Statin therapy and cardiovascular protection in type 2 diabetes: The role of baseline LDL-Cholesterol levels. A systematic review and meta-analysis of observational studies.

AIM: The guidelines recommend statins to prevent cardiovascular events in patients with type 2 diabetes (T2D) however, the importance of baseline LDL-Cholesterol (LDL-C) levels remains controversial. This study aimed to determine the association of statin use in T2D patients with major adverse cardiovascular events (MACE) and all-cause mortality and whether this association differs by baseline LDL-C levels. DATA SYNTHESIS: Medline, Embase, and Web of Science were systematically searched from inception until January 2022. Observational studies in patients with T2D comparing statin users vs non-users, with reports of the baseline LDL-C levels, were included. Random-effects meta-analysis and meta-regression were performed to estimate the overall effect on the risk of all-cause mortality and MACE (a composite of myocardial infarction, heart failure, stroke, and revascularization events) and the modification in the association by baseline LDL-C levels. We categorized studies according to their baseline LDL-C levels into 1) <100 mg/dl (2.59 mmol/l), 2) 100-130 mg/dl (2.59-3.37 mmol/l) and 3) >130 mg/dl (3.37 mmol/l) categories. A total of 9 cohort studies (n = 403,411 individuals) fulfilled our criteria. The follow-up duration ranged from 1.7 to 8 years. The overall combined estimate showed that statin therapy was associated with a significantly lower risk of MACE (Hazard Ratio (HR): 0.70 [95% CI 0.59 to 0.83], Absolute risk reduction percentage (ARR%): 3.19% [95%CI 0.88 to 5.50%) and all-cause mortality (HR: 0.60 [95% CI 0.46 to 0.79], ARR%: 5.23% [95% CI 2.18 to 8.28%), but varied, albeit not statistically significant, by baseline LDL-C levels. Studies with baseline LDL-C levels higher than 130 mg/dl had the greatest reduction of MACE (HR: 0.58 [95% CI 0.37 to 0.90]) and all-cause mortality risk (HR: 0.51 [95% CI [ 0.29 to 0.90]). The HRs of MACE in studies with LDL-C levels of 100-130 mg/dl and <100 mg/dl categories were respectively (0.70 [95% CI 0.59 to 0.83]) and (0.83 [95% CI [0.68 to 1.00]); and that of all-cause mortality were respectively (0.62 [95% CI 0.38 to 1.01]) and (0.67 [95% CI [0.44 to 1.02]). Statin use changes the HRs of MACE (0.99 [95%CI, 0.98 to 0.99]; P = 0.04) and all-cause mortality (0.99 [95% CI 0.98 to 1.01]; P = 0.8) per each mg/dl increase in baseline LDL-C level in meta-regression analyses. CONCLUSION: Statin therapy in patients with T2D was associated with reduced risk of MACE and all-cause mortality. Significant differences across studies with different baseline LDL-C levels were not observed.

Burden of cardiometabolic disorders and lifetime risk of new-onset atrial fibrillation among men and women: the Rotterdam Study.

AIMS: To examine the association between the burden of cardiometabolic disorders with new-onset AF and lifetime risk of AF incidence among men and women. METHODS: 4,101 men and 5,421 women free of AF at baseline (1996 to 2008) from the population-based Rotterdam Study were included. Sex-specific Cox proportional hazards regression models were used to assess the association between the burden of cardiometabolic disorders and risk of new-onset AF. Remaining lifetime risk for AF was estimated at index ages of 55, 65, and 75 years up to age 108. RESULTS: Mean age at baseline was 65.5 ± 9.4 years. Median follow-up time was 12.8 years. In the fully adjusted model, a stronger association was found between larger burden of cardiometabolic disorders and incident AF among women [hazard ratio (HR): 1.33 and 95% conference interval (CI): 1.22-1.46], compared to men [1.18 (1.08-1.29)] (P for sex-interaction <0.05). The lifetime risk for AF significantly increased with the number of cardiometabolic disorders among both sexes. At an index age of 55 years, the lifetime risks (95% CIs) for AF were 27.1% (20.8-33.4), 26.5% (22.8-30.5), 29.9% (26.7-33.2), 30.8% (25.7-35.8), and 33.3% (23.1-43.6) among men, for 0, 1, 2, 3, and ≥4 comorbid cardiometabolic disorders. Corresponding risks were15.8% (10.5-21.2), 23.0% (19.8-26.2), 29.7% (26.8-32.6), 26.2% (20.8-31.6), and 34.2% (17.3-51.1) among women. CONCLUSIONS: We observed a significant combined impact of cardiometabolic disorders on AF risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of AF, especially at a young index age.

The present study examined the association between the burden of cardiometabolic disorders with new-onset atrial fibrillation and lifetime risk of atrial fibrillation incidence among 4101 men and 5421 women from the Rotterdam Study cohort. We observed a significant combined impact of cardiometabolic disorders on atrial fibrillation risk, in particular among women. Participants with cardiometabolic multimorbidity had a significantly higher lifetime risk of atrial fibrillation, especially at a young index age. A stronger association was found between larger burden of cardiometabolic disorders and incident atrial fibrillation among women [hazard ratio: 1.33 and 95% conference interval: 1.22-1.46], compared to men [1.18 (1.08-1.29)] (P for sex-interaction <0.05). Among participants aged 55 years or older, the lifetime risk of atrial fibrillation was 25.2% among healthy men and 16.3% among healthy women. Individuals with cardiometabolic multimorbidity exhibited a markedly escalated lifetime risk of atrial fibrillation, particularly evident at a younger age.

Metabolic disorders mediate the relation of miscarriage with cardiovascular diseases.

AIMS: The extent to which the contribution of pregnancy loss to cardiovascular diseases (CVDs) can be explained by metabolic disorders is poorly elucidated but holds insights for reducing long-term cardiovascular risk. The aim of this study is to investigate the mediating effects of hypertension, diabetes mellitus (DM), and lipoprotein metabolism disorders on the association of miscarriage and stillbirth with coronary heart disease (CHD), stroke, heart failure, atrial fibrillation, and composite outcomes. METHODS AND RESULTS: A total of 163 283 ever-gravid women (age 55.3 ± 7.9 years) from the UK Biobank cohort without established metabolic disorders and CVDs were included and followed from 2007 to 2010 baseline until December 2020. Causal mediation analyses were used to estimate the proportion mediated. Hypertension mediated 11.1% (95% confidence interval, 3.7-18.5%) of the association between a history of miscarriage and incident CHD. Approximately, 9.5% (4.1-14.8%) of the effect of recurrent miscarriages on incident CHD was via hypertension, 8.4% (2.5-14.3%) of the effect was via lipoprotein metabolism disorders, 1.7% (0.5-2.9%) of the effect was via DM, and 10.7% (0.2-21.1%) of the effect of recurrent miscarriages on incident stroke was via hypertension. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages), followed by lipoprotein metabolism disorders and DM. CONCLUSION: Hypertension, DM, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. In particular, hypertension mediated a large proportion of the relationship between miscarriage and atherosclerotic CVD.

Hypertension, diabetes, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages). Women who have experienced miscarriage should be regularly monitored for possible required interventions on blood pressure, blood lipids, and glucose to reduce their long-term cardiovascular risk. Our findings contribute to ongoing research efforts to better understand the pathogenesis of pregnancy loss leading to CVD. In particular, we identified metabolic disorders processes as potential mediators. Implications: Our findings warrant early monitoring and intensive (preventive) treatment of hypertension and lipoprotein metabolism disorders among women who experience miscarriage(s) to lower their burden of later-life clinical cardiovascular events.

Sex Differences in the Association Between Serum Testosterone and Kidney Function in the General Population.

Introduction: Testosterone might prevent kidney function decline, although evidence is limited in men and lacking in women from the general population. We investigated the association between serum testosterone and kidney function in men and women from a large population-based cohort study. Methods: Participants aged ≥45 years with available measurements of serum testosterone, sex hormone-binding globulin (SHBG), creatinine, and cystatine C were included. Assessments of kidney function included baseline assessments of the estimated glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys), and the urine albumin-to-creatinine ratio (ACR), and repeated assessments of eGFRcreat. Linear regression and linear mixed models were used to assess the associations of serum free and total testosterone with kidney function, stratified for sex. Results: A total of 4095 men and 5389 women (mean age 65.2 years) were included. In men, higher free testosterone was associated with lower eGFRcreat (beta -0.63, 95% confidence interval [CI]: -1.05; -0.21), higher eGFRcys (beta 0.56, 95% CI: 0.07; 1.05), and lower ACR (beta -0.25, 95% CI: -0.35; -0.16) at baseline. Higher total testosterone was associated with higher baseline and follow-up eGFRcreat, and with lower eGFRcreat when additionally adjusted for SHBG. In women, higher free testosterone was associated with lower baseline eGFRcreat and eGFRcys (beta -1.03, 95% CI: -1.36; -0.71; beta -1.07, 95% CI: -1.44; -0.70; respectively) and lower eGFRcreat over time (beta -0.78, 95% CI: -1.10; -0.46), but not with ACR. Conclusions: eGFRcys might be a better parameter than eGFRcreat for the association of testosterone with kidney function, although further studies investigating this are needed. Furthermore, we identified sex differences in the association between testosterone and kidney function, with a positive association in men and a negative association in women.

Higher testosterone is associated with open-angle glaucoma in women: a genetic predisposition?

BACKGROUND: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +). METHODS: Participants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration. RESULTS: In men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]: - 3.54 [- 7.02; - 0.06] per nmol/L and - 2.18 [- 4.11; - 0.25] per nmol/L, respectively). CONCLUSIONS: In women, higher testosterone levels increased the risk of iOAG. Both IOP-dependent and IOP-independent mechanisms may underlie this association. Managing testosterone levels may be particularly relevant for the prevention of neurodegeneration in the eye. Future research should confirm these findings.

Cardiovascular risk profiles in patients with inflammatory bowel disease differ from matched controls from the general population.

AIMS: Inflammatory bowel disease (IBD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). We compared cardiovascular disease (CVD) risk factors and 10-year risk in IBD patients to the general population. METHODS AND RESULTS: In this cross-sectional study, consecutive IBD patients ≥45 years were included. History of ASCVD and CVD risk factors (smoking, hypertension, overweight, hypercholesterolaemia, diabetes, and metabolic syndrome) were assessed. The Systematic COronary Risk Evaluation (SCORE2) algorithm was used to estimate 10-year CVD risk. One to four age/sex-matched controls were derived from the prospective population-based Rotterdam Study cohort. In total, 235 IBD patients were included {56% women, median age 59 years [interquartile range (IQR) 51-66]} and matched to 829 controls [56% women, median age 61 years (IQR 56-67)]. Inflammatory bowel disease patients experienced ASCVD events more often compared with matched controls [odds ratio (OR) 2.01, 95% confidence interval (CI) 1.23-3.27], specifically heart failure (OR 2.02, 95% CI 1.02-4.01) and coronary heart disease (OR 2.01, 95% CI 1.7-3.13). Inflammatory bowel disease patients showed lower odds of overweight (OR 0.48, 95% CI 0.35-0.66) and hypercholesterolaemia (OR 0.45, 95% CI 0.31-0.65) and higher odds of hypertension (OR 1.67, 95% CI 1.19-2.32), as well as higher waist circumference (+4 cm, P = 0.006) and triglyceride levels (+0.6 mmol/L, P < 0.001) as compared with controls. Mean 10-year CVD risk was 4.0% [standard deviation (SD) ±2.6] in 135 IBD patients vs. 6.0% (SD ±1.6) in 506 controls. CONCLUSION: The increased CVD risk in IBD is discrepant with the 10-year CVD risk estimate. Systematic COronary Risk Evaluation may underestimate CVD risk in IBD patients due to differing CVD risk profiles compared with the general population, including a lower prevalence of hypercholesterolaemia and overweight and a higher prevalence of hypertension, abdominal obesity, and hypertriglyceridaemia.

The unfavourable CVD risk profiles in IBD patients compared with the general population are discrepant with the calculated 10-year CVD risk with the SCORE2 algorithm. Cardiovascular disease risk profiles in IBD patients differ from age/sex-matched controls, including a lower prevalence of hypercholesterolaemia and overweight and a higher prevalence of CVD history, hypertension, abdominal obesity, and hypertriglyceridaemia.Systematic COronary Risk Evaluation was comparable between IBD patients and controls; however, the proportion of patients with 10-year CVD risk above the treatment threshold was lower among IBD patients.

Association Between Sex-Specific Risk Factors and Risk of New-Onset Atrial Fibrillation Among Women.

Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors associated with AF development in women is warranted. Objective: To investigate the linear and potential nonlinear associations between sex-specific risk factors and the risk of new-onset AF in women. Design, Setting, and Participants: This population-based cohort study obtained data from the 2006 to 2010 UK Biobank study, a cohort of more than 500 000 participants aged 40 to 69 years. Participants were women without AF and history of hysterectomy and/or bilateral oophorectomy at baseline. Median follow-up period for AF onset was 11.6 years, and follow-up ended on October 3, 2020. Exposures: Self-reported, sex-specific risk factors, including age at menarche, history of irregular menstrual cycle, menopause status, age at menopause, years after menopause, age at first live birth, years after last birth, history of spontaneous miscarriages, history of stillbirths, number of live births, and total reproductive years. Main Outcomes and Measures: The primary outcome was new-onset AF, which was defined by the use of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I48. Results: A total of 235 191 women (mean [SD] age, 55.7 [8.1] years) were included in the present study. During follow-up, 4629 (2.0%) women experienced new-onset AF. In multivariable-adjusted models, history of irregular menstrual cycle was associated with higher AF risk (hazard ratio [HR], 1.34; 95% CI, 1.01-1.79). Both early menarche (age 7-11 years; HR, 1.10 [95% CI, 1.00-1.21]) and late menarche (age 13-18 years; HR, 1.08 [95% CI, 1.00-1.17]) were associated with AF incidence. Early menopause (age 35-44 years; HR, 1.24 [95% CI, 1.10-1.39]) and delayed menopause (age ≥60 years; HR, 1.34 [95% CI, 1.10-1.78]) were associated with higher risk of AF. Compared with women with 1 to 2 live births, those with 0 live births (HR, 1.13; 95% CI, 1.04-1.24) or 7 or more live births (HR, 1.67; 95% CI, 1.03-2.70) both had significantly higher AF risk. Conclusions and Relevance: Results of this study suggest that irregular menstrual cycles, nulliparity, and multiparity were associated with higher risk of new-onset AF among women. The results highlight the importance of taking into account the reproductive history of women in devising screening strategies for AF prevention.

Imaging-based body fat depots and new-onset atrial fibrillation in general population: a prospective cohort study.

BACKGROUND: Obesity is a well-established risk factor for atrial fibrillation (AF). Whether body fat depots differentially associate with AF development remains unknown. METHODS: In the prospective population-based Rotterdam Study, body composition was assessed using dual-energy X-ray absorptiometry (DXA) and liver and epicardial fat using computed tomography (CT). A body composition score was constructed by adding tertile scores of each fat depot. Principal component analysis was conducted to identify potential body fat distribution patterns. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (HR; 95% CI) per 1-standard deviation increase in corresponding fat depots to enable comparisons. RESULTS: Over a median follow-up of 9.6 and 8.6 years, 395 (11.4%) and 172 (8.0%) AF cases were ascertained in the DXA and the CT analyses, respectively. After adjustments for cardiovascular risk factors, absolute fat mass (HR; 95% CI 1.33; 1.05-1.68), gynoid fat mass (HR; 95% CI 1.36; 1.12-1.65), epicardial fat mass (HR; 95% CI 1.27; 1.09-1.48), and android-to-gynoid fat ratio (HR; 95% CI 0.81; 0.70-0.94) were independently associated with new-onset AF. After further adjustment for lean mass, associations between fat mass (HR; 95% CI 1.17; 1.04-1.32), gynoid fat mass (HR; 95% CI 1.21; 1.08-1.37), and android-to-gynoid fat ratio (HR; 95% CI 0.84; 0.72-0.97) remained statistically significant. Larger body fat score was associated with a higher AF risk (HR; 95% CI 1.10; 1.02-1.20). Borderline significant association was found between a subcutaneous fat predominant pattern with AF onset (HR; 95% CI 1.21; 0.98-1.49). CONCLUSIONS: Various body fat depots were associated with new-onset AF. Total fat mass and gynoid fat mass were independently associated with AF after adjustment for body size. The inverse association between android-to-gynoid fat ratio with AF presents a novel finding. A significant dose-response relationship between body fat accumulation and AF was observed. Our results underscore the predominant role of subcutaneous fat on AF development among a middle-aged and elderly population. Associations betw2een body fat depots, fat distribution and new-onset atrial fibrillation. ABBREVIATIONS: AF, atrial fibrillation.

Sex steroids and sex steroid-binding globulin levels amongst middle-aged and elderly men and women from general population.

BACKGROUND AND AIMS: Availability of age- and sex-specific reference values for sex steroids and sex steroid-binding globulin (SHBG) levels allows for appropriate interpretation of research findings and their clinical applications. We report the sex-specific distribution and reference levels of sex steroids, including total estradiol, total testosterone and (calculated) free androgen index (cFAI), SHBG and other androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione across age. METHODS: Using data from 3291 participants from the prospective population-based Rotterdam Study (2006-2008), we visualised the distribution of sex steroids and SHBG levels by calculating and depicting the 5th, 25th, 50th, 75th and 95th percentiles per year and per age-year across 5-year age bands to provide reference value ranges in men and women. Total estradiol and SHBG were measured using automated immunoassay and androgens using liquid chromatography-mass spectrometry (LC-MS/MS). RESULT: Mean age was 56.8 (range 45.6-79.9) years in men and 56.9 (range 45.7-79.9) years in women. Amongst men, total estradiol and SHBG showed an increasing trend from 45 years onwards. In women, total estradiol and SHBG showed a decreasing trend from 45 years until the age of 60. From 60 years onwards, SHBG showed an increasing trend. For total testosterone, a clear declining trend was observed amongst men but not women. Other androgens showed a similar decreasing trend in both sexes from 45 years onwards. DISCUSSION AND CONCLUSION: Our study underlines sex-specific trends in sex steroids and SHBG levels with ageing. This warrants taking into account sex- and age-specific reference values for sex steroids and SHBG when investigating their impact on health outcomes to prevent controversial results and allow for their appropriate clinical application.

Longitudinal Anthropometric Measures and Risk of New-Onset Atrial Fibrillation Among Community-Dwelling Men and Women.

OBJECTIVE: To assess the sex-specific evolution of various anthropometric measures and the association of their longitudinal trajectories with new-onset atrial fibrillation (AF). METHODS: Among 5266 men and 7218 women free of AF at baseline from the prospective population-based Rotterdam Study, each anthropometric measure was measured 1 to 5 times from 1989 to 2014. Anthropometric measures were standardized to obtain hazard ratios per 1 SD increase to enable comparison. Joint models were used to assess the longitudinal association between anthropometric measures and incident AF. Use of the joint models is a preferred method for simultaneous analyses of repeated measurements and survival data for conferring less biased estimates. RESULTS: Mean (SD) age was 63.9 (8.9) years for men and 64.9 (9.8) years for women. Median follow-up time was 10.5 years. Longitudinal evolution of weight, height, waist circumference, hip circumference, and body mass index was associated with an increased risk of new-onset AF in both men and women. In joint models, larger height in men (hazard ratio [95% credible interval] per 1 SD, 1.27 [1.17 to 1.38]) and weight in women (1.24 [1.16 to 1.34]) showed the largest associations with AF. In joint models, waist to hip ratio was significantly associated with incident AF only in women (1.10 [1.03 to 1.18]). CONCLUSION: Considering the entire longitudinal trajectories in joint models, anthropometric measures were positively associated with an increased risk for new-onset AF among men and women in the general population. Increase in measure of central obesity showed a stronger association with increased risk of AF onset among women compared with men.

Associations of Sex Steroids and Sex Hormone-Binding Globulin with Non-Alcoholic Fatty Liver Disease: A Population-Based Study and Meta-Analysis.

BACKGROUND: Prior studies have reported inconsistent results or less well-explored associations between sex hormones and non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the associations of NAFLD with sex steroids and sex hormone-binding globulin (SHBG) in the population-based study and conduct a comprehensive systematic review and meta-analysis of all published observational studies. METHODS: Analyses included 755 men and 1109 women with available data on sex steroids, SHBG, and ultrasound-based NAFLD from the Rotterdam Study. Multivariable regression models were used to examine the associations. Additionally, we searched five databases from inception to 1 April 2022 and performed a systematic review and meta-analysis. Random-effects (DerSimonian-Laird) method was used for meta-analysis, odds ratios (ORs) were calculated for the effect estimate, subgroup and leave-one-out sensitivity analyses were conducted, and meta-regression was performed to explore the pooled statistics with high heterogeneity. RESULTS: In the Rotterdam Study, lower levels of SHBG were associated with NAFLD in both sexes, while lower testosterone was associated with NAFLD only among women. Similarly, the meta-analysis of 16 studies indicated no sex-specific association between SHBG and NAFLD (men: OR = 0.37, 95%CI 0.21-0.53; women: OR = 0.40, 95%CI 0.21-0.60), yet there was a sex-specific association between testosterone and NAFLD (men: OR = 0.59, 95%CI 0.42-0.76; women: OR = 1.06, 95%CI 0.68-1.44). Moreover, men with NAFLD had lower estradiol levels than those without NAFLD. CONCLUSIONS: Lower SHBG levels were associated with NAFLD in both sexes, but testosterone levels were associated in a sex-specific manner. In addition, our results showed estradiol with the potential as a protective factor for NAFLD in healthy men.

Sex-specific added value of cardiac biomarkers for 10-year cardiovascular risk prediction.

AIMS: To evaluate the sex-specific predictive value of N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT) and creatine kinase myocardial band (CK-MB) for 10-year risk prediction of coronary heart disease (CHD), stroke, heart failure (HF) and composite outcomes. METHODS: Five-thousand four-hundred thirty individuals (mean age 68.6 years, 59.9% women) from the Rotterdam Study, with biomarker measurements between 1997 and 2001, were included. Participants were followed until 2015. We fitted 'basic' models using traditional cardiovascular risk factors. Improvements in c-statistics and net reclassification improvement (NRI) for events and non-events were calculated. RESULTS: During a median follow-up of 14 years, 747 (13.8%), 563 (10.4%), and 664 (12.2%) participants were diagnosed with CHD, stroke, and HF, respectively. NT-proBNP improved the discriminative performance of the 'basic' model for all endpoints (c-statistic improvements ranging from 0.007 to 0.050) and provided significant event-NRI for HF (14.3% in women; 10.7% in men) and for stroke in men (9.3%). The addition of hs-cTnT increased c-statistic for CHD in women by 0.029 (95% CI, 0.011-0.047) and for HF in men by 0.034 (95% CI, 0.014-0.053), and provided significant event-NRI for CHD (10.3%) and HF (7.8%) in women, and for stroke (8.4%) in men. The added predictive value of CK-MB was limited. CONCLUSION: NT-proBNP and hs-cTnT provided added predictive value for various cardiovascular outcomes above traditional risk factors. Sex differences were observed in the predictive performance of these biomarkers.

Sex-specific anthropometric and blood pressure trajectories and risk of incident atrial fibrillation: the Rotterdam Study.

AIMS: To investigate sex-specific longitudinal trajectories of various obesity-related measures and blood pressure at the population level and further assess the impact of these trajectories on new-onset atrial fibrillation (AF). METHODS AND RESULTS: Participants with ≥2 repeated assessments for various risk factors from the population-based Rotterdam Study were included. Latent class linear mixed models were fitted to identify the potential classes. Cox proportional-hazard models were used to assess the association between risk factors' trajectories and the risk of new-onset AF, with the most favourable trajectory as reference. Among 7367 participants (mean baseline age: 73 years, 58.8% women), after a median follow-up time of 8.9 years (interquartile range: 5.3-10.4), 769 (11.4%) participants developed new-onset AF. After adjustments for cardiovascular risk factors, persistent-increasing body mass index (BMI) trajectory carried a higher risk for AF [hazard ratio, 95% confidence interval: (1.39; 1.05-1.85) in men and (1.60; 1.19-2.15) in women], compared with the lower-and-stable BMI trajectory. Trajectories of elevated-and-stable waist circumference (WC) in women (1.53; 1.09-2.15) and elevated-and-stable hip circumference (HC) in men (1.83; 1.11-3.03) were associated with incident AF. For systolic blood pressure (SBP), the initially hypertensive trajectory carried the largest risk for AF among women (1.79; 1.21-2.65) and men (1.82; 1.13-2.95). Diastolic blood pressure trajectories were significantly associated with AF risk among women but not among men. CONCLUSION: Longitudinal trajectories of weight, BMI, WC, HC, and SBP were associated with new-onset AF in both men and women. Diastolic blood pressure trajectories were additionally associated with AF in women. Our results highlight the importance of assessing long-term exposure to risk factors for AF prevention among men and women.

Long-term association of pregnancy and maternal brain structure: the Rotterdam Study.

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in women's lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of pregnancy on maternal brain structure remain unknown. We investigated a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume (ß = 0.14, 95% CI = 0.09-0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings suggest that pregnancy and childbirth are associated with robust long-term changes in brain structure involving a larger global gray matter volume that persists for decades. Future studies are warranted to further investigate the mechanism and physiological relevance of these differences in brain morphology.

Prevalence of microvascular angina among patients with stable symptoms in the absence of obstructive coronary artery disease: a systematic review.

Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. We defined MVA using three definitions: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia test result, (ii) suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups. Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischaemia test, 28% for suspected MVA using specific modalities for MVA, and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50. In patients with stable symptoms of ischaemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD.

Impaired fasting glucose, type 2 diabetes mellitus, and lifetime risk of cardiovascular disease among women and men: the Rotterdam Study.

INTRODUCTION: Data on sex-specific lifetime risk of cardiovascular disease (CVD) across the glycemic spectrum, in particular in impaired fasting glucose (IFG) state, are scarce. Whether overweight/obesity modifies the CVD burden also remains unclear. RESEARCH DESIGN AND METHODS: Using a prospective population-based Rotterdam Study, normoglycemia, IFG, and type 2 diabetes mellitus (T2D) were defined. First incident cases of coronary heart disease, heart failure, and stroke during a follow-up time until January 1, 2015 were identified and formed the composite CVD end point. The remaining lifetime risks of CVD were estimated in each glucose category at 55, 65, 75, and 85 years of age, using a modified version of survival analysis adjusted for the competing risk of death. RESULTS: Among 5698 women and 3803 men free of CVD at baseline, the mean age was 64.5 years (SD 9.6) and 60.0% of participants were women. At age 55 years, the remaining lifetime risk of any CVD event among women was 55.1% (95% CI 48.3 to 61.9) for IFG, compared with 52.7% (95% CI 49.5 to 55.9) for normoglycemia and 61.5% (95% CI 54.7 to 68.3) for T2D. For men, the remaining lifetime risk of any CVD event was 62.1% (95% CI 55.2 to 69.1) for IFG, compared with 59.1% (95% CI 55.5 to 62.7) for normoglycemia and 60.3% (95% CI 53.1 to 67.5) for T2D. At age 55 years, the lifetime risk for incident CVD was higher, although not statistically significant, among women and men with IFG who were overweight or had obesity compared with normal-weight women and men. CONCLUSION: IFG carried a large lifetime risk for incident CVD among both women and men compared with normoglycemia. In particular among men, the risk was comparable to that of T2D. Overweight/Obesity modifies the risk and conferred a larger burden of lifetime CVD risk among women and men with IFG.

Aging, Cardiovascular Risk, and SHBG Levels in Men and Women From the General Population.

AIMS: Prior studies have reported inconsistent results for the association between sex hormone-binding globulin (SHBG) and cardiovascular disease among men and women. Although it is suggested that SHBG levels change with aging, the exact trend of SHBG across age and cardiovascular risk and the underlying mechanisms of these changes remain to be elucidated. METHODS: Using data of 3264 men and women from a large population-based cohort study, we first visualized the distribution of serum SHBG levels across age. Second, we computed a cardiovascular risk factor sum score and investigated the mean SHBG levels across categories of the risk factor sum score and stratified per age-category. Next, linear regression models were used to investigate the associations between serum SHBG levels and age and potential regulators of SHBG, including body mass index (BMI), fasting insulin, sex steroids, thyroxine, and triglycerides. RESULTS: Among men, a linear increase in SHBG levels with age and among women a U-shaped pattern was observed. Participants with larger number of cardiovascular risk factors had lower SHBG levels. When stratified by age, older participants had higher SHBG levels. A multivariate model including total testosterone and triglyceride levels in men and total testosterone, triglycerides, BMI, and fasting insulin in women explained, respectively, 46.2% and 31.8% of the variance in SHBG levels. CONCLUSION: We observed a clear sex-specific pattern for SHBG levels with age. Our findings highlight the importance of taking into account the age-related changes in SHBG levels to avoid controversial results in the assessment of the cardiovascular risk associated with SHBG.