Stein Harald Johnsen

Carotid Atherosclerosis Is a Stronger Predictor of Myocardial Infarction in Women Than in Men: A 6-Year Follow-Up Study of 6226 Persons: The Tromsø Study

Background and Purpose— Ultrasound of carotid arteries provides measures of intima media thickness (IMT) and plaque, both widely used as surrogate measures of cardiovascular disease. Although IMT and plaques are highly intercorrelated, the relationship between carotid plaque and IMT and cardiovascular disease has been conflicting. In this prospective, population-based study, we measured carotid IMT, total plaque area, and plaque echogenicity as predictors for first-ever myocardial infarction (MI). Methods— IMT, total plaque area, and plaque echogenicity were measured in 6226 men and women aged 25 to 84 years with no previous MI. The subjects were followed for 6 years and incident MI was registered. Results— During follow-up, MI occurred in 6.6% of men and 3.0% of women. The adjusted relative risk (RR; 95% CI) between the highest plaque area tertile versus no plaque was 1.56 (1.04 to 2.36) in men and 3.95 (2.16 to 7.19) in women. In women, there was a significant trend toward a higher MI risk with more echolucent plaque. The adjusted RR (95% CI) in the highest versus lowest IMT quartile was 1.73 (0.98 to 3.06) in men and 2.86 (1.07 to 7.65) in women. When we excluded bulb IMT from analyses, IMT did not predict MI in either sex. Conclusions— In a general population, carotid plaque area was a stronger predictor of first-ever MI than was IMT. Carotid atherosclerosis was a stronger risk factor for MI in women than in men. In women, the risk of MI increased with plaque echolucency.

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.

Monocyte Count Is a Predictor of Novel Plaque Formation. A 7-Year Follow-up Study of 2610 Persons Without Carotid Plaque at Baseline. The Tromsø Study

Background and Purpose— Activation of monocytes and differentiation into lipid-laden macrophages are fundamental events in generation of atherosclerotic lesions. There exist few data on monocyte activity and the risk for atherosclerosis. In this prospective population-based study, we examined whether monocyte count in blood is a predictor of future plaque formation in persons without pre-existing carotid atherosclerosis. Methods— At baseline, we measured monocyte count, white cell count (WCC), fibrinogen, intima-media thickness (IMT), and traditional cardiovascular risk factors in 2610 men and women aged 25 to 82 years who on ultrasound had no plaque in their right carotid artery. After 7 years of follow-up, a new ultrasound screening was performed and the number of novel plaques was grouped as none, 1 plaque, and 2 or more plaques. Results— In multivariate analysis, monocyte count, age, sex, total cholesterol, current smoking, systolic blood pressure, and IMT were independent predictors of novel plaque formation. No significant association was found between plaque formation and either WCC or fibrinogen. For 1 standard deviation (0.17×109) increase in monocyte count, the risk of being in a higher plaque category increased by 18% (OR, 1.18; 95% CI, 1.08 to 1.29). In the highest monocyte quartile, the risk for having plaque compared with the lowest quartile was 1.85 (OR) (95% confidence interval, 1.41 to 2.43). Repeating the analysis without IMT did not change the monocyte estimate. Excluding subjects with cardiovascular disease and diabetes mellitus from analysis neither changed the monocyte estimate. Conclusion— Monocyte count is an independent predictor of future plaque formation in subjects without pre-existing carotid atherosclerosis.

Elevated High-Density Lipoprotein Cholesterol Levels Are Protective Against Plaque Progression A Follow-Up Study of 1952 Persons With Carotid Atherosclerosis The Tromsø Study

Background—There is an inverse relationship between HDL cholesterol and coronary heart disease. Experimental studies have indicated that HDL cholesterol may exert an antiatherogenic effect by inducing regression of atherosclerotic plaques and by turning lipid-rich plaques into more fibrotic lesions. In this prospective, population-based ultrasound study, we investigated how HDL cholesterol relates to carotid plaque progression. Methods and Results—The study included 1952 men and women aged 25 to 82 years who had at least 1 plaque present in the right carotid artery at baseline examination (1994). All plaque images were computer processed to yield a measure of plaque area in square millimeters and echogenicity, expressed as the gray-scale median. After 7 years of follow-up, a new ultrasound screening was performed, and the changes in plaque area and echogenicity were assessed. In a multivariable adjusted model, HDL cholesterol, age, systolic blood pressure, and current smoking were independent predictors of plaque growth. For a 1-SD (0.41 mmol/L) lower HDL cholesterol level, mean (SE) plaque area increased by 0.93 mm2 (0.44 mm2; P=0.03). When users of lipid-lowering drugs were excluded from analysis, the HDL estimate was strengthened (&bgr;=1.46 mm2, P=0.002). Although plaque area increased in 70% of cases, and most plaques became more echogenic over the follow-up interval, the plaques that became more echolucent grew more in size than those that became more echogenic (P=0.002). Conclusions—This study shows that a high level of HDL cholesterol reduces plaque growth in subjects with preexisting carotid atherosclerosis. Transformation of the plaque mass into higher echogenicity is associated with reduced growth. Our findings may indicate that HDL cholesterol stabilizes plaques and counteracts their growth by reducing their lipid content and inflammation.

Risk Factors for Progression of Carotid Intima-Media Thickness and Total Plaque Area A 13-Year Follow-Up Study: The Tromsø Study

Background and Purpose Data on risk factors for progression of intima-media thickness (IMT) and plaque are scarce. The objective was to determine long-term risk factors for total plaque area (TPA) and IMT as well as risk factors for progression (&Dgr;TPA and &Dgr;IMT). Methods Subjects were 1307 men and 1436 women who participated in a longitudinal population-based study with ultrasound examination of the right carotid artery at baseline and after 13 years of follow-up. Total cholesterol, high-density lipoprotein cholesterol, blood pressure, body mass index, and information about smoking habits, prevalent diabetes, and cardiovascular disease were obtained at baseline. Carotid atherosclerosis was assessed as TPA and mean IMT of plaque-free segments of the common carotid artery. Associations between z-scores of risk factors and carotid atherosclerosis were assessed in multiple linear regression models. Results In multivariable models, total cholesterol, systolic blood pressure, and smoking were stronger predictors of follow-up TPA than of IMT, whereas sex and age were stronger predictors of IMT. Total cholesterol (standardized &bgr;=0.081), systolic blood pressure (standardized &bgr;=0.062), and smoking (standardized &bgr;=0.107) were significant predictors of &Dgr;TPA, whereas only total cholesterol (standardized &bgr;=0.084) was an independent predictor of &Dgr;IMT. The variance explained by traditional cardiovascular risk factors was somewhat greater for TPA than for IMT. Conclusions The cardiovascular risk factors total cholesterol, smoking, and systolic blood pressure were stronger long-term predictors of TPA and TPA progression than for IMT and IMT progression.

Atherosclerosis in Abdominal Aortic Aneurysms: A Causal Event or a Process Running in Parallel? The Tromsø Study

Objective—The pathogenesis of abdominal aortic aneurysm (AAA) formation is poorly understood. We investigated the relationship between carotid, femoral, and coronary atherosclerosis and abdominal aortic diameter, and whether atherosclerosis was a risk marker for AAA. Methods and Results—Ultrasound of the right carotid artery, the common femoral artery, and the abdominal aorta was performed in 6446 men and women from a general population. The burden of atherosclerosis was assessed as carotid total plaque area, common femoral lumen diameter, and self-reported coronary heart disease. An AAA was defined as maximal infrarenal aortic diameter ≥30 mm. No dose-response relationship was found between carotid atherosclerosis and abdominal aortic diameter <27 mm. However, significantly more atherosclerosis and coronary heart disease was found in aortic diameter ≥27 mm and in AAAs. The age- and sex-adjusted odds ratio (OR) (95% CI) for AAA in the top total plaque area quintile was 2.3 (1.5 to 3.4), as compared with subjects without plaques. The adjusted OR (95% CI) was 1.7 (1.1 to 2.6). No independent association was found between femoral lumen diameter and AAA. Conclusion—The lack of a consistent dose-response relationship between atherosclerosis and abdominal aortic diameter suggests that atherosclerosis may not be a causal event in AAA but develops in parallel with or secondary to aneurismal dilatation.

Carotid Atherosclerosis Predicts Lower Cognitive Test Results: A 7-Year Follow-Up Study of 4,371 Stroke-Free Subjects – The Tromsø Study

Background: Carotid artery atherosclerosis is a major risk factor for stroke and subsequent cognitive impairment. Prospective population studies have shown associations between carotid intima-media thickness (IMT) and stenosis and cognitive decline and dementia in elderly stroke-free persons, whereas results in the middle-aged are conflicting. Methods: In this prospective population-based study, 4,371 stroke-free middle-aged participants underwent carotid ultrasound examination and assessment of vascular risk factors at baseline and were tested for cognitive function 7 years later. Associations between IMT, number of plaques and total plaque area and cognitive test scores on verbal memory test, digit symbol-coding test and tapping test were assessed in linear regression models. Results: In the multivariable analyses adjusted for sex, age, education, depression and vascular risk factors, the presence of plaques was significantly associated with lower test scores on the verbal memory test (p = 0.01) and on the digit symbol-coding test (p = 0.03). The number of plaques (p = 0.01) and the total plaque area (p = 0.02) were associated with lower scores on the verbal memory test. No significant association was seen between common carotid artery IMT and cognitive test scores. The tapping test was not associated with the carotid ultrasound variables. Conclusions: In this middle-aged general population, subclinical carotid atherosclerosis measured as the presence of plaques, number of plaques and total plaque area were independent long-term predictors of lower cognitive test scores.

The metabolic syndrome and progression of carotid atherosclerosis over 13 years. The Tromsø study

BackgroundThe metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease. In this study, we examine if metabolic syndrome predicts progression of atherosclerosis over 13 years.MethodsParticipants were 1442 men and 1532 women in the population-based Tromsø Study who underwent carotid ultrasound examinations at baseline in the 4th (1994–5) and at follow-up in the 6th survey (2007–8). Of these, 278 men and 273 women fulfilled the criteria for the MetS, defined according to a modified version of the National Cholesterol Education Program Adult Treatment Panel III (NCEP, ATPIII). Carotid atherosclerosis was assessed as total plaque area (TPA) and mean intima-media thickness (IMT) at follow-up and as change in IMT and TPA from baseline to follow-up. Associations between MetS and its components and carotid atherosclerosis were assessed in linear regression models adjusted for age, total cholesterol and daily smoking, stratified by sex.ResultsIMT and TPA levels at follow-up (p < 0.0001) and progression of TPA (p = 0.02) were higher in the MetS group compared to the non-MetS group. In stepwise multivariable models, MetS was associated with TPA (β = 0.372 mm2, p = 0.009) and IMT (β = 0.051 mm, p < 0.0001) in men, and with IMT (β = 0.045 mm, p = 0.001) in women after 13 years of follow-up, but not with progression of IMT or TPA. In analyses stratified by age, MetS predicted progression of IMT (β = 0.043 mm, p = 0.046) and TPA (β = 1.02 mm2, p = 0.002) in men below 50 years of age. Hypertension was predictive of follow-up TPA and IMT in both genders and of progression of TPA in women. Impaired glucose tolerance was associated with follow up levels of IMT and TPA as well as progression in IMT in men. None of the other components of MetS were associated with progression of atherosclerosis.ConclusionsSubjects with MetS had higher levels of IMT and TPA at follow up than those without MetS. Mets predicted progression of IMT and TPA in those below 50 years of age, but not in other age groups, indicating that MetS may be involved in the initiation of the atherosclerotic process.

Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population – the Tromsø study

Summary.  Background: Intervention studies in animal models suggest that osteoprotegerin (OPG) functions as an inhibitor or marker of atherosclerosis, whereas one prospective epidemiological study in humans indicated that OPG was an independent risk factor for progression of atherosclerosis. Objective: To study the association between serum levels of OPG, soluble RANK ligand (sRANKL) and carotid artery plaque formation and plaque growth. Patients/methods: The prevalence of carotid plaque and plaque area were assessed by ultrasonographic imaging at baseline and after 7 years follow‐up in 2191 men and 2329 women who participated in a population‐based study. Results: OPG was significantly associated with atherosclerotic plaque burden and cardiovascular risk factors such as age, body mass index, blood pressure, total cholesterol, HDL cholesterol, HbA1c and fibrinogen at baseline, but not with sRANKL. In subjects without plaque at baseline, OPG predicted plaque formation in crude analysis in both women and men, but not after adjustment for age and other atherosclerotic risk factors. OPG predicted plaque growth in women (+1.8 mm2, 0.6–3.0) (mean, 95% CI) per 1 SD increase in OPG (P = 0.003), whereas no associations were demonstrated in men (0.1 mm2 (−1.3–1.4), P = 0.93). Soluble RANKL did not predict plaque formation or plaque growth. Conclusions: OPG was an independent predictor of plaque growth in women, but not in men, suggesting gender‐specific actions of OPG in plaque growth. OPG was not associated with novel plaque formation.

Individual progression of carotid intima media thickness as a surrogate for vascular risk (PROG-IMT): Rationale and design of a meta-analysis project

Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data. Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points. Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan.