and socioeconomic status. Associations were examined in relation to risk factors and were stratified by baseline levels of atherosclerosis and prevalent ischemic heart disease., Results: The effect of reactivity on atherosclerotic progression depended on socioeconomic status. Men who had heightened cardiovascular responsiveness to stress and were born into poor families, received little education, or had low incomes had the greatest atherosclerotic progression., Conclusions: An understanding of associations between individual risk factors and disease should be based on etiologic hypotheses that are conceived at the population level and involve fundamental social and economic causes of disease. This study demonstrates how examining the interaction of an individual biological predisposition will low socioeconomic status over the life course is etiologically informative for understanding the progression of atherosclerotic vascular disease.

The importance of hope has long been recognized, whereas a lack of hope, or "giving up," is generally believed to have a negative impact on psychological well-being and physical health. Recently, hopelessness has been identified as a strong, independent predictor of cardiovascular disease morbidity and mortality in both American and Finnish populations. In this study we examined the association between high levels of hopelessness and progression of carotid atherosclerosis in participants (n = 942) in the Kuopio Ischemic Heart Disease Study, a population-based study of middle-aged men from eastern Finland who underwent carotid ultrasonography at baseline and 4 years later. Men reporting high levels of hopelessness at baseline had faster progression of carotid atherosclerosis, assessed by four measures of intima-media thickening (IMT), than men reporting low to moderate levels of hopelessness. Further analyses revealed significant interactions between hopelessness and initial level of atherosclerosis, such that the effects of high hopelessness on progression were greatest among men who had baseline mean IMT values at or above the median. Moreover, progression was greatest among men reporting high levels of hopelessness at both baseline and follow-up. Traditional coronary risk factors and use of cholesterol-lowering and antihypertensive medications did not account for much variance in the observed relationships. These findings indicate that hopelessness contributes to accelerated progression of carotid atherosclerosis, particularly among men with early evidence of atherosclerosis, and that chronically high levels of hopelessness may be especially detrimental. Additional research is needed to identify the contributory pathways and/or mechanisms underlying these relationships.

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.

Socioeconomic status (SES) is importantly associated with cardiovascular morbidity and mortality, but no information exists on the relationship between SES and progression of atherosclerotic vascular disease. We investigated the association between education and income and the 4-year progression of carotid atherosclerosis in a population-based sample of Finnish men. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to estimate changes in maximum and mean intima-media thickness (IMT) and maximum plaque height across levels of SES in 1022 men. Associations between SES and atherosclerotic progression were examined in relation to risk factors and stratified by baseline levels of atherosclerosis and prevalent ischemic heart disease (IHD). There were significant, inverse, graded relationships between levels of education and income for all three progression measures, which were largely unaffected by risk factor adjustment. For education, the age- and baseline IMT-adjusted maximum progression for those with primary schooling or less was 0.28 mm and for those who graduated from high school, 0.24 mm (P = .05). Compared with the lowest SES group, men with the highest SES had 14% to 29% less atherosclerotic progression, depending on the measure used. Associations of the same magnitude were evident in subgroups without advanced baseline IMT and in men who were free of IHD. These results show that men with poor education and low income have significantly greater progression of carotid atherosclerosis than men with more advantages. The findings strengthen the contention that SES plays a significant role early in the atherosclerotic disease process and that reducing the burden of atherosclerotic vascular disease associated with lower SES will require approaches that focus on all stages of the life course.

Objective: To examine the combined influence of workplace demands and changes in blood pressure induced by stress on the progression of carotid atherosclerosis., Design: Population based follow up study of unestablished as well as traditional risk factors for carotid atherosclerosis, ischaemic heart disease, and other outcomes., Setting: Eastern Finland., Subjects: 591 men aged 42-60 who were fully employed at baseline and had complete data on the measures of carotid atherosclerosis, job demands, blood pressure reactivity, and covariates., Main Outcome Measures: Change in ultrasonographically assessed intima-media thickness of the right and left common carotid arteries from baseline to 4 year follow up., Results: Significant interactions between workplace demands and stress induced reactivity were observed for all measures of progression (P < 0.04). Men with large changes in systolic blood pressure (20 mm Hg or greater) in anticipation of a maximal exercise test and with high job demands had 10-40% greater progression of mean (0.138 v 0.123 mm) and maximum (0.320 v 0.261 mm) intima-media thickness and plaque height (0.347 v 0.264) than men who were less reactive and had fewer job demands. Similar results were obtained after excluding men with prevalent ischaemic heart disease at baseline. Findings were strongest among men with at least 20% stenosis or non-stenotic plaque at baseline. In this subgroup reactive men with high job demands had more than 46% greater atherosclerotic progression than the others. Adjustment for atherosclerotic risk factors did not alter the results., Conclusions: Men who showed stress induced blood pressure reactivity and who reported high job demands experienced the greatest atherosclerotic progression, showing the association between dispositional risk characteristics and contextual determinants of disease and suggesting that behaviourally evoked cardiovascular reactivity may have a role in atherogenesis.

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.

The oxidative modification of human low density lipoprotein (LDL) has been widely investigated. However, there are no data concerning the oxidation susceptibility of combined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein fraction, although all of them are atherogenic and contain antioxidants such as alpha-tocopherol. We investigated the oxidation susceptibility and oxidation resistance of VLDL + LDL (including IDL) fraction by induction with CuCl2 and its relation to plasma alpha-tocopherol concentration and lipid standardised alpha-tocopherol concentration in 406 non-vitamin E-supplemented men from eastern Finland. Even thought we did not give oral vitamin E or any other antioxidant supplementation to our study participants, we observed a significant, consistent relationship between measurements of oxidation resistance and plasma content of vitamin E. In the multivariate regression model, a high plasma content of vitamin E or lipid standardised vitamin E concentration were the most important determinants of lag time to maximal oxidation rate (standardised regression coefficient = 0.244, P < 0.0001 for vitamin E and 0.211, P < 0.0001 for lipid standardised vitamin E). After statistical adjustment for age, use of cigarettes, hypolipidemic medication (yes vs. no), month of the measurements, plasma concentrations of total ascorbic acid (ascorbic acid + dehydroascorbic acid), beta-carotene and phospholipids, serum concentrations of LDL cholesterol and triglycerides and dietary intake of linoleic acid, the lag time to maximal oxidation rate was 10% (95% C.I. 6.0-13.5%) longer in men in the highest fifth than in the lowest fifth of plasma vitamin E content (P < 0.0001 for trend). When the fifths of lipid standardised vitamin E were compared, the lag time to maximal oxidation rate was 6% (95% C.I. 1.8-10.1%) longer in men in the highest than in the lowest fifth (P < 0.0001 for trend). Our data suggest that alpha-tocopherol is an important antioxidant preventing the in vitro oxidation of VLDL + LDL fraction even in non-supplemented subjects.

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.

The Kuopio Atherosclerosis Prevention Study is the first population-based, double-blind trial in the primary prevention of carotid and femoral atherosclerosis. A total of 447 subjects with serum low density lipoprotein (LDL) cholesterol levels > or = 155 mg/dl (> or = 4.0 mmol/liter) and total cholesterol levels < 290 mg/dl (< 7.5 mmol/liter) were randomly assigned to receive either pravastatin 40 mg/day or placebo for 3 years. Atherosclerotic progression in 424 men was assessed with B-mode ultrasonography. Pravastatin reduced the rate of progression by 45% (95% confidence interval [CI]: 16-69%, p = 0.005) in carotid arteries and by 66% (95% CI: 30-90%, p = 0.002) in the common carotid arteries. The treatment effect in the carotid arteries was greater in subjects with thick arterial walls at baseline, in smokers, and in subjects with low plasma alpha-tocopherol. Subjects who received pravastatin had a higher antioxidative capacity of LDL, a longer oxidation lag of very low density lipoprotein (VLDL) plus LDL, and a reduced oxidation rate of VLDL plus LDL in vitro. These data establish the antiatherogenic effect of lowering LDL cholesterol levels by pravastatin therapy in hypercholesterolemic men in a primary prevention setting and suggest that part of the antiatherogenic effect of pravastatin may be due to an improvement in the resistance of atherogenic lipoproteins to oxidation.

We studied prospectively the association of hostility and anger suppression by the use of ultrasonographically assessed 2-year progression of carotid atherosclerosis (PCA) in a sample of 119 middle-aged men from eastern Finland. Based on measures of cynical distrust, impatience-irritability, anger-in, and anger-control, four variants of hostility-by-anger suppression model were tested with multiple regression analysis. In addition to the previously established risk factors (i.e., serum low-density lipoprotein cholesterol concentration, smoking, and old age), cynical distrust and anger-control significantly predicted PCA. There was about a two-fold accelerated PCA in the group with high cynical distrust and high anger-control even after we controlled for the established biological risk factors and possible confounding background variables. The impact of the independent variables on PCA seemed to be additive rather than synergistic. These results, based on a relatively small, but nonselected population sample, extend previous results of angiographic studies.

Objectives: The aim of the study was to find the most important determinants of early atherosclerosis in the carotid and femoral arteries., Design: Carotid and femoral maximal intima media thickness (IMT) was measured 19 months after the first of 4 risk factor measurements., Setting: Department of Community Health and General Practice, University of Kuopio, and Occupational Health Care in Pyhäsalmi Mine, Finland., Subjects: The subjects comprised 60 male volunteers aged from 32 to 65 years from amongst 277 workers at the Pyhäsalmi Mine, Finland. Subjects were invited for an ultrasound examination, in order of serum total cholesterol content, until the required figure of 60 cases was achieved., Main Outcome Measures: Carotid and femoral maximal intima media thickness., Results: Systolic blood pressure (P < 0.01), serum total cholesterol (P < 0.01), age (P = 0.01) and pack-years smoked (P = 0.02) were independent determinants of maximal carotid artery IMT, and total cholesterol (P = 0.01), age (P = 0.03) and pack-years smoked (P = 0.01) for maximal femoral artery IMT. For the latter, plasma fibrinogen concentration (P = 0.10) was the next factor to enter the multiple regression model. Body mass index, heart rate, serum HDL cholesterol, triglycerides, urate, apolipoprotein A1, antithrombin III, lipid peroxides, vitamin E and plasma vitamin C had no significant association with either maximal carotid or femoral IMT or the mean of the carotid and femoral IMT., Conclusions: Systolic blood pressure, serum total cholesterol, age and pack-years smoked are the most important determinants of early atherosclerosis in the carotid artery and total cholesterol, age and pack-years smoked in the femoral artery. Prevention should take into consideration these findings. The role of plasma fibrinogen and oxidized low density lipoprotein would require re-evaluation in larger populations studied longitudinally.

The relation of serum total homocysteine and lipoprotein(a) (Lp(a)) with the incidence of atherosclerotic disease was investigated among 7424 men and women aged 40-64 years free of atherosclerotic disease at baseline in 1977. During the 9-year follow-up, 134 male and 131 female cases with either myocardial infarction or stroke were identified. For each case a control subject was selected belonging to the same sex and 5-year age group. Serum samples collected in 1977 were stored at -20 degrees C and analyzed in 1991. The mean serum homocysteine concentration of male cases and controls was 9.99 mumol/l and 9.82 mumol/l at baseline and that of female cases and controls 9.58 mumol/l and 9.24 mumol/l, respectively. The median serum Lp(a) concentration of male cases and controls was 73 mg/l and 108 mg/l and that of female cases and controls 113 mg/l and 91 mg/l, respectively. The differences between cases and controls were not statistically significant. There was also no significant association between either homocysteine or Lp(a) and atherosclerotic disease, myocardial infarction or stroke in logistic regression analyses. The odds ratios varied from 1.00 to 1.26 for homocysteine and from 0.81 to 1.06 for Lp(a). The results of this prospective population-based study do not support the hypotheses that serum homocysteine or Lp(a) are risk factors for atherosclerotic disease. The lack of association between serum homocysteine and atherosclerotic disease may be due to the exceptionally low gene frequency predisposing to homocysteinemia in Finland.

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.

Ophthalmological examination was made for 447 hypercholesterolemic middle-aged Eastern Finnish men participating in the Kuopio Atherosclerosis Prevention Study (KAPS) in order to evaluate the prevalence of corneal arcus, its risk factors, and possible association with atherosclerosis. The degree of atherosclerosis was assessed by ultrasonographic examination of carotid and femoral arteries. Corneal arcus in either eye was observed in 51.4% of the participants. Old age and high LDL cholesterol concentration were associated with the presence of corneal arcus. Corneal arcus had a close relationship with ultrasonographically assessed atherosclerosis.

Oxidative modification of LDL renders it immunogenic and autoantibodies to epitopes of oxidised LDL, such as malondialdehyde (MDA)-lysine, are found in serum and recognise material in atheromatous tissue. However, there has been no prospective study to assess the importance of oxidised LDL among patients with vascular disease. We compared the titre of autoantibodies to MDA-modified LDL and native LDL in baseline serum samples of 30 eastern Finnish men with accelerated two-year progression of carotid atherosclerosis and 30 age-matched controls without progression. Neither group had specific antibody binding to native LDL. A titre was defined as a ratio of antibody binding to MDA-LDL/binding to native LDL. Cases had a significantly higher titre to MDA-LDL (2.67 vs 2.06, p = 0.003). Cases also had a greater proportion of smokers (37% vs 3%), higher LDL cholesterol (4.2 mmol/l vs 3.6 mmol/l), and higher serum copper concentration (1.14 mg/l vs 1.04 mg/l). Even after adjusting for these variables and the severity of baseline atherosclerosis, the difference in antibody titre remained significant in a multifactorial logistic model (p = 0.031). Thus, the titre of autoantibodies to MDA-LDL was an independent predictor of the progression of carotid atherosclerosis in these Finnish men. Our data provide further support for a role of oxidatively modified LDL in atherogenesis.

As ultrasonographically assessed carotid arteriosclerosis is being used as a surrogate measure for coronary arteriosclerosis, we performed a prospective longitudinal study of the association of our high-resolution ultrasound assessment of extracranial carotid morphology with the risk of acute coronary events in 1,288 eastern Finnish men. The presence of any structural changes in the common carotid arteries or carotid bulbs was associated with a 3.29-fold (95% confidence interval, 1.31-8.29; p = 0.0074), intimal-medial thickening with a 2.17-fold (95% confidence interval, 0.70-6.74; p = NS), small carotid plaques with a 4.15-fold (95% confidence interval, 1.51-11.47; p less than 0.01), and large ("stenotic") plaques with a 6.71-fold (95% confidence interval, 1.33-33.91; p less than 0.01) risk of acute myocardial infarction compared with men free of any structural changes in the carotid artery wall at baseline. These data confirm the close relation between carotid artery wall morphology and coronary heart disease.

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.

Objective: To investigate the interactions between serum copper, selenium, and low density lipoprotein cholesterol concentrations with regard to the progression of carotid atherosclerosis., Design: Longitudinal study of a cohort of middle aged men followed up for 24 months., Setting: Epidemiological survey of the population of seven communities in eastern Finland., Subjects: 126 men aged 42, 48, 54, or 60 at examination randomly selected from a population based sample of 2682 men., Main Outcome Measures: Increase in maximal carotid intima media thickness., Results: The mean increase in the maximal common carotid intima media thickness after two years was greater in men with high serum copper concentrations (0.16 mm compared with 0.08 mm in men with concentrations less than 17.6 mumol/l; p = 0.010), those with low serum selenium concentrations (0.15 mm compared with 0.09 mm in men with concentrations greater than or equal to 1.40 mumol/l; p = 0.035), and those with raised serum low density lipoprotein cholesterol concentrations (0.15 mm compared with 0.08 mm in men with concentrations less than 4.0 mmol/l; p = 0.032) after adjustment for age and cigarette pack years in a three way analysis of covariance. A raised serum low density lipoprotein concentration was associated with accelerated progression of atherosclerosis only in men with higher than median serum copper concentrations (net difference 0.22 mm; p less than 0.001 for two way interaction), and this synergism was even more pronounced in men with serum selenium concentrations below the median value (net difference 0.41 mm; p = 0.042 for three way interaction)., Conclusion: These data provide evidence of a synergistic effect of copper (a pro-oxidant), a low serum concentration of selenium (a cofactor of an enzyme that scavenges free radicals), and low density lipoprotein cholesterol concentration in atherogenesis.

We investigated the determinants of maximal intima-media thickness of common carotid arteries in a population-based sample of 1224 Eastern Finnish men aged 42, 48, 54 or 60 years. A high-resolution B-mode ultrasonographic examination was performed as part of the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The maximal intima-media thickness (IMT) varied between 0.48 mm and 4.09 mm (mean value +/- SD, 0.94 mm +/- 0.38 mm). Age (standardized partial coefficient, beta = 0.238, P less than 0.0001), ambulatory pulse pressure (beta = 0.130, P less than 0.0001), cigarette-years of smoking (beta = 0.125, P less than 0.0001), serum LDL cholesterol concentration (beta = 0.125, P less than 0.0001), history of ischaemic heart disease (beta = 0.125, P less than 0.0001), pre-exercise systolic blood pressure (beta = 0.070, P = 0.0113) and diabetes (beta = 0.068, P = 0.0072) were most strongly associated with IMT. This study confirms the role of systolic blood pressure, smoking and serum LDL cholesterol levels as major risk factors for increased carotid intima-media thickness.

We investigated the association of systolic and diastolic blood pressure and hypertension with two different manifestations of carotid atherosclerosis in a random population sample of 1165 Eastern Finnish men aged 42, 48, 54 or 60 years, examined in the Kuopio Ischaemic Heart Disease Risk Factor Study. Carotid atherosclerosis was assessed with high-resolution B-mode ultrasonography. Men with a casual sitting systolic blood pressure of 175 mmHg or more had a 3.17-fold (95% confidence interval 1.79-5.61) prevalence of intima-media thickening--adjusted for age, smoking, S-LDL-cholesterol, IHD history and diabetes--compared to men with lower systolic pressures. The relative prevalence of carotid plaques in men with raised systolic pressures. The relative prevalence of carotid plaques in men with raised systolic blood pressure was 2.61 (95% confidence interval 1.44-4.72) in relation to men with no lesions. Our findings suggest that systolic but not diastolic hypertension is associated with an increased prevalence of both early and advanced atherosclerotic lesions in carotid arteries.

High-resolution B-mode ultrasonography enables quantitative measurement of the thickness of the intima-media layer of superficial large arteries noninvasively. We investigated the inter- and intra-observer variability of this measurement in the common carotid arteries in 10 randomly selected men. The maximal right and left carotid intima-media thickness (IMT) was measured with calipers during the scanning from frozen images by four observers in a blinded fashion. Three observers also repeated the scanning and the measurements twice with a week's intervals, with no knowledge of the previous readings. The inter-observer coefficient of variation (CV) was 10.5%. The intra-observer CV (mean of right and left CCA) was 5.4-5.8% for the three observers who carried out the measurements three times. The mean absolute difference between the first and third measurement was 0.087 mm. The intra-observer variation accounted for only 4% of the total measurement variability, 96% being attributable to inter-observer variation. These data show that most of the measurement variability in ultrasonographic B-mode IMT measurements is due to differences between observers, whereas the within-observer variability over time appears proportionately very small.

We investigated the association of elevated serum low density lipoprotein (LDL) cholesterol levels, smoking and hypertension with different manifestations of carotid atherosclerosis in a population-based sample of 720 Eastern Finnish men aged 42, 48, 54 or 60 years, examined in the Kuopio Ischaemic Heart Disease Risk Factor Study. Carotid atherosclerosis was assessed with high-resolution B-mode ultrasonography. Men who had neither a history nor symptoms of cardiovascular disease with serum LDL cholesterol concentration in the highest tertile (4.17 mM or more) had 3.40-fold (95% confidence interval (CI) 1.98-5.84) age-, smoking- and hypertension-adjusted probability of intimal-medial thickening as compared to men in the lowest serum LDL cholesterol tertile. The odds ratio for carotid plaque versus intimal-medial thickening was only 1.03 (95% CI 0.47-2.28). The respective odds ratios for smoking (28 pack-years or more) were 1.62 (95% CI 0.79-3.32) and 3.02 (95% CI 1.41-6.47) and those for hypertension were 1.10 (95% CI 0.70-1.73) and 0.99 (95% CI 0.53-1.84). Our findings suggest that elevated serum LDL cholesterol concentration associates with an increased risk of common carotid arterial wall thickening, whereas smoking is associated more strongly with carotid plaques than intimal-medial thickening. Our cross-sectional data do not support association between hypertension and either manifestation of carotid atherosclerosis.

We investigated the progression of carotid atherosclerosis in a population-based sample of 100 Eastern Finnish men aged 42, 48, 54 or 60 years. A high-resolution B-mode ultrasonographic examination was repeated after a follow-up of 24 months for each subject. The intimal-medial thickness (IMT) in the common carotid artery increased by -0.06 mm to 0.90 mm (mean 0.12 mm, SD 0.20 mm). Age (standardised partial coefficient, beta = 0.325, P = 0.0003), serum LDL cholesterol concentration (beta = 0.229, P = 0.0011), pack-years of smoking (beta = 0.274, P = 0.0023), blood leukocyte count (beta = 0.201, P = 0.0239), and platelet aggregability (beta = 0.165, P = 0.0646), measured at baseline, were the strongest predictors of atherosclerosis progression. Neither hypertension, current blood pressure level, serum HDL cholesterol nor serum HDL2 cholesterol concentration at the baseline examination had any association with the change of IMT over 2 yrs.

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.