Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.

AIMS: To identify robust circulating predictors for incident atrial fibrillation (AF) using classical regressions and machine learning (ML) techniques within a broad spectrum of candidate variables. METHODS AND RESULTS: In pooled European community cohorts (n = 42 280 individuals), 14 routinely available biomarkers mirroring distinct pathophysiological pathways including lipids, inflammation, renal, and myocardium-specific markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI]) were examined in relation to incident AF using Cox regressions and distinct ML methods. Of 42 280 individuals (21 843 women [51.7%]; median [interquartile range, IQR] age, 52.2 [42.7, 62.0] years), 1496 (3.5%) developed AF during a median follow-up time of 5.7 years. In multivariable-adjusted Cox-regression analysis, NT-proBNP was the strongest circulating predictor of incident AF [hazard ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001]. Further, hsTnI [HR per SD, 1.18 (95% CI, 1.13-1.22); P < 0.001], cystatin C [HR per SD, 1.16 (95% CI, 1.10-1.23); P < 0.001], and C-reactive protein [HR per SD, 1.08 (95% CI, 1.02-1.14); P = 0.012] correlated positively with incident AF. Applying various ML techniques, a high inter-method consistency of selected candidate variables was observed. NT-proBNP was identified as the blood-based marker with the highest predictive value for incident AF. Relevant clinical predictors were age, the use of antihypertensive medication, and body mass index. CONCLUSION: Using different variable selection procedures including ML methods, NT-proBNP consistently remained the strongest blood-based predictor of incident AF and ranked before classical cardiovascular risk factors. The clinical benefit of these findings for identifying at-risk individuals for targeted AF screening needs to be elucidated and tested prospectively.

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.

Prevalence of intracranial artery stenosis in a general population using 3D-time of flight magnetic resonance angiography.

BACKGROUND: Data on prevalence of intracranial artery stenosis (ICAS) in Western populations is sparse. The aim of the study was to assess the prevalence and risk factors for ICAS in a mainly Caucasian general population. METHODS: We assessed the prevalence of ICAS in 1847 men and women aged 40 to 84 years who participated in a cross-sectional population-based study, using 3-dimensional time-of-flight 3 Tesla magnetic resonance angiography. ICAS was defined as a focal luminal flow diameter reduction of ≥50 %. The association between cardiovascular risk factor levels and ICAS was assessed by multivariable regression analysis. RESULTS: The overall prevalence of ICAS was 6.0 % (95 % confidence interval (CI) 5.0-7.2), 4.3 % (95 % CI 3.1-5.7) in women and 8.0 % (95 % CI 6.3-10.0) in men. The prevalence increased by age from 0.8 % in 40-54 years age group to 15.2 % in the 75-84 years age group. The majority of stenoses was located to the internal carotid artery (52.2 %), followed by the posterior circulation (33.1 %), the middle cerebral artery (10.8 %) and the anterior cerebral artery (3.8 %). The risk of ICAS was independently associated with higher age, male sex, hypertension, hyperlipidemia, diabetes mellitus, current smoking and higher BMI. CONCLUSIONS: The prevalence of ICAS in a general population of Caucasians was relatively high and similar to the prevalence of extracranial internal carotid artery stenosis in previous population-based studies.

Obesity Does Not Protect From Subarachnoid Hemorrhage: Pooled Analyses of 3 Large Prospective Nordic Cohorts.

BACKGROUND: Several population-based cohort studies have related higher body mass index (BMI) to a decreased risk of subarachnoid hemorrhage (SAH). The main objective of our study was to investigate whether the previously reported inverse association can be explained by modifying effects of the most important risk factors of SAH-smoking and hypertension. METHODS: We conducted a collaborative study of three prospective population-based Nordic cohorts by combining comprehensive baseline data from 211 972 adult participants collected between 1972 and 2012, with follow-up until the end of 2018. Primarily, we compared the risk of SAH between three BMI categories: (1) low (BMI<22.5), (2) moderate (BMI: 22.5-29.9), and (3) high (BMI≥30) BMI and evaluated the modifying effects of smoking and hypertension on the associations. RESULTS: We identified 831 SAH events (mean age 62 years, 55% women) during the total follow-up of 4.7 million person-years. Compared with the moderate BMI category, persons with low BMI had an elevated risk for SAH (adjusted hazard ratio [HR], 1.30 [1.09-1.55]), whereas no significant risk difference was found in high BMI category (HR, 0.91 [0.73-1.13]). However, we only found the increased risk of low BMI in smokers (HR, 1.49 [1.19-1.88]) and in hypertensive men (HR, 1.72 [1.18-2.50]), but not in nonsmokers (HR, 1.02 [0.76-1.37]) or in men with normal blood pressure values (HR, 0.98 [0.63-1.54]; interaction HRs, 1.68 [1.18-2.41], P=0.004 between low BMI and smoking and 1.76 [0.98-3.13], P=0.06 between low BMI and hypertension in men). CONCLUSIONS: Smoking and hypertension appear to explain, at least partly, the previously reported inverse association between BMI and the risk of SAH. Therefore, the independent role of BMI in the risk of SAH is likely modest.

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.

Urinary orosomucoid is associated with diastolic dysfunction and carotid arteriopathy in the general population. Cross-sectional data from the Tromsø study.

Objectives. Urinary albumin excretion is a risk marker for cardiovascular disease (CVD). Studies suggest that urinary orosomucoid may be a more sensitive marker of general endothelial dysfunction than albuminuria. The aim of this population-based cross-sectional study was to examine the associations between urinary orosomucoid to creatinine ratio (UOCR), urinary albumin to creatinine ratio (UACR) and subclinical CVD. Design. From the Tromsø Study (2007/2008), we included all men and women who had measurements of urinary orosomucoid (n = 7181). Among these, 6963 were examined with ultrasound of the right carotid artery and 2245 with echocardiography. We assessed the associations between urinary markers and subclinical CVD measured as intima media thickness of the carotid artery, presence and area of carotid plaque and diastolic dysfunction (DD). UOCR and UACR were dichotomized as upper quartile versus the three lowest. Results. High UOCR, adjusted for UACR, age, cardiovascular risk factors and kidney function, was associated with presence of DD in men (OR: 3.18, 95% CI [1.27, 7.95], p = .013), and presence of plaque (OR: 1.20, 95% CI [1.01, 1.44], p = .038) and intima media thickness in women (OR: 1.34, 95% CI [1.09, 1.65], p = .005). Analyses showed no significant interaction between sex and UOCR for any endpoints. UACR was not significantly associated with DD, but the associations with intima media thickness and plaque were of magnitudes comparable to those observed for UOCR. Conclusions. UOCR was positively associated with subclinical CVD. We need prospective studies to confirm whether UOCR is a clinically useful biomarker and to study possible sex differences.

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

AIMS: There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts. METHODS AND RESULTS: In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF. CONCLUSIONS: In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.

Decompressive hemicraniectomy for space-occupying brain infarction: Nationwide population-based registry study.

OBJECTIVE: We analyzed data from the Norwegian Stroke Registry (NSR) to study access to and outcomes of decompressive hemicraniectomy for brain infarction in a nationwide routine clinical setting. We also discretionary assessed whether the outcomes were comparable with those achieved in randomized controlled trials (RCTs), and whether the use was in accordance with guidelines. METHODS: The NSR is a nationwide (population 5.3 million) clinical quality registry. We included all stroke-cases operated in 2017 through 2019, and retrieved data on baseline characteristics, treatment and functional outcome after three months (dichotomized modified Rankin Scale score; favorable (0-3) or unfavorable (4-6)). Crude treatment rates and the expected proportion of patients transferred from a local hospital to a stroke-center for the operation were estimated, based on the total population's distribution of residency. RESULTS: The 68 cases were 17 (25%) women and 51 (75%) men with a median National Institute of Health Stroke Scale (NIHSS) score on admission of 14.0 (inter-quartile range (IQR) 11.0) and a median time from onset to hemicraniectomy of 34.3 (IQR 40.9) hours. The crude treatment rate varied between regions from 0.29 to 1.40 operations per 100,000 population per year, and the proportion transferred from a local hospital (50%) was lower than expected (68%). A favorable outcome was achieved in 20/52 (38.5%) cases. CONCLUSIONS: The findings indicate gender- and geographic-inequalities in access. Among operated cases, outcomes were comparable with those reported from RCTs, and the use in accordance with recommendations in the current guidelines from the American Stroke Association.

Long-Term Survival, Causes of Death, and Trends in 5-Year Mortality After Intracerebral Hemorrhage: The Tromsø Study.

BACKGROUND AND PURPOSE: Data on long-term survival after intracerebral hemorrhage (ICH) are scarce. In a population-based nested case-control study, we compared long-term survival and causes of death within 5 years in 30-day survivors of first-ever ICH and controls, assessed the impact of cardiovascular risk factors on 5-year mortality, and analyzed time trend in 5-year mortality in ICH patients over 2 decades. METHODS: We included 219 participants from the population-based Tromsø Study, who after the baseline participation had a first-ever ICH between 1994 to 2013 and 1095 age- and sex-matched participants without ICH. Cumulative survival was presented using the Kaplan-Meier method. Hazard ratios (HRs) for mortality and for the association between cardiovascular risk factors and 5-year mortality in 30-day survivors were estimated by stratified Cox proportional hazards models. Trend in 5-year mortality was assessed by logistic regression. RESULTS: Risk of death during follow-up (median time, 4.8 years) was increased in the ICH group compared with controls (HR, 1.62 [95% CI, 1.27-2.06]). Cardiovascular disease was the leading cause of death, with a higher proportion in ICH patients (22.9% versus 9.0%; P<0.001). Smoking increased the risk of 5-year mortality in cases and controls (HR, 1.59 [95% CI, 1.15-2.19]), whereas serum cholesterol was associated with 5-year mortality in cases only (HR, 1.39 [95% CI, 1.04-1.86]). Use of anticoagulants at ICH onset increased the risk of death (HR, 2.09 [95% CI, 1.09-4.00]). There was no difference according to ICH location (HR, 1.15 [95% CI, 0.56-2.37]). Five-year mortality did not change during the study period (odds ratio per calendar year, 1.01 [95% CI, 0.93-1.09]). CONCLUSIONS: Survival rates were significantly lower in cases than in controls, driven by a 2-fold increased risk of cardiovascular death. Smoking, serum cholesterol, and use of anticoagulant drugs were associated with increased risk of death in ICH patients. Five-year mortality rates in ICH patients remained stable over time.

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke.

BACKGROUND: About one in five strokes occur during sleep (wake-up stroke). People with wake-up strokes have previously been considered to be ineligible for thrombolytic treatment because the time of stroke onset is unknown. However, recent studies suggest benefit from recanalisation therapies in selected patients. OBJECTIVES: To assess the effects of intravenous thrombolysis and endovascular thrombectomy versus control in people with acute ischaemic stroke presenting on awakening from sleep. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last search 24 of May 2021). In addition, we searched the following electronic databases in May 2021: Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 4 of 12, April 2021) in the Cochrane Library, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We searched the Stroke Trials Registry (last search 7 December 2017, as the site is currently inactive). We also screened references lists of relevant trials, contacted trialists, and undertook forward tracking of relevant references. SELECTION CRITERIA: Randomised controlled trials (RCTs) of intravenous thrombolytic drugs or endovascular thrombectomy treatments in people with acute ischaemic stroke presenting upon awakening. DATA COLLECTION AND ANALYSIS: Two review authors applied the inclusion criteria, extracted data, and assessed risk of bias and the certainty of the evidence using the GRADE approach. We obtained both published and unpublished data for participants with wake-up strokes. We excluded participants with strokes of unknown onset if the symptoms did not begin upon awakening. MAIN RESULTS: We included seven trials with a total of 980 participants, of which five trials with 775 participants investigated intravenous thrombolytic treatment and two trials with 205 participants investigated endovascular thrombectomy in large vessel occlusion in the anterior intracranial circulation. All trials used advanced imaging for selecting patients to treat. For intravenous thrombolytic treatment, good functional outcome (defined as modified Rankin Scale score 0 to 2) at 90 days follow-up was observed in 66% of participants randomised to thrombolytic treatment and 58% of participants randomised to control (risk ratio (RR) 1.13, 95% confidence interval (CI) 1.01 to 1.26; P = 0.03; 763 participants, 5 RCTs; high-certainty evidence). Seven per cent of participants randomised to intravenous thrombolytic treatment and 10% of participants randomised to control had died at 90 days follow-up (RR 0.68, 95% CI 0.43 to 1.07; P = 0.09; 763 participants, 5 RCTs; high-certainty evidence). Symptomatic intracranial haemorrhage occurred in 3% of participants randomised to intravenous thrombolytic treatment and 1% of participants randomised to control (RR 3.47, 95% CI 0.98 to 12.26; P = 0.05; 754 participants, 4 RCTs; high-certainty evidence). For endovascular thrombectomy of large vessel occlusion, good functional outcome at 90 days follow-up was observed in 46% of participants randomised to endovascular thrombectomy and 9% of participants randomised to control (RR 5.12, 95% CI 2.57 to 10.17; P < 0.001; 205 participants, 2 RCTs; high-certainty evidence). Twenty-two per cent of participants randomised to endovascular thrombectomy and 33% of participants randomised to control had died at 90 days follow-up (RR 0.68, 95% CI 0.43 to 1.07; P = 0.10; 205 participants, 2 RCTs; high-certainty evidence). AUTHORS' CONCLUSIONS: In selected patients with acute ischaemic wake-up stroke, both intravenous thrombolytic treatment and endovascular thrombectomy of large vessel occlusion improved functional outcome without increasing the risk of death. However, a possible increased risk of symptomatic intracranial haemorrhage associated with thrombolytic treatment cannot be ruled out. The criteria used for selecting patients to treatment differed between the trials. All studies were relatively small, and six of the seven studies were terminated early. More studies are warranted in order to determine the optimal criteria for selecting patients for treatment.

Long-term blood pressure trajectories and incident atrial fibrillation in women and men: the Tromsø Study.

AIMS: To explore sex-specific associations between long-term individual blood pressure (BP) patterns and risk of incident atrial fibrillation (AF) in the general population. METHODS AND RESULTS: Blood pressure was measured in 8376 women and 7670 men who attended at least two of the three population-based Tromsø Study surveys conducted in 1986-87, 1994-95, and 2001. Participants were followed for incident AF throughout 2013. Latent mixed modelling was used to identify long-term trajectories of systolic BP and hypertension. Cox regression was used to estimate associations between the identified trajectories and incident AF. Elevated systolic BP throughout the exposure period (1986-2001) independently and differentially increased risk of AF in women and men. In women, having elevated systolic BP trajectories doubled AF risk compared to having persistently low levels, irrespective of whether systolic BP increased, decreased, or was persistently high over time, with hazard ratios of 1.88 (95% confidence interval 1.37-2.58), 2.32 (1.61-3.35), and 1.94 (1.28-2.94), respectively. In men, those with elevated systolic BP that continued to increase over time had a 50% increased AF risk: 1.51 (1.09-2.10). When compared to those persistently normotensive, women developing hypertension during the exposure period, and women and men with hypertension throughout the exposure period had 1.40 (1.06-1.86), 2.75 (1.99-3.80), and 1.36 (1.10-1.68) times increased risk of AF, respectively. CONCLUSION: Long-term BP and hypertension trajectories were associated with increased incidence of AF in both women and men, but the associations were stronger in women.

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Temporal relations between atrial fibrillation and ischaemic stroke and their prognostic impact on mortality.

AIMS: Limited evidence is available on the temporal relationship between atrial fibrillation (AF) and ischaemic stroke and their impact on mortality in the community. We sought to understand the temporal relationship of AF and ischaemic stroke and to determine the sequence of disease onset in relation to mortality. METHODS AND RESULTS: Across five prospective community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project we assessed baseline cardiovascular risk factors in 100 132 individuals, median age 46.1 (25th-75th percentile 35.8-57.5) years, 48.4% men. We followed them for incident ischaemic stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Over a median follow-up of 16.1 years, N = 4555 individuals were diagnosed solely with AF, N = 2269 had an ischaemic stroke but no AF diagnosed, and N = 898 developed both, ischaemic stroke and AF. Temporal relationships showed a clustering of diagnosis of both diseases within the years around the diagnosis of the other disease. In multivariable-adjusted Cox regression analyses with time-dependent covariates subsequent diagnosis of AF after ischaemic stroke was associated with increased mortality [hazard ratio (HR) 4.05, 95% confidence interval (CI) 2.17-7.54; P < 0.001] which was also apparent when ischaemic stroke followed after the diagnosis of AF (HR 3.08, 95% CI 1.90-5.00; P < 0.001). CONCLUSION: The temporal relations of ischaemic stroke and AF appear to be bidirectional. Ischaemic stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Future research needs to investigate the common underlying systemic disease processes.

The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis.

BACKGROUND: Few reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers. METHODS: Four thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure - body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) - and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c). RESULTS: There was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm2, 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators. CONCLUSIONS: Abdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.

Does insomnia modify the association between C-reactive protein and migraine? The Tromsø Study 2015-2016.

BACKGROUND: The relationship between high sensitivity C-reactive protein and migraine is unclear. The aim of this cross-sectional population-based study was to investigate the association between high sensitivity C-reactive protein and types of headache, and to evaluate the impact of insomnia on this association. METHODS: A total of 20,486 (63%) out of 32,591 invited, aged ≥40 years or older, participated in the seventh wave of the Tromsø study conducted in 2015-2016 and had valid information on headache, insomnia and high sensitivity C-reactive protein. The influence of insomnia on the association between questionnaire-based diagnoses of headache and elevated high sensitivity C-reactive protein defined as >3.0 mg/L was assessed using multiple logistic regression, estimating prevalence odds ratio with 95% confidence intervals. RESULTS: A total of 6290 participants (30.7%) suffered from headache during the last year. Among these, 1736 (8.5%) fulfilled the criteria of migraine, 991 (4.8%) had migraine with aura, 746 (3.6%) migraine without aura (3.8%), and 4554 (22.2%) had non-migrainous headache. In the final multi-adjusted analysis, elevated high sensitivity C-reactive protein was associated with headache (odds ratio 1.10, 95% confidence interval 1.01-1.20), migraine (odds ratio 1.17, 95% confidence interval 1.01-1.35), and migraine with aura (odds ratio 1.23, 95% confidence interval 1.01-1.53). No association was found between elevated high sensitivity C-reactive protein and migraine without aura or non-migrainous headache. The association between high sensitivity C-reactive protein and migraine was strongly dependent on insomnia status. Among individuals with insomnia, elevated high sensitivity C-reactive protein was associated with migraine (odds ratio 1.49, 95% confidence interval 1.02-2.17), and migraine with aura (odds ratio 1.59, 95% confidence interval 1.03-2.45), whereas no such relationship was found among those without insomnia. CONCLUSIONS: In this cross-sectional study, participants with migraine, in particular migraine with aura, were more likely to have elevated high sensitivity C-reactive protein, evident only among those with insomnia.

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe).

BACKGROUND: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. METHODS: In N=79 793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1-97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. RESULTS: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12-1.23 in women versus 1.31; 95% CI 1.25-1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81-0.90 versus 0.92; 95% CI, 0.88-0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. CONCLUSIONS: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.

The independent and joint associations of physical activity and body mass index with myocardial infarction: The Tromsø Study.

Physical activity and overweight are associated with myocardial infarction (MI). However, their joint association with MI remains unclear. Our objective was to examine the independent and joint association between leisure-time physical activity (LTPA), body mass index (BMI) and MI. This prospective cohort study included 16,572 men and women (47.5% women) aged 20-54 years who took part in the second Tromsø Study. At baseline in 1979-80 LTPA was assessed by questionnaire. Data on MI was collected and adjudicated through hospital and causes of death registries between 1979 and 2013. Cox proportional hazards models were used to examine the independent and joint associations between LTPA, BMI and MI. The final sample included 16,104 individuals. During a median follow up of 34 years, 1613 incident cases of MI were recorded. Physical inactivity and elevated BMI were both independently associated with MI (p for trend 0.02 and <0.001). In joint analyses, normal weight, inactive individuals had a 20% higher risk of MI compared to their active counterparts (hazard ratio (HR) 1.20 (1.02-1.41)). The highest risk of MI was seen in obese, inactive individuals when compared to normal weight, active individuals (HR 3.20 (2.30-4.44)). The risk of MI increased with increasing BMI regardless of the activity level. HRs were lower for active compared to inactive individuals within the same BMI category. The findings suggest that LTPA and BMI are independently associated with risk of MI. LTPA seems to attenuate but not eliminate the risk of MI associated with excess bodyweight.

Hypothetical interventions to prevent stroke: an application of the parametric g-formula to a healthy middle-aged population.

The effects of interventions on multiple lifestyle and metabolic risk factors, initiated in midlife or later in a healthy population, on the long-term risk of first-ever stroke is not known. A particular methodological challenge in observational studies is to estimate the unbiased effect of a time-varying exposure in presence of time-varying confounders, if those confounders are affected by prior exposure. In such cases, the parametric g-formula can be applied to estimate an unbiased effect. We applied the parametric g-formula to estimate the 18-years (1994-2012) cumulative stroke risk under different scenarios of hypothetical interventions on levels of blood pressure, cholesterol, weight, physical activity, smoking and alcohol intake; and compared these to the observed scenario, to calculate the population risk ratios and risk differences. Among 14,796 eligible participants in the prospective, population-based Tromsø study (baseline mean age 46.1 years, 51% women), the observed 18-years stroke risk was 5.9%. A feasible joint hypothetical intervention on six lifestyle and metabolic risk factors would reduce the 18-year stroke risk by 32% (95% confidence interval 16, 44). A combination of more intensive interventions reduced the estimated 18-years stroke risk by 64% (95% confidence interval 40, 80). Blood pressure reduction and quitting smoking significantly reduced the risk when applied separately.