European Journal of Preventive Cardiology

Background The postmenopausal period is associated with a more adverse cardiometabolic risk factor profile as well as unfavourable cardiac remodelling patterns. However, it remains unclear whether and how the associations between risk factors and cardiac remodelling differ before and after menopause and in the corresponding age groups in men. Methods We used cross-sectional data from the baseline examination of the population-based German National Cohort (NAKO, age range 19-74 years). Cardiovascular resonance imaging (CMR) was performed on 3T MRI, and morphofunctional data of both ventricles were derived from standard short-axis cine balanced steady-state free precession. Associations between cardiometabolic risk factors and cardiac parameters were evaluated using adjusted multivariable linear regression, stratified by menopausal status in women and age group (<50 / [&ge;]50 years) in men. Results The final sample comprised 20,152 participants (40% women; mean age 47{+/-}12 years) from the NAKO MRI subsample. Cardiometabolic risk factor profiles differed across the stratified groups, with higher systolic blood pressure and less favourable lipid profiles in older participants. Ventricular volumes declined and concentric remodelling increased with age in both sexes, with a steeper age-related pattern observed in women than in men. Higher BMI in women was associated with higher left ventricular concentricity index (LVCI) in postmenopausal than in premenopausal women (0.097 vs. 0.047; p for difference = 0.016). Associations between triglycerides and ventricular volumes were strongest in premenopausal women and significantly stronger than in men younger than 50 years (e.g., right ventricular end-diastolic volume (RVEDV): -0.173 vs. -0.064, p for difference < 0.001). Sleep problems were more strongly associated with cardiac parameters in men, with significant sex differences in older men compared with postmenopausal women (e.g. left ventricular end-diastolic volume (LVEDV): -0.105 vs. 0.043, p for difference = 0.023). Conclusions Less favourable cardiac remodelling observed in postmenopausal women appeared to be associated with a higher burden of cardiometabolic risk factors rather than stronger associations between these risk factors and cardiac structure. Several associations showed sex- and age-specific patterns, including Body Mass Index (BMI), triglyceride levels, and sleep problems. These findings highlight the importance of controlling cardiometabolic risk factors across adulthood, and raising awareness for sex-specific differences.

BackgroundBlood biomarkers can characterize the atrial substrate, helping to elucidate mechanisms of atrial fibrillation (AF) development. Understanding whether sedentary behavior affects AF-related biomarkers is key for future prevention strategies. MethodsWe studied 252 participants in PREDIMED-Plus, a multicenter randomized trial in Spain for the primary prevention of cardiovascular disease. A wrist-worn accelerometer was used to measure physical activity (PA) in a week at baseline and at least once during follow-up at years 3 and 5. Blood samples were collected at each time point to measure selected cardiovascular biomarkers: propeptide of procollagen type I, high-sensitivity (hs) troponin T (hsTnT), hs C-reactive protein, 3-nitrotyrosine, and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP). Sedentary time was assessed as inactive time (< 1.5 METs in waking time). Using isotemporal substitution, we analyzed the impact of replacing 30-min sedentary time per day with low-intensity PA (LPA, 1.5-3 METs), moderate to vigorous PA (MVPA, > 3 METs) and time in bed (time difference between going to bed and getting up) on log-transformed biomarkers cross-sectionally and longitudinally, using linear regression and mixed models. ResultsAt baseline, 252 eligible participants averaged 65 years of age (SD 4.9), and BMI 32.2 kg/m{superscript 2} (SD 3.3), and 40% were female. Cross-sectionally, replacing 30-min sedentary time with LPA, MVPA, or time in bed had no significant association with biomarkers. After 5 years, replacing baseline 30-min of sedentary time per day with LPA or MVPA was associated with lower hs-TnT concentrations compared to baseline (-4%, 95% CI - 8%, -1%; -2%, 95% CI -7%, 4%, respectively). Substituting 30-min sedentary time with LPA or MVPA showed nonsignificant reductions in NT-proBNP (-3%, 95% CI -11%, 5%; - 8%, 95% CI -20%, 5%, respectively), but not a consistent association with other biomarkers. ConclusionIn overweight/obese individuals, prolonged sedentary time, when compared to engaging in PA, was associated with unfavorable changes of hs-TnT over 5 years, but no significant impact on other AF-related biomarkers.

BackgroundIllicit use of anabolic androgenic steroids (AAS) is common among recreational athletes, yet comprehensive studies on adverse cardiovascular outcomes, especially in female AAS users, are lacking. MethodsA cross-sectional study of recreational athletes of women and men was conducted, involving active and previous AAS users and non-users aged [&ge;]18 years. Previous use was defined as discontinuation of AAS at least three months prior to study. Primary outcomes included atherosclerosis (carotid, femoral, and coronary artery plaques) and cardiac function, assessed using vascular ultrasound, coronary computed tomography angiography and echocardiography. ResultsMedian age was 36 years for active users (n=80, 19 women), 35 years for previous users (n=26, 8 women), and 40 years for non-users (n=58, 16 women) (p=NS). Median AAS usage period was 2.2 years for both active and previous users; the latter group had discontinued intake 2.5 years before study (range: 3 months to 29 years). There was no group differences when comparing the number of femoral/carotid artery plaques, the coronary artery calcium (CAC) score or the number of non-calcified plaques. However, confounder-adjusted logistic regression showed associations between cumulative AAS use and a positive CAC score (OR: 1.23, 95% CI: 1.09-1.39, p=0.001) and the presence of non-calcified plaque (OR: 1.17, 95% CI: 1.05-1.30, p=0.004), respectively, when comparing previous and ongoing users vs. non-users. These associations were also present in men, but not women. Moreover, >5 years of AAS use increased the fraction of athletes with increased severity of calcifications (p=0.043). Echocardiography showed that active AAS using males and females had impaired left ventricular global longitudinal strain (LVGLS) and right ventricular global longitudinal strain (RVGLS) compared to sex-matched non-users (p<0.001). Multivariable analysis showed that cumulative AAS use correlated with worsening of LVGLS (p=0.002) and RVGLS (p=0.001). Finally, after 5 years of cumulative AAS use, nearly all athletes had ventricular mass above and left ventricular ejection fraction below the median of normal range. ConclusionIn men, the cumulative lifetime AAS exposure was an independent predictor of coronary atherosclerosis. However, both male and female AAS users share risks of myocardial dysfunction, underscoring significant cardiovascular risks across genders. CLINICAL PERSPECTIVEKey observations from the study: O_LIIn recreational athletes, the accumulated lifetime AAS exposure associates with a higher prevalence of non-calcified plaques and coronary artery calcification in male recreational athletes. C_LIO_LIOur study suggests that more than 5 years of AAS use constitutes a threshold beyond which the development of coronary calcifications significantly increases compared to non-users. C_LIO_LIIn addition to compromised left ventricular systolic and diastolic function, AAS users exhibited significantly reduced right ventricular function, indicating a biventricular cardiac impact of AAS. C_LIO_LIMale and female AAS users showed similar patterns of cardiac deterioration. C_LI These findings highlight the significant cardiovascular risks associated with AAS use in both male and female recreational athletes, underscoring the importance of targeted research, educational programs, information campaigns, and intervention strategies for this population, regardless of gender.

ImportanceCholesterol content in high-density lipoprotein particles (HDL-C) is associated inversely with coronary heart disease (CHD), but findings from Mendelian randomization studies and randomized trials of HDL-C raising drugs have questioned whether this link is causal. However, these analyses do not exclude a causal role for specific HDL sub-fractions of different density, mobility, size and composition. ObjectiveTo determine whether sub-components of the HDL pathway exhibit differing relationships with CHD risk. DesignIn seven longitudinal studies, we used factor analysis to reduce 21 measures of HDL particle size and lipid content to a smaller number of factors representing different components of the HDL pathway. We constructed factor scores and modelled their associations on CHD risk in adjusted Cox regression analyses. We pooled results using random-effects meta-analysis. SettingSeven population-, individual-, occupational- or community-based longitudinal studies in the UK and Finland. Participants28,597 participants (49% female, mean age 59.6 years) contributed to the analysis. ExposuresSub-components of the HDL pathway, characterized by 21 measures of HDL size and lipid content based on nuclear magnetic resonance spectroscopy. Main OutcomesIncident fatal or non-fatal CHD. ResultsWe identified 4 HDL components with highly replicable across studies; 3 were indices of particle size/composition (extra-large (XL), large (L) and medium/small (MS)), and the other an index of triglycerides (TG) carried in HDL of all sizes. After up to 17 years of follow-up, 4179 incident CHD cases occurred. After adjusting for age, sex, ethnicity, smoking, systolic blood pressure, body mass index, diabetes and LDL-C, higher levels of the XL and MS factors were linked to a reduced risk of CHD (hazard ratio per 1 standard deviation (SD) increase 0.88 [95% CI 0.85, 0.92] and 0.91 [0.87, 0.94]). In contrast, a SD increase in the level of the TG factor was associated with increased risk of CHD (1.10 [1.07, 1.14]). Conclusions and RelevanceWe found qualitative differences between sub-components of the HDL pathway and the risk of developing CHD. Discovery of the biological determinants of these components, possibly through genetic analysis, will facilitate selection of drug targets and inform trial design. Key PointsO_ST_ABSQuestionC_ST_ABSCan investigation of sub-components of the high-density lipoprotein (HDL) pathway, measured through nuclear magnetic resonance spectroscopy, point to specific therapeutic targets for prevention of coronary heart disease (CHD)? FindingsUsing individual-level data from seven longitudinal studies including 28,597 participants and 4197 CHD events, we identified two components of the HDL pathway that were associated with reduced, and one that was associated with increased, risk of CHD. MeaningThese sub-components of the HDL pathway, if causally related to atherogenesis, offer a route to more precise therapeutic targets for prevention of CHD.

BackgroundSex hormone alterations, such as estrogen deficiency or testosterone excess, substantially increase cardiovascular disease (CVD) risk in females. Dietary fibre and its microbial by-products, short-chain fatty acids (SCFAs), have cardioprotective effects, but it remains unclear whether these benefits extend to females with an altered sex hormone profile. In this study, we aim to investigate whether dietary fibre intake, measured via plasma acetate--the most abundant SCFA--is associated with improved cardiovascular outcomes in females with altered sex hormone profiles. MethodsThis cohort study included 116,235 female participants from the UK Biobank and Biobank Japan with up to 10 years of follow-up. We analysed early menopause (as a surrogate for estrogen insufficiency) and plasma free testosterone (in a subset). The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were blood pressure. Proteomics analyses explored potential mechanisms. ResultsAcetate levels were associated with lower 10-year MACE incidence (-0.618/1000 woman-year, HR=0.900, p=0.002) and systolic blood pressure (-0.231 mmHg per 1 SD, p<0.001) in the UK Biobank. High acetate levels attenuated the increased MACE risk associated with early menopause (HR=1.158, p=0.057) compared with low acetate (HR=1.425, p<0.001), with similar patterns replicated in Biobank Japan (high: HR=1.322, p=0.090; low: HR=1.385, p=0.042). Proteomics analyses suggested a mechanism involving pro-inflammatory proteins. Moreover, high acetate levels attenuated the increased MACE associated with elevated free testosterone in the UK Biobank (high: HR=1.238, p=0.024; low: HR=1.056, p=0.666). A significant interaction between acetate and free testosterone on systolic blood pressure indicated that the effect of rising testosterone on blunting acetates effect ({beta}=0.167, 95% CI: [5.212x10-2-2.818x10-1], p=0.004) was partially mediated by central obesity (waist-to-hip ratio). ConclusionsHigher plasma acetate levels were associated with lower cardiovascular risk, particularly in females with early menopause or elevated free testosterone, potentially via inflammatory pathways. These findings underscore the importance of hormonal context in shaping cardiometabolic resilience and support personalised CVD prevention strategies for females with altered sex hormone profiles, including increasing dietary fibre intake.

BackgroundTestosterone deficiency in men has historically been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. The potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to investigate if there could be potential benefits of TRT on cardiovascular disease risk and, if so, uncover the underlying mechanisms. MethodsA comprehensive literature search for Level A evidence in multiple databases (PubMed, Embase, Cochrane Library) was conducted, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, cohort studies, review articles and experimental studies published between 1999 and 2024 that investigated the association between TRT and cardiovascular outcomes in men. The primary outcome was the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality. Secondary outcomes included changes in ejection fraction, lipid profiles, side effects, and other cardiovascular risk factors. ResultsFrom 3,727 records identified using the selected criteria, a total of 51 studies were selected for the meta-analysis, comprising 4 RCTs, 9 cohort studies, 6 experimental studies, 23 review articles, 4 systematic reviews, and 5 meta-analyses, with a combined sample size of approximately 3,134,054 men. The findings from the meta-analysis suggests an 18% reduction in the risk of cardiovascular events among men receiving TRT compared to those receiving a placebo. TRT was found to be associated with significant improvements in ejection fraction, lipid profiles (reduction in total cholesterol and low-density lipoprotein cholesterol), and other cardiovascular risk factors, including insulin resistance and inflammatory markers. Potential mechanisms underlying the cardioprotective effects of TRT include improvements in endothelial function, vasodilation, and myocardial remodeling. Subgroup analyses revealed that the beneficial effects of TRT were more pronounced in men with established cardiovascular disease or risk factors, such as diabetes or metabolic syndrome. ConclusionThis systematic review and meta-analysis of high-quality evidence suggest that testosterone deficiency is associated with an increased risk of cardiovascular disease. Conversely, TRT is associated with a reduced risk of cardiovascular events, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was linked to a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors. Despite the relatively large sample size, further long-term studies are needed to confirm these findings and establish optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention.

Background: Cardiovascular diseases (CVD) are more common in lower occupational classes, but the mediating role of health behaviours remains unclear. This study aimed to quantify the extent to which health behaviours mediate the association between occupational class and CVD, evaluate their relative contributions to CVD risk, and assess occupational class differences in the effects of health behaviours. Methods: Municipal employees from Helsinki, aged 40-60 at baseline, were followed from 2000-2002 (response rate 67%) to 2022. CVD events were identified from national registers, including hospitalizations, long-term sickness absence, disability pensions, and mortality. Counterfactual mediation analysis using additive survival regression was used to assess the contribution of health behaviours - excessive alcohol consumption, smoking, unhealthy diet, and insufficient physical activity - to the association of occupational class and CVD. Occupational class differences in the effects of health behaviours were assessed with Cox regression. Results: During follow-up, 50% of participants in the low occupational class and 46% in the high occupational class had a CVD event. All unhealthy behaviours except heavy alcohol use were more common in the low occupational class. Health behaviours explained approximately 40% of the excess risk of CVD when moving from high occupational class to low occupational class. Insufficient physical activity (HR 1.44, 95% CI 1.35-1.54) was the strongest predictor of CVD. Unhealthy diet was more strongly associated with CVD in the high occupational class. Conclusion: Health behaviours explained a part of occupational class inequalities in CVD, but most of the inequality remained unexplained, highlighting broader social determinants.

BackgroundData remain sparse regarding the impact of chronic stress on cardiovascular disease (CVD) risk factors and outcomes. Prior work has been limited by incomplete assessments of perceived stress and focus on single stress domains. We evaluated the association between a composite measure of perceived stress and CVD risk factors and outcomes. MethodsParticipants from the Dallas Heart Study phase 2 (2007-2009) without prevalent CVD who completed questionnaire assessments of perceived stress were included (n=2685). Individual perceived stress subcomponents (generalized stress, psychosocial, financial, and neighborhood stress) were standardized and integrated into a single cumulative stress score (CSS) with equal weighting for each component. Associations between CSS and demographics, psychosocial variables and cardiac risk factors were assessed in univariable and multivariable analyses. Cox proportional hazards models were used to determine associations of the CSS with atherosclerotic CVD (ASCVD) and Global CVD (ASCVD, heart failure, and atrial fibrillation) after adjustment for demographics and traditional risk factors. ResultsMedian age of the study population was 48 years, 55% were female, 49% Black and 15% Hispanic/Latinx. CSS was higher among participants who were younger, female, Black or Hispanic, and those with lower income and educational attainment (p<.0001 for each). Higher CSS was associated with self-report of racial/ethnic discrimination, lack of health insurance and last medical contact > one year previously (p<.0001 for each). In multivariable regression models adjusting for age, gender, race/ethnicity, income and education, higher CSS associated with hypertension, smoking, and higher body mass index, waist circumference Hemoglobin A1C, hs-CRP and sedentary time (p< 0.01 for each). Over a median follow-up of 12.4 years, higher CSS associated with ASCVD (adjusted HR 1.22 per SD, 95% CI 1.01-1.47) and Global CVD (HR 1.20, 95% CI 1.03-1.40). No interactions were seen between CSS, demographic factors, and outcomes. ConclusionComposite multidimensional assessments of perceived stress may help to identify individuals at risk for CVD who may be targeted for stress mitigation or enhanced prevention strategies. These approaches may be best focused on vulnerable populations, given the higher burden of stress in women, Black and Hispanic individuals, and those with lower income and education. WHAT IS NEW?O_LIA novel measure of cumulative stress was created that integrates generalized, psychosocial, financial, and neighborhood perceived stress. C_LIO_LICumulative stress was higher among women, Black and Hispanic participants, younger individuals and persons with lower income and educational attainment and was associated with adverse health behaviors and increased burden of cardiovascular disease (CVD) risk factors. C_LIO_LIIn a diverse cohort, higher cumulative stress associated with incident CVD after adjustment for demographics and traditional risk factors. No interactions were seen based on demographic factors. C_LI CLINICAL IMPLICATIONSO_LIAlthough associations of chronic stress with CVD were similar across demographic subgroups, the higher burden of stress among younger individuals, women, Black and Hispanic participants, and those with lower SES suggests that CVD risk associated with higher stress affects marginalized groups disproportionately. C_LIO_LICumulative Stress is associated with modifiable risk factors and health behaviors. Future studies should explore targeting behavioral modification and risk factor reduction programs, as well as stress reduction strategies, to individuals with high cumulative stress. C_LIO_LIAdditional research is needed to uncover mechanisms that underly the association between chronic stress and cardiovascular disease. C_LI

Background: Regular exercise is a highly effective yet underutilized strategy to reduce cardiometabolic disease burden. Whether brief structured exercise programs confer lasting cardiometabolic benefits remains unclear. The STRRIDE-Prediabetes Reunion study examined legacy effects of exercise training on cardiorespiratory fitness, body composition, and cardiometabolic health. Methods: Seventy-three participants (71.3 {+/-} 7.2 years; 64% women; 77% White) completed Reunion assessments ~11 years after completing one of four 6-month interventions differing in exercise amount, intensity, and inclusion of diet-induced weight loss. Linear mixed effects models evaluated longitudinal trajectories; secondary analyses examined baseline-adjusted associations among short-term intervention response and Reunion outcomes. Results: Abdominal adiposity improved across all groups from baseline to Reunion, with waist circumference decreasing ~3 cm over the follow-up period. In contrast, cardiorespiratory fitness and fat-free mass declined significantly. A significant group by time interaction was observed for total fat mass (p=0.01), with continued fat mass reductions observed in women randomized to high amount exercise. After baseline adjustment, greater short-term intervention response was associated with more favorable Reunion outcomes across fitness, body composition, and cardiometabolic domains; fat-free mass showed the strongest association ({beta}=0.84, p<0.0001). Conclusions: In older adults with prediabetes, the STRRIDE-Prediabetes interventions produced several legacy health effects persisting more than a decade later. Legacy effects differed by sex and exercise dose, and short-term intervention response relative to baseline was associated with long-term outcomes, supporting targeted exercise strategies to preserve cardiometabolic health and functional independence with aging.

Introduction: Menopause may coincide with rising Lp(a) levels, a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Characterizing changes in Lp(a) across menopause may inform risk stratification and testing recommendations. Methods: We examined changes in serum Lp(a) levels by menopausal status among women with Lp(a) measured at visits 1 and 2 in the UK Biobank. Lp(a) analyses were examined by menopausal status: those who underwent menopause (N=415), those who remained premenopausal (N=532), and those who remained postmenopausal (N=3,615) between visits. We examined the change in Lp(a) between visits stratified by visit 1 Lp(a) levels. The primary outcome was incident Lp(a) 125 nmol/L at visit 2, estimated using Poisson regression with adjustment for baseline age. Results: Data were available for 4,562 women (mean age at visit 1 = 57{+/-}7 years; median Lp(a) at visit 1 = 22 (IQR: 47) nmol/L; median time between visits = 4 (IQR: 1) years). At visit 1, median Lp(a) was slightly higher in postmenopausal women (23 nmol/L) than premenopausal women (19 nmol/L). Overall, median changes in Lp(a) between visits 1 and 2 were modest. Among women with intermediate visit 1 Lp(a) levels (75-125 nmol/L), those who transitioned through menopause experienced a median increase of 34.9 (-6.7, 53.0) nmol/L between visits, an approximately fourfold greater increase than for women who remained pre- (7.9 nmol/L) or postmenopausal (8.0 nmol/L). Further, 56% of women with intermediate visit 1 Lp(a) levels who transitioned through menopause between visits had incident Lp(a) 125 nmol/L at visit 2, compared with 29% and 28% of women who remained pre- or postmenopausal, representing an age-adjusted risk ratio of 2.26 (95% CI: 1.31, 3.90). Conclusion: Relying on a single lifetime Lp(a) measurement may miss clinically relevant increases during menopause. Repeat testing in women as they age may improve identification of those at high risk for ASCVD.

Evidence supports associations of lifestyle-including diet and physical activity--and weight with cognitive functioning, but the pathways responsible for these associations have not been fully elucidated. Because healthier lifestyles have been associated with better left atrial structure and function, which in turn is associated with better cognitive functioning, we tested the hypothesis that left atrial structure and function is a potential mediator of the association between lifestyles and cognition. We included 476 participants with overweight or obesity and metabolic syndrome from three centers in Spain who underwent lifestyle assessment and transthoracic echocardiography at baseline and had repeated measurements of the Trail Making A test, a measure of executive function, at baseline and at the two-year follow-up. We conducted mediation analyses to test if measures of left atrial structure and function mediated associations between adherence to the Mediterranean diet scores, physical activity, or weight at baseline, and two-year change in Trail Making A scores. The analysis did not find an effect between these factors and Trail Making A scores, and no indirect effects mediated through the echocardiographic measurements. The modest sample size in this analysis is a limitation, and larger studies should be conducted to determine potential cardiovascular factors mediating the association between lifestyle and cognition.

ObjectivesHypothalamic-pituitary-adrenal (HPA) dysregulation is a postulated risk factor for cardiovascular disease but results from previous studies have been mixed. We examined cross-sectional associations of diurnal patterns of salivary cortisol with 10 subclinical measures of cardiovascular disease (including pulse wave velocity, carotid intima-media thickness, and measures of heart structure and function), and prospective associations of cortisol variation with cardiovascular (CV) and non-cardiovascular (NCV) mortality. MethodsWe included up to 1,263 participants of the MRC National Survey for Health and Development birth cohort, who had participated in serial diurnal salivary cortisol sampling in 2006-2010 (aged 60-64 years). We used multivariable linear and multinomial logistic regression to estimate associations of cortisol awakening response (CAR), slope and area under the curve (AUC) with subclinical cardiovascular measures, and multivariable Cox regression to estimate associations of the three cortisol metrics with all-cause, CV and NCV mortality. ResultsAll associations with subclinical cardiovascular measures were weak and most were compatible with the null hypothesis. Each standard deviation (SD) higher cortisol AUC was associated with a 1.9% (95%-CI 0.3-3.5) higher pulse wave velocity. A shallow cortisol slope (per SD gradient) was associated with a 1.4% lower intima media thickness (95%-CI -2.6, - 0.2), and lower odds of concentric remodelling (OR 0.83, 95%-CI 0.70-0.99). Given the multiple analyses performed, these could be chance findings. AUC, cortisol slope and CAR were not convincingly associated with cardiovascular or total mortality, although the 95% confidence intervals of hazard ratio estimates were wide. ConclusionsThis study provides little evidence for clinically important associations of salivary cortisol and subclinical cardiovascular measures and mortality.

IntroductionIdiopathic intracranial hypertension (IIH) is associated with increased cardiovascular disease (CVD) risk, but the relative contributions of obesity versus IIH-specific factors remain unclear. This study aims to disentangle the effects of obesity and IIH on stroke and CVD risk, building upon previous research suggesting a two-fold increased risk of cardiovascular events in women with IIH compared to BMI-matched controls. MethodsWe conducted an obesity-adjusted risk analysis using Indirect Standardization analysis based on Adderley et al. study which utilized data from a cohort of 2,760 women with IIH and 27,125 matched healthy controls from The Health Improvement Network (THIN) database. We employed innovative statistical models to adjust for the confounding effects of obesity, estimating the risk of ischemic stroke and cardiovascular disease attributable to IIH independent of obesity. Four distinct models were used to elucidate the complex interrelationships between IIH, obesity, and CVD risk. ResultsOur analysis revealed that IIH confers additional cardiovascular risk beyond that attributed to obesity alone. Risk ratios for various cardiovascular outcomes were consistently elevated across models comparing IIH patients to controls within the same obesity strata. A striking synergistic effect between IIH and obesity was observed, with the composite CVD risk reaching a risk ratio of 6.19 (95% CI: 4.58-8.36, p<0.001) in obese IIH patients compared to non-obese controls. ConclusionsThis study provides compelling evidence for a nuanced relationship between IIH, obesity, and cardiovascular risk. IIH appears to confer substantial cardiovascular risk independent of obesity, necessitating a paradigm shift in IIH management to encompass comprehensive cardiovascular risk mitigation. Further research is needed to elucidate the underlying mechanisms and develop targeted interventions for this unique patient population.

BackgroundChronic psychological distress has been associated with increased risk of cardiovascular disease (CVD). However, mechanistic evidence explaining the observed associations remains limited and, with data are particularly sparse among women. This study examined if a metabolite profile linked with distress would be associated with increased risk of CVD. MethodsA plasma metabolite-based distress score (MDS) of twenty metabolites was derived in a cross-sectional, 1:1 matched case-control dataset (n=558 women) in the Nurses Health Study (NHS). We then calculated this score in two other cohorts, the Womens Health Initiative Observational Cohort (WHI-OS) and the Prevencion con Dieta Mediterranea (PREDIMED) trial, and tested association with risk of developing adjudicated measures of CVD in each cohort. We considered incident coronary heart disease (CHD) in the WHI-OS dataset which included 944 postmenopausal women (472 CHD cases; mean time to event of 5.8 years), and incident CVD (including stroke, myocardial infarction, CVD death) in the PREDIMED dataset which included 980 men and women (224 CVD cases, mean time to event of 3.1 years). ResultsIn the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 14% increased risk of incident CHD (odds ratio [OR]=1.14, 95% CI: 1.03 - 1.26), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol (OR=1.09; 95% CI: 0.98 - 1.21). Of the component metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk. In PREDIMED, each one SD increase in the MDS was associated with a 17% increased incident CVD risk (OR=1.17, 95% CI: 1.00 - 1.38), after adjusting for risk factors including total and HDL cholesterol. Similar associations were observed in men and women. Four individual metabolites in the MDS were associated with incident CVD risk in fully adjusted models in PREDIMED. Biliverdin and C36:5 PC plasmalogen had inverse associations, whereas C16:0 ceramide and C18:0 LPE each had positive associations with CVD risk. ConclusionsOur study sheds light on the key molecular alterations that characterize chronic distress and are predictive of subsequent CVD risk in men and women. These findings provide additional evidence for the role of distress in CVD development.

ObjectiveTo examine the association between Atherogenic Index of Plasma (AIP) and subclinical myocardial injury (SCMI), and their combined impact on cardiovascular disease (CVD) mortality in the general population. MethodsThis analysis included 7,093 participants without CVD from the Third National Health and Nutrition Examination Survey. AIP was calculated as the logarithmic ratio of triglycerides to HDL cholesterol. Participants were stratified into low or high AIP groups based on the median AIP value (0.958). Electrocardiographic SCMI was defined as Cardiac Infarction/Injury Score [&ge;]10 points. CVD mortality data were obtained from the National Death Index. Multivariable logistic regression models assessed the baseline cross-sectional association between AIP and SCMI, while Cox proportional hazards models examined the relationship between different baseline AIP/SCMI groups and CVD mortality. ResultsHigh AIP was associated with increased odds of SCMI [OR(95% CI): 1.20(1.07-1.35)] in multivariable logistic regression analysis. In multivariable Cox proportional hazard models, compared to participants with low AIP and absent SCMI, those with SCMI had a higher risk of CVD mortality regardless of AIP level [(HR(95% CI) 1.28(1.05-1.57) and 1.33(1.10-1.60)]. However, high AIP without SCMI was not associated with CVD mortality [HR (95% CI) 0.94(0.79-1.11)]. ConclusionsHigh AIP was associated with an increased risk of SCMI. SCMI was linked to a higher risk of CVD mortality regardless of AIP levels, while high AIP was only associated with CVD mortality when SCMI was present, suggesting that the reported adverse outcomes linked to high AIP may be driven by the development of SCMI.

BackgroundIntensive lifestyle intervention(ILI) in type 2 diabetes(T2D) improves cardiometabolic risk factors. Sex differences in these responses may be driven by the sex hormones testosterone(T), estradiol(E2), and sex hormone binding globulin(SHBG). We evaluated whether baseline sex hormone levels modify ILI effects on cardiometabolic risk factors ie, heterogeneity of treatment effect(HTE), and whether these modifications differ by sex. MethodsStudy included 2,260 Look AHEAD participants(1,093 postmenopausal females; 1,167 males, mean age 60 years) randomized to ILI or diabetes support and education with sex hormone measurements. We used linear mixed-effects models, stratified by sex and adjusted for age, race, study site, medications and baseline weight, to examine the association between baseline T, E2, and SHBG with change in lipids, hemoglobin A1c(HbA1c), systolic and diastolic blood pressure(BP), weight, and waist circumference(WC) over an 8-year follow-up. HTE was assessed using a three way interaction term between baseline hormone levels, time and randomization arm. Permutation tests controlled for multiple comparisons. ResultsIn males, lower baseline E2 and total T significantly augmented ILI-induced triglyceride reductions(p=0.019 and 0.008, respectively) throughout follow up. Higher SHBG enhanced LDL-C lowering in females(p=0.018) and HDL-C increases in males(p=0.043). Higher baseline total T predicted greater long-term weight(p=0.013 females; 0.003 males) and WC loss(p=0.061 females; 0.035 males), while fewer hormone interactions were observed for BP and HbA1c. ConclusionsMales with greater endogenous total T achieved larger reductions in triglycerides, weight, and WC, whereas females with higher total T had greater HDL-C improvements and those with higher SHBG experienced more BP lowering. Hormone profiling may guide personalized lifestyle prescriptions to improve long term cardiometabolic benefits. Clinical PerspectiveO_LIWhat Is New? Baseline sex hormone levels especially estradiol in males and testosterone/SHBG in females, sex-specifically modify the cardiometabolic benefits of intensive lifestyle intervention in type 2 diabetes. C_LIO_LIWhat Are the Clinical Implications? Endogenous hormone profiles may help clinicians personalize diet and exercise programs and guide adjunctive therapies to maximize lipid, blood pressure, and adiposity outcomes in females and males with T2D. C_LI

BackgroundAngiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are commonly prescribed alongside exercise to manage hypertension in individuals with metabolic syndrome (MetS). However, their potential to interfere with exercise-induced physiological adaptations remains unclear. MethodsIn this prospective, parallel-group study, 62 sedentary obese adults with MetS completed a 16-week supervised high-intensity interval training (HIIT) program. Participants were either chronically medicated with ACEi or ARBs (antihypertensive medication group, AHM, n=27) or a non-medicated control group (CONTROL, n=35). Primary outcomes included changes in resting and graded exercise blood pressure, MetS components, and cardiorespiratory fitness (CRF). ResultsBoth groups exhibited significant comparable improvements (all p time x group > 0.05) in cardiometabolic health (MetS Z-score; AHM -0.22{+/-}0.42; CONTROL - 0.30{+/-}0.33; p time < 0.001) and CRF (VO2MAX: AHM 3.9{+/-}2.1; CONTROL 5.0{+/-}3.1 mL{middle dot}kg-{superscript 1}{middle dot}min-{superscript 1}; p time = 0.003). Resting blood pressure decreased similarly in both groups (Mean Arterial Pressure: AHM -4.2{+/-}8.7; CONTROL -6.5{+/-}6.3 mmHg; both p time = 0.005; p time x group > 0.05). Additionally, antihypertensive medication did not interfere with the maximal (MAP; p time = 0.008) and submaximal (DBP; p time = 0.047) blood pressure exercise responses following training with no significant time x group interaction (both p > 0.05) ConclusionsChronic treatment with angiotensin antagonist medication to treat hypertension does not restrain the effects of supervised HIIT program on improving cardiovascular function, cardiorespiratory fitness, or reducing the components of MetS. Our findings support aerobic exercise training as an effective nonpharmacological co-therapy for hypertensive patients treated with angiotensin antagonists.

ObjectiveLow-grade inflammation in the young may contribute to the early development of adverse cardiometabolic risk profiles. We assessed whether measures of glycoprotein acetylation (GlycA) were better able to detect the development of these changes compared to the more commonly used biomarker high-sensitivity C-reactive protein (CRP), and investigated whether these relationships differed in an adolescent compared to young adult cohort. Research Design and MethodsA total of 3306 adolescents (Avon Longitudinal Study of Parents and Children - ALSPAC; mean age 15.4{+/-}0.3; n=1750) and young adults (Cardiovascular Risk in Young Finns Study - YFS; mean age 32.1{+/-}5.0; n=1556) were included. Inflammatory biomarkers (GlycA/CRP), body composition (BMI / waist circumference) and cardiometabolic risk factors (blood pressure, triglycerides, HDL-c, glucose, insulin, and homeostasis model of insulin resistance [HOMA_IR]), were measured at baseline and again in 9-10 year follow-up. Metabolic Syndrome (MetS) was defined using adolescent-specific National Cholesterol Education Programme (NCEP) guidelines in ALSPAC and standard NCEP guidelines in YFS. ResultsGlycA levels showed greater within-subject correlation over the 9-10 year duration of follow-up in both cohorts when compared to CRP, particularly in the younger adolescent group. In adjusted models, only GlycA was found to increase in line with cardiometabolic risk factor burden at baseline, and to predict adverse changes in several cardiometabolic risk factors in follow-up. In both cohorts, GlycA predicted future risk of MetS (OR [95%CI] for Q4 vs. Q1 = 1.95 [1.08,3.53] and 2.74 [1.30,5.73] for ALSPAC and YFS, respectively), whereas CRP showed a neutral or even negative relationship in fully-adjusted models (OR [95%CI] = 0.50 [0.29,0.86] and 0.93 [0.53,1.64]). ConclusionsChronic inflammation is associated with adverse cardiometabolic risk profiles from as early as adolescence and predicts risk of future cardiometabolic risk and MetS in up to 10 year follow-up. GlycA may be a more sensitive inflammatory biomarker to CRP for detecting early cardiometabolic and cardiovascular risk in the young.

ObjectiveTo investigate how genetic variations in obesity-related genes affect the AMPK signaling pathway and contribute to the pathophysiology of cardiovascular disease in the context of obesity. BackgroundThe global rise in obesity presents serious public health challenges, significantly increasing the risk of comorbidities such as type 2 diabetes and cardiovascular disease. Genetic predisposition plays a critical role in obesity, with several genes influencing metabolic regulation. AMP-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis. Disruptions in its signaling pathway may contribute to metabolic dysfunction and cardiovascular complications. Understanding how genetic variations impact AMPK signaling is essential for the development of targeted interventions. MethodsA systematic literature review was conducted using databases including PubMed, MEDLINE, Google Scholar, and both open-access and subscription-based journals. The search focused on studies examining genetic variations in obesity-associated genes--FTO, MC4R, LEP, LEPR, PCSK1, PPARG, BDNF, SIM1, TBC1D1, ADRB3, UCP1, and SH2B1--and their impact on AMPK signaling. No date restrictions were applied. Articles were selected based on predefined inclusion criteria and assessed in accordance with PRISMA guidelines to evaluate the mechanisms linking genetic variants with AMPK modulation, energy balance, inflammation, and cardiovascular risk. ResultsGenetic variants in the selected obesity-related genes were found to significantly influence AMPK activation. These alterations led to impaired energy expenditure, increased lipid storage, and disturbances in glucose metabolism. Dysregulation of AMPK signaling also promoted chronic low-grade inflammation and endothelial dysfunction--factors closely associated with elevated cardiovascular disease risk. The findings underscore the pivotal role of gene-AMPK interactions in metabolic and cardiovascular health. ConclusionGenetic variations in obesity-related genes impair AMPK activation, disrupting energy metabolism and promoting inflammation and vascular dysfunction. This contributes to increased cardiovascular risk in obese individuals. Personalized therapies targeting AMPK activation and gene-specific pathways may offer promising strategies to counteract obesity-induced metabolic dysregulation and improve cardiovascular outcomes.

BackgroundThis population-based prospective cohort study aimed to investigate whether accelerometer-measured step count is associated with incident cardiovascular disease (CVD), independently from genetic risk. MethodsThe study included participants in the UK Biobank with valid accelerometer and genetic data and without prevalent CVD at baseline. Genetic risk for CVD was categorised as low (1st fifth), moderate (2nd-4th fifths), and high (5th fifth). Median daily step count was categorised as low (<6,500), moderate (6,500-12,499), and high ([&ge;]12,500). The association of genetic risk and step count with incident CVD, defined as a composite of coronary artery disease and ischaemic stroke, was examined using adjusted Cox proportional hazards models. ResultsOf 84,286 participants, 4,847 were diagnosed with CVD during follow-up (median 7.9 years). High genetic risk and low daily step count had a log-additive association with incident CVD. In low genetic risk individuals, step count was not associated with incident CVD. However, in the moderate and high genetic risk groups, those with low step counts had 24% (HR 1.24; 95% Confidence Interval [CI] 1.10-1.40) and 37% (HR 1.37; 95% CI 1.14-1.65) higher risk of incident CVD compared to those with high step counts. There was an inverse dose-response association between the hazard of CVD and step counts up to 10,000 steps/day, which then plateaued in moderate and high genetic risk groups. ConclusionsHigh daily step count was associated with lower CVD risk in individuals with moderate and high genetic risk, indicating that walking should be encouraged for all, especially those predisposed to CVD.