Sex Differences In Cardiovascular Disease Research Articles

Sex differences in cardiovascular disease in relation to socioeconomic position in the NAKO study

Abstract Background Low socioeconomic position (SEP) is associated with cardiovascular disease (CVD) risk; yet, the underlying pathways are not fully clear and may affect sexes differently. We investigated sex differences in the relationship of SEP with prevalent CVD, cardiovascular risk factors (CRF) and estimated cardiovascular risk in a contemporaneous German population. Methods Data derived from the baseline examination of 204,780 participants in population-based German National Cohort (NAKO). Logistic, multinomial, and linear regression models were used to estimate sex-specific odds ratios (OR) and beta-coefficients with 95% confidence intervals (CI) of CVD, CRF and very high-risk score (SCORE2 ≥7.5% (age 40-49 years) or ≥ 10% (age 50-69 years)) associated with educational attainment and relative income. Women-to-men ratios of ORs (RORs) with 95%-CI were estimated. Results In women compared to men, low vs. high SEP was more strongly associated with obesity, overweight, self-reported myocardial infarction and hypertension, elevated blood pressure values, antihypertensive medication, and alcohol consumption, but less strongly related to smoking. In women with the lowest vs. highest educational level, the OR for a very high 10-year CVD risk was 3.61 (95%-CI 2.88; 4.53), compared to 1.72 (95%-CI 1.51; 1.96) in men. The women-to-men-ROR was 2.33 (95%-CI 1.78; 3.05), attenuated after age-adjustments. For the comparison of low vs. high relative income, the odds of having a very high 10-year CVD risk was 2.55 (95%-CI 2.04; 3.18) in women, and 2.25 (95%-CI 2.08; 2.42) in men (women-to-men ROR, 1.31 (95%-CI 1.05; 1.63). Conclusions In both sexes, there was an inverse graded relationship between SEP and the likelihood of prevalent CVD and CRF, with stronger associations in women than in men. Although women had a lower estimated 10-year CVD risk compared to men, the likelihood of having a very high CVD risk conferred by low SEP vs. a high one was higher in women than in men.

Sex Differences in The Functional Morphology of Coronary Arteries in Embryonic Mice.

Sex differences in the development and progression of cardiovascular disease manifest across multiple life stages. These differences are associated with variations in cardiovascular morphology and function between the sexes. Although estrogens and sex hormones are associated with sex differences in cardiovascular diseases in reproductive adults, the molecular mechanisms of cardiovascular sex differences during development are largely unknown. Thus, we investigated sex differences in cardiovascular development. We employed a newly-developed coronary arteriogram system to visualize the morphology of the coronary arteries in murine anterior surface ventricles at embryonic day 17.5 by injecting nano-particle ink at a constant pressure. No sex difference was found in the length of ventricle. Based on the boundary value of the distribution of that length, the hearts were divided into "long" and "short" groups, and the diameters of the left coronary arteries were analyzed. The mean diameter of the coronary arteries was significantly smaller in females than in males only in the group with the longer length of ventricle. This ventricular size-specific sex difference was observed in the presence of vasodilators such as NOC7. When NOC7 was perfused into the left coronary arteries of embryonic day 17.5 mice, females with longer ventricles showed larger left coronary arteries than males. These sex differences in vasodilation capacity suggest that factors related to drug reactivity such as signaling pathways are present at a late embryonic stage. These results indicate that sex differences in the functional morphology of the left coronary arteries exist at a late embryonic stage in mice.

Sex-Specific Cardiovascular Risk Factors and Treatment in Females With T2DM and CVD: Developments and Knowledge Gaps

Abstract Purpose There are large disparities in the impact of diabetes on cardiovascular disease (CVD) risk and outcomes by sex and gender. Achieving health equity requires understanding risks and medication efficacy in female patients, especially now, as novel pharmacologic treatments are transforming the diabetes and CVD treatment landscape. This review examines 2 bodies of research that can inform sex differences in CVD in patients with diabetes: female-specific risk factors for CVD and sex-related limitations of clinical trial research in evaluating novel diabetes and CVD treatments. Methods Two literature searches were performed using Ovid Medline(R) All. The first retrieved manuscripts covering sex and gender differences related to CVD risk and therapies and diabetes. The second focused on randomized controlled trial data on sex/gender differences and GLP-1/SGLT-2/DPP-4 drugs. Results Female-specific risk factors for CVD include early menarche, premature or early menopause, irregular cycles and polycystic ovary syndrome; pregnancy; adverse pregnancy outcomes; history of breast cancer; and autoimmune diseases. Clinical trials of novel pharmacological treatments for diabetes and CVD have undersampled female populations, and clinical characteristics of male and female participants have differed significantly. Thus, evidence to evaluate potential sex differences in treatment efficacy and side effects has been lacking. Conclusion To improve health of female patients with diabetes, sex-specific cardiovascular risk factors should be taken into account in screening and treatment decisions. Further, studies of cardiovascular and diabetes medications must ensure adequate representation by sex and report participant characteristics and outcomes by sex.

Sex Differences in Cardiovascular Disease-Related Hospitalization and Mortality in Japan - Analysis of Health Records From a Nationwide Claim-Based Database, the Japanese Registry of All Cardiac and Vascular Disease (JROAD).

The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease. This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD. Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.

Sex Differences in Cardiovascular Diseases: Exploring the Role of Microbiota and Immunity.

Cardiovascular diseases (CVDs) are the most common cause of mortality and morbidity in Western countries, thus representing a global health concern. CVDs show different patterns in terms of the prevalence and presentation in men and women. The role of sex hormones has been extensively implicated in these sex-specific differences, due to the presence of the menstrual cycle and menopause in women. Moreover, the gut microbiota (GM) has been implicated in cardiovascular health, considering the growing evidence that it is involved in determining the development of specific diseases. In particular, gut-derived metabolites have been linked to CVDs and kidney disorders, which can in turn promote the progression of CVDs. Considering the differences in the composition of GM between men and women, it is possible that gut microbiota act as a mediator in regard to the sex disparities in CVDs. This narrative review aims to comprehensively review the interplay between sex, GM, and CVDs, discussing potential mechanisms and therapeutic options.

Sex and the Risk of Atheromatous and Nonatheromatous Cardiovascular Disease in CKD: Findings From the CKD-REIN Cohort Study

Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ between atheromatous (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study. Prospective cohort study. Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France. Sex. Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic stroke, and arrhythmias). Multivariable cause-specific Cox proportional hazards models. 1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m2) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m2 and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m2. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied. Cardiovascular biomarkers and sex hormones were not assessed. This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.

Sex inequalities in cardiovascular risk prediction.

Evaluate sex differences in cardiovascular disease (CVD) risk prediction, including use of i) optimal sex-specific risk predictors and ii) sex-specific risk thresholds. Prospective cohort study using UK Biobank, including 121,724 and 182,632 healthy men and women, respectively, aged 38-73 years at baseline. There were 11,899 (men) and 9,110 (women) incident CVD cases (hospitalization or mortality) with median 12.1 years follow-up. We used recalibrated Pooled Cohort Equations (PCE, 7.5% 10-year risk threshold as per US guidelines), QRISK3 (10% 10-year risk threshold as per UK guidelines) and Cox survival models using sparse sex-specific variable sets (via LASSO stability selection) to predict CVD risk separately in men and women. LASSO stability selection included 12 variables in common between men and women, with three additional variables selected for men and one for women. C-statistics were slightly lower for PCE than QRISK3 and models using stably-selected variables, but were similar between men and women: 0.67 [0.66-0.68], 0.70 [0.69-0.71], and 0.71 [0.70-0.72] in men and 0.69 [0.68-0.70], 0.72 [0.71-0.73], and 0.72 [0.71-0.73] in women for PCE, QRISK3 and models using stably-selected variables, respectively. At current clinically implemented risk thresholds, test sensitivity was markedly lower in women than men for all models: at 7.5% 10-year risk, sensitivity was 65.1% and 68.2% in men and 24.0% and 33.4% in women for PCE and models using stably-selected variables, respectively; at 10% 10-year risk, sensitivity was 53.7% and 52.3% in men and 16.8% and 20.2% in women for QRISK3 and models using stably-selected variables, respectively. Specificity was correspondingly higher in women than men. However, the sensitivity in women at 5% 10-year risk threshold increased to 50.1%, 58.5% and 55.7% for PCE, QRISK3 and models using stably-selected variables, respectively. Use of sparse sex-specific variables improved CVD risk prediction compared with PCE but not QRISK3. At current risk thresholds, PCE and QRISK3 work less well for women than men but sensitivity was improved in women using a 5% 10-year risk threshold. Use of sex-specific risk thresholds should be considered in any re-evaluation of CVD risk calculators. Cardiovascular disease (CVD) risk prediction is an important component of clinical risk management and disease prevention. We find that at risk prediction thresholds used by currently applied risk prediction algorithms (PCE 7.5% 10-year risk threshold in the US and QRISK3 10% risk threshold in the UK), sensitivity of these risk prediction tools is markedly lower in women than in men. This sex inequality implies that women are proportionately less likely to receive appropriate clinical management including lipid-lowering therapy. If the risk prediction threshold is lowered to 5% 10-year risk in women, then sensitivity in women is substantially increased.

Role of Ovarian Hormones on proBDNF Levels in the Rostral Ventrolateral Medulla: Influences Related to Neuronal Plasticity and Sympathetic Control of Blood Pressure

Introduction: Rates of cardiovascular disease (CVD) are lower in females of reproductive age when compared to age-matched males. However, at the onset of menopause, a period characterized by decreases in ovarian hormones, there is a marked and dramatic rise in the incidence of CVD in females. Therefore, the presence of ovarian hormones may serve a cardioprotective role due to actions on several target organs, including the brain. In the brainstem, the rostral ventrolateral medulla (RVLM) has been implicated in CVD due to its direct impact on blood pressure. The RVLM also contains receptors for both the pro- and mature forms of brain-derived neurotrophic factor (proBDNF and mBDNF), a key neurotrophin which has been linked to ovarian hormones by the existence of an estrogen response element (ERE) on the bdnf gene. While mBDNF positively influences neuroplasticity by increasing connectivity between neurons (i.e., increased dendritic branching). Alternatively, proBDNF can decrease neuronal excitability—and potentially reduce RVLM overactivity—via structural actions which oppose those enacted by mBDNF. Ovarian hormones may modulate neuronal activity in the RVLM via ERE-mediated effects on proBDNF expression, providing a mechanism for the “cardioprotective” effects observed in females of reproductive age. Hypothesis: We hypothesized that the presence of ovarian hormones maintains proBDNF levels in the RVLM, minimizing activation of the RVLM, thus conferring cardioprotection. Methods: Four-week-old female Sprague-Dawley rats received ovariectomy (OVX) or sham surgery (n=5 and n=4, respectively). Rats were sacrificed at 16 weeks of age and the hindbrain was cut into 80μm coronal sections, from which the RVLM was isolated by tissue punches. Using the caudal pole of the facial nucelus as a landmark, punches were pooled into 4 discrete rostrocaudal subregions. Western blotting was performed to determine proBDNF levels in the RVLM relative to the loading control GAPDH. Results: Average proBDNF expression appeared higher in the RVLM of sham versus OVX females at all rostrocaudal levels; however, this difference did not reach statistical significance (p=0.169, main effect), perhaps due to lower sample sizes. There were no significant rostrocaudal variations in proBDNF expression (p=0.598, main effect), nor was there a significant interaction between main effects (p=0.687). Conclusions: These results suggest that the presence of ovarian hormones may maintain proBDNF expression in the RVLM; however, greater sample sizes will likely provide more definitive conclusions. Additionally, future studies could also address potential sex differences by examining the influence of ovarian hormones on expression of mBDNF. We anticipate our studies will illuminate the relationship between ovarian hormones and cardioprotection via the RVLM, thus providing insight into sex differences in CVD. R01-HL161233, APS and WSU Summer Undergraduate Research Fellowships. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex-specific lifetime risk of cardiovascular events: the European Prospective Investigation into Cancer-Norfolk prospective population cohort study.

Better understanding of sex differences in cardiovascular disease (CVD) is essential in tailoring appropriate preventative strategies. Using a large population-based study with follow-up >25 years, we aimed to determine sex-specific lifetime risks of incident CVD and cardiovascular (CV) mortality amongst populations with and without prevalent CVD. Participants were drawn from the European Prospective Investigation into Cancer-Norfolk and followed up for a median of 26.2 years. Sex-specific lifetime risks were ascertained accounting for the competing risk of death. Models were adjusted for ethnicity and time-updated covariates: material deprivation, CV risk factors, lifestyle factors, comorbidities, and medication. A total of 23 859 participants [54.5% women; mean age (standard deviation) 59.2 (9.3) years at baseline] were included. Adjusted lifetime risks of incident CVD were higher in men than in women (69.1 vs. 57.7% at age 75): cause-specific hazard ratio (cHR) (99% confidence interval)-1.49 (1.41-1.57), while the risks of CV mortality at age 75 were 4.4% (men) and 3.1% (women): cHR-1.42 (1.31-1.54). Myocardial infarction was the predominant first presentation in men until the eighth decade. In women, the first CVD manifestations after their sixth decade were predominantly atrial fibrillation and stroke. The male-associated excess relative risks of incident CVD and CV mortality were halved in people with prevalent CVD. We characterized the sex-specific lifetime CV risks in a large cohort. Men had substantially higher risk of incident CVD and CV mortality than women, which was attenuated amongst people with prevalent CVD. Our findings provide an evidence base for sex-specific CV prevention.

Abstract 15923: Sexually Dimorphic Heart Phenotypes in Mice Lacking Chromatin Factors in Cardiomyocytes

Introduction: Sex differences in cardiovascular disease have been attributed to differences in lifestyle or sex hormones; less is known of genetic components that cause differences in heart disease between men and women. We have characterized a role for the ZMYND8 chromatin reader in maintaining cardiac function through modulation of enhancer activity in cardiomyocytes. ZMYND8 has been reported to interact with H3K4 histone demethylases KDM5C and KDM5D, which are encoded from genes residing on sex chromosomes ( Kdm5c on X and Kdm5d on Y). KDM5C and KDM5D have diverged over millions of years of sex chromosome evolution and their functional congruency is unknown. Hypothesis: We hypothesize that sex differences in cardiovascular disease are due, at least in part, to differences in functionality of genes residing on the sex chromosomes. Methods: We constructed Zmynd8-cKO mice using the cardiomyocyte-specific Myh6-Cre Tg/0 line and an established Zmynd8 flox allele. We also introduced a Kdm5c flox allele to the Myh6-Cre Tg/0 line to generate Kdm5c-cKO females and Kdm5c-cKO hemizygous males. These mice were evaluated by lifespan analyses, echocardiography, and molecular analyses (RNA-seq and ChIP-seq). Results: While both male and female Zmynd8 - cKO mice develop enlarged hearts, reduced contractility, and illegitimate expression of certain genes normally found in skeletal muscle, female mice have a 10% reduction in lifespan compared to males; this sex difference in lifespan is not seen in Cre-only mice. We tested the necessity for Kdm5c in cardiomyocytes and found that its deletion also leads to premature death in a dosage dependent manner compared to Cre-only mice. Interestingly, Myh6-Cre Tg/0 ; X 5c-flox /Y hemizygous males have a 20% shorter lifespan than Myh6-Cre Tg/0 ; X 5c-flox /X + heterozygous females, suggesting differences between KDM5C and KDM5D functionality. Conclusions: Our results provide evidence of sexually dimorphic heart defects linked to chromatin regulators, including a gene-pair found on the sex chromosomes. We are deliniating the molecular underpinnings of these observations including changes to histone marks and gene expression in these knockout models.

Sex Differences in Autonomic Blood Pressure Regulation: Sex Chromosome Complement and Hormonal Involvement

Although several lines of evidence from different studies highlight sex differences in cardiovascular diseases, to date, most studies have been focused on males, with the idea that males and females are similar, differing only in the magnitude of the response. However, the principles learned in male models cannot and should not be extrapolated to women and, therefore, it is important to study in greater detail not only the differences between the sexes but also the physiological intertwining of the underlying genetic and hormonal mechanisms of sexual dimorphism. This review explores the sex disparities in the autonomic nervous system regulation of blood pressure (particularly baroreceptor function), with special emphasis on sex hormones and sex chromosome complement factors involved in sexually dimorphic autonomic blood pressure regulation. A more detailed understanding of the sources of physiological disparities between the sexes may also help in understanding the differences between the sexes in rates of cardiovascular disease and may also aid in designing future improvements for sex-tailored therapeutic treatments.

Association Between Risk Factors in Childhood and Sex Differences in Prevalence of Carotid Artery Plaques and Intima-Media Thickness in Mid-Adulthood in the Childhood Determinants of Adult Health Study.

Background The origins of sex differences in cardiovascular diseases are not well understood. We examined the contribution of childhood risk factors to sex differences in adult carotid artery plaques and intima-media thickness (carotid IMT). Methods and Results Children in the 1985 Australian Schools Health and Fitness Survey were followed up whentheywereaged 36 to 49 years (2014-19, n=1085-1281). Log binomial and linear regression examined sex differences in adult carotid plaques (n=1089) or carotid IMT (n=1283). Childhood sociodemographic, psychosocial, and biomedical risk factors that might contribute to sex differences in carotid IMT/plaques were examined using purposeful model building with additional adjustment for equivalent adult risk factors in sensitivity analyses. Women less often had carotid plaques (10%) than men (17%). The sex difference in the prevalence of plaques (relativerisk[RR] unadjusted 0.59 [95% CI, 0.43 to 0.80]) was reduced by adjustment for childhood school achievement and systolic blood pressure (RRadjusted 0.65 [95% CI, 0.47 to 0.90]). Additional adjustment for adult education and systolic blood pressure further reduced sex difference (RR adjusted 0.72 [95% CI, 0.49 to 1.06]). Women (mean±SD 0.61±0.07) had thinner carotid IMT than men (mean±SD 0.66±0.09). The sex difference in carotid IMT (β unadjusted -0.051 [95% CI, -0.061 to -0.042]) reduced with adjustment for childhood waist circumference and systolic blood pressure (β adjusted -0.047 [95% CI, -0.057 to -0.037]) and further reduced with adjustment for adult waist circumference and systolic blood pressure (β adjusted -0.034 [95% CI, -0.048 to -0.019]). Conclusions Some childhood factors contributed to adult sex differences in plaques and carotid IMT. Prevention strategies across the life course are important to reduce adult sex differences in cardiovascular diseases.

Supplemental Materials for Dei Cas A (JCEM 2023) Sex differences in cardiovascular disease and cardiovascular risk estimation in patients with type 1 diabetes.

Supplemental Materials for Dei Cas A (JCEM 2023) Sex differences in cardiovascular disease and cardiovascular risk estimation in patients with type 1 diabetes.

Supplemental Materials for Dei Cas A (JCEM 2023) Sex differences in cardiovascular disease and cardiovascular risk estimation in patients with type 1 diabetes.

Supplemental Materials for Dei Cas A (JCEM 2023) Sex differences in cardiovascular disease and cardiovascular risk estimation in patients with type 1 diabetes.

Emerging vascular cell-specific roles for mineralocorticoid receptor: implications for understanding sex differences in cardiovascular disease.

As growing evidence implicates extrarenal mineralocorticoid receptor (MR) in cardiovascular disease (CVD), recent studies have defined both cell- and sex-specific roles. MR is expressed in vascular smooth muscle (SMC) and endothelial cells (ECs). This review integrates published data from the past 5 years to identify novel roles for vascular MR in CVD, with a focus on understanding sex differences. Four areas are reviewed in which there is recently expanded understanding of the cell type- or sex-specific role of MR in 1) obesity-induced microvascular endothelial dysfunction, 2) vascular inflammation in atherosclerosis, 3) pulmonary hypertension, and 4) chronic kidney disease (CKD)-related CVD. The review focuses on preclinical data on each topic describing new mechanistic paradigms, cell type-specific mechanisms, sexual dimorphism if addressed, and clinical implications are then considered. New data support that MR drives vascular dysfunction induced by cardiovascular risk factors via sexually dimorphic mechanisms. In females, EC-MR contributes to obesity-induced endothelial dysfunction by regulating epithelial sodium channel expression and by inhibiting estrogen-induced nitric oxide production. In males with hyperlipidemia, EC-MR promotes large vessel inflammation by genomic regulation of leukocyte adhesion molecules, which is inhibited by the estrogen receptor. In pulmonary hypertension models, MRs in EC and SMC contribute to distinct components of disease pathologies including pulmonary vessel remodeling and RV dysfunction. Despite a female predominance in pulmonary hypertension, sex-specific roles for MR have not been explored. Vascular MR has also been directly implicated in CKD-related vascular dysfunction, independent of blood pressure. Despite these advances, sex differences in MR function remain understudied.

LDL-C control according to risk: Is there a gender paradox?

Background and Aims : Background Low density lipoprotein cholesterol (LDL-C) treatment goals used for cardiovascular disease (CVD) prevention. Sex differences in CVD have been reported and women are less likely to receive statin therapy for secondary prevention. Nevertheless, little is known about gender according to risk categories Aims

Sex/Gender- and Age-Related Differences in β-Adrenergic Receptor Signaling in Cardiovascular Diseases.

Sex differences in cardiovascular disease (CVD) are often recognized from experimental and clinical studies examining the prevalence, manifestations, and response to therapies. Compared to age-matched men, women tend to have reduced CV risk and a better prognosis in the premenopausal period. However, with menopause, this risk increases exponentially, surpassing that of men. Although several mechanisms have been provided, including sex hormones, an emerging role in these sex differences has been suggested for β-adrenergic receptor (β-AR) signaling. Importantly, β-ARs are the most important G protein-coupled receptors (GPCRs), expressed in almost all the cell types of the CV system, and involved in physiological and pathophysiological processes. Consistent with their role, for decades, βARs have been considered the first targets for rational drug design to fight CVDs. Of note, β-ARs are seemingly associated with different CV outcomes in females compared with males. In addition, even if there is a critical inverse correlation between β-AR responsiveness and aging, it has been reported that gender is crucially involved in this age-related effect. This review will discuss how β-ARs impact the CV risk and response to anti-CVD therapies, also concerning sex and age. Further, we will explore how estrogens impact β-AR signaling in women.

Illuminating the Mechanisms Underlying Sex Differences in Cardiovascular Disease.

Sex is a key risk factor for many types of cardiovascular disease. It is imperative to understand the mechanisms underlying sex differences to devise optimal preventive and therapeutic approaches for all individuals. Both biological sex (determined by sex chromosomes and gonadal hormones) and gender (social and cultural behaviors associated with femininity or masculinity) influence differences between men and women in disease susceptibility and pathology. Here, we focus on the application of experimental mouse models that elucidate the influence of 2 components of biological sex-sex chromosome complement (XX or XY) and gonad type (ovaries or testes). These models have revealed that in addition to well-known effects of gonadal hormones, sex chromosome complement influences cardiovascular risk factors, such as plasma cholesterol levels and adiposity, as well as the development of atherosclerosis and pulmonary hypertension. One mechanism by which sex chromosome dosage influences cardiometabolic traits is through sex-biased expression of X chromosome genes that escape X inactivation. These include chromatin-modifying enzymes that regulate gene expression throughout the genome. The identification of factors that determine sex-biased gene expression and cardiometabolic traits will expand our mechanistic understanding of cardiovascular disease processes and provide insight into sex differences that remain throughout the lifespan as gonadal hormone levels alter with age.

Sex differences in cardiovascular medication prescription: an interview with Dr Sanne Peters.

Bibliography Dr Sanne Peters is an Associate Professor at The George Institute for Global Health and a Senior Lecturer at Imperial College London. She is also Associate Professor at the University Medical Center Utrecht. After completing her MSc in Epidemiology in 2009, she obtained a PhD in Epidemiology from Utrecht University in 2012. Her PhD focused on subclinical imaging measures of atherosclerosis as a means to identify people at high-risk for future cardiovascular disease. As part of her PhD training, she spent 6 months at The George Institute in Sydney. This is where she started her research on sex differences in cardiovascular disease. In 2013, she was awarded a postdoctoral fellowship, which enabled her to continue her work on sex differences at the University of Cambridge. In 2014, she was offered a position at the George Institute offices at the University of Oxford (now in collaboration with Imperial College London). In 2018, she relocated back to the Netherlands and was also appointed as Associate Professor in Utrecht.

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate.

The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.