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Cardiovascular disease and brain disorders, such as depression and cognitive dysfunction, are highly prevalent conditions and are among the leading causes limiting patient’s quality of life. A growing body of evidence has shown an intimate crosstalk between the heart and the brain, resulting from a complex network of several physiological and neurohumoral circuits. From a pathophysiological perspective, both organs share common risk factors, such as hypertension, diabetes, smoking or dyslipidaemia, and are similarly affected by systemic inflammation, atherosclerosis, and dysfunction of the neuroendocrine system. In addition, there is an increasing awareness that physiological interactions between the two organs play important roles in potentiating disease and that sex- and gender-related differences modify those interactions between the heart and the brain over the entire lifespan. The present review summarizes contemporary evidence of the effect of sex on heart–brain interactions and how these influence pathogenesis, clinical manifestation, and treatment responses of specific heart and brain diseases.

Cardiovascular diseases (CVD) remain the leading cause of mortality worldwide. Although major diagnostic and therapeutic advances have significantly improved the prognosis of patients with CVD in the past decades, these advances have less benefited women than age-matched men. Noninvasive cardiac imaging plays a key role in the diagnosis of CVD. Despite shared imaging features and strategies between both sexes, there are critical sex disparities that warrant careful consideration, related to the selection of the most suited imaging techniques, to technical limitations, and to specific diseases that are overrepresented in the female population. Taking these sex disparities into consideration holds promise to improve management and alleviate the burden of CVD in women. In this review, we summarize the specific features of cardiac imaging in four of the most common presentations of CVD in the female population including coronary artery disease, heart failure, pregnancy complications, and heart disease in oncology, thereby highlighting contemporary strengths and limitations. We further propose diagnostic algorithms tailored to women that might help in selecting the most appropriate imaging modality.

Animal studies show a pivotal role of dihydrotestosterone (DHT) in pressure overload-induced myocardial hypertrophy and dysfunction. The aim of our study was to evaluate the role of DHT levels and myocardial hypertrophy and myocardial protein expression in patients with severe aortic valve stenosis (AS). Forty-three patients [median age 68 (41-80) yr] with severe AS and indication for surgical aortic valve replacement (SAVR) were prospectively enrolled. Cardiac magnetic resonance imaging including analysis of left ventricular muscle mass (LVM), fibrosis and function, and laboratory tests including serum DHT levels were performed before and after SAVR. During SAVR, left ventricular (LV) biopsies were performed for proteomic profiling. Serum DHT levels correlated positively with indexed LVM (LVMi

Background A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. Methods Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [F-18]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [F-18]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. Results Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 +/- 1.0 vs. 22.2 +/- 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 +/- 1.2 vs. 27.3 +/- 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 +/- 0.04 vs. 1.23 +/- 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. Conclusion Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients., European Journal of Nuclear Medicine and Molecular Imaging, 49, ISSN:1619-7070, ISSN:1619-7089

In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.

Background: Patients with cardiac complaints but without confirmed diagnosis of coronary heart disease by angiography frequently develop cardiac events in the following years. This follow-up study ...

Coronary artery disease (CAD) is the single leading cause of death in Europe and the most common form of cardiovascular disease. Little is known about awareness in the European population. A cross-sectional telephone survey of 2609 individuals from six European countries was conducted to gather information on perceptions of CAD, risk factors, preventive measures, knowledge of heart attack symptoms and ability to seek emergency medical care. Level of awareness was compared according to gender, age, socioeconomic status (SES) and educational level. Women were approximately five times less likely than men to consider heart disease as a main health issue or leading cause of death (OR = 0.224, 95% CI: 0.178–0.280, OR = 0.196, 95% CI: 0.171–0.226). Additionally, women were significantly less likely to have ever had a cardiovascular screening test (OR = 0.515, 95% CI: 0.459–0.578). Only 16.3% of men and 15.3% of women were able to spontaneously identify the main symptoms of a heart attack. Almost half of the sample failed to state that they would call emergency services in case of a cardiac event. Significant differences according to age, SES and education were found for many indicators amongst both men and women. Development of a European strategy targeting improved awareness of CAD and reduced gender and social inequalities within the European population is warranted.

Adverse effects of psychological stress on physical and mental health, especially in older age, are well documented. How perceived stress relates to the epigenetic clock measure, DNA methylation age acceleration (DNAmAA), is less well understood and existing studies reported inconsistent results.DNAmAA was estimated from five epigenetic clocks (7-CpG, Horvath’s, Hannum’s, PhenoAge and GrimAge DNAmAA). Cohen’s Perceived Stress Scale (PSS) was used as marker of psychological stress.We analyzed data from 1,100 Berlin Aging Study II (BASE-II) participants assessed as part of the GendAge study (mean age = 75.6 years, SD = 3.8 years, 52.1% women).In a first step, we replicated well-established associations of perceived stress with morbidity, frailty, and symptoms of depression in the BASE-II cohort studied here. In a second step, we did not find any statistically significant association of perceived stress with any of the five epigenetic clocks in multiple linear regression analyses that adjusted for covariates.Although the body of literature suggests an association between higher DNAmAA and stress or trauma during early childhood, the current study found no evidence for an association of perception of stress with DNAmAA in older people. We discuss possible reasons for the lack of associations and highlight directions for future research.

This study aimed to paradigmatically show the development of a gender score that can be used as either an adjustment or a matching variable to separate the effects of gender versus biological sex in a sample of older adults.Our sample comprised 1100 participants from the Berlin Aging Study II (52% women, mean [standard deviation] age = 75.6 [3.8] years). The gender score included a multitude of gender-related variables and was constructed via logistic regression. In models of health outcomes, it was used as an adjustment variable in regression analyses as well as a matching variable to match older men and women according to their gender.Matching by gender substantially reduced sample size to n = 340. Analyses (either adjusting for gender or matching men and women according to gender) revealed that female sex was independently associated with lower grip strength (B = -14.47, 95% confidence interval [CI] = -15.51 to -13.44), better cognitive performance (B = 3.47, 95% CI = 1.94 to 5.0), higher pulse wave velocity (B = 0.19, 95% CI = 0.06 to 0.31), lower body mass index (B = -0.97, 95% CI = -1.74 to -0.21), and lower rates of metabolic syndrome (odds ratio = 0.53, 95% CI = 0.37 to 0.77). In addition, both sex and gender were independently associated with cognitive performance and depression.Calculating a gender score allows for the inclusion of a large number of variables, creating parsimonious models that are adaptable to different data sets and alternative gender definitions. Depending on the research question and the sample properties, the gender score can be used as either an adjustment or a matching variable.Trial Registration: DRKS-Deutsches Register Klinischer Studien (Study ID: DRKS00016157).

DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by 5 different DNAm age measures. Two-wave longitudinal data were available for 1 083 participants of the Berlin Aging Study II who were reexamined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried’s frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), finger-floor distance, Mini-Mental State Examination, Center for Epidemiologic Studies—Depression scale, activities of daily living, instrumented ADL, and mini nutritional assessment. Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL, and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analysis of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath’s clock, Hannum’s clock PhenoAge, and GrimAge) with functional assessments. In conclusion, neither rLTL nor 7-CpG DNAmAA was able to predict impairment in the analyzed assessments over a ~7-year time course. Similarly, DNAmAA estimated from 5 epigenetic clocks was not a good cross-sectional marker of health deterioration either.

Introduction: There is evidence of an association between markers of cardiac injury and cognition in patients with cardiovascular disease. We hypothesized that levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with cognitive performance and cognitive decline in a population of predominantly healthy older adults. Methods: We included 1,226 predominantly healthy adults ≥60 years from the Berlin Aging Study II. Participants were recruited from the general population of the Berlin metropolitan area from 2009 to 2014. At baseline, participants underwent measurement of hs-cTnT and cognitive testing using the extended Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-Plus) battery. In addition, the Digit Symbol Substitution Test (DSST) was performed at baseline and at follow-up (7.3 ± 1.4 years after the baseline visit). The CERAD test results were summarized into four cognitive domains (processing speed, executive function, visuo-construction, and memory). After summing-up the respective raw scores, we calculated standardized z scores. We performed unadjusted and adjusted linear regression models to assess links between hs-cTnT and cognitive domains. We used linear mixed models to analyze associations between hs-cTnT and cognitive decline according to changes in DSST scores over time. Results: The mean age of study participants at baseline was 68.5 (±3.6) years, 49% were female, and median hs-cTnT levels were 6 ng/L (IQR 4–8 ng/L). We detected no significant association between hs-cTnT and different cognitive domains at baseline after adjustment for age, sex, education, and cardiovascular risk factors. Hs-cTnT was associated with cognitive decline, which remained statistically significant after full adjustment (adjusted beta-coefficient −0.82 (−1.28 to −0.36), p = 0.001). After stratification for sex, the association with hs-cTnT remained statistically significant in men but not in women. Conclusion: Higher hs-cTnT levels in older men are associated with cognitive decline measured with the DSST.

Sociocultural gender is a complex construct encompassing different aspects of individuals' life, whereas sex refers to biological factors. These terms are often misused, although they impact differently on individuals' health. Recognizing the role of sex and gender on health status is fundamental in the pursuit of a personalized medicine. Aim of the current study was to investigate the awareness in approaching clinical and research questions on the impact of sex and gender on health among European internists. Clinicians affiliated with the European Federation of Internal Medicine from 33 countries participated to the study on a voluntary basis between January 1st, 2018 and July 31st, 2019. Internists' awareness and knowledge on sex and gender issues in clinical medicine were measured by an online anonymized 7-item survey. A total of 1323 European internists responded to the survey of which 57% were women, mostly young or middle-aged (78%), and practicing in public general medicine services (74.5%). The majority (79%) recognized that sex and gender are not interchangeable terms, though a wide discrepancy exists on what clinicians think sex and gender concepts incorporate. Biological sex and sociocultural gender were recognized as determinants of health mainly in cardiovascular and autoimmune/rheumatic diseases. Up to 80% of respondents acknowledged the low participation of female individuals in trials and more than 60% the lack of sex-specific clinical guidelines. Internists also express the willingness of getting more knowledge on the impact of sex and gender in cerebrovascular/cognitive and inflammatory bowel diseases. Biological sex and sociocultural gender are factors influencing health and disease. Although awareness and knowledge remain suboptimal across European internists, most acknowledge the underrepresentation of female subjects in trials, the lack of sex-specific guidelines and the need of being more informed on sex and gender-based differences in diseases.

Aims Hypertensive disorders occur in women with peripartum cardiomyopathy (PPCM). How often hypertensive disorders co-exist, and to what extent they impact outcomes, is less clear. We describe differences in phenotype and outcomes in women with PPCM with and without hypertensive disorders during pregnancy. Methods and results The European Society of Cardiology EURObservational Research Programme PPCM Registry enrolled women with PPCM from 2012-2018. Three groups were examined: (i) women without hypertension (PPCM-noHTN); (ii) women with hypertension but without pre-eclampsia (PPCM-HTN); (iii) women with pre-eclampsia (PPCM-PE). Maternal (6-month) and neonatal outcomes were compared. Of 735 women included, 452 (61.5%) had PPCM-noHTN, 99 (13.5%) had PPCM-HTN and 184 (25.0%) had PPCM-PE. Compared to women with PPCM-noHTN, women with PPCM-PE had more severe symptoms (New York Heart Association class IV in 44.4% vs. 29.9%, P < 0.001), more frequent signs of heart failure (pulmonary rales in 70.7% vs. 55.4%, P = 0.002), a higher baseline left ventricular ejection fraction (LVEF) (32.7% vs. 30.7%, P = 0.005) and a smaller left ventricular end-diastolic diameter (57.4 +/- 6.7 mm vs. 59.8 +/- 8.1 mm, P = 0.001). There were no differences in the frequencies of death from any cause, rehospitalization for any cause, stroke, or thromboembolic events. Compared to women with PPCM-noHTN, women with PPCM-PE had a greater likelihood of left ventricular recovery (LVEF >= 50%) (adjusted odds ratio 2.08, 95% confidence interval 1.21-3.57) and an adverse neonatal outcome (composite of termination, miscarriage, low birth weight or neonatal death) (adjusted odds ratio 2.84, 95% confidence interval 1.66-4.87). Conclusion Differences exist in phenotype, recovery of cardiac function and neonatal outcomes according to hypertensive status in women with PPCM.

BACKGROUND: Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and β blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and β blockers in patients with HFrEF.METHODS: We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and β blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF.FINDINGS: Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, pINTERPRETATION: This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and β blockers than men, and brings into question what the true optimal medical therapy is for women versus men.FUNDING: European Commission.

The downregulation of AMP-activated protein kinase (AMPK) activity contributes to numerous pathologies. Recent reports suggest that the elevation of cellular cAMP promotes AMPK activity. However, the source of the cAMP pool that controls AMPK activity remains unknown. Mammalian cells possess two cAMP sources: membrane-bound adenylyl cyclase (tmAC) and intracellularly localized, type 10 soluble adenylyl cyclase (sAC). Due to the localization of sAC and AMPK in similar intracellular compartments, we hypothesized that sAC may control AMPK activity. In this study, sAC expression and activity were manipulated in H9C2 cells, adult rat cardiomyocytes or endothelial cells. sAC knockdown depleted the cellular cAMP content and decreased AMPK activity in an EPAC-dependent manner. Functionally, sAC knockdown reduced cellular ATP content, increased mitochondrial ROS formation and led to mitochondrial depolarization. Furthermore, sAC downregulation led to EPAC-dependent mitophagy disturbance, indicated by an increased mitochondrial mass and unaffected mitochondrial biogenesis. Consistently, sAC overexpression or stimulation with bicarbonate significantly increased AMPK activity and cellular ATP content. In contrast, tmAC inhibition or stimulation produced no effect on AMPK activity. Therefore, the sAC-EPAC axis may regulate basal and induced AMPK activity and support mitophagy, cellular energy and redox homeostasis. The study argues for sAC as a potential target in treating pathologies associated with AMPK downregulation.

Aging is associated with increased inflammation and alterations in mitochondrial biogenesis, which promote the development of cardiovascular diseases. Emerging evidence suggests a role for sirtuins, which are NAD+-dependent deacetylases, in the regulation of cardiovascular inflammation and mitochondrial biogenesis. Sirtuins are regulated by sex or sex hormones and are decreased during aging in animal models. We hypothesized that age-related alterations in cardiac Sirt1 and Sirt3 occur in the human heart and examined whether these changes are associated with a decrease in anti-oxidative defense, inflammatory state and mitochondrial biogenesis. Using human ventricular tissue from young (17-40 years old) and old (50-68 years old) individuals, we found significantly lower Sirt1 and Sirt3 expression in old female hearts than in young female hearts. Additionally, lower expression of the anti-oxidative protein SOD2 was observed in old female hearts than in young female hearts. Aging in female hearts was associated with a significant increase in the number of cardiac macrophages and pro-inflammatory cytokines, as well as NF-kB upregulation, indicating a pro-inflammatory shift. Aging-associated pathways in the male hearts were different, and no changes in Sirt1 and Sirt3 or cardiovascular inflammation were observed. In conclusion, the present study revealed a female sex-specific downregulation of Sirt1 and Sirt3 in aged hearts, as well as a decline in mitochondrial anti-oxidative defense and a pro-inflammatory shift in old female hearts but not in male hearts.

Women with known cardiovascular diseases (CVD) and a desire to have children should receive a timely comprehensive counselling before becoming pregnant. This is critical as the foundation for an informed decision-making process of the mother and her family. Furthermore, a detailed interdisciplinary management plan should be developed and discussed with the patient. The modified World Health Organization (mWHO) classification should be applied for maternal cardiovascular risk stratification. Although the prevalence of aortic pathologies is infrequent, they are often life-threatening conditions. Following the recent advances in terms of surgical management and anticoagulation, the adequate management of valvular heart disease is particularly challenging. Cardiomyopathies during pregnancy are associated with high maternal mortality and severe cardiovascular complications, such as progressive heart failure and thromboembolic events; however, novel treatment options have recently become available.Frauen mit bekannten Herz-Kreislauf-Erkrankungen und Kinderwunsch sollten rechtzeitig vor der Schwangerschaft eine umfassende Beratung erhalten. Diese ist als Grundlage einer informierten Entscheidungsfindung für Mütter und deren Familien unabdingbar. Des Weiteren sollte ein Behandlungsplan interdisziplinär erstellt und mit den Patientinnen besprochen werden. Zur Risikobewertung in der Schwangerschaft sollte die modifizierte Klassifikation der Weltgesundheitsorganisation (mWHO) verwendet werden. Auch wenn es sich bei Erkrankungen der Aorta um seltene Pathologien handelt, sind diese häufig lebensbedrohlich. Herzklappenerkrankungen sind häufiger. Aufgrund neuer Möglichkeiten in der Chirurgie und der Antikoagulation stellt die Therapie von Herzklappenerkrankungen eine besondere Herausforderung dar. Kardiomyopathien in der Schwangerschaft können Todesfälle und schwere kardiovaskulärer Komplikationen, wie eine fortschreitende Herzinsuffizienz oder thromboembolische Ereignisse, verursachen. Mittlerweile sind jedoch neuartige Behandlungsmöglichkeiten verfügbar.

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:23 issue:4 pages:527-540 ispartof: location:England status: published

Gender refers to the socially constructed roles, behaviours, expressions and identities of girls, women, boys, men and gender diverse people. Gender-related factors are seldom assessed as determinants of health outcomes, despite their powerful contribution. The Gender Outcomes INternational Group: to Further Well-being Development (GOING-FWD) project developed a standard five-step methodology applicable to retrospectively identify gender-related factors and assess their relationship to outcomes across selected cohorts of non-communicable chronic diseases from Austria, Canada, Spain, Sweden. Step 1 (identification of gender-related variables): Based on the gender framework of the Women Health Research Network (ie, identity, role, relations and institutionalised gender), and available literature for a certain disease, an optimal ‘wish-list’ of gender-related variables was created and discussed by experts. Step 2 (definition of outcomes): Data dictionaries were screened for clinical and patient-relevant outcomes, using the International Consortium for Health Outcome Measurement framework. Step 3 (building of feasible final list): a cross-validation between variables per database and the ‘wish-list’ was performed. Step 4 (retrospective data harmonisation): The harmonisation potential of variables was evaluated. Step 5 (definition of data structure and analysis): The following analytic strategies were identified: (1) local analysis of data not transferable followed by a meta-analysis combining study-level estimates; (2) centrally performed federated analysis of data, with the individual-level participant data remaining on local servers; (3) synthesising the data locally and performing a pooled analysis on the synthetic data and (4) central analysis of pooled transferable data. The application of the GOING-FWD multistep approach can help guide investigators to analyse gender and its impact on outcomes in previously collected data.

In addition to biological sex, gender, defined as the sociocultural dimension of being a woman or a man, plays a central role in health. However, there are so far few approaches to quantify gender in a retrospective manner in existing study datasets. We therefore aimed to develop a methodology that can be retrospectively applied to assess gender in existing cohorts. We used baseline data from the Berlin Aging Study II (BASE-II), obtained in 2009–2014 from 1869 participants aged 60 years and older. We identified 13 gender-related variables and used them to construct a gender score by using primary component and logistic regression analyses. Of these, nine variables contributed to a gender score: chronic stress, marital status, risk-taking behaviour, personality attributes: agreeableness, neuroticism, extraversion, loneliness, conscientiousness, and level of education. Females and males differed significantly in the distribution of the gender score, but a significant overlap was also found. Thus, we were able to develop a gender score in a retrospective manner from already collected data that characterized participants in addition to biological sex. This approach will allow researchers to introduce the notion of gender retrospectively into a large number of studies. Supplementary Information The online version contains supplementary material available at 10.1186/s13293-020-00351-2.

PurposeThe study ‘Sex- and gender-sensitive prevention of cardiovascular and metabolic disease in older adults in Germany’, the GendAge study, focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of sex and gender differences. It is based on a follow-up examination of a subsample (older group) of the Berlin Aging Study II (BASE-II).ParticipantsThe GendAge study assessments took place between 22 June 2018 and 10 March 2020. A total of 1100 participants (older BASE-II subsample, aged ≥65 years) with baseline data assessed at least by one of the BASE-II partner sites were investigated in the follow-up. These participants had a mean age of 75.6 years (SD ±3.8), with a mean follow-up at 7.4 years (SD ±1.5).Findings to dateData from different domains such as internal medicine, geriatrics, immunology and psychology were collected, with a focus on cardiometabolic diseases and in the context of sex and gender differences. Diabetes mellitus type 2 was reported by 15.6% and 8.6% of men and women, respectively. In contrast, this disease was diagnosed in 20.7% of men and 13.3% of women, indicating that a substantial proportion of almost 30% was unaware of the disease. Echocardiography revealed that left ventricular ejection fraction was higher in women than in men, in agreement with previous reports.Future plansA gender questionnaire assessing sociocultural aspects implemented as part of the follow-up described here will allow to calculate a gender score and its evaluation based on the newly collected data. At the same time, the other BASE-II research foci established over the past 10 years will be continued and strengthened by the BASE-II transition into a longitudinal study with follow-up data on the older subsample.Trial registration numberDRKS00016157.

In the LoDoCo2 trial, patients with chronic coronary disease who received colchicine had a lower risk of cardiovascular events than those who received placebo but did not have a corresponding lower risk of death. Clonal hematopoiesis of indeterminate potential (CHIP ; the presence of leukemia-associated gene mutations in patients without detectable hematologic cancer) increases in incidence with age, and clones that consist of at least 10% of circulating nucleated cells are found in 10 to 15% of adults who are older than 70 years of age.1 CHIP is associated with increased cardiovascular morbidity and mortality owing to accelerated atherosclerosis caused by proinflammatory interactions between endothelium and clonal monocytes (mediated by the NLRP3 inflammasome).

This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Hypertensive disorders are the most common medical complications in the peripartum period associated with a substantial increase in morbidity and mortality. Hypertension in the peripartum period may be due to the continuation of pre-existing or gestational hypertension, de novo development of pre-eclampsia or it may be also induced by some drugs used for analgesia or suppression of postpartum haemorrhage. Women with severe hypertension and hypertensive emergencies are at high risk of life-threatening complications, therefore, despite the lack of evidence-based data, based on expert opinion, antihypertensive treatment is recommended. Labetalol intravenously and methyldopa orally are then the two most frequently used drugs. Short-acting oral nifedipine is suggested to be used only if other drugs or iv access are not available. Induction of labour is associated with improved maternal outcome and should be advised for women with gestational hypertension or mild pre-eclampsia at 37 weeks’ gestation. This position paper provides the first interdisciplinary approach to the management of hypertension in the peripartum period based on the best available evidence and expert consensus.

Background Emerging evidence from China suggests that coronavirus disease 2019 (COVID-19) is deadlier for infected men than women with a 2.8% fatality rate being reported in Chinese men versus 1.7% in women. Further, sex-disaggregated data for COVID-19 in several European countries show a similar number of cases between the sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular conditions. The mechanisms accounting for the reduced case fatality rate in women are currently unclear but may offer potential to develop novel risk stratification tools and therapeutic options for women and men. Content The present review summarizes latest clinical and epidemiological evidence for gender and sex differences in COVID-19 from Europe and China. We discuss potential sex-specific mechanisms modulating the course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) entry receptors angiotensin converting enzyme (ACE) 2 receptor and TMPRSS2 as well as sex hormone-driven innate and adaptive immune responses and immunoaging. Finally, we elucidate the impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID-19 and discuss sex specific aspects of antiviral therapies. Conclusion The sex and gender disparities observed in COVID-19 vulnerability emphasize the need to better understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must include prospective sex- and gender-sensitive analyses.

Sex/gender differences pose a challenge in the care of patients with chronic coronary artery disease (CAD) especially in the resident sector. The aim of the AURORA trial was to obtain a nationwide overview on how resident cardiologists deal with sex/gender-specific aspects of symptomatic chronic CAD in their medical routine care and in the interplay with general practitioners, as well as derive insights out of it for general practice.Between October 2018 and April 2019 a survey among German cardiologists (n = 360) in the outpatient sector was performed using a structured questionnaire. Items focused on the cardiologists' personal assessment of sex/gender aspects in the diagnosis and treatment and consequences for the overall medical care of patients with chronic CAD.The range of symptoms of chronic CAD in male and female patients was differently assessed by the participating male or female cardiologists. General practitioners referred men at an earlier stage than women to a cardiologist for further testing. In male and female patients with non-obstructive CAD cardiovascular risk was largely assessed as comparable to patients with obstructive CAD. In terms of medical care, it was shown that therapeutic decisions made by cardiologists were generally considered and continued by the general practitioners.Results from previous trials on sex/gender differences in ischemic heart disease have made their way into medical care. However, they also show potential for optimization in diagnosis, treatment and collaboration between resident cardiologists and general practitioners. Overall the results indicate that sex/gender differences in chronic CAD gain more medical attention. However, there is a current lack of concise sex-specific guidelines for prevention, diagnosis and treatment.

Background Arterial stiffness is tightly linked to hypertension. Sex differences in hypertension and arterial stiffness have already been established, yet the role of sex hormones is not precisely defined. This study examined age and sex differences of arterial wave reflection and associations with endogenous and exogenous sex hormones in women. Methods Pulse wave analysis was performed with an oscillometric device in 590 male and 400 female participants of the Berlin Aging Study II. Participants have been recruited from two age-strata, 22-35 years and 60-82 years. Data on exposures and potential confounders, including medication, have been collected at baseline visit. Results Aumentation index (AIx) and pulse wave velocity increased with age. Mean AIx was higher in women than in men. Multivariable regression analysis showed a positive association between use of oral contraceptive pills (OCPs) and AIx controlling for confounders (age, BMI, current smoking, central blood pressure), with a significantly higher mean AIx in OCP-users compared with nonusers (mean group difference: 4.41; 95% confidence interval 1.61-7.22). Per quartile decrease in estradiol level AIx increased by 1.72 (95% confidence interval 0.43-3.00). In OCP users endogenous estradiol was largely suppressed. Conclusion The findings suggest important sex differences in measures of arterial wave reflection, with a higher mean AIx observed in women compared with men. OCPs may promote the development of hypertension by increasing AIx. Suppressed endogenous estradiol levels may be responsible for this increased wave reflection due to increased vasotonus of the small and medium arteries.

Item does not contain fulltext AIM: The aim of our study was to describe right atrial (RA) and right ventricular (RV) function, assessed by Doppler tissue imaging and 2D speckle tracking echocardiography (2DSTE), in women with signs of early impaired left ventricular diastolic function (DD). METHODS AND RESULTS: In a cross-sectional trial, standard parameters of diastolic and right heart function were investigated in 438 women of the Berlin Female Risk Evaluation (BEFRI) study. In a subset of women, average peak systolic RA strain (RAS), as well as the average peak systolic RV strain of the free wall (RVS free wall) and of all RV segments (average RV strain; RVS Avg), was analyzed using 2DSTE. Compared to women with normal diastolic function (DD0), RAS, RVS free wall and RVS Avg were significantly reduced in DD (43.1% +/- 11.9%, -26.7% +/- 5.6%, and -23.3% +/- 3.5% in DD0; vs 35.1% +/- 10.4%, -23.9% +/- 5.5%, and -20.6% +/- 3.8% in DD; P < .01). Peak RV myocardial velocity (RV-IVV) and acceleration during isovolumetric contraction (RV-IVA) were markedly higher in DD (15.0 +/- 3.9 cm/s and 3.1 +/- 1.0 m/s(2) in DD vs 11.9 +/- 3.2 cm/s and 2.8 +/- 0.8 m/s(2) in DD0; P < .05). RAS and RV-IVV were significantly associated with DD after adjustment to age, BMI, and left atrial strain in multivariate regression analysis. CONCLUSION: Systolic right heart function is significantly altered in DD. DTI as well as 2DSTE constitute sensitive echocardiographic tools that enable the diagnosis of impaired right heart mechanics in early-staged DD.

Major differences between men and women exist in epidemiology, manifestation, pathophysiology, treatment, and outcome of cardiovascular diseases (CVD), such as coronary artery disease, pressure overload, hypertension, cardiomyopathy, and heart failure. Corresponding sex differences have been studied in a number of animal models, and mechanistic investigations have been undertaken to analyze the observed sex differences. We summarize the biological mechanisms of sex differences in CVD focusing on three main areas, i.e., genetic mechanisms, epigenetic mechanisms, as well as sex hormones and their receptors. We discuss relevant subtypes of sex hormone receptors, as well as genomic and nongenomic, activational and organizational effects of sex hormones. We describe the interaction of sex hormones with intracellular signaling relevant for cardiovascular cells and the cardiovascular system. Sex, sex hormones, and their receptors may affect a number of cellular processes by their synergistic action on multiple targets. We discuss in detail sex differences in organelle function and in biological processes. We conclude that there is a need for a more detailed understanding of sex differences and their underlying mechanisms, which holds the potential to design new drugs that target sex-specific cardiovascular mechanisms and affect phenotypes. The comparison of both sexes may lead to the identification of protective or maladaptive mechanisms in one sex that could serve as a novel therapeutic target in one sex or in both.

Aims Recent data from national registries suggest that acute heart failure (AHF) outcomes might vary in men and women, however, it is not known whether this observation is universal. The aim of this study was to evaluate the association of biological sex and 1-year all-cause mortality in patients with AHF in various regions of the world. Methods and results We analysed several AHF cohorts including GREAT registry (22 523 patients, mostly from Europe and Asia) and OPTIMIZE-HF (26 376 patients from the USA). Clinical characteristics and medication use at discharge were collected. Hazard ratios (HRs) for 1-year mortality according to biological sex were calculated using a Cox proportional hazards regression model with adjustment for baseline characteristics (e.g. age, comorbidities, clinical and laboratory parameters at admission, left ventricular ejection fraction). In the GREAT registry, women had a lower risk of death in the year following AHF [HR 0.86 (0.79–0.94), P Conclusion Globally women with AHF have a lower 1-year mortality and less evidenced-based treatment than men. Differences among countries need further investigation. Our findings merit consideration when designing future global clinical trials in AHF.

The prevalence of cardiometabolic disorders in both women and men has increased worldwide and is linked to a rise in obesity and obesity-associated associated clustering of other cardiometabolic risk factors such as hypertension, impaired glucose regulation and dyslipidemia. However, the predominance of common types of cardiometabolic disorders such as heart failure, atrial fibrillation and ischemic heart disease is sex specific, and our identification of these and the underlying mechanisms is only just emerging. New evidence suggests that sex hormones, sex-specific molecular mechanisms and gender influence glucose and lipid metabolisms, as well as cardiac energy metabolism, and function. Here we review sex differences in cardiometabolic risk factors, associated preclinical and clinical cardiac disorders and potential therapeutic avenues.

Chronic pressure overload due to aortic valve stenosis leads to pathological cardiac hypertrophy and heart failure. Hypertrophy is accompanied by an increase in myocyte surface area, which requires a proportional increase in the number of cell-cell and cell-matrix contacts to withstand enhanced workload. In a proteomic analysis we identified nerve injury-induced protein 1 (Ninjurin1), a 16kDa transmembrane cell-surface protein involved in cell adhesion and nerve repair, to be increased in hypertrophic hearts from patients with aortic stenosis. We hypothesised that Ninjurin1 is involved in myocyte hypertrophy. We analyzed cardiac biopsies from aortic-stenosis patients and control patients undergoing elective heart surgery. We studied cardiac hypertrophy in mice after transverse aortic constriction and angiotensin II infusions, and performed mechanistic analyses in cultured myocytes. We assessed the physiological role of ninjurin1 in zebrafish during heart and skeletal muscle development. Ninjurin1 was increased in hearts of aortic stenosis patients, compared to controls, as well as in hearts from mice with cardiac hypertrophy. Besides the 16kDa Ninjurin1 (Ninjurin1-16) we detected a 24kDa variant of Ninjurin1 (Ninjurin1-24), which was predominantly expressed during myocyte hypertrophy. We disclosed that the higher molecular weight of Ninjurin1-24 was caused by N-glycosylation. Ninjurin1-16 was contained in the cytoplasm of myocytes where it colocalized with stress-fibers. In contrast, Ninjurin1-24 was localized at myocyte membranes. Gain and loss-of-function experiments showed that Ninjurin1-24 plays a role in myocyte hypertrophy and myogenic differentiation in vitro. Reduced levels of ninjurin1 impaired cardiac and skeletal muscle development in zebrafish. We conclude that Ninjurin1 contributes to myocyte growth and differentiation, and that these effects are mainly mediated by N-glycosylated Ninjurin1-24.

A new modular, outcome-based, interdisciplinary curriculum was introduced for undergraduate medical education at one of the largest European medical faculties. A key stated institutional goal was to systematically integrate sex and gender medicine and gender perspectives into the curriculum in order to foster adequate gender-related knowledge and skills for future doctors concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and research of diseases.A change agent was integrated directly into the curriculum development team to facilitate interactions with all key players of the curricular development process. The gender change agent established a supporting organizational framework of all stakeholders, and developed a 10-step approach including identification, selection, placing relevant sex and gender medicine-related issues in the curricular planning sessions, counseling of faculty members, and monitoring of the integration achieved.With this approach, quantitatively sex and gender medicine-related content was widely integrated throughout all teaching and learning formats and from early basic science to later clinical modules (94 lectures, 33 seminars, and 16 practical courses). Gender perspectives involve 5% of the learning objectives and represent an integral part of the assessment program. Qualitatively, the relevance of gender (sociocultural) differences was combined with sex (biological) differences in disease manifestation throughout the curriculum.The appointment of a change agent facilitates the development of systematic approaches that can be a key and serve as practice models to successfully integrate new overarching curricular perspectives and dimensions--in this case sex and gender medicine--into a new medical curriculum.

This study sought to summarize all available evidence on sex differences in adverse drug reactions (ADRs) to heart failure (HF) medication.Women are more likely to experience ADRs than men, and these reactions may negatively affect women's immediate and long-term health. HF in particular is associated with increased ADR risk because of the high number of comorbidities and older age. However, little is known about ADRs in women with HF who are treated with guideline-recommended drugs.A systematic search of PubMed and EMBASE was performed to collect all available information on ADRs to angiotensin-converting enzyme inhibitors, β-blockers, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, ivabradine, and digoxin in both women and men with HF.The search identified 155 eligible records, of which only 11 (7%) reported ADR data for women and men separately. Sex-stratified reporting of ADRs did not increase over the last decades. Six of the 11 studies did not report sex differences. Three studies reported a higher risk of angiotensin-converting enzyme inhibitor-related ADRs in women, 1 study showed higher digoxin-related mortality risk for women, and 1 study reported a higher risk of mineralocorticoid receptor antagonist-related ADRs in men. No sex differences in ADRs were reported for angiotensin II receptor blockers and β-blockers. Sex-stratified data were not available for ivabradine.These results underline the scarcity of ADR data stratified by sex. The study investigators call for a change in standard scientific practice toward reporting of ADR data for women and men separately.

AIM We aim to determine normative reference data of phasic right atrial (RA) strain and to investigate determinants, possible clinical implications as well as feasibility and reproducibility of RA strain analysis. METHODS AND RESULTS Right atrial strain was analyzed in 266 participants of the cross-sectional Berlin Female Risk Evaluation (BEFRI) study using 2D speckle-tracking echocardiography (2D STE). To determine reference values, phasic RA strain was determined in a subgroup of 123 individuals without known cardiovascular diseases or risk factors. Mean RA reservoir strain (RAS), RA conduit, and contraction strain in this reference group were 44.9 ± 11.6%, 27.1 ± 9.5%, and 17.0 ± 5.9%, respectively. Regarding possible clinical implications, RAS was significantly reduced in women with a BMI ≥ 25, compared with women with a BMI

AimsSex differences in cardiac fibrosis point to the regulatory role of 17β-Estradiol (E2) in cardiac fibroblasts (CF). We, therefore, asked whether male and female CF in rodent and human models are differentially susceptible to E2, and whether this is related to sex-specific activation of estrogen receptor alpha (ERα) and beta (ERβ).Methods and resultsIn female rat CF (rCF), 24 h E2-treatment (10−8 M) led to a significant down-regulation of collagen I and III expression, whereas both collagens were up-regulated in male rCF. E2-induced sex-specific collagen regulation was also detected in human CF, indicating that this regulation is conserved across species. Using specific ERα- and ERβ-agonists (10−7 M) for 24 h, we identified ERα as repressive and ERβ as inducing factor in female and male rCF, respectively. In addition, E2-induced ERα phosphorylation at Ser118 only in female rCF, whereas Ser105 phosphorylation of ERβ was exclusively found in male rCF. Further, in female rCF we found both ER bound to the collagen I and III promoters using chromatin immunoprecipitation assays. In contrast, in male rCF only ERβ bound to both promoters. In engineered connective tissues (ECT) from rCF, collagen I and III mRNA were down-regulated in female ECT and up-regulated in male ECT by E2. This was accompanied by an impaired condensation of female ECT, whereas male ECT showed an increased condensation and stiffness upon E2-treatment, analysed by rheological measurements. Finally, we confirmed the E2-effect on both collagens in an in vivo mouse model with ovariectomy for E2 depletion, E2 substitution, and pressure overload by transverse aortic constriction.ConclusionThe mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERβ signaling in CFs.

Item does not contain fulltext BACKGROUND: Cardiovascular diseases are the main cause of mortality for women worldwide, yet their impact is frequently underestimated. To raise awareness for preventative lifestyle measures other contacts with the healthcare system should be exploited. We analyzed access patterns to other healthcare specialists and population screening measures to identify options for opportunistic counseling on cardiovascular risk. MATERIALS AND METHODS: We enrolled 1062 randomly selected German urban women aged 25-74 years in 2012-2013, divided into 5 age bands. Women were asked about sociodemographic characteristics, clinical and gynecological history, physician attendance patterns, screening behavior and primary sources of health and preventative information, and clinical examination attendance. RESULTS: Obstetrician/gynecologists (OBGYN) were the most frequently consulted physicians within the last 12 months (75.3%), more than general practitioners (GP; 74%). Attendance rates to OBGYNs were not affected by education or income, solely a body mass index (BMI) >30 associated with significantly reduced rates of attendance (OR = 0.4, CI 95% = 0.17-0.78, p = 0.009). Women with low to medium Framingham risk scores were more likely to attend an OBGYN than a GP if they attended only one specialist. Attendance of population screening measures is limited (

Article en libre accès; Women and men, female and male animals and cells are biologically different, and acknowledgement of this fact is critical to advancing medicine. However, incorporating concepts of sex-specific analysis in basic research is largely neglected, introducing bias into translational findings, clinical concepts and drug development. Research funding agencies recently approached these issues but implementation of policy changes in the scientific community is still limited, probably due to deficits in concepts, knowledge and proper methodology. This expert review is based on the EUGenMed project (www.eugenmed.eu) developing a roadmap for implementing sex and gender in biomedical and health research. For sake of clarity and conciseness, examples are mainly taken from the cardiovascular field that may serve as a paradigm for others, since a significant amount of knowledge how sex and oestrogen determine the manifestation of many cardiovascular diseases (CVD) has been accumulated. As main concepts for implementation of sex in basic research, the study of primary cell and animals of both sexes, the study of the influence of genetic vs. hormonal factors and the analysis of sex chromosomes and sex specific statistics in genome wide association studies (GWAS) are discussed. The review also discusses methodological issues, and analyses strength, weaknesses, opportunities and threats in implementing sex-sensitive aspects into basic research.

Depression is common in heart failure (HF) and associated with adverse outcomes. This study aimed to investigate incidence rates and predictors of depression in patients sampled from four subprojects of the German Competence Network Heart Failure.Eight hundred thirty nine symptomatic HF patients free of depression at baseline underwent repeat depression screening (Patient Health Questionnaire, PHQ-9) after 12 months. Ordered logistic regression analysis was employed to search for predictors of incident depression.Incident minor (major) depression was observed in 61 (7.3%) and 47 (5.6%) of the population. Depression was recurrent in 15 (25%) and 16 (34%), respectively. Multiple regression analysis revealed seven variables predicting minor or major depression: Previous depressive episode (odds ratio [OR] 4.04, 95% confidence interval [CI] 2.37-6.89, p ≤ 0.001), previous resuscitation (OR 2.44, CI 1.23-4.81, p=0.010), current smoking (OR 2.06, CI 1.08-3.50, p=0.008),4 visits/year to general practitioner (OR 1.67, CI 1.06-2.63, p=0.026), New York Heart Association class (OR 1.54/class, 95% CI 1.05-2.25, p=0.027), PHQ-9 baseline sum-score (OR 1.18/point, CI 1.11-1.27, p0.001), and SF-36 physical functioning (OR 1.08/-5 points, CI 1.03-1.13, p=0.002).In these HF patients initially free of depression annual incidence rates were high. Several independent predictors allowed identification of patients at particular risk. Although obtained in a selected cohort these findings call, in view of the grave prognosis of HF patients with comorbid depression, for regular depression screening and development of specific supportive strategies to improve patient care and outcomes in HF.

Different stimuli confer mechanical and hormonal stress to the heart. Pressure overload (PO) affects the myocardium, kidney, and peripheral fat. The latter may be considered simultaneously as a novel end organ and as a mediator in cardiovascular damage and, by its interplay with the heart, contributes to the development of pathological myocardial hypertrophy (MH). In contrast to pathological MH, in physiological MH the heart serves as an end organ for recurrent pressure spikes without the development of pathology. Complex stressors such as mineralocorticoid excess and salt challenge induce complex pathological cardiac and renal phenotypes. Understanding the underlying sex-specific mechanisms mediating these processes may help to design new therapeutic strategies. The major goal of this review is to analyze sex differences in physiological and pathological forms of cardiovascular stress and its effects on different organs, including the heart, kidney, and peripheral fat. Exercise-induced physiological MH differs markedly from pathological MH resulting from hypertension, valve disease, or other challenges. Physiological MH is reversible, associated with improved cardiac function and lack of fibrosis.1 At the level of cardiac metabolism, MH during the course of physical training is accompanied by enhanced fatty acid oxidation and reduced glucose use. ### Clinical Impact and Relevance in Humans Studies in humans comparing exercise-mediated MH in both sexes are limited. Left ventricular mass (LVM) is significantly increased in male endurance athletes by 36±14% compared with untrained control subjects.2 In young adult elite athletes, both sexes exhibited similar increases in LVM and LVM indices when compared with their sex-matched sedentary controls.3 However, limitations of these studies in humans have to be taken into account: despite a comparable training duration (hours/week and years at elite level) in female and male athletes, no detailed information about training intensity was provided.3 Putative sex differences in training intensity might have influenced exercise-induced cardiac remodeling. A lower …

Chronic increased workload of the human heart causes ventricular hypertrophy, re-expression of the atrial essential myosin light chain (hALC-1), and improved contractile function. Although hALC-1 is an important positive inotropic regulator of the human heart, little is known about its regulation. Therefore, we investigated the role of the sex hormone 17β-estradiol (E2) on hALC-1 gene expression, the underlying molecular mechanisms, and the impact of this regulatory process on cardiac contractile function. We showed that E2 attenuated hALC-1 expression in human atrial tissues of both sexes and in human ventricular AC16 cells. E2 induced the nuclear translocation of estrogen receptor alpha (ERα) and hALC-1 in AC16 cells, where they cooperatively regulate the transcriptional activity of hALC-1 gene promoter. E2-activated ERα required the estrogen response element (ERE) motif within the hALC-1 gene promoter to reduce its transcriptional activity (vehicle: 15.55 ± 4.80 vs. E2: 6.51 ± 3.69; ~2 fold). This inhibitory effect was potentiated in the presence of hALC-1 (vehicle: 11.13 ± 3.66 vs. E2: 2.18 ± 1.10; ~5 fold), and thus, hALC-1 acts as a co-repressor of ERα-mediated transcription. Yeast two-hybrid screening of a human heart cDNA library revealed that ERα interacts physically with hALC-1 in the presence of E2. This interaction was confirmed by Co-Immunoprecipitation and immunofluorescence in human atrium. As a further novel effect, we showed that chronic E2-treatment of adult mouse cardiomyocytes overexpressing hALC-1 resulted in reduced cell-shortening amplitude and twitching kinetics of these cells independent of Ca2+ activation levels. Together, our data showed that the expression of hALC-1 gene is, at least partly, regulated by E2/ERα, while hALC-1 acts as a co-repressor. The inotropic effect of hALC-1 overexpression in cardiomyocytes can be significantly repressed by E2.

Aims The purpose of this study is to describe disease presentation, co-morbidities, diagnosis and initial therapeutic management of patients with peripartum cardiomyopathy (PPCM) living in countries belonging to the European Society of Cardiology (ESC) vs. non-ESC countries. Methods and results Out of 500 patients with PPCM entered by 31 March 2016, we report on data of the first 411 patients with completed case record forms (from 43 countries) entered into this ongoing registry. There were marked differences in socio-demographic parameters such as Human Development Index, GINI index on inequality, and Health Expenditure in PPCM patients from ESC vs. non-ESC countries (P < 0.001 each). Ethnicity was Caucasian (34%), Black African (25.8%), Asian (21.8%), and Middle Eastern backgrounds (16.4%). Despite the huge disparities in socio-demographic factors and ethnic backgrounds, baseline characteristics are remarkably similar. Drug therapy initiated post-partum included ACE inhibitors/ARBs and mineralocorticoid receptor antagonists with identical frequencies in ESC vs. non-ESC countries. However, in non-ESC countries, there was significantly less use of beta-blockers (70.3% vs. 91.9%) and ivabradine (1.4% vs. 17.1%), but more use of diuretics (91.3% vs. 68.8%), digoxin (37.0% vs. 18.0%), and bromocriptine (32.6% vs. 7.1%) (P < 0.001). More patients in non-ESC vs. ESC countries continued to have symptomatic heart failure after 1 month (92.3% vs. 81.3%, P < 0.001). Venous thrombo-embolic events, arterial embolizations, and cerebrovascular accidents were documented in 28 of 411 patients (6.8%). Neonatal death rate was 3.1%. Conclusion PPCM occurs in women from different ethnic backgrounds globally. Despite marked differences in socio-economic background, mode of presentation was largely similar. Embolic events and persistent heart failure were common within 1 month post-diagnosis and required intensive, multidisciplinary management.

The present study reports markers of vascular function among a general female population and shows that left ventricular diastolic dysfunction (LVDD) is significantly associated with pathological PWV (⩾9.7 m/s), a waist circumference >80 cm and age., The present study determines the prevalence of vascular dysfunction and arterial stiffness (ASt) in a female urban population by measuring the brachial augmentation index (AIx) and aortic pulse wave velocity (PWV). The study tests the hypothesis that the measurement of AIx and PWV is useful in addition to that of traditional cardiovascular risk factors when assessing the risk for left ventricular diastolic dysfunction (LVDD). This cross-sectional study recruited 965 women aged 25–75 years from 12 districts of Berlin. The ASt indices, brachial AIx, aortic PWV and the central blood pressure were measured by an oscillometric method. A randomly selected subgroup (n=343) was examined by echocardiography. Trans-mitral inflow E/A ratio and diastolic mitral annulus velocity (é) were assessed. Questionnaires, medical history and blood sampling were used for the evaluation of individual risk factors. Normal vascular function was found in 55% of the women included. The prevalence of women with pathological AIx only (AIx ⩾ −10%, PWV normal) was 21.5%, whereas 17.9% were affected by increased AIx and PWV (AIx ⩾ −10%, PWV ⩾9.7 m/s), and 6% with only pathological PWV values. The prevalence of LVDD was 31.7%. LVDD was significantly associated with pathological PWV ⩾ 9.7 m/s [OR: 1.27, 95%CI: 1.02–1.57], age [OR: 4.17, 95%CI: 2.87–6.07] and a waist circumference >80 cm [OR: 3.61, 95%CI: 1.85–7.04] in multiple regression analysis. The high prevalence of markers for vascular dysfunction and ASt in a general female population and their importance as a mediator of diastolic dysfunction should encourage implementation of aortic PWV measurement to improve cardiovascular-risk assessment in particular to identify subclinical myocardial diastolic dysfunction.

Biological sex significantly affects the presentation, outcome of treatment and progression of disease. However, the role of sex has yet underestimated consequences for physiology and pathology. We put forward that a better understanding of the effects of sex in pathophysiology and the underlying mechanisms is necessary. This may facilitate the identification of targets that respond to specific therapies, thereby contributing towards a more appropriate and individualised medical care for both men and women.