Sex Differences Research Articles

Regional variation of age-related blood pressure trajectories and their association with blood pressure control rates, disability-adjusted life years and death

Abstract Background/Introduction While the relationship between blood pressure (BP) changes and increasing age is well described, age-related BP trajectories may vary substantially across different populations and associated with differential CV risk and outcomes. Purpose The dataset of the May Measurement Month (MMM) international campaigns enables a unique investigation of regional, socio-economic and sex differences in age-BP trajectories and their association with major public-health outcomes. Method Global BP data from more than 4,5 million adult (≥18 years) screenees obtained during the cross-sectional MMM campaigns in 2017, 2018, 2019, and 2021 were used for analysis. Average BP and slopes of BP changes across age groups were calculated within regional, socio-economic and sex strata. BP slopes of individuals between 30 and 70 years of age were derived from adjusted linear regression models, along with baseline BP estimates at young age. These BP slopes were correlated in regression models adjusted for baseline BP at young age with country-specific all-cause rates of DALYs (Disability-Adjusted Life Years), death (both from Global Burden of Disease Study 2019), life expectancy (World Bank data SP.DYN.LE00.IN 2019) and BP control rates (NCD Risk Factor Collaboration). Results Age-related BP changes differed distinctly across global geographic regions, income levels, and between sexes. The steepest increase in BP with age was observed in populations from Africa and Europe, whereas a more gradual rise in BP with increasing age was seen in South-East Asian populations. Women had lower BP levels than men at younger ages (twenties and thirties), but subsequently experienced a more pronounced age-related BP increase resulting in diminishing sex differences across older age groups. Geographically divergent age-related BP trajectories were significantly associated with major national public health indicators. Globally, the steeper the age-related BP slope, the stronger the association with poor BP control (β = -0.46 [95% CI: -0.74; -0.19], p=0.001), increased DALY’s (β = 66155.68 [95% CI: 44847.0; 87464.36], p<0.001) and death rates. (β = 1017.3 [95% CI: 351.72; 1682.89], p=0.003). Conclusion Age-related BP trajectories vary considerably across global populations and contribute considerably to the variability in BP-related risks and adverse outcomes across regions. Effective public health strategies may require region-specific targeting of lifestyle and other factors contributing to adverse BP trajectories to improve health outcomes.Average blood pressure by ageAssiciations with public health metrics

Impact of sex, age, comorbidities, and culprit lesion location on symptoms in patients with non-ST-segment elevation myocardial infarction

Abstract Background Among patients with non-ST-segment elevation myocardial infarction (NSTEMI) about 80% present with chest discomfort. Others have less obvious symptoms, but early diagnosis is crucial. Sex differences in symptoms have been reported to delay diagnosis in about half of women. This study aims to analyze the symptoms and its disparities caused by sex, age, comorbidities, and culprit lesion location. Methods Patients presenting with troponin elevation and at least one angiographically confirmed atherosclerotic lesion causing the myocardial ischemia (culprit lesion) between February 2018 and July 2023 were prospectively included in a single-center, all-comers, real-world registry. Results Information regarding symptoms was available for 842 NSTEMI patients with an identifiable culprit lesion. Chest discomfort was reported by 684 patients (81.2%), dyspnea by 361 (42.9%) with it being the primary symptom in 102 (12.1%), and atypical symptoms by 317 (37.6%) with it being the primary symptom in 56 (6.7%). Concretely, dizziness or syncope was reported by 82 patients (9.7%), nausea, vomiting or any other gastrointestinal symptoms by 73 (8.7%), epigastric, shoulder, arm, back, neck or jaw pain by 57 (6.8%), diaphoresis by 66 (7.8%), other vegetative symptoms like palpitations or anxiety by 56 (6.7%), fatigue by 37 (4.4%), and neurologic symptoms like sensory or motor impairments by 28 (3.3%). In women, the primary complaint was less often chest discomfort (76.3 vs. 82.9%, p=0.040), more often atypical symptoms (9.8 vs. 5.6%, p=0.049) and equally often dyspnea (14.0 vs. 11.5%, p=0.403). Gastrointestinal symptoms were more often reported by women (13.5 vs. 7.0%, p=0.006). Elderly, i.e., age ≥80 years, reported chest discomfort less often (75.4 vs. 83.0%, p=0.023), dyspnea more often (19.5 vs. 9.9%, p<0.001) and atypical symptoms equally often (5.1 vs. 7.1%, p=0.418). Likewise, diabetic had chest discomfort less often (74.3 vs. 84.5%, p<0.001), dyspnea more often (18.2 vs. 9.2%, p<0.001), and atypical symptoms equally often (7.4 vs. 6.3%, p=0.633). No differences regarding primary symptoms were observed for dyslipidemia (82.1 vs. 78.9% for chest discomfort, 12.1 vs. 12.1% for dyspnea, 5.8 vs. 9.0% for atypical symptoms, p>0.05 for all) and obesity (84.5 vs. 81.2% for chest discomfort, 9.8 vs. 12.5% for dyspnea, 5.7 vs. 6.3% for atypical symptoms, p>0.05 for all). For LM culprit lesions, dyspnea was more often the primary symptom compared to LAD, LCX, and RCA culprit lesions (17.4% for LM vs. 13.6% for LAD, 5.7% for LCX, and 13.2% for RCA, p=0.023), while no differences were observed for chest pain (73.9% for LM, 80.6% for LAD, 86.1% for LCX, and 80.2% for RCA, p=0.235) and atypical symptoms (8.7% for LM, 5.9% for LAD, 8.1% for LCX, and 6.6% for RCA, p=0.758). Conclusions Chest discomfort is significantly less often the primary symptom of NSTEMI in women, elderly and diabetic making these groups more vulnerable for delayed diagnosis or misdiagnosis.

Sex differences in atherogenic lipid profile following acute coronary syndrome

Abstract Background Despite significant advancements in lipid-lowering therapy, the management of dyslipidemia remains challenging in patients with acute coronary syndrome (ACS). Significant differences are shown in lipid panels and management between different sexes following ACS. Objective To shed light on the alterations and characteristics of atherogenic lipoproteins and the characteristics of patients who achieve LDL-C targets after statin treatment, harnessing real-world data from electronic health records of patients with ACS after their discharge between sexes. Methods The data in the present study were derived from the iHeart program sponsored by the Chinese Cardiovascular Association. Eligible patients with a diagnosis of ACS from January 2014 to December 2021 during hospitalisation and having at least one lipid panel record after discharge within 12 months were enrolled. We analysed the control of atherogenic lipid profiles between sexes. The primary outcome was the achievement of the LDL-C target, defined as LDL-C <1.8 mmol/L. A multivariable logistic regression model was used to assess the associations between patient characteristics and LDL-C achievement. Results Between 2012 and 2021, 4861 patients (1299 [26.7%] women) were hospitalised with a primary diagnosis of ACS (49.2% STEMI, 13.8% NSTEMI, and 33.8% UA). The mean age was 64.9 (12.4) years. In contrast to a higher proportion of AMI in men, more prevalence of UA was observed in women. Women had more cardiovascular comorbidities than men and were more likely to receive lipid-lowering therapies, blood pressure-lowering therapies, glucose-lowering therapies, and antiplatelet medications at discharge. In both men and women, TC, TG, LDL-C, ApoB, and non-HDL-C levels significantly decreased within 12 months (P<0.05). Women had less reduction in atherogenic lipid profile than men. The rate of LDL-C <1.8 mmol/L was similar between sexes (14.3% vs16.1%; P=0.136) at baseline, whereas within 12 months after discharge, women had a much lower achievement rate of LDL-C target than men (34.6% vs 45.6%; P<0.001). The risk factors for non-achievement of the LDL-C target in men were revascularisation, history of MI, atrial fibrillation, newly diagnosed MI, and high baseline LDL-C levels. For women, the risk factor was hypertension and diabetes. Conclusion Substantial sex disparities were observed in the management of atherogenic lipids. Despite a higher likelihood of receiving guideline-recommended medical therapy at discharge, women had poorer lipid control compared to men, especially among those with NSTEMI.

Sex differences in the expression of metabolic and pro-inflammatory markers in the initial post-COVID-19 phase

Abstract Cardiovascular complications are a common manifestation of post-acute COVID-19 infection. Post-COVID-19 syndrome is often associated with the female sex and exacerbated inflammation; however, the underlying molecular mechanisms of this sex difference remain poorly understood. In the present study, we aimed to investigate several metabolic, mitochondrial, autophagy, oxidative stress, and inflammatory markers in peripheral blood mononuclear cells (PBMCs) and plasma isolated from older (>75) male and female patients at the initial phase (1-2 weeks) after COVID-19 pneumonia. Age-matched non-infected women and men were used as a control group. We found a significantly higher plasma TNF-α in post-COVID-19 women, but not in men, compared to the control group. Similarly, a significant elevation of IL-1β and IL-18 mRNA in PBMCs from post-COVID-19 women, but not men, was observed. These effects were associated with marked activation of AMPK (defined as pAMPK/AMPK ratio), suggesting potential metabolic stress in female post-COVID-19 PBMCs. Further analysis revealed increased expression of mitochondrial genes, which may be due to AMPK activation as a compensatory reaction to metabolic stress. Analysis of autophagy or oxidative stress (serum 8-OHdG) markers did not reveal any differences between the groups investigated. We conclude that women in the initial phase of post-COVID-19 have elevated expression of inflammatory markers in plasma and in immune cells, which is associated with metabolic stress. This may contribute to the cardiovascular complications in female post-COVID-19 patients.

Sex-specific association of NT-proBNP with clinically inapparent structural heart disease in the general population: results from the STAAB study

Abstract Background Guidelines recommend echocardiography in subjects beyond defined levels of natriuretic peptides. The ACC/AHA guidelines on heart failure (HF) state echocardiographic signs of structural heart disease (SHD) that define the precursor stage B of heart failure. Purpose To study the age- and sex-specific association between echocardiographically assessed structural heart disease (echoSHD) and NT-proBNP levels in the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Study participants were recruited between 12/2013 and 10/2017 from the source population without preceding HF diagnosis, stratified for sex and age (30-79 years). For this analysis, we excluded participants with previously diagnosed coronary artery disease. EchoSHD was accepted if one of the following criteria, diagnosed according to current echo guidelines, was detectable at echocardiography: left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction, moderate-to-severe LV valve disease, and LV diastolic dysfunction. Results Of 4,649 subjects analysed (93.6% of STAAB participants, age 30-79 years, 53.5% women), 863 (18.6%) had echoSHD. NT-proBNP depended strongly on age and sex (figure). Frequencies of echoSHD varied between women (23.0%) and men (13.5%; P<0.001). EchoSHD was associated with increased NT-proBNP levels in both women (geometric mean ratio 1.18, 95%CI 1.09–1.27, P<0.001; figure) and men (ratio 1.62, 1.46–1.79, P<0.001); P<0.001 for different ratios in both sexes. Of note, age did not influence these ratios as well as their difference (P=0.34 and P=0.95, resp.). Conclusion Clinically inapparent echoSHD was associated with higher levels of NT-proBNP, of a magnitude that was relevant in men. The sex difference in the strength of this relationship might be due to different pathophysiological processes leading to SHD and ultimately HF in women and men. It might also indicate the need for adopted definitions of echoSHD in women. Our results further point towards the need of age- and sex-specific NT-proBNP thresholds.NTproBNP according to sex, age, and SHD

Sex differences in outcomes of patients with cardiogenic shock due to acute myocardial infarction: a systematic review and epidemiological meta-analysis

Abstract Background Women are at higher risk of mortality from ST-elevation myocardial infarction (1) when compared to men. There is a lack of consensus among studies examining the effect of sex on outcomes from cardiogenic shock due to acute myocardial infarction (AMI-CS) (2-5). In this systematic review and meta-analysis, we sought to assess the relationship between outcomes of AMI-CS and sex. Purpose To examine sex-related differences in mortality in patients with cardiogenic shock secondary to acute myocardial infarction (AMI-CS). Methods Cochrane Central, PubMed, MEDLINE and EMBASE were searched in February 2023 for studies reporting in-hospital or 30-day sex-specific mortality in patients with cardiogenic shock. Inclusion criteria consisted of observational or randomised controlled trials of adult patients with cardiogenic shock that reported unadjusted or adjusted (by odds or risk ratio) mortality rates by sex. In-hospital or 30-day mortality were treated as equivalent. Data were extracted for study size, number of men and women, unadjusted and adjusted mortality rates, and factors used in multivariable analysis. Studies were assessed for risk of bias and publication bias. Meta-analysis was performed using DerSimonian-Laird random effects model with inverse variant weighting, due to predicted high heterogeneity of included studies. Data are reported as odds ratios (ORs) with 95% confidence interval (CI). P values were adjusted for multiple comparison using Holm-Bonferonni correction. The primary outcomes were unadjusted and adjusted sex-specific mortality rates due to AMI-cardiogenic shock. Results 4,286 studies were identified and 37 met inclusion criteria, pooling a total of 630,890 patients. Raw 30-day/in-hospital mortality of females with AMI-cardiogenic shock was 41.2% compared to 32.3% in males. Unadjusted OR for mortality in females was 1.42 (95% CI 1.31–1.55, p <0.001, t2 = 0.02, I2 = 70.3%), and the adjusted OR was 1.11 (95% CI 1.04–1.20, p <0.001, t2 = 0.01, I2 = 76.8%). Eight studies included data on use of mechanical circulatory support (MCS), which was used in 31.2% of females compared to 39.9% of males. OR for use of MCS in females compared to males was 0.71 (95% CI 0.66–0.77, p < 0.001, t2 = 0.003, I2 = 35.2%). Conclusions Women with AMI-related cardiogenic shock are at greater risk of death compared to male patients and are less often treated with MCS. Potential explanations include residual confounding factors, differences in AMI-cardiogenic shock pathophysiology between men and women, and sex-related differences in healthcare behaviours, but we cannot exclude the effect of systemic bias on outcomes. Further research is required to address the causes of sex disparities in outcomes and ensure equitable management of AMI-cardiogenic shock in women.Unadjusted sex outcomes from AMI-CSAdjusted sex outcomes from AMI-CS

Sex differences in reporting of statin-associated diabetes mellitus to the US Food and Drug Administration

Abstract Background Statins have been reported to precipitate diabetes mellitus (DM) in some patients. Limited evidence suggests that this occurs in women more frequently than men, but direct comparisons of rates of reporting of statin-associated DM between men and women are lacking. Purpose To determine whether there are sex-specific differences in post-marketing reporting of statin-associated DM. Methods We conducted a retrospective pharmacovigilance analysis of spontaneously reported adverse drug events (ADEs) submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System between January 1997 and September 2023. A Proportional Reporting Ratio (PRR) was used to identify the rate of reported statin-associated DM ADEs relative to the rate of DM ADEs reported with all other medications. We compared signals of disproportionate reporting (SDRs) between men and women using a modified relative odds ratio (ROR). Results During the study period, there were two-fold as many reports of statin-associated DM in women than in men (14,793 versus 7,307, respectively), despite the fact there were only 7% more non-DM statin ADEs reported in women compared to men (512,134 versus 480,849, respectively). Compared to the background rate of reporting for all ADEs (0.6%), statin-induced DM was disproportionally reported for all subjects in aggregate (2.1%, PRR=3.7) as well as for men only (1.5%, PRR=2.4) and for women only (2.9%, PRR=5.3). Significant PRRs for DM were observed with each statin and for all statins collectively (Figure 1). Statins were reported as the primary- or secondary-suspected cause of DM in women with considerably greater frequency than in men (58% versus 29%, respectively). Rates of reporting of statin-associated DM were higher in women than in men for all statins, with the greatest difference being observed with atorvastatin (ROR 3.0), and the lowest difference being observed with rosuvastatin (ROR 1.2) (Figure 1). Conclusions Post-marketing ADE surveillance data suggest a markedly higher rate of incident DM associated with statins than with other medications and a higher rate of reporting of statin-associated DM in women than in men. Future studies should consider sex-moderated mechanisms of statin-associated DM.Figure 1

Prevalence of potentially inappropriate medication use in the older population living in Germany

Abstract Background Potentially inappropriate medications (PIM) are medicines for which the risks for adverse events (AEs) usually outweigh the clinical benefits in older adults. PIM is associated with an increased risk of AEs, hospitalizations, mortality and higher health care costs. This analysis presents the prevalence of PIM use and associated factors in people aged 66+ years living in Germany. Methods Data from the nationally representative Study on Health of Older People in Germany (Gesundheit 65+) conducted between 2021-2023 by the Robert Koch Institute, was analyzed. All medicines used, prescribed and over-the-counter (OTC), in the 7 days before the interview were classified into anatomical therapeutic chemical codes. PIM use was identified based on the PRISCUS 2.0 list. Weighted prevalences and associated factors for PIM use are presented. Results 96% of the sample (N = 1,474) took at least 1 medication in the 7 days before the interview. The prevalence of PIM use was 29% (95% CI: 26%-32%), 23% took 1 PIM and 6% 2+. There were no sex differences but a significant increase with age: 23% in the age group 66-74, 33% in the age group 75-84, and 39% in the age group 85 + (29% 1 PIM and 10% 2+). People with a low educational level had a PIM prevalence of 32% compared to 21% in those with a high educational level. Among those reporting having chronic diseases, the PIM prevalence was 34% compared to 19% among those not reporting them. The prevalence of PIM increased with the number of medicines used: 13% in 1-4 medicines, 31% in 5-9 medicines, and 53% in 10+ medicines. The most frequently used PIM in this sample was ginkgo biloba leaf extract (plant-based antidementia drug) followed by diclofenac (non-steroidal anti-inflammatory drug), and then by tricyclic antidepressant drugs (opipramol and amitriptyline). Conclusions PIM use was higher than suggested by prescription data analysis. It was associated with higher age, chronic diseases, polypharmacy and a low educational level. Key messages • PIM use was common, affecting more people with chronic diseases, older age groups and people with a low educational level. • Strategies to promote and monitor appropriate medication use are needed.

Prospective comparison of temporal myocardial function in men vs women after anterior ST-elevation myocardial infarction

Abstract Background Compared to men, women have been reported to have increased morbidity and mortality after ST-elevation myocardial infarction (STEMI), but sex differences in cardiac function in the acute and subacute phases of STEMI are incompletely understood. Objective To prospectively compare changes in cardiac function over the acute and subacute phases after anterior STEMI with timely reperfusion in women versus men. Methods The Stunning in Takotsubo versus Acute Myocardial Infarction (STAMI) study prospectively enrolled 94 men and 36 women with anterior STEMI. Echocardiography and blood sampling were performed within 4 hours of admission and at 1, 2, 3, 7, 14 and 30 days after admission. The primary outcome was akinesia recovery, defined as the difference in the per cent akinesia observed at baseline versus follow-up. Secondary outcomes included wall motion score index (WMSI), left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Mixed effects linear regression or zero-inflated tobit models with random intercepts were used to model echocardiographic parameters over time. Results Baseline patient characteristics were similar in both groups. The difference between women and men in akinesia recovery at 30 days was 8.4% (95% confidence interval [CI] 1.23-14.99). The covariate-adjusted Bayesian posterior probability that akinesia recovery and WMSI improvement at 30 days are more significant in women than men were 95% and 99%, respectively. Similar but less pronounced trends towards greater improvement in women than men were observed for LVEF and GLS. Conclusions After anterior STEMI with timely reperfusion, cardiac dysfunction recovered to a greater extent in women than in men.

Sex differences in the substrate of atrial fibrillation and the outcome of thoracoscopic ablation

Abstract Background Women with atrial fibrillation (AF) suffer more from AF symptoms, a lower quality of life, and have an enhanced risk of stroke. The AF recurrence after ablation is higher in women than in men. We hypothesize that sex specific differences in the atrial fibrotic substrate underlie these differences in clinical outcome. Here, we sought to characterize atrial fibrosis and fibrosis formation in the left atrial appendage (LAA) of women and men undergoing thoracoscopic ablation of AF. Methods We used the excised LAA of 30 female and 30 male patients with persistent AF undergoing thoracoscopic AF ablation. Patients were matched for age. In addition propensity score matching was also conducted for adjusting intermediary variables such as AF duration, Age ≥ 75, Body mass index (BMI), and CHA2DS2-VASc score ≥ 4. LAAs were stained with picrosirius red to quantify collagen and with vimentin for fibroblasts. Images were analyzed automatically (Image J version 1.50i) using color deconvolution to identify the area fraction of collagen and fibroblast. Results Women had similar age as men (66.4±7.76 vs 66.1 ±7.57, P= 0.85) but had a trend toward more cardiovascular risk factors [CHA2DS2-VASc score ≥ 4, (23.3 vs 6.7)%, P=0.07]. The total percentage of fibroblasts was larger in women 14.98 (9.79-24.95) % than men 13 (5.85-17.46) %, P=.018. In addition, in women fibroblasts were located more in epicardially and endocardially than in the interstitium.[women 8.18 (5.06-13.36) % vs men 6.49 (2.73-9.92) % , P=0.005].There was not a remarkable differences in total amount of collagen between the groups [women 16.03 (9.67-26.98) % vs men 15.50 (9.50-20.90) %, P=0.57 ], but there was a trend towards more epicardial and endocardial collagen in women than men [11.81(5.75-22.11)% vs 10.24 (6.06-15.10) % , P=0.06]. Conclusion We demonstrate more epicardial and endocardial fibroblasts in the LAA of women compared to men with persistent AF. There was similarly a trend towards more epicardia and endocardial but not interstitial collagen deposition. These findings may –at least in part- underlie sex specific differences in AF pathophysiology and ablation outcome.

Sex differences in left ventricular dilatation in patients with significant aortic regurgitation: prognostic implications

Abstract Background Left ventricular (LV) dilatation is a strong indicator of adverse outcome in patients with aortic regurgitation (AR). Accordingly, current guidelines recommend the use of LV end-systolic diameter index (LVESDi) as one of the criteria to trigger aortic valve surgery (AVS) in patients with severe AR, but with the same threshold regardless of gender. Purpose To assess sex differences in LV remodeling using both volumetric and linear measurements in a large cohort of patients with significant AR (moderate or greater) and to investigate their prognostic implications. Methods A total of 1070 patients (56 ± 18 years, 691 men) were included. The primary outcome was all-cause mortality. Results Women presented with older age (58 ± 19 vs. 55 ± 17, p=0.023) and more advanced heart failure (HF) symptoms than men (NYHA class III-IV 12% vs. 9%, p=0.017). Men showed significantly larger LVESDi (21 ± 5 vs. 20 ± 5 mm/m2, p=0.013) and LV end-systolic volume index (LVESVi 37 ± 28 vs. 26 ± 17 ml/m2 p<0.001). During a median follow-up of 89 (IQR, 54-132) months, 168 patients died. Women had lower survival rates at 3, 5, and 10 years of follow-up compared to men (92% vs. 94.3%; 85% vs. 89.7% and 75.3% vs. 84.1%, p=0.005) (Figure 1). Spline curve analysis revealed that the threshold of LVESDi associated with an increased risk of mortality was 20 mm/m2 for both sexes. In turn, the threshold for LVESVi was 40 ml/m2 for women and 45 ml/m2 for men. Univariable Cox regression models were constructed separately for men and women. The variables associated with all-cause mortality were age, NYHA class III-IV, and AVS as time-dependent covariate in women, and age, diabetes, AVS as time-dependent covariate, and LAVI (left atrial volume index) in men. These parameters were used as a basal multivariable Cox regression model on top of which LVESDi >20 mm/m2 (Model 1), LVESVi >40 ml/m2 for women and 45 ml/m2 for men (Model 2) were added (Table 1A). LVESVi >40 ml/m2 was not a significant univariate predictor in men. In women, LVESDi >20 mm/m2 (HR: 2.046, 95%CI 1.244-3.419; p=0.006) and LVESVi >40 ml/m2 (HR 1.758, CI 1.095-2.825; p=0.020) showed an independent association with all-cause mortality among other factors (Table 1A). In men, death was independently associated with LVESDi >20 mm/m2 (HR 1.979, 95%CI 1.255-3.121; p=0.003) and LVESVi >45 ml/m2 (HR 2.388, 1.522-3.746; p<0.001), among other factors (Table 1A). Moreover, when added to a basal model that included clinical and echocardiographic variables associated with prognosis, LV dilatation based on volumetric LV enlargement resulted in a greater discriminatory power for both genders (Table 1B). Conclusion Men and women have a similar LVESDi threshold of 20 mm/m2, which is associated with an increased risk of death. However, their respective cut-off values for LVESVi differ, with the optimal threshold for women being 40 ml/m2 and for men 45 ml/m2.

First Insights into the Fecal Metabolome of Healthy, Free-Roaming Giraffes (Giraffa camelopardalis): An Untargeted GCxGC/TOF-MS Metabolomics Study

Background/Objectives: This study provides the first insights to the fecal metabolome of the giraffe (Giraffa camelopardalis). By using untargeted metabolomics via gas chromatography time-of-flight mass spectrometry (GCxGC/TOF-MS), this study primarily aims to provide results of the impact that external stimuli, such as supplemental feeding (SF) practices, seasonal variation and sex, might have on the fecal metabolome composition of healthy, free-roaming giraffes. Methods: Untargeted GCxGC/TOF-MS analysis was applied to the feces collected from thirteen giraffes (six males and seven females) from six different locations within the central Free State Province of South Africa over a period of two years. Statistical analysis of the generated data was used to identify the metabolites that were significantly different between the giraffes located in environments that provided SF and others where the giraffes only fed on the natural available vegetation. The same metabolomics analysis was used to investigate metabolite concentrations that were significantly different between the wet and dry seasons for a single giraffe male provided with SF over the two-year period, as well as for age and sex differences. Results: A total of 2042 features were detected from 26 giraffe fecal samples. Clear variations between fecal metabolome profiles were confirmed, with higher levels of amino acid-related and carbohydrate-related metabolites for giraffes receiving SF. In addition, a separation between the obtained profiles of samples collected from a single adult male giraffe during the wet and dry seasons was identified. Differences, such as higher levels of carbohydrate-related metabolites and organic compounds during the wet season were noted. Distinct variations in profiles were also identified for the metabolites from fecal samples collected from the six males and seven females, with higher concentrations in carbohydrate-related metabolites and alkanes for female giraffes comparatively. Conclusions: This is the first study to investigate the composition of the fecal metabolome of free-roaming giraffes, as well as the effects that external factors, such as environmental exposures, feeding practices, seasonal variations, age and sex, have on it. This novel use of fecal metabolomics assists in developing non-invasive techniques to determine giraffe populations’ health that do not require additional stressors such as capture, restraint and blood collection. Ultimately, such non-invasive advances are beneficial towards the conservation of wildlife species on a larger scale.

Investigating the effect of chronic stress, depressive-like pathology and cognitive impairments on acute myocardial infarction: sex-differentiated effects

Abstract Background/Introduction Depression is an independent risk factor for cardiovascular disease (CVD) with the prevalence rates being higher in women than men in the general population and among patients with CVD. Furthermore, an association between myocardial infarction and cognitive deficits has been proposed, but the pathophysiological mechanisms that are responsible for the brain-heart axis interaction have not been elucidated. Purpose The present study aims to: 1) evaluate sex differences in the effect of chronic unpredictable stress (CUS) on myocardial infarct size (IS) and 2) determine the molecular pathways affected by CUS in the heart. Methods Adult male and female C57BL/6J mice, were randomly divided into 4 groups (n=7/group): CON (Control, sham surgery), iCON (Control, myocardial ischemia/reperfusion (IR)), STR (Stress, sham surgery) and iSTR (Stress, IR). Mice were intermittently exposed to the CUS protocol consisted of 4 different stressors for 6 consecutive weeks. Locomotor activity (open field-OF), anxiety-like alterations (OF, elevated plus-maze-EPM test), depressive-like pathology (tail suspension test- TST) and cognition (Y-maze and Novel Object Recognition-NOR tests) were evaluated. After behavioral evaluation, the animals were subjected to 30 min I followed by 24 h of R or sham surgery and infarct size (IS) was determined via double Evan’s Blue and triphenyltetrazolium chloride staining. In a second series of experiments (n=5/group), the ischemic part of the myocardium was collected at 24h R and subjected to label free proteomic analysis, in order to identify alterations associated with the effect of CUS and IR. Results CUS induced anxiety, depressive-like pathology and cognitive deficits as indicated by the increased time spent in the closed arms of the EPM (p<0.005), the increased immobility time (TST, p<0.05), the reduced preference for the novel object (NOR, p<0.05), and the significant body weight reduction (p<0.001), in both male and female mice. CUS significantly increased IS (p<0.001) in both male and female mice. Proteomic analysis revealed that CUS affected the heart proteome, related to endoplasmic reticulum stress, mitochondrial damage and apoptosis, of both sexes in the absence of IR. Female mice were more susceptible to IR damage in absence of CUS with 248 significant genes (FDR<0.05) being deregulated mainly belonging to Keap-Nrf2-ARE signaling pathway, in contrast to 168 significant genes in male mice. In male mice, CUS exacerbated the IR injury proteome changes mainly related to induction of apoptosis and mitochondrial dysregulation (292 significant genes, FDR<0.05 for males vs 102 for females). Conclusions Chronic exposure to stress increases depressive-like pathology and cognitive deficits, leading to heart proteome alterations and increased IS in both sexes. Sex differences were observed indicating that the coexistence of CUS and IR render the male heart more susceptible to myocardial damage.

Sex differences in cancer incidence amongst people with cardiovascular disease: a large British population study

Abstract Background Studies have shown that patients with cardiovascular disease (CVD) have an incremental risk of death due to noncardiac causes. This is especially attributable to cancer developments during long term follow up. The two diseases share pathophysiological mechanisms that extend beyond traditional risk factors. With well-established sex disparities in CVD, it becomes imperative to investigate whether similar sex-based differences exist in both the incidence of cancer and cancer-related mortality, in participants with CVD vs those without CVD. Purpose We aim to analyse the sex differences in incident cancer and cancer-related mortality between people with and without CVD. Methods Participants were drawn from a large British population based prospective cohort study and followed up for a median of 26.2 years. Participants were stratified by sex and whether they developed CVD over the study follow-up. The cumulative incidence of cancer, excluding non-melanoma skin cancers were calculated. Sex-specific lifetime risks were determined accounting for competing risks of death. Cause-specific hazard ratios were determined using Royston-Parmar models. Models were adjusted for ethnicity and time-updated covaries, including material deprivation, CV risk factors, lifestyle factors, comorbidities, and medication. Participants’ CVD status was time-updated over the study follow-up as this was diagnosed. Results Out of a total of 22, 534 participants, free of cancer at baseline, 53.7% were women. Mean (standard deviation) age was 58.6 (9.3) for women and 59.5 (9.3) for men, at baseline. Men were older and had more comorbidities. Hypertension and obesity were risk factors more prevalent amongst men, while women were more likely to be smokers at baseline. Participants with CVD had more comorbidities, were more likely to smoke, have higher HbA1cs and be obese than those without CVD. The adjusted lifetime risks of incident cancer in participants with CVD at age 75 were higher in men (13.9%) compared to women (10.1%). This translates into a cause-specific hazard ratio (cHR) (99% confidence interval) for incident cancer (men vs. women) of 1.41 (1.27 - 1.55). Similar findings were demonstrated in participants with no CVD (10.2% for men and 8.2% for women), corresponding to a cHR of 1.27 (1.15 - 1.40). Furthermore, men had a higher risk of cancer-related mortality compared to women in participants with CVD 1.54 (1.33 - 1.78), as well as among participants without CVD 1.34 (1.17 - 1.53). Conclusion Our study showed an association between CVD and the lifetime cancer risk in both sexes after extensive adjustment. Furthermore, we show that men have a higher risk of cancer incidence and cancer-related mortality than women, regardless of comorbid CVD. However, these associations, were stronger in participants with CVD. It is vital to identify driving forces of such disparities to achieve health equity.

Sex-differences in the clinical features, managements and outcomes of early-onset atherosclerotic coronary artery disease in China

Abstract Background/Introduction There is an alarming rise in the incidence of atherosclerotic coronary artery disease (CAD) among young adults, particularly in young women. Sex disparities of early-onset CAD in the context of contemporary cardiovascular practice are not well understood. Purpose We aimed to delineate the differences in clinical profiles and prognosis between young men and women with established early-onset CAD. Methods This is a nationwide, hospital-based, longitudinal prospective cohort study. Young patients (aged ≥18 years and ≤ 45 years) with angiographically confirmed severe atherosclerotic obstructive coronary arteries (luminal narrowing ≥ 70%) were included from 38 hospitals across China between May 2017 and May 2020. Coronary risk factors, clinical features and treatments were compared between men and women at baseline. Participants were followed for 3 years. The outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), unplanned revascularization, and ischemic stroke. The Cox regression analyses were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) for outcome. Results There were 1524 patients (female: 4.4%) included in this study. The female patients were older than the male patients (41.1±4.0 years for females vs. 39.6±4.4 years for males, p=0.006). They showed a lower prevalence of hypertension, lipid disorders, and smoking or drinking (all p<0.01). The female patients were less likely to have at least 1 modifiable risk factors (female: n=45 (67.2%) vs. male: n=1382 [94.6 %], p<0.001); they showed more favorable laboratory results at baseline, including lipids, serum creatinine and uric acid (all p<0.05) as compared to male patients. Besides, young females presented more often with stable angina on admission, whereas young males tended to present with acute MI (p<0.001). There was no significant sex difference in Gensini Score (p=0.15). Female patients were less likely to undergo revascularization procedures than male patients (73.1% vs. 85.3%, p=0.01). During the 3 years of follow-up, female patients were at a significantly higher risk of MACE compared to their male counterparts (13.4% vs. 5.8%, adjusted HR: 3.07, 95% CI:1.36–6.94, p=0.007) after adjusting for age, smoking, drinking, body mass index, hypertension, diabetes, dyslipidemia, diagnosis and revascularization. Conclusions Distinct sex disparities, unfavorable to young females, were documented among patients with early-onset CAD, with the largest gaps noted in the treatment and prognosis. Despite more favorable baseline profiles, young female patients had insufficient care and 3-fold greater risk for MACE compared to young males. These results highlight the need for strengthening the treatment strategies for this vulnerable disease entity.Figure 1

Sex differences in RNA transcripts in dilated cardiomyopathy

Abstract Introduction Dilated cardiomyopathy (DCM) is the most common cardiomyopathy and a major cause of heart failure. Differences in clinical presentation and phenotype exist in men and women but the reason for this is not clear. The analysis of the RNA transcripts (mRNA sequencing) offers an opportunity to provide a link between the genome, the proteome, and the phenotype. The aim of this study was to explore sex differences using mRNA sequencing in patients with DCM. Method Our database, an observational prospective cohort study, includes patients referred for suspected cardiomyopathy. The database includes data on patients’ characteristics, symptoms, diagnostic procedures, treatments, cardiac devices, and outcome. Endomyocardial biopsy from the right ventricle was collected and total RNA, including miRNA and other small RNA, was isolated. RNA sequencing and library preparation was performed. Following quality check, reads were aligned to GRCh38 reference genome by STAR (v2.7.10a). Sex-specific differential expression analysis between individuals diagnosed with DCM (cases) versus non-confirmed cardiomyopathy (controls) was performed using DESeq2 (v.1.38.3) adjusting for age, RNA integrity number and systolic blood pressure. After controlling for multiple testing using the Benjamini-Hochberg method, genes with a corrected P-value < 0.05 were considered as being differentially expressed. Gene-set enrichment analysis on differentially expressed genes was performed via Enrichr tool using Descartes cell types and tissues, KEGG biological pathways, DisGeNET, and Gene Ontology Biological Processes (GOBP). Results Patients´characteristics in women and men with DCM is presented in table 1. There was no difference in outcome in men and women (data not shown). Differential expression analyses with transcriptomic data comparing DCM (n=43) versus controls (n=22) stratified by sex (DCM n= 9, (20.9%) women and controls n=7, (30.4%) women) was performed. There was no overlap between differentially expressed genes between sexes (Figure 1). In men gene set enrichment analyses showed that differentially expressed genes were related to pathways involved in dilated and hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (KEGG). Interestingly, these analyses revealed an enrichment of genes related to platelet biology, namely precursors (Descartes), activation (GOBP, KEGG) and platelet disorder (DisGeNET). In women, HLA-DQB1 was more expressed in DCM. HLA-DQB1 is associated with celiac disease, narcolepsy, and type 1 diabetes. Consistently, the enrichment analyses showed an enrichment of genes involved in autoimmune diseases (DisGeNET). Conclusion Women and men with DCM exhibit differently activated RNA transcripts although no difference in phenotype was observed. This may indicate that although DCM can be caused by similar factors in women and men the transcriptome is differently activated which warrants further investigation.Table 1.

Sex differences related changes in cardiac structure and function after ST-segment elevation myocardial infarction

Abstract Background Sex disparities in presentation, treatment, and outcomes after ST-segment Elevation Myocardial Infarction (STEMI) are well recognized. However, little is known about sex related changes in cardiac structure and function following a STEMI in this contemporary era of early PCI. Purpose To compare sex differences in change of echocardiographic parameters of structure and function following a first-time STEMI. Methods This echocardiographic study involved 380 non-diabetic first-time STEMI patients. Structural and functional parameters were evaluated during initial hospitalization (median 1 day after presentation) and at 4-months. Adverse remodelling was defined as a 20% increase in left ventricular end-diastolic volume (LVEDV) at 4 months compared to the hospitalisation echo. Functional parameters included left ventricular ejection fraction (LVEF) and wall motion score index (WMSI). According to current guidelines, eccentric hypertrophy was defined as left ventricular mass index (LVMI) >95 g/m2 for women and >115 g/m2 for men with a relative wall thickness (RWT) ≤0.42; concentric hypertrophy was defined as LVMI >95 g/m2 for women and >115 g/m2 for men with RWT >0.42. The different patterns in geometry were assessed at 4-months. Results Among 380 patients, comprising 285 males and 95 females, females had a higher prevalence of hypertension (42% vs. 25.6%, p=0.004), lower hemoglobin levels (8.40 mmol/l vs. 9.10, p<0.001), and higher plasma NT-proBNP concentrations upon admission (132 ng/L vs 67, p<0.001) and after 24 hours (1322 ng/l vs 784, p<0.001). During the initial echocardiogram conducted upon hospitalization, as well as during the echocardiogram at 4 months, women had significantly lower LV diameters, LV volumes, LV mass, LAVI and wall thickness compared to man. However, during both evaluations women showed higher E/e’ ratio’s and LVEF. The change in echocardiographic variables between both timepoints did not differ significantly between sexes. Furthermore, no significant difference in LV geometry patterns (eccentric or concentric) were observed between sexes and adverse LV remodelling was similar between both groups at approximately 22-23% (p=0.991). Conclusions Although differences exist between sexes in patient characteristics and individual echocardiographic parameters, no disparity is observed in geometry patterns, adverse LV remodelling, or the change in echocardiographic parameters after STEMI.

8.G. Scientific session: The German National Cohort (NAKO): Current state, follow up data collection and selected results

Abstract This workshop aims to give an overview on current state and selected results of the German National Cohort (NAKO). NAKO is the largest, multidisciplinary population-based cohort study in Germany. The overall aims of NAKO are: 1) to elucidate pathways to major chronic diseases such as diabetes, cancer, cardiovascular, pulmonary, neuro-psychiatric, and infectious diseases, focusing on determinants and exposures (e.g., socioeconomic, psychosocial, behavioural, occupational, and environmental factors); 2) to assess regional differences; and to improve prevention and early detection of disease. Between 2014 and 2019 more than 205,000 men and women aged 20-74 years at baseline were recruited in 18 study centres across Germany. During their examination participants underwent an extensive programme including a face-to-face interview, self-administered, computer-based questionnaires, in-depth biomedical examinations, and the collection of various bio-samples. In addition, at 5 study centres a subgroup of almost 31,000, received whole-body magnet resonance imaging (MRI). In 4-5 year intervals, all study participants are re-invited for examination at the study centres. The first re-examination started in October 2018 and will be finished in July 2024. In parallel the pilot phase for the second re-examination will start in May 2024. The programme for both re-examinations is similar to the baseline programme. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. During the COVID-19 pandemic two supplemental questionnaires focusing on pandemic-related aspects were provided to all NAKO participants at two different time points. The first COVID-19 questionnaire collected data on more than 160,000 participants during the first COVID-19-related lockdown in Spring 2020. The questionnaire included questions on general state of health, Sars-CoV-2 symptoms, changes in psychosocial, socioeconomic, and behavioural factors (e.g., physical activity). The workshop session consists of four presentations. The first presentation will provide insights into the extensive examination programme of NAKO, will give a short overview on the current state and plans for follow-up of data collection. In addition, it will briefly inform about possibilities to get access to NAKO data. Furthermore, the workshop will include three presentations on selected results of NAKO to demonstrate its broad research scope. The presentations will focus on the following topics: 1) cardiovascular disease and sex differences according to socioeconomic position, 2) cognitive functioning according to income, employment and living alone, 3) physical activity and changes during the COVID-19 pandemic. Key messages • Due to the large sample size, and the broad research scope, NAKO provides an excellent resource to scientists form different research disciplines and enforces interdisciplinary collaborations. • The workshop will be informative to researchers who are planning to work with NAKO data as data access within the European Union/the European Economic Area is open since spring 2024.

Sex differences in management of LDL-cholesterol in patients with chronic coronary syndrome

Abstract Background Effective management of low-density lipoprotein cholesterol (LDL-C) is crucial for preventing recurrent cardiovascular (CV) events in patients with chronic coronary syndrome (CCS). Sex may impact the LDL-C management, by gender bias and/or sex-specific responses to pharmacological interventions. Purpose We examined sex-specific LDL-C management in CCS patients, assessing target achievement rates and their implications for CV outcomes. Methods In the international CLARIFY registry, we included 22,134 CCS patients with baseline LDL-C measurements. LDL-C levels were monitored annually over the 5-year follow-up period. Target LDL-C was set at 100 mg/dL, in line with prevailing recommendations at that time. Sex-specific differences in LDL-C were adjusted for age, geographical region and indication for lipid lowering drugs (stroke, MI, PAD). The primary endpoint was the incidence of MACE, defined as CV death or MI during the 5-year follow-up, evaluated using multivariable analysis adjusted for known predictors of recurrent CV events in CCS patients. Results Of 22,134 patients, 21.6% were women. Upon inclusion (6.5 ± 6.3 years after CCS diagnosis), women were more likely than men to have LDL-C levels above the recommended threshold (45.6% vs. 37.4%; aOR 1.47, 95%CI 1.38-1.58, p<0.001) and less likely to receive statin treatment (82.7% vs. 85.4%, p<0.001). Although women and men had comparable numbers of LDL-C measurements during follow-up, the discrepancies endured over the 5-year observation period, with women consistently showing lower likelihoods of achieving LDL-C targets at 1, 2, 3, 4, and 5 years post-inclusion (p<0.001 for all time points). Overall, women were less likely than men to have all available LDL-C concentrations within the target range (37.8% vs. 44.6%; aOR 0.70, 95% CI 0.64-0.76, p<0.001) and more likely to never reach the target LDL-C goal during follow-up (22.6% vs. 17.5%; aOR 1.43, 95% CI 1.32-1.55, p<0.001). Failing to achieve at least one LDL-C concentration below 100 mg/dL was associated with an increased risk of subsequent MACE (adjusted HR 1.57, 95%CI 1.38-1.77, p<0.001), with similar associations observed in both men (aHR 1.66, 95% CI 1.44-1.91, p<0.001) and women (aHR 1.31, 95% CI 1.01-1.70, p=0.05). Conclusion In patients with CCS, women consistently showed lower likelihood of reaching LDL-C targets throughout follow-up compared to men, even after adjusting for age, geographical region and other statin indications. Notably, women were more likely to have no LDL-C concentration within recommended range during follow-up, which is particularly concerning given its association with an increased risk of CV events. A contributing factor to this sex disparity in LDL-C control is women's lower likelihood of receiving lipid-lowering drugs than men. These results highlight the need for tailored interventions to address sex-related disparities in LDL-C management and improve cardiovascular outcomes in CCS patients.

Sex differences in aortic prognosis in Marfan patients, a retrospective longitudinal study from the REPAG registry

Abstract Introduction Previous studies(1-4) have suggested a more favourable aortic outcome among women with Marfan syndrome (MFS), although the precise underlying mechanism remains not completely understood. In this retrospective longitudinal study, we aim to evaluate sex differences in aortic events in a large cohort of Marfan patients seen in 11 tertiary centres in Spain. Methods Patients with diagnosis of Marfan syndrome (MFS) were included. Data on aortic events (AE) including elective aortic surgeries, acute aortic syndrome or death were incorporated. Survival free of the combined endpoint of death or first aortic event (elective aortic surgery or acute aortic syndrome) was compared between male and female by the Kaplan-Meier curves, log-rank test and subsequent Cox regression analysis. Results A total of 442 patients with MFS where included, 48.2% female and 56.2% index cases. Although systemic score and proband proportion was not different between both sexes, the diagnosis was earlier in males (p=0.01) (Table). Furthermore, among adult patients, males exhibited greater height, weight, and body surface area (BSA). Absolute aortic root diameter at baseline was greater in males, but not BSA-indexed diameters or z-scores. Combined endpoint of death or aortic event was observed in 192 patients (120 male, 72 female, p=<0.00001). Female sex had better survival free of the combined endpoint in a multivariable Cox analysis (HR 0.41 95% CI=0.30–0.55) with a mean survival free of the combined endpoint of 41.3yrs in male and 61.4 years in females (p<0.0001) (Figure).Although a higher proportion of elective aortic interventions as first event was observed in males (66.7% vs 52.8%), the proportion of type A dissections was similar between both sexes (26.7 vs 26.4%) with increased frequency of type B dissections in females as first aortic event (4.2 vs 15.3%) (p=0.026) Conclusions Male patients with MFS present higher aortic root diameters but similar BSA-indexed and zscores than females. Survival free of first aortic event or death is reduced in male with MFS, with greater frequency of elective aortic intervention. Although this last is driven by absolute aortic diameter, no increase on type A dissection was observed in women. These findings might suggest a potentially less aggressive manifestation of proximal aortic disease in women with MFS.Table:Comparison male and female Marfan