Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials.

OBJECTIVES: In the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, patients were randomly assigned to homocysteine-lowering B-vitamins or no such treatment. We investigated their effects on cardiovascular outcomes in the trial populations combined, during the trials and during an extended follow-up, and performed exploratory analyses to determine the usefulness of homocysteine as a predictor of cardiovascular outcomes. DESIGN: Pooling of data from two randomized controlled trials (1998-2005) with extended post-trial observational follow-up until 1 January 2008. SETTING: Thirty-six hospitals in Norway. SUBJECTS: 6837 patients with ischaemic heart disease. INTERVENTIONS: One capsule per day containing folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg), or folic acid plus vitamin B12, or vitamin B6 alone or placebo. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (MACEs; cardiovascular death, acute myocardial infarction or stroke) during the trials and cardiovascular mortality during the extended follow-up. RESULTS: Folic acid plus vitamin B12 treatment lowered homocysteine levels by 25% but did not influence MACE incidence (hazard ratio, 1.07; 95% CI, 0.95-1.21) during 39 months of follow-up, or cardiovascular mortality (hazard ratio, 1.12; 95% CI, 0.95-1.31) during 78 months of follow-up, when compared to no such treatment. Baseline homocysteine level was not independently associated with study outcomes. However, homocysteine concentration measured after 1-2 months of folic acid plus vitamin B12 treatment was a strong predictor of MACEs. CONCLUSION: We found no short- or long-term benefit of folic acid plus vitamin B12 on cardiovascular outcomes in patients with ischaemic heart disease. Our data suggest that cardiovascular risk prediction by plasma total homocysteine concentration may be confined to the homocysteine fraction that does not respond to B-vitamins.

Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: the tromsø study.

BACKGROUND: The purpose of the study was to assess in a prospective design whether plaque morphology is associated with risk of ischemic stroke and other cerebrovascular events in subjects with carotid stenosis. METHODS AND RESULTS: A total of 223 subjects with carotid stenosis (123 with 35% to 49% degree of stenosis, 100 with 50% to 99% stenosis) and 215 control subjects matched by age and sex who participated in a population health survey at baseline were followed up for 3 years. Plaque echogenicity was assessed by ultrasound at baseline and scored as echolucent, predominantly echolucent, predominantly echogenic, or echogenic. Forty-four subjects experienced >/=1 ischemic cerebrovascular events in the follow-up period. Plaque echogenicity, degree of stenosis, and white blood cell count were independent predictors of cerebrovascular events. The unadjusted relative risk for cerebrovascular events was 13.0 (95% CI 4.5 to 37.4) in subjects with echolucent plaques and 3.7 (95% CI 0.7 to 18.2) in subjects with echogenic plaques when subjects without stenosis were used as the reference. The adjusted relative risk for cerebrovascular events in subjects with echolucent plaques was 4.6 (95% CI 1.1 to 18.9), and there was a significant linear trend (P=0.015) for higher risk with increasing plaque echolucency. The adjusted relative risk for a 10% increase in the degree of stenosis was 1.2 (95% CI 1.04 to 1.4). CONCLUSIONS: Subjects with echolucent atherosclerotic plaques have increased risk of ischemic cerebrovascular events independent of degree of stenosis and cardiovascular risk factors. Subjects at high risk for ischemic vascular events may be identified by ultrasound assessment of plaque morphology.

Low levels of high-density lipoprotein cholesterol are associated with echolucent carotid artery plaques: the tromsø study.

BACKGROUND AND PURPOSE: Ultrasound-assessed plaque morphology is an independent predictor of ischemic stroke. The purpose of this population-based cross-sectional nested case-control study was to examine the risk factors associated with carotid plaque morphology. METHODS: Ultrasonography of the right carotid artery was conducted on 6727 participants in a population health survey (response rate 79%). Plaque echogenicity, defined as reflectance of the emitted ultrasound signal, was scored as echolucent, predominantly echolucent, predominantly echogenic, or echogenic. Information on cardiovascular risk factors in all 216 participants who had carotid stenosis and in 223 control subjects matched by age and sex who did not have carotid stenosis was obtained from measurements of blood pressure, weight, height, and nonfasting blood samples and from a self-administered questionnaire. RESULTS: In both univariate and multivariate analyses, low levels of HDL cholesterol and increasing degree of stenosis were independently associated with an increased risk of having an echolucent plaque. For 1-SD increase in HDL cholesterol, the adjusted odds of being in a lower plaque echogenicity category decreased by approximately 30% (OR 0.69, 95% CI 0.52 to 0.93). CONCLUSIONS: These findings indicate that low levels of HDL cholesterol are associated with an increased risk of having echolucent, rupture-prone atherosclerotic plaques.

Insulin resistance in hypertension is associated with body fat rather than blood pressure.

The insulin resistance syndrome has been characterized by hypertension, upper body obesity, insulin resistance, hyperinsulinemia, glucose intolerance, and hypertriglyceridemia. Previous studies are inconsistent regarding the relationship between blood pressure and insulin resistance. We therefore compared the metabolic profile in 60 hypertensive subjects (mean+/-SD arterial pressure, 116+/-7 mm Hg) and 60 normotensive subjects (mean arterial pressure, 88+/-5 mm Hg) matched for age, gender, and body mass index. Hypertensives had significantly higher waist-to-hip ratio than normotensives (P=0.002). The groups did not differ in fasting plasma glucose (0.2 mmol/L, P=0.09), insulin (6 pmol/L, P=0.14), insulin sensitivity index (-0.01 micromol x kg(-1) x min(-1) x pmol/L(-1), P=0.7), and suppression of nonesterified fatty acids during a hyperglycemic clamp (1%, P=0.40). There were significant differences in fasting levels of C-peptide (50 pmol/L, P=0.004) and proinsulin (2 pmol/L, P=0.01), 2-hour postload levels of glucose (0.8 mmol/L, P=0.01) and insulin (84 pmol/L, P=0.01) after oral glucose challenge, and hepatic glucose production during the clamp (2.87 micromol x kg(-1) x min(-1), P=0.02). These differences were not significant when controlling for waist-to-hip ratio. Body mass index and waist-to-hip ratio were similarly associated with the insulin sensitivity index in the hypertensive (r=-0.59, P=0.0001 and r=-0.32, P=0.05) and normotensive (r=-0.58, P=0.0001 and r=-0.39, P=0.05) groups. Hypertension per se is not associated with insulin resistance. However, even small increments in both body mass index and waist-to-hip ratio, as often seen in hypertension, may lead to impairment in insulin sensitivity, probably mediated through altered lipid metabolism.

Plasma saturated and linoleic fatty acids are independently associated with blood pressure.

The role of individual fatty acids in blood pressure regulation is unclear. We studied the cross-sectional relationship of blood pressure, total plasma phospholipid fatty acid concentrations, and proportions of individual fatty acids among participants in a population study. Blood pressure was measured automatically, and plasma phospholipid fatty acids were determined by gas-liquid chromatography in 4033 healthy men 40 to 42 years old. Significant positive linear associations existed between total fatty acids and saturated fatty acids and blood pressure, whereas polyunsaturated linoleic acid was inversely associated with blood pressure. In multiple regression analyses, a 2-SD increase in total fatty acids was associated with an increase of 6.0 (95% CI, 5.1 to 6.8) mm Hg systolic blood pressure. A 2-SD increase in saturated palmitic acid was associated with 1.4 (95% CI, 0.5 to 2.3) mm Hg increase in systolic blood pressure. In contrast, a 2-SD increase in polyunsaturated linoleic acid was associated with a 1.9 (95% CI, 1.0 to 2.8) mm Hg decrease in systolic blood pressure. We conclude that plasma levels of total fatty acids, saturated fatty acids, and polyunsaturated linoleic acid are independently associated with blood pressure. The present study supports the hypothesis that the composition of dietary fat influences blood pressure.

Serum calcium and cardiovascular risk factors and diseases: the Tromsø study.

Total serum calcium levels were measured in 12 865 men and 14 293 women, between the ages of 25 and 97 years, in the Tromsø Study during 1994 and 1995. With the use of a sex-specific multiple linear regression model with age, calcium, body mass index, cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and pulse as possible covariates, serum calcium was significantly (P<0.001) and positively associated with systolic and diastolic blood pressure, serum cholesterol, and HDL cholesterol in both sexes. A similar but weaker association was observed between serum calcium and triglycerides in men (P<0.01). In all age groups, serum calcium levels were higher in men with a history of myocardial infarction than in those without, and the difference was significant (P<0.0001) in a linear regression analysis adjusted for age. When all the other variables were also included in a logistic regression model, serum calcium was a highly significant (P<0.0001) predictor of myocardial infarction in men, with an odds ratio of 1.2 per 0.1 mmol/L increase in serum calcium. In women, a nonsignificant trend was again seen. Because the free or ionized form of calcium is the physiologically important form and serum calcium was not corrected for serum albumin in our study, the results must be interpreted with caution. However, it appears likely that serum calcium is a predictor of cardiovascular disease in men.

Calcium from dairy products, vitamin D intake, and blood pressure: the Tromso Study.

BACKGROUND: The present epidemiologic study was conducted in Tromso, Northern Norway, in 1994-1995. OBJECTIVE: The objective was to evaluate the relation between calcium intake from dairy products and the intake of vitamin D on systolic and diastolic blood pressure. DESIGN: Subjects who were taking drugs for hypertension or heart disease, those taking calcium tablets, subjects reporting cardiovascular disease, and pregnant women were excluded, leaving 7543 men and 8053 women aged 25-69 y for analysis. Calcium and vitamin D intakes were calculated from a food-frequency questionnaire. RESULTS: After correction for age, body mass index, alcohol and coffee consumption, physical activity, cigarette smoking, and vitamin D intake, there was a significant linear decrease in systolic and diastolic blood pressure with increasing dairy calcium intake in both sexes (P < 0.05). However, the difference in blood pressure between subjects with the highest and those with the lowest calcium intake was

Habitual fish consumption, plasma phospholipid fatty acids, and serum lipids: the Tromsø study.

We examined the cross-sectional relationships between the frequency of habitual fish consumption, plasma phospholipid fatty acids, and serum lipids and lipoproteins in 152 men and women. There was a significant association between fish consumption starting from 1 dish/wk and plasma n-3, n-6, and n-9 fatty acids. Plasma eicosapentaenoic acid (EPA; 20: 5n-3) reflected fish consumption to a greater extent than did docosahexaenoic acid (DHA;22:6n-3). Triglycerides decreased (P less than 0.05) with fish consumption. In multivariate analysis in which anthropometric and lifestyle factors were controlled for, EPA correlated inversely with triglycerides (P less than 0.05) and positively with high-density-lipoprotein (HDL) cholesterol and apolipoprotein A-I (both P less than 0.001). In contrast, DHA did not correlate with triglycerides and showed negative associations to HDL cholesterol and apolipoprotein A-I (both P less than 0.001). Platelet phospholipid EPA, but not DHA, was associated with lower triglyceride and higher HDL-cholesterol concentrations (both P less than 0.05). This study suggests that long-term intake of small amounts of fish has biological effects, and that EPA and DHA have divergent relations with lipoprotein metabolism.

Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids.

To compare the effects of highly purified ethyl ester concentrates of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on serum lipids, apolipoproteins, and serum phospholipid fatty acids in humans, we conducted a double-blind, placebo-controlled, parallel design intervention study. Healthy nonsmoking men (n = 234) aged 36-56 y were randomly assigned to dietary supplementation with 3.8 g EPA/d, 3.6 g DHA/d, or 4.0 g corn oil/d (placebo) for 7 wk. Serum triacylglycerols decreased 26% (P < 0.0001) in the DHA group and 21% (P = 0.0001) in the EPA group compared with the corn oil group. Although not significant, net decreases in serum triacylglycerols were consistently greater in the DHA group across all quartiles of baseline triacylglycerol concentrations. Serum high-density-lipoprotein cholesterol increased 0.06 mmol/L (P = 0.0002) in the DHA group. In the EPA group, serum total cholesterol decreased 0.15 mmol/L (P = 0.02) and apolipoprotein A-I decreased 0.04 g/L (P = 0.0003). In the DHA group, serum phospholipid DHA increased by 69% and EPA increased by 29%, indicating retroconversion of DHA to EPA. In the EPA group, serum phospholipid EPA increased by 297% whereas DHA decreased by 15%, suggesting that EPA is not elongated to DHA in humans. The serum phospholipid ratio of n-3 to n-6 fatty acids increased in both groups, whereas the relative changes in n-6 fatty acids suggested possible alterations in liver desaturation activity in the DHA group. We conclude that both DHA and EPA decrease serum triacylglycerols, but have differential effects on lipoprotein and fatty acid metabolism in humans.

Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans.

The hemodynamic effects of highly purified eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) have not been evaluated in humans. We therefore conducted a randomized, double-blind, parallel-design intervention study to assess possible separate effects of EPA and DHA on blood pressure, heart rate, and cardiac mechanics. Healthy, nonsmoking men aged 36-56 y (n = 224) were randomly assigned to dietary supplementation with 4 g/d of ethyl ester concentrates of DHA or EPA or 4 g corn oil/d (control). Mean blood pressure at baseline was 122/77 mm Hg and was positively associated with concentrations of serum phospholipid saturated fatty acids. Blood pressure did not change during the intervention. Mean heart rate at baseline was 63.4 beats/min; it decreased 2.2 beats/min in the DHA group (P = 0.006 compared with control), increased 1.9 beats/min in the EPA group (P = 0.04 compared with control), and remained practically unchanged in the control group. In a pooled analysis, changes in heart rate were independent of baseline heart rate and were associated with changes in concentrations of serum phospholipid DHA and docosapentaenoic acid (22:5n-3). Echocardiography in a subsample of 52 men showed improved left ventricular diastolic filling in the marine oil groups compared with the corn oil group (P = 0.02). In contrast, an increase in plasma concentrations of saturated fatty acids was associated with delayed diastolic filling. We conclude that dietary DHA and EPA influence heart rate and that the fatty acid composition of plasma phospholipids may affect cardiac mechanics in humans.

Age and sex differences in the relationship between inherited and lifestyle risk factors and subclinical carotid atherosclerosis: the Tromsø study.

BACKGROUND: Ultrasound measurement of carotid artery intima-media thickness (IMT) is regarded as a valid index of atherosclerosis. Age and sex differences in the distribution of, and risk factors for, IMT have not been investigated thoroughly. METHODS: In 1994-1995 a total of 6408 men and women aged 25-84 years living in the municipality of Tromsø, Norway, underwent ultrasound examination of carotid artery IMT and measurements of cardiovascular risk factors. RESULTS: Age, systolic blood pressure, total cholesterol, HDL cholesterol, body mass index, and smoking were independent predictors of IMT in both sexes. Fibrinogen levels and physical activity were associated with IMT in men only, whereas triglyceride levels were associated with IMT independently of HDL cholesterol in women only. A family history of cardiovascular disease (CVD) was an independent predictor of IMT in both sexes, also when controlling for traditional CVD risk factors. The magnitude of the association between most risk factors and IMT did not differ depending on age, but the effects of physical activity and triglycerides were more pronounced at higher age. CONCLUSION: These data suggest that there are significant age and sex differences in the distribution and the determinants of subclinical atherosclerosis.

Population based study on serum ionised calcium, serum parathyroid hormone, and blood pressure. The Tromsø study.

OBJECTIVE: To study associations between serum ionised calcium, serum parathyroid hormone (PTH) and blood pressure. DESIGN: A population based, cross-sectional study was used. METHODS: Blood pressure, body mass index, serum ionised calcium and serum PTH were measured in 460 males and 486 females in the Tromso study in 1994/1995. None were on medication for hypertension. The data were analysed with a multiple linear regression model. RESULTS: When looking at subjects with serum ionised calcium<1.39mmol/l, there was a significant negative association (P<0.01) between serum ionised calcium and PTH. There was no association between blood pressure and serum ionised calcium. In both sexes there was a significant positive association between age and serum PTH (P<0.01). For women, but not for men, there was a significant positive association between serum PTH and systolic and diastolic blood pressure (P<0.01). Within each age group there was a difference in both systolic and diastolic blood pressure of 3-10mmHg between the upper and lower serum PTH halves of the female population. Females with hypertension had significantly higher serum PTH levels than the normotensive females (P<0.01). CONCLUSION: Serum PTH is strongly and positively associated with blood pressure in women.

Primary hyperparathyroidism detected in a health screening. The Trømsø study.

Serum calcium was measured in 12,339 men and 13,394 women ages 25 to 75. Primary hyperparathyroidism, defined as a combination of serum calcium and parathyroid hormone (PTH) levels within the extreme or upper normal range, was diagnosed in 17 men and 47 women. The prevalence in both sexes increased with age. When 42 subjects with asymptomatic primary hyperparathyroidism were followed for 3 years, no significant increase in serum calcium or PTH was seen. In a subgroup of 473 men and 517 women ages 50 to 75, serum PTH was measured along with serum calcium. Depending on the criteria used to define primary hyperparathyroidism, the prevalence in older women within this subgroup ranged from 3.6% to 13.9%. The study concluded that a high prevalence of primary hyperparathyroidism exists in older women, although the progression of the disease, judging by serum calcium and PTH measurements, appears to be very slow.

Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: The Tromsø Study.

Early menopause has been associated with higher prevalence and incidence of cardiovascular disease and death than late menopause, indicating that early loss of ovarian function and subsequent deficiency of estrogen may promote such diseases. No population-based studies have, however, examined the relation between age at menopause and atherosclerosis. We assessed the prevalence and the extent of carotid atherosclerosis by high-resolution B-mode ultrasound in 2588 postmenopausal women who participated in a population health survey. Information about age at menopause and menarche, parity, use of hormone replacement therapy, and prevalent diseases was collected, and cardiovascular risk factor levels were measured. Women with late menopause and women who ever had used postmenopausal estrogens had significantly less atherosclerosis than women with early menopause and those with never use of estrogen. This study provides further support for the hypothesis that estrogen protects women against cardiovascular disease.

The reproducibility of dietary data from a self-administered questionnaire. The Tromsø Study.

The reproducibility of a self-administered questionnaire about dietary habits was assessed by comparing answers from 201 men and women to identical questions posed in two surveys separated by approximately one year. In spite of possible changes in the diet in the time period between the two surveys, the concordance between the information was high, both concerning type of food item most commonly eaten and the frequency with which the food items were consumed. The highest reproducibility was found for food items consumed habitually (e.g. alcohol) or often (e.g. coffee). The results are in accordance with most other similar studies, and support the use of self-administered questionnaires in nutritional epidemiology.

Serum total homocysteine and coronary heart disease.

BACKGROUND: Several studies have observed high plasma levels of homocysteine among patients with coronary heart disease (CHD). The only prospective study was based on US physicians, and concluded that homocysteine was associated with subsequent myocardial infarction (MI). However, the association was limited to those above a threshold level of homocysteine. METHODS: We conducted a nested case-control study among the 21,826 subjects, aged 12-61 years, who were surveyed in the municipality of Tromsø, Norway. Among those free from MI at the screening, 123 later developed CHD. Four controls were selected for each case. RESULTS: Level of homocysteine was higher in cases than in controls (12.7 +/- 4.7 versus 11.3 +/- 3.7 mumol/l (mean +/- SD); P = 0.002). The relative risk for a 4 mumol/l increase in serum homocysteine was 1.41 (95% confidence interval (CI): 1.16-1.71). Adjusting for possible confounders reduced the relative risk to 1.32 (95% CI: 1.05-1.65). There was no threshold level above which serum homocysteine is associated with CHD events. CONCLUSIONS: In the general population serum total homocysteine is an independent risk factor for CHD with no threshold level.

Population-based study of the relationship among muscle morphology, insulin action, and hypertension.

To examine whether changes in muscle morphology are linked to the metabolic abnormalities associated with the insulin resistance syndrome, muscle morphology and the metabolic profile were examined in 52 individuals with untreated hypertension (mean arterial pressure [MAP] = 117+/-7 mm Hg) and 38 carefully matched controls (MAP = 89+/-5 mm Hg). Oral glucose tolerance tests and hyperglycemic clamps were performed for measurements of insulin action on glucose disposal and suppression of nonesterified fatty acids (NEFA). Fully automated, computer-aided techniques were used for morphometric measurements of muscle biopsies from m. vastus lateralis. The hypertensive and normotensive groups did not differ in insulin sensitivity to glucose disposal (0.18+/-0.16 v. 0.19+/-0.13 micromol/kg/min/pmol/L; P = .20) and NEFA suppression (87.5+/-7.3 v. 87.2+/-9.4%, P>0.30) during a hyperglycemic clamp. The groups were similar in the proportion of types 1, 2a, and 2b muscle fibers, fiber size, and capillary density. Fiber roundness (ratio of fiber perimeter squared to fiber area) differed in the hypertensive (1.51+/-0.07) and normotensive (1.58+/-0.12, P = .004) groups, showing that the muscle fibers in the hypertensive group were more rounded in shape, a nonspecific change often seen after minimal ischemic lesions. The quotient expressing fiber roundness was associated with systolic (r = -0.29, P = .01) and diastolic (r = -0.32, P = .005) blood pressure. We conclude that persons with mild and moderate hypertension do not have abnormalities in muscle morphology that could explain the impairment of insulin action often observed in this condition. However, hypertensive individuals have increased muscle fiber roundness. It is wondered whether hypertension may be a condition with defects in the regulation of the transmembranous ion transport, leading to raised intracellular sodium concentration, swelling of the cytoplasma, and roundening of the fibers.

Insulin kinetics, insulin action, and muscle morphology in lean or slightly overweight persons with impaired glucose tolerance.

Glucose intolerance is influenced by body fat mass, as well as muscle fiber composition. To examine the relation between the metabolic profile and muscle morphology in this condition, we performed muscle biopsies and hyperglycemic clamps to determine insulin secretion and clearance, and the insulin effects on glucose disposal and nonesterified fatty acids (NEFA) in 45 glucose intolerant persons (body mass index [BMI], 27.8 +/- 3.0 kg/m2) and 45 normoglycemic controls (BMI, 25.8 +/- 2.7 kg/m2) (P = .001). After adjustment for BMI, glucose-intolerant subjects had lower first-phase insulin release (726 v 954 pmol/L, P = .04). Glucose-intolerant subjects and controls differed in fasting insulin, insulin clearance, and insulin sensitivity to glucose disposal before, but not after, standardizing for BMI. During the clamp, glucose-intolerant subjects had less NEFA suppression and elevated levels of NEFA compared with controls (85% +/- 9% v 90% +/- 6%, P = .02; and 70 +/- 42 micromol/L v 45 +/- 28 micromol/L, P = .01). Glucose-intolerant subjects also had a higher percentage of insulin-insensitive, type 2b muscle fibers, which are not adapted for fat oxidation (7% +/- 9% v 9% +/- 9%, P = .003). BMI was not associated with NEFA suppression or the percentage of type 2b muscle fibers in either group. In conclusion, glucose-intolerant persons have impaired first-phase insulin release, an elevated percentage of type 2b muscle fibers, and increased NEFA availability. Reduced insulin clearance, hyperinsulinemia, and insulin resistance were associated with small increments in BMI.

Dietary supplementation with highly purified eicosapentaenoic acid and docosahexaenoic acid does not influence PAI-1 activity.

Impaired fibrinolysis due to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) is a risk factor for atherothrombotic disease. Many studies have reported a positive correlation between serum triglycerides and PAI-1 activity. Dietary intervention with very long n-3 fatty acids from marine sources is known to decrease serum triglycerides, but an adverse increase in PAI-1 activity has been reported in some studies. A double blind, placebo controlled study was conducted among 224 middle-aged (ages 36-56), healthy, non-smoking men in which the participants were randomly assigned to daily supplementation with 3.8 g eicosapentaenoic acid/d, 3.6 g docosahexaenoic acid/d, or 4.0 g corn oil/d (placebo) for 7 weeks. PAI-1 activity increased by 2.35+/-6.24 U/ml (28%), 1.15+/-6.74 U/ml (14%), and 1.33+/-5.64 U/ml (22%) during dietary supplementation with eicosapentaenoic acid, docosahexaenoic acid, and corn oil, respectively, but the changes were not significantly different between groups. There was no relationship between change in concentrations of serum triglycerides or phospholipid n-3 fatty acids and change in PAI-1 activity. At baseline, analysis was performed to investigate the influence of dietary lipids, blood lipids, and serum fatty acids on plasma concentrations of PAI-1 activity. Dietary intake of saturated fat correlated directly with PAI-1 both in crude analysis and after adjustment for age and body mass index (kg/m(2)). Furthermore, PAI-1 was associated with body mass index, apo-B100, serum triglycerides, and the concentration of n-6 polyunsaturated fatty acids in serum. In a multiple regression analysis, 21% of the variation in PAI-1 activity could be explained by these variables. Plasma PAI-1 activity did not correlate with dietary intake or serum concentrations of n-3 polyunsaturated fatty acids. In a review of 17 trials, including 935 subjects that assessed the effect of n-3 fatty acids on PAI-1 activity, an overall 17.7% increase in PAI-1 activity was estimated by n-3 supplementation. However, only two studies were able to demonstrate a significant increase in PAI-1 attributable to n-3 fatty acid supplementation. We conclude that there is no strong evidence for an unfavourable, clinically relevant effect of n-3 fatty acids on PAI-1 activity in plasma.

Serum lipids and regulation of tissue factor-induced coagulation in middle-aged men.

Formation of an occlusive thrombus by exposure of tissue factor (TF) to circulating blood and subsequent triggering of coagulation by TF-activated factor VII (FVIIa) complexes on ruptured atherosclerotic plaques is thought to be a key event in myocardial infarction. Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of TF-induced coagulation in which the anticoagulant function most probably is restricted to free TFPI in human plasma. The present study was undertaken to assess the interrelations between serum lipids and components of TF-induced coagulation in 234 apparently healthy men aged 36-56 years recruited from the general population. Plasma free TFPI antigen (Ag) was positively correlated (P < .001) with total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B (apoB-100), fibrinogen, total amount of FVII (FVIIam), coagulation activity of factor VII (FVIIc), and FVIIa. The significant predictors for free TFPI Ag were total cholesterol, triglycerides, fibrinogen, FVIIc, and age, which explained 33% of the plasma variation in free TFPI Ag assessed by multiple regression analysis. A highly significant (P < .0001) linear trend for increase in atherogenic lipids (i.e., total cholesterol and triglycerides), FVII (i.e., FVIIc and FVIIa), and fibrinogen across quartiles of TFPI Ag was demonstrated after adjustment for confounders. These findings may indicate a compensatory increase in plasma free TFPI with lipid and hemostatic risk factors for atherothrombotic diseases in healthy middle-aged men.