The stenotic carotid artery plaque : prevalence, risk factors and relations to clinical disease : the Tromsø study

Stroke is the second leading cause of death in the world and is responsible for a high percentage of major disability, requiring substantial resources spent on care and rehabilitation. Atherosclerosis due to lipid accumulation in the vessel wall with formation of stenotic atheromatous plaques in the carotid bifurcation and/or the internal carotid artery is an important cause of stroke. In 1991, two large, multi-center trials reported that carotid endarterectomy was of benefit to patients with a degree of stenosis above 70%, and thus showed that the degree of stenosis was a major risk factor for ipsilateral stroke. However, it is well known that many high-grade stenoses remain stable and never cause cerebrovascular events, while others develop rapidly and produce serious, potentially life-threatening disease. While the majority of patients presenting with transient ischemic attack (TIA) and stroke has an ipsilateral carotid lesion, only about half of them have a hemodynamically significant carotid stenosis. Only 5-15% of strokes are heralded by a TIA. This has led to a search for additional risk factors which might help identify the individuals with a high risk for stroke

Trends in prevalence of ultrasound-assessed carotid atherosclerosis in a general population over time. The Tromsø Study 1994-2016

Background: During the past decades, there has been a shift in risk factor levels in many high-income countries, with decrease in smoking, blood pressure and cholesterol levels, while body mass index, obesity and diabetes increase. The diverging trends may have opposite effects on prevalence of atherosclerosis. We aimed to assess carotid plaque prevalence and the association with risk factor levels in a general population over a period of 22 years. Methods: Prevalence of plaque, number of plaques and total plaque area in the carotid arteries were assessed in three repeated cross-sectional surveys of the population-based Tromsø Study from 1994 through 2016. The number of participants from the first to the last survey was 6362, 7069 and 3021. All surveys included physical examinations, questionnaires, and blood samples. Multivariable logistic regression analysis models were fitted to assess the relationship between risk factors and carotid plaque. Results: We found no significant change in plaque burden over a period of 22 years, neither when measured as plaque presence, plaque number or total plaque area. Plaques were more frequent in men (70%) than in women (59.4%) and increased by age. Systolic blood pressure and smoking increased, while BMI and diabetes decreased over time both in participants with and without plaque. Most risk factors remained higher in participants with plaque than in plaque- free participants while cholesterol levels decreased and reached similar levels in both groups. Age, male sex, systolic blood pressure, smoking, diabetes and HDL cholesterol (inverse) were associated with plaque prevalence. Conclusions: Plaque prevalence remained stable in the observation period. Favorable reductions in systolic blood pressure, cholesterol and smoking may have been partly counteracted by increased diabetes prevalence. Risk factor levels remained higher in participants with plaque than in plaque-free participants, indicating a potential for further improvement in primary prevention of carotid atherosclerosis

Data from national health registers as endpoints for the Tromsø Study: Correctness and completeness of stroke diagnoses

Aim: To assess whether stroke diagnoses in national health registers are sufficiently correct and complete to replace manual collection of endpoint data for the Tromsø Study, a population-based epidemiological study. Method: Using the Tromsø Study Cardiovascular Disease Register for 2013–2014 as the gold standard, we calculated correctness (defined as positive predictive value, PPV) and completeness (defined as sensitivity) of stroke cases in four different data subsets derived from the Norwegian Patient Register and the Norwegian Stroke Register. We calculated the sensitivity and PPV with 95% confidence intervals (CIs) assuming a normal approximation of the binomial distribution. Results: In the Norwegian Stroke Register we found a sensitivity of 79.8% (95% CI 74.2–85.4) and a PPV of 97.5% (95% CI 95.1–99.9). In the Norwegian Patient Register the sensitivity was 86.4% (95% CI 81.6–91.1) and the PPV was 84.2% (95% CI 79.2–89.2). The overall highest levels were found in a subset based on a linkage between the Norwegian Stroke Register and the Norwegian Patient Register, with a sensitivity of 88.9% (95% CI 84.5–93.3), and a PPV of 89.3% (95% CI 85.0–93.6). Conclusions: Data from the Norwegian Patient Register and from the linked data set between the Norwegian Patient Register and the Norwegian Stroke Register had acceptable levels of correctness and completeness to be considered as endpoint sources for the Tromsø Study Cardiovascular Disease Register. The benefits of using data from national registers as endpoints in epidemiological studies must be weighed against the impact of potentially decreased data quality

Wake-up stroke and unknown-onset stroke; occurrence and characteristics from the nationwide Norwegian Stroke Register

Introduction: Population-based knowledge of the characteristics of wake-up stroke and unknown-onset stroke is limited. We compared occurrence and characteristics of ischaemic and haemorrhagic wake-up stroke, unknown-onset stroke and known-onset stroke in a nationwide register-based study. Patients and methods: We included patients registered in the Norwegian Stroke Register from 2012 through 2019. Age, sex, risk factors, clinical characteristics, acute stroke treatment and discharge destination were compared according to stroke type and time of onset. Results: Of the 60,320 patients included, 11,451 (19%) had wake-up stroke, 11,098 (18.4%) had unknown time of onset and 37,771 (62.6%) had known symptom onset. The proportion of haemorrhagic stroke was lower among wakeup stroke patients (1107/11,451, 9.7%, 95% CI: 9.1–10.2) than for known-onset stroke (5230/37,771, 13.8%, 95% CI: 13.5–14.2) and for unknown-onset stroke (1850/11,098, 16.7%, 95% CI: 16.0–17.4). Mild stroke (NIHSS Discussion and conclusions: Ischaemic wake-up strokes shared baseline characteristics with known-onset strokes, but tended to be milder. Ischaemic unknown-onset stroke patients differed significantly from wake-up stroke, emphasising the importance of considering them as separate entities

Pain tolerance after stroke: The Tromsø study

Background: Stroke lesions might alter pain processing and modulation by affecting the widely distributed network of brain regions involved. We aimed to compare pain tolerance in stroke survivors and stroke-free persons in the general population, with and without chronic pain. Methods: We included all participants of the sixth and seventh wave of the population-based Tromsø Study who had been tested with the cold pressor test (hand in cold water bath, 3°C, maximum time 106 s in the sixth wave and 120 s in the seventh) and who had information on previous stroke status and covariates. Data on stroke status were obtained from the Tromsø Study Cardiovascular Disease Register and the Norwegian Stroke Register. Cox regression models were fitted using stroke prior to study attendance as the independent variable, cold pressor endurance time as time variable and hand withdrawal from cold water as event. Statistical adjustments were made for age, sex, diabetes, hypertension, hyperlipidaemia, body mass index and smoking. Results: In total 21,837 participants were included, 311 of them with previous stroke. Stroke was associated with decreased cold pain tolerance time, with 28% increased hazard of hand withdrawal (hazard ratio [HR] 1.28, 95% CI 1.10–1.50). The effect was similar in participants with (HR 1.28, 95% CI 0.99–1.66) and without chronic pain (HR 1.29, 95% CI 1.04–1.59). Conclusions: Stroke survivors, with and without chronic pain, had lower cold pressor pain tolerance, with possible clinical implications for pain in this group. Significance: We found lower pain tolerance in participants with previous stroke compared to stroke-free participants of a large, population-based study. The association was present both in those with and without chronic pain. The results may warrant increased awareness by health professionals towards pain experienced by stroke patients in response to injuries, diseases and procedures

Prevalence of unruptured intracranial aneurysms: impact of different definitions-the Tromsø Study

Background - Management of incidental unruptured intracranial aneurysms (UIAs) remains challenging and depends on their risk of rupture, estimated from the assumed prevalence of aneurysms and the incidence of aneurysmal subarachnoid haemorrhage. Reported prevalence varies, and consistent criteria for definition of UIAs are lacking. We aimed to study the prevalence of UIAs in a general population according to different definitions of aneurysm. Methods - Cross-sectional population-based study using 3-dimensional time-of-flight 3 Tesla MR angiography to identify size, type and location of UIAs in 1862 adults aged 40–84 years. Size was measured as the maximal distance between any two points in the aneurysm sac. Prevalence was estimated for different diameter cutoffs (≥1, 2 and 3 mm) with and without inclusion of extradural aneurysms. Results - The overall prevalence of intradural saccular aneurysms ≥2 mm was 6.6% (95% CI 5.4% to 7.6%), 7.5% (95% CI 5.9% to 9.2%) in women and 5.5% (95% CI 4.1% to 7.2%) in men. Depending on the definition of an aneurysm, the overall prevalence ranged from 3.8% (95% CI 3.0% to 4.8%) for intradural aneurysms ≥3 mm to 8.3% (95% CI 7.1% to 9.7%) when both intradural and extradural aneurysms ≥1 mm were included. Conclusion - Prevalence in this study was higher than previously observed in other Western populations and was substantially influenced by definitions according to size and extradural or intradural location. The high prevalence of UIAs sized <5 mm may suggest lower rupture risk than previously estimated. Consensus on more robust and consistent radiological definitions of UIAs is warranted

Serum osteoprotegerin and renal function in the general population: The Tromsø Study

The following article: Vik, A., Brodin, E.E., Mathiesen, E.B., Brox, J., Jørgensen, L., Njølstad, I., ... Hansen, J.-B. (2017). Serum osteoprotegerin and renal function in the general population: The Tromsø Study. Clinical Kidney Journal, 10(1), 38-44. https://doi.org/10.1093/ckj/sfw095, has been accepted for publication in Clinical Kidney Journal Published by Oxford University Press. Source at https://doi.org/10.1093/ckj/sfw095. Published manuscript version, licensed CC BY-NC-ND 4.0.Background: Serum osteoprotegerin (OPG) is elevated in patients with chronic kidney disease (CKD) and increases with decreasing renal function. However, there are limited data regarding the association between OPG and renal function in the general population. The aim of the present study was to explore the relation between serum OPG and renal function in subjects recruited from the general population. Methods: We conducted a cross-sectional study with 6689 participants recruited from the general population in Tromsø, Norway. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equations. OPG was modelled both as a continuous and categorical variable. General linear models and linear regression with adjustment for possible confounders were used to study the association between OPG and eGFR. Analyses were stratified by the median age, as serum OPG and age displayed a significant interaction on eGFR. Results: In participants ≤62.2 years with normal renal function (eGFR ≥90 mL/min/1.73 m2) eGFR increased by 0.35 mL/min/1.73 m2 (95% CI 0.13–0.56) per 1 standard deviation (SD) increase in serum OPG after multiple adjustment. In participants older than the median age with impaired renal function (eGFR 2), eGFR decreased by 1.54 (95% CI −2.06 to −1.01) per 1 SD increase in serum OPG. Conclusions: OPG was associated with an increased eGFR in younger subjects with normal renal function and with a decreased eGFR in older subjects with reduced renal function. Our findings imply that the association between OPG and eGFR varies with age and renal function

Genetic variations in the Vitamin D receptor predict type 2 diabetes and myocardial infarction in a community-based population: The tromsø study

Background Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population. Methods and Findings Measurements and DNA were obtained from the participants in the Tromsø Study in 1994– 1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05–1.49) for T2D and 1.14 (1.02–1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints. Conclusions The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed

Population distribution of traditional and the emerging cardiovascular risk factors carotid plaque and IMT: the REFINE-Reykjavik study with comparison with the Tromsø study

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOBJECTIVES: Population statistics for carotid plaque and cardiovascular risk factors reported in scientific journals are usually presented as averages for the population or age and sex adjusted, rather than sex and age groups. Important population differences about atherosclerosis and cardiovascular risk factors may thus be missed. We compare the distribution of cardiovascular risk factors, carotids plaque and carotid intima-media thickness (CIMT) in two population-based studies. METHODS: Carotid artery atherosclerotic plaque prevalence and risk factors levels for cardiovascular disease by sex in 5-year age groups from the Risk Evaluation For Infarct Estimates Reykjavik study (REFINE-Reykjavik study) were compared with data from the Tromsø 6 study. RESULTS: The threshold of carotid plaque presence in the Tromsø 6 study fell between minimal and moderate plaque defined in the REFINE-Reykjavik study reflecting carotid plaque prevalence. The prevalence of minimal carotid plaque in the REFINE-Reykjavik study was 47% in men (40-69 years old) and 38% in women and 11% in men and 7% in women of moderate plaque. The prevalence of any plaque in the Tromsø 6 study was 35% in men and 27% in women. The mean (CIMT) was similar in the studies. In the Tromsø 6 study mean systolic blood pressure was 8 mm Hg higher in men and 10 mm Hg higher in women, mean low-density lipoprotein was 0.5 mmol/L higher in men and 0.3 mmol/L higher in women and the prevalence of smoking was 4% higher in men and 9% higher in women. However, body mass index was 0.8 kg/m2 higher in men and 0.9 kg/m2 in women in the REFINE-Reykjavik study. CONCLUSION: Comparison between Iceland and Norway revealed differences in the prevalence of carotid plaque, which was assumed to be due to different definition of plaque. However, clinically significant differences in conventional cardiovascular risk factors were seen. This underscores the importance of detailed comparison of population data across different populations.RANNIS (The Icelandic Centre for Research) Hjartavernd (Icelandic Heart Association

Joint effect of myocardial infarction and obesity on the risk of venous thromboembolism: The Tromsø Study

Background: Myocardial infarction (MI) is associated with an increased risk of venous thromboembolism (VTE). Obesity is a recognized risk factor for both MI and VTE. Whether obesity further increases the risk of VTE in MI patients is scarcely investigated. Aim: To study the joint effect of MI and obesity on the risk of VTE. Methods: Study participants (n = 29 410) were recruited from three surveys of the Tromsø Study (conducted in 1994–1995, 2001, and 2007–2008) and followed up through 2014. All incident MI and VTE cases during follow-up were recorded. Cox regression models with MI as a time-dependent variable were used to estimate hazard ratios (HRs) of VTE (adjusted for age and sex) by combinations of MI exposure and obesity status. Joint effects were assessed by calculating relative excess risk and attributable proportion (AP) due to interaction. Results: During a median of 19.6 years of follow-up, 2090 study participants experienced an MI and 784 experienced a VTE. Among those with MI, 55 developed a subsequent VTE, yielding an overall incidence rate (IR) of VTE of 5.3 per 1000 personyears (95% confidence interval [CI]: 4.1–6.9). In the combined exposure group (MI+/ Obesity+), the IR was 11.3 per 1000 person-years, and the adjusted HR indicated a 3-fold increased risk of VTE (HR 3.16, 95% CI: 1.99–4.99) compared to the reference group (MI−/Obesity−). The corresponding AP was 0.46 (95% CI: 0.17–0.74). Conclusions: The combination of MI and obesity yielded a supra-additive effect on VTE risk of which 46% of the VTE events were attributed to the interaction