Kaare H. Bønaa

Echolucent Plaques Are Associated With High Risk of Ischemic Cerebrovascular Events in Carotid Stenosis The Tromsø Study

BackgroundThe 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 ResultsA 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). ConclusionsSubjects 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.

Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension: a population-based intervention trial from the Tromsø study.

Studies of whether polyunsaturated fatty acids in fish oil--in particular, eicosapentaenoic and docosahexaenoic acids--lower blood pressure have varied in design and results. We conducted a population-based, randomized, 10-week dietary-supplementation trial in which the effects of 6 g per day of 85 percent eicosapentaenoic and docosahexaenoic acids were compared with those of 6 g per day of corn oil in 156 men and women with previously untreated stable, mild essential hypertension. The mean systolic blood pressure fell by 4.6 mm Hg (P = 0.002), and diastolic pressure by 3.0 mm Hg (P = 0.0002) in the group receiving fish oil; there was no significant change in the group receiving corn oil. The differences between the groups remained significant for both systolic (6.4 mm Hg; P = 0.0025) and diastolic (2.8 mm Hg; P = 0.029) pressure after control for anthropometric, lifestyle, and dietary variables. The decreases in blood pressure were larger as concentrations of plasma phospholipid n-3 fatty acids increased (P = 0.027). Dietary supplementation with fish oil did not change mean blood pressure in the subjects who ate fish three or more times a week as part of their usual diet, or in those who had a base-line concentration of plasma phospholipid n-3 fatty acids above 175.1 mg per liter. We conclude that eicosapentaenoic and docosahexaenoic acids reduce blood pressure in essential hypertension, depending on increases in plasma phospholipid n-3 fatty acids.

Risk Factors Related to Carotid Intima-Media Thickness and Plaque in Children With Familial Hypercholesterolemia and Control Subjects

To assess the relationship between risk factors for cardiovascular disease and early atherosclerotic changes in the carotid artery, we measured carotid intima-media thickness by B-mode ultrasonography in 61 boys and 29 girls 10 to 19 years old with familial hypercholesterolemia (FH) and 30 control subjects matched for age and sex. All were nonsmokers, and all the FH adolescents had a known mutation in the LDL receptor gene. Mean intima-media thickness in the far wall of the carotid bulb was greater (P = .03) in the FH group than in the control subjects: 0.54 mm (95% confidence interval [CI], 0.52 to 0.56) versus 0.50 mm (95% CI, 0.47 to 0.52). In the entire group, mean and maximum intima-media thicknesses in the carotid bulb were positively associated with levels of apolipoprotein B and fibrinogen after control for pubertal stage (r = .19 to .24; P < .05), as was male sex. Plasma total homocysteine was similar in the FH and control groups and was associated with mean and maximum intima-media thicknesses in the far wall of the common carotid artery and carotid bulb after control for pubertal stage (r = .22 to .28; P < .05). With the exception of the relation between plasma fibrinogen level and mean carotid bulb intima-media thickness, these associations were essentially unchanged in stepwise multiple linear regression analyses, allowing for the entry of BMI and level of HDL cholesterol into the analysis. Carotid artery plaque was present in 10% of the children with FH versus none of the control subjects. Children with plaque had a higher mean cholesterol-years score than children without plaque. These findings suggest that the classic lipid and hemostatic risk factors as well as plasma total homocysteine are associated with markers of early carotid atherosclerosis from the second decade of life. B-mode ultrasonography may prove to be a useful tool in risk stratification of children with FH.

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12

CONTEXT Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES Cancer incidence, cancer mortality, and all-cause mortality. RESULTS During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00671346.

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals

BACKGROUND Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99–1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.

Carotid Plaque Area and Intima-Media Thickness in Prediction of First-Ever Ischemic Stroke A 10-Year Follow-Up of 6584 Men and Women: The Tromsø Study

Background and Purpose— Carotid plaque and intima-media thickness (IMT) are recognized as risk factors for ischemic stroke, but their predictive value has been debated and varies between studies. The purpose of this longitudinal population-based study was to assess the risk of ischemic stroke associated with plaque area and IMT in the carotid artery. Methods— IMT and total plaque area in the right carotid artery were measured with ultrasound in 3240 men and 3344 women aged 25 to 84 years who participated in a population health study in 1994 to 1995. First-ever ischemic strokes were identified through linkage to hospital and national diagnosis registries, with follow-up until December 31, 2005. Results— Incident ischemic strokes occurred in 7.3% (n=235) of men and 4.8% (n=162) of women. The hazard ratio for 1 SD increase in square-root-transformed plaque area was 1.23 (95% CI, 1.09–1.38; P=0.0009) in men and 1.19 (95% CI, 1.01–1.41; P=0.04) in women when adjusted for other cardiovascular risk factors. The multivariable-adjusted hazard ratio in the highest quartile of plaque area versus no plaque was 1.73 (95% CI, 1.19–2.52; P=0.004) in men and 1.62 (95% CI, 1.04–2.53; P=0.03) in women. The multivariable-adjusted hazard ratio for 1 SD increase in IMT was 1.08 (95% CI, 0.95–1.22; P=0.2) in men and 1.24 (95% CI, 1.05–1.48; P=0.01) in women. There were no differences in stroke risk across quartiles of IMT in multivariable analysis. Conclusions— In the present study, total plaque area appears to be a stronger predictor than IMT for first-ever ischemic stroke.

Validity of Self-Reported Stroke The Tromsø Study

BACKGROUND AND PURPOSE The aim of this study was to validate the diagnosis of self-reported stroke. METHODS During 1994-1995, 27 159 people attended a population health survey in the community of Tromso, Norway, a response rate of 77%. A total of 418 attenders reported a history of stroke. In 1997, all individuals with a self-reported stroke who were still living in the community (n=362) were invited to a clinical reexamination. For each of the 269 people who were reexamined, a person who reported no history of stroke was selected and was reexamined in the same way. RESULTS On the basis of the reexamination, 213 (79.2%) of the self-reported strokes were confirmed. Thirteen individuals (4.8%) had a possible stroke. The remaining 43 individuals had either transient ischemic attack (TIA; n=18), traumatic head injuries (n=16), or perinatal cerebral damage, complicated migraine, syncope, possible TIA, or cerebral aneurysm without bleeding (n=9). Among the confirmed strokes, 30 (14.1%) were hemorrhagic and 118 (55.4%) were thromboembolic. Of the 30 hemorrhages, 16 were subarachnoidal bleedings, 10 due to ruptured aneurysms. The histories of stroke, including both the symptoms and the signs, often had a paucity of details and precision, making it impossible to classify 65 stroke victims (30.5%) into stroke subtypes. The positive predictive value (PPV) of a self-reported stroke was 0.79. The PPV was significantly (P=0.016) greater in men (0.88) than in women (0.73). Individuals older than 60 years had a significantly greater PPV than those younger than 60 years (PPV 0.83 and 0.73, respectively; P=0.05). Hypertension was associated with a greater PPV, whereas a history of either ischemic heart disease, diabetes mellitus, lung disease, or depression had no impact on the PPV. The estimated sensitivity of self-reported stroke in the survey population was approximately 80% and the specificity was 99%. CONCLUSIONS We conclude that a self-administered questionnaire can be used to assess the prevalence of stroke in epidemiological research.

Reduced neuropsychological test performance in asymptomatic carotid stenosis: The Tromsø Study

Objective: To assess the relationship between asymptomatic carotid stenosis, neuropsychological test performance, and silent MRI lesions. Methods: Performance on several neuropsychological tests was compared in 189 subjects with ultrasound-assessed carotid stenosis and 201 control subjects without carotid stenosis, recruited from a population health study. Subjects with a previous history of stroke were excluded. The test battery included tests of attention, psychomotor speed, memory, language, speed of information processing, motor functioning, intelligence, and depression. Sagittal T1-weighted and axial and coronal T2-weighted spin echo MRI was performed, and presence of MRI lesions (white matter hyperintensities, lacunar and cortical infarcts) was recorded. Results: Subjects with carotid stenosis had significantly lower levels of performance in tests of attention, psychomotor speed, memory, and motor functioning, independent of MRI lesions. There were no significant differences in tests of speed of information processing, word association, or depression. Cortical infarcts and white matter hyperintensities were equally distributed among persons with and without carotid stenosis. Lacunar infarcts were more frequent in the stenosis group (p = 0.03). Conclusions: Carotid stenosis was associated with poorer neuropsychological performance. This could not be explained by a higher proportion of silent MRI lesions in persons with asymptomatic carotid stenosis, making it less likely that the cognitive impairment was caused by silent emboli.

Reproducibility of Ultrasound Assessment of Carotid Plaque Occurrence, Thickness, and Morphology The Tromsø Study

BACKGROUND AND PURPOSE Ultrasonography is increasingly used in vascular research, but there is limited information about the reproducibility of the ultrasound method for screening purposes. In this study the reproducibility of ultrasound assessment of carotid plaque occurrence, thickness, and morphology was examined within the setting of a population health survey. METHODS In 1994/1995, 6720 participants in the Tromsø Study, Norway, underwent B-mode ultrasound scanning of the right carotid artery. The between- and within-sonographer reproducibility of ultrasound assessment of plaque occurrence and thickness was estimated by repeated scanning of a random sample of 107 participants. The between- and within-sonographer reproducibility of plaque morphology classification (echogenicity, four categories and heterogeneity, two categories) was determined by repeated reading of videotaped images of 119 randomly selected arteries with plaques. RESULTS Between- and within-sonographer agreement on plaque occurrence was substantial with kappa values (95% CI) of 0.72 (0.60 to 0.84) and 0.76 (0.63 to 0.89), respectively. Reproducibility of plaque thickness measurements was moderate, with mean absolute differences ranging between 0.25 and 0.55 mm (coefficients of variation between 13.8% and 22.4%). Agreement on plaque morphology classification was high, with kappa values ranging between 0.54 and 0.73. CONCLUSIONS Population screening using B-mode ultrasound provides a valuable means for the detection and morphological evaluation of carotid plaques, whereas measurements of plaque thickness are subject to considerable measurement error.

Association between blood pressure and serum lipids in a population. The Tromsø Study.

BackgroundHigh blood pressure has been associated with elevated atherogenic blood lipid fractions, but epidemiological surveys often give inconsistent results across population subgroups. A better understanding of the relation between blood pressure and blood lipids may provide insight into the mechanism(s) whereby hypertension is associated with increased risk of coronary heart disease. Methods and ResultsWe assessed the cross-sectional relations of serum total cholesterol, high density lipoprotein (HDL) cholesterol, non-HDL cholesterol (total minus HDL cholesterol), and triglyceride levels with blood pressure in a population of 8,081 men 20-54 years old and 7,663 women 20-49 years old. Stratified analyses and multivariable methods were used to control for potential confounding anthropometric and lifestyle variables. Total and non-HDL cholesterol levels increased significantly with increasing systolic or diastolic blood pressure in both sexes. Men 20-29 years old had steeper regression slopes for blood pressure by total cholesterol level than did women of similar age. In men, the association between blood pressure and total cholesterol level decreased with age, whereas in women, it increased with age. Body mass index modified the relation, whereas smoking, physical activity, and alcohol consumption had little influence on the association. Triglyceride levels increased with blood pressure, but this relation was weak in lean subjects. HDL cholesterol level correlated positively with blood pressure in population subgroups having a high alcohol consumption. ConclusionsThese results support the hypothesis that there are biological interrelations between blood pressure and blood lipids that may influence the mechanisms whereby blood pressure is associated with risk of coronary heart disease.