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There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension., Competing Interests: Conflict of interest: E.G.: Bayer Health, NOKLUS, Fürst laboratories; I.S. Amgen, Astra Zeneca, Daiichi Sankio, Medtronic, Merck Sharpe & Dohme, Novartis, Recordati, Sanofi and Servier; SB Daiichi Sankyo; Merck, Sanofi, Menarini and Servier; C.B. Menarini Corporate, Servier, Novo Nordisk and Novartis; R.M.B. Medtronic; C.C.: none; V.C.: none; F.D.: none; M.F.: none; T.K.: TK Medtronics, and ReCor Medical; M.L.L.: Bayer Health, Sanofi, Bristol Myers Squibb and Pfizer; AHEMM: Organon, Novartis, Abbott and Omron; F.M.: Medtronic, ReCor Medical, Astra-Zeneca, Bayer, Boerhringer-Ingelheim, Medtronic, Merck and ReCor Medical; A.S.M.: Servier and SCAI; T.M.: none; G.P.: none; G.d.S.: none., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

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.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Overall, men have roughly twice the risk of myocardial infarction (MI) compared to women, but what causes this contrast is unclear. Identification of subgroups where the gender contrast in risk is particularly low or high, may provide new insight. In the search for such subgroups, we focus on gender-specific effects of established coronary heart disease (CHD) risk factors. Heterogeneity across age groups is also explored., Methods: Population-based prospective study from Tromsø, Norway, comprising 33,859 individuals (51% women); 2746 individuals (854 women) received a diagnosis of MI during follow-up at ages 35-94 years. Incidence rate ratios (IRR) were calculated as estimates of relative risk in Poisson regression analyses., Results: The association between total cholesterol and risk of MI was stronger for men than women, and IRR for men vs. women accordingly increased with increasing cholesterol, but the risk was higher for men in all subgroups (IRR in range 1.63-3.27), except among older people with low cholesterol levels. The adverse effect of increasing blood pressure (BP) was stronger for women, and IRR for gender diminished with increasing systolic (from 3.90 to 1.38) and diastolic BP (from 2.87 to 1.54). The gender contrast in risk was also substantially reduced in smokers ≥75 years. Associations with high-density lipoprotein cholesterol (HDL-C) did not differ between genders., Conclusions: Gender heterogeneity in associations with total cholesterol but not HDL-C indicates gender differences in associations with non-HDL-C. The stronger association with BP in women may relate to more severe hypertension-induced left ventricular hypertrophy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: It is proposed that 20% to 40% of the decline in first-ever stroke incidence is attributed to the improvement of risk factor control. We estimated the impact of modifiable cardiovascular risk factors on the changing incidence of ischemic stroke (IS) between 1995 and 2012, using individual person data from repeated surveys in a general population., Methods: The proportion of the IS incidence decline explained by change in each risk factor over time was estimated from 1995 to 2012 by Poisson regression among 26 329 participants who attended the fourth Tromsø survey in 1994 to 1995. Hazard ratios for IS were estimated with Cox proportional hazards regression among 27 936 participants who attended at least 1 of the Tromsø surveys in 1994 to 1995, 2001, or 2007 to 2008. Age- and sex-adjusted means or prevalences of risk factors over time were estimated by generalized estimating equations., Results: There were 1226 first-ever IS during 367 636 person-years of follow-up. Changes in cardiovascular risk factors accounted for 57% of the decrease in IS incidence from 1995 to 2012. The most important contributors were decreasing mean systolic blood pressure and smoking prevalence, accounting for 26% and 17% of the observed decline, respectively. Conversely, increasing diabetes mellitus prevalence contributed negatively to the declining IS incidence., Conclusions: Changes in cardiovascular risk factors explained 57% of the decrease in IS incidence from 1995 to 2012. Reduction in systolic blood pressure and prevalence of smoking were the most important contributors., (© 2017 American Heart Association, Inc.)

High blood pressure is a modifiable risk factor for cardiovascular disease. Previous studies showing a blood pressure decline in recent decades lack data to follow individuals born in different decades from early and middle adulthood to older age. We investigated changes in age-specific blood pressure by repeated measurements in 37973 women and men born 1905 to 1977 (aged 20-89 years) examined ≤5× between 1979 and 2008 in the population-based Tromsø Study. Mixed models were used to estimate time trends. Mean systolic and diastolic blood pressure decreased from 1979 to 2008 in both genders in the age groups 30 to 89 years. The decrease was similar in the 80th percentile and the 20th percentile of the population blood pressure distribution. The decrease in systolic blood pressure in age group 40 to 49 years was 10.6 mm Hg in women and 4.5 mm Hg in men. Systolic blood pressure increased with age in women and men born 1920 to 1949, whereas a decrease or flattening of curve was observed in the younger birth cohorts. Thus, we found both time periodic and cohort effects, and trends were more pronounced in women than in men. The findings suggest changes in blood pressure in the population rather than an effect of treatment of high-risk individuals., (© 2015 American Heart Association, Inc.)

Background: Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods: In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings: We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation: In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths. [ABSTRACT FROM AUTHOR]

Background: Single measurements of modifiable risk factors may underestimate associations with outcomes in cohorts. We aimed to compare risk estimates of myocardial infarction (MI) and venous thromboembolism (VTE) by atherosclerotic risk factors during long follow-up using time-fixed analyses without and with correction for regression dilution and time-varying analyses. Methods: The study included 5970 subjects enrolled in the fourth survey of the Tromsø Study (1994/95). Blood pressure, lipid levels, body mass index (BMI), diabetes and smoking status were measured at baseline, and subjects still alive at the fifth (2001/02, n = 5179) and sixth (2007/08, n = 4391) survey were re-measured. Incident events of MI (n = 714) and VTE (n = 214) were recorded until December 2010. Time-fixed and time-varying Cox regression models were used to estimate hazard ratios (HR) for MI and VTE adjusted for age and sex. Results: Variations in BMI, blood pressure and lipid levels were small, and did not alter the risk estimates when time-varying analyses were compared to time-fixed analyses. For MI, variables that changed considerably over time yielded the greatest changes in risk estimates (HR for smoking changed from 1.80 (95% CI 1.55–2.10) to 2.08 (95% CI 1.78–2.42)). For VTE, only BMI was associated with increased risk in both time-fixed and time-varying analysis, but the risk estimates weakened in the time-varying analysis. Correction of time-fixed HRs with Rosner´s method tended to overestimate risk estimates compared to time-varying analysis. Comment: For MI and VTE, risk estimates based on baseline and repeated measures corresponded well, whereas correction for regression dilution tended to overestimate risks. [ABSTRACT FROM AUTHOR]

Objective To investigate the validity of self-reported information about hypertensive disorders in previous pregnancies among women participating in the fourth survey of the Tromsø Study. Design Retrospective cohort study with case-control design. Population Parous women participating in the fourth survey of the Tromsø Study. Methods Medical records including partograms of 200 randomly selected women who had answered positively to whether they had hypertension and/or proteinuria during one or more of their previous pregnancies (cases) and 200 women who had answered negatively (controls) were studied. The cases and controls were matched for age. The investigators were blinded to the allocation of cases and controls until data collection was finished. Main outcome measures Self-reported and actual prevalence of hypertensive pregnancy disorders and predictive value of self-reported hypertension and/or proteinuria in previous pregnancies. Results Clinical data were missing for 23.5% (94/400) of the participants (50 cases and 44 controls). A total of 80% (120/150) of cases and 57.1% (89/156) of controls had answered the question on whether or not they had high blood pressure and/or proteinuria during their pregnancies correctly (positive predictive value 0.800; negative predictive value 0.571). The proportion of false-positive cases declined with increasing age while the proportion of false-negative controls increased until 55 years of age. Conclusions We found good concordance between self-reported hypertension and/or proteinuria during previous pregnancies and actual clinical findings among the cases. However, there was a tendency towards under-reporting among controls. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore sex-specific associations between systolic blood pressure (SBP), hypertension, and the risk of incident atrial fibrillation (AF) subtypes, including paroxysmal, persistent, and permanent AF, in a general population. A total of 13,137 women and 11,667 men who participated in the fourth survey of the Tromsø Study (1994–1995) were followed up for incident AF until the end of 2016. Cox proportional hazards regression analysis was conducted using fractional polynomials for SBP to provide sex- and AF-subtype-specific hazard ratios (HRs) for SBP. An SBP of 120 mmHg was used as the reference. Models were adjusted for other cardiovascular risk factors. Over a mean follow-up of 17.6 ± 6.6 years, incident AF occurred in 914 (7.0%) women (501 with paroxysmal/persistent AF and 413 with permanent AF) and 1104 (9.5%) men (606 with paroxysmal/persistent AF and 498 with permanent AF). In women, an SBP of 180 mmHg was associated with an HR of 2.10 (95% confidence interval [CI] 1.60–2.76) for paroxysmal/persistent AF and an HR of 1.80 (95% CI 1.33–2.44) for permanent AF. In men, an SBP of 180 mmHg was associated with an HR of 1.90 (95% CI 1.46–2.46) for paroxysmal/persistent AF, while there was no association with the risk of permanent AF. In conclusion, increasing SBP was associated with an increased risk of both paroxysmal/persistent AF and permanent AF in women, but only paroxysmal/persistent AF in men. Our findings highlight the importance of sex-specific risk stratification and optimizing blood pressure management for the prevention of AF subtypes in clinical practice. [ABSTRACT FROM AUTHOR]