Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

The effect of genetic variation in estrogen transportation and metabolism on the severity of menopause symptoms: A study from the RIGHT 10K cohort.

OBJECTIVE: The severity of menopause-related symptoms varies considerably among women. The determinants of this variation are incompletely understood. The aim of this study was to assess the association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. METHODS: This was a cross-sectional study of 60 peri- and postmenopausal women in the Mayo Clinic RIGHT study (which involved sequencing of genes involved in drug metabolism and transport), who had also been evaluated in the Women's Health Clinic at Mayo Clinic in Rochester, MN. All participants completed the Menopause Rating Scale (MRS) for assessment of menopause symptoms, including hot flashes. The association between severity of menopause symptoms and the variation in genes encoding 8 enzymes and transporters involved in estrogen metabolism was evaluated. RESULTS: Lower CYP3A4 activity and higher COMT activity were associated with lower severity of somatic menopause symptoms (p = 0.04 and 0.06, respectively). These associations did not persist after adjustment for hormone therapy use. No differences in MRS scores or hot flash severity were noted among other genetic variant groups. Age at natural menopause was not affected by variations in the genes studied. CONCLUSION: The current study did not show an association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Further studies with larger sample sizes may be required to understand this potentially complex association.

Associations between pituitary-ovarian hormones and cognition in recently menopausal women independent of type of hormone therapy.

OBJECTIVES: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group. METHODS: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 µg/day transdermal 17ß (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17ß-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty. RESULTS: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17ß-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time. SUMMARY: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation. GOV NUMBERS: NCT00154180, NCT00623311.

Cardiometabolic measures and cognition in early menopause - Analysis of baseline data from a randomized controlled trial.

OBJECTIVE: The relationships between cardiometabolic indices and cognition were examined in recently menopausal women. METHODS: Cross-sectional analysis of baseline data from the KEEPS (Kronos Early Estrogen Prevention Study)-Cognitive ancillary study (n = 621). Cognitive performance was assessed by the Modified Mini Mental Status (3MS) score (primary outcome). Physical cardiometabolic indices included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and blood pressure (BP). Biochemical cardiometabolic indices included serum levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL (non-HDL-C), triglycerides (TG), fasting serum glucose (FSG), and insulin resistance (HOMA-IR). Socio-demographic variables included age, race/ethnicity, education, and lifestyle (physical activity, smoking). Central adiposity was defined as WC > 88 cm (>35 in) and WHR > 0.8. Separate stepwise multivariable analyses (GLM, ordinal logistic regression and logistic regression) assessed relationships between 3MS scores (as continuous, in tertiles and dichotomized at 90 respectively) with the measures of central adiposity (predictor variables); socio-demographic variables (age, time since menopause, race, educational status and lifestyle) and cardiometabolic variables (BP, lipids, FSG, HOMA-IR and hs-CRP) were examined as covariates. The final multivariable models included time since menopause, race, ethnicity, educational status, strenuous exercise, BMI ≥30 kg/m2, non-HDL-C and hs-CRP as covariates. Due to the high collinearity between the two indices of central adiposity, within each analytic strategy, separate models examined the respective associations of WC > 88 cm and WHR > 0.8 with 3MS score. RESULTS: On adjusted analyses, indices of central adiposity were independent predictors of significantly lower 3MS scores (p < 0.05). Consistency in this relationship was observed across the three different multivariable regression analytic approaches (GLM, ordinal and logistic regression). CONCLUSIONS: Among recently menopausal women, WC > 88 cm and WHR > 0.8 were associated with significantly lower cognitive function, as reflected by lower 3MS scores. The mechanisms that might explain the observed negative implications of central adiposity for cognitive function warrant further study.

Sex disparities in management and outcomes of cardiac arrest complicating acute myocardial infarction in the United States.

BACKGROUND: There have been limited large scale studies assessing sex disparities in the outcomes of cardiac arrest (CA) complicating acute myocardial infarction (AMI). METHODS AND RESULTS: Using the National Inpatient Sample (2000-2017), we identified adult admissions (≥18 years) with AMI and CA. Outcomes of interest included sex disparities in coronary angiography (early [hospital day zero] and overall), time to angiography, percutaneous coronary angiography (PCI), mechanical circulatory support (MCS) use, in-hospital mortality, hospitalization costs, hospital length of stay and discharge disposition. In the period between January 1, 2000-December 31, 2017, 11,622,528 admissions for AMI were identified, of which 584,216 (5.0%) were complicated by CA. Men had a higher frequency of CA compared to women (5.4% vs. 4.4%; p < 0.001). Women were on average older (70.4 ± 13.6 vs 65.0 ± 13.1 years), of black race (12.6% vs 7.9%), with higher comorbidity, presenting with non-ST-segment-elevation AMI (36.4% vs 32.3%) and had a non-shockable rhythm (47.6% vs 33.3%); all p < 0.001. Women received less frequent coronary angiography (56.0% vs 66.2%), early coronary angiography (32.0% vs 40.2%), PCI (40.4% vs 49.7%), MCS (17.6% vs 22.0%), and CABG (8.3% vs 10.8%), with a longer median time to angiography (all p < 0.001). Women had higher in-hospital mortality (52.6% vs 40.6%, adjusted odds ratio 1.13 [95% confidence interval 1.11-1.14]; p < 0.001), shorter length of hospital stays, lower hospitalization costs and less frequent discharges to home. CONCLUSION: Despite no difference in guideline recommendations for men and women with AMI-CA, there appears to be a systematic difference in the use of evidence-based care that disadvantages women.

Sex differences in acute cardiovascular care: a review and needs assessment.

Despite significant progress in the care of patients suffering from cardiovascular disease, there remains a persistent sex disparity in the diagnosis, management, and outcomes of these patients. These sex disparities are seen across the spectrum of cardiovascular care, but, are especially pronounced in acute cardiovascular care. The spectrum of acute cardiovascular care encompasses critically ill or tenuous patients with cardiovascular conditions that require urgent or emergent decision-making and interventions. In this narrative review, the disparities in the clinical course, management, and outcomes of six commonly encountered acute cardiovascular conditions, some with a known sex-predilection will be discussed within the basis of underlying sex differences in physiology, anatomy, and pharmacology with the goal of identifying areas where improvement in clinical approaches are needed.

Heterogeneity in treatment effects across diverse populations.

Differences in patient characteristics, including age, sex, and race influence the safety and effectiveness of drugs, biologic products, and medical devices. Here we provide a summary of the topics discussed during the opening panel at the 2018 Johns Hopkins Center for Excellence in Regulatory Science and Innovation symposium on Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities. The goal of this session was to provide a brief overview of FDA-regulated therapeutics, including drugs, biologics and medical devices, and some of the major sources of heterogeneity of treatment effects (HTE) related to patient demographics, such as age, sex and race. The panel discussed the US Food and Drug Administration's role in reviewing and regulating drugs, devices, and biologic products and the challenges associated with ensuring that diverse patient populations benefit from these therapeutics. Ultimately, ensuring diverse demographic inclusion in clinical trials, and designing basic and clinical research studies to account for the intended patient population's age, sex, race, and genetic factors among other characteristics, will lead to better, safer therapies for diverse patient populations.

Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study.

OBJECTIVES: Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. DESIGN: Retrospective cohort study. SETTING: Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. PARTICIPANTS: The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1-Q3)=58 (47-66). PRIMARY AND SECONDARY OUTCOME MEASURES: Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient's medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. RESULTS: From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). CONCLUSIONS: These findings support the importance of sex as a biological variable to be factored into pain management studies.

Improving clinical outcomes through attention to sex and hormones in research.

Biological sex, fluctuations in sex steroid hormones throughout life and gender as a social construct all influence every aspect of health and disease. Yet, for decades, most basic and clinical studies have included only male individuals. As modern health care moves towards personalized medicine, it is clear that considering sex and hormonal status in basic and clinical studies will bring precision to the development of novel therapeutics and treatment paradigms. To this end, funding, regulatory and policy agencies now require inclusion of female animals and women in basic and clinical studies. However, inclusion of female animals and women often does not mean that information regarding potential hormonal interactions with pharmacological treatments or clinical outcomes is available. All sex steroid hormones can interact with receptors for drug targets, metabolism and transport. Genetic variation in receptors or in enzymatic function might contribute to sex differences in therapeutic efficacy and adverse drug reactions. Outcomes from clinical trials are often not reported by sex, and, if the data are available, they are not translated into clinical practice guidelines. This Review will provide a historical perspective for the current state of research related to hormone trials and provide concrete strategies that, if implemented, will improve the health of all people.

Longitudinal cohorts for harnessing the electronic health record for disease prediction in a US population.

PURPOSE: The depth and breadth of clinical data within electronic health record (EHR) systems paired with innovative machine learning methods can be leveraged to identify novel risk factors for complex diseases. However, analysing the EHR is challenging due to complexity and quality of the data. Therefore, we developed large electronic population-based cohorts with comprehensive harmonised and processed EHR data. PARTICIPANTS: All individuals 30 years of age or older who resided in Olmsted County, Minnesota on 1 January 2006 were identified for the discovery cohort. Algorithms to define a variety of patient characteristics were developed and validated, thus building a comprehensive risk profile for each patient. Patients are followed for incident diseases and ageing-related outcomes. Using the same methods, an independent validation cohort was assembled by identifying all individuals 30 years of age or older who resided in the largely rural 26-county area of southern Minnesota and western Wisconsin on 1 January 2013. FINDINGS TO DATE: For the discovery cohort, 76 255 individuals (median age 49; 53% women) were identified from which a total of 9 644 221 laboratory results; 9 513 840 diagnosis codes; 10 924 291 procedure codes; 1 277 231 outpatient drug prescriptions; 966 136 heart rate measurements and 1 159 836 blood pressure (BP) measurements were retrieved during the baseline time period. The most prevalent conditions in this cohort were hyperlipidaemia, hypertension and arthritis. For the validation cohort, 333 460 individuals (median age 54; 52% women) were identified and to date, a total of 19 926 750 diagnosis codes, 10 527 444 heart rate measurements and 7 356 344 BP measurements were retrieved during baseline. FUTURE PLANS: Using advanced machine learning approaches, these electronic cohorts will be used to identify novel sex-specific risk factors for complex diseases. These approaches will allow us to address several challenges with the use of EHR.

Peripheral Markers of Neurovascular Unit Integrity and Amyloid-ß in the Brains of Menopausal Women.

BACKGROUND: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer's disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. OBJECTIVE: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-ß deposition in menopausal women. METHODS: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-ß positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17ß-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-ß 1-42 (Aß1-42), neuron specific class III ß-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-ß deposition regressed on these PCs. RESULTS: Only the number of microvesicles positive for Aß1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-ß deposition was significant (p = 0.045). CONCLUSION: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-ß deposition.

Sleep quality and cortical amyloid-ß deposition in postmenopausal women of the Kronos early estrogen prevention study.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17ß-estradiol may reduce the accumulation of cortical amyloid-ß. However, how menopausal hormone therapies modify the associations of amyloid-ß accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-ß deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17ß-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-ß deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-ß accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-ß accumulation.

Association of adverse childhood experiences with menopausal symptoms: Results from the Data Registry on Experiences of Aging, Menopause and Sexuality (DREAMS).

OBJECTIVE: To examine the association of adverse childhood experiences (ACEs) with overall menopausal symptom burden in midlife women. STUDY DESIGN: This was a cross-sectional study of women between the ages of 40 and 65 years who were seen for specialty consultation in the Menopause and Women's Sexual Health Clinic, Mayo Clinic, Rochester, MN between May 1, 2015 and December 31, 2016. MAIN OUTCOME MEASURES: Participants completed the ACE questionnaire to assess childhood abuse and neglect, the Menopause Rating Scale (MRS) to assess menopausal symptom burden, the Patient Health Questionnaire (PHQ-9) to assess depression, the Generalized Anxiety Disorder questionnaire (GAD-7) to assess anxiety, and provided information on current abuse (physical, sexual and verbal/emotional). RESULTS: Women meeting inclusion criteria (N = 1670) had a median age of 53.7 years (interquartile range: 49.1, 58.0). Of these women, 977 (58.5 %) reported any ACE and 288 (17.2 %) reported ≥4 ACEs. As menopausal symptoms increased in severity from the first to fourth quartile, the odds ratio of ACE 1-3 (vs. 0) increased from 1 to 2.50 (trend p < 0.01), and the odds ratio of ACE ≥ 4 (vs. 0) increased from 1 to 9.61 (trend p < 0.01), a pattern that was consistent across all menopausal symptom domains. The association between severe menopausal symptoms and higher childhood adversity (ACE score 1-3 or ≥4 vs. ACE = 0) remained significant after adjusting for age, partner status, education, employment, depression, anxiety, and hormone therapy use (OR 1.84 and 4.51, p < 0.01). CONCLUSION: In this large cross-sectional study, there was a significant association between childhood adversity and self-reported menopausal symptoms that persisted even after adjustment for multiple confounders. These associations highlight the importance of screening women with bothersome menopausal symptoms for childhood adversity, and of offering appropriate management and counseling for the adverse experiences, when indicated.

Sex Disparities in the Use and Outcomes of Temporary Mechanical Circulatory Support for Acute Myocardial Infarction-Cardiogenic Shock.

Background: There are limited sex-specific data on patients receiving temporary mechanical circulatory support (MCS) for acute myocardial infarction-cardiogenic shock (AMI-CS). Methods: All admissions with AMI-CS with MCS use were identified using the National Inpatient Sample from 2005 to 2016. Outcomes of interest included in-hospital mortality, discharge disposition, use of palliative care and do-not-resuscitate (DNR) status, and receipt of durable left ventricular assist device (LVAD) and cardiac transplantation. Results: In AMI-CS admissions during this 12-year period, MCS was used more frequently in men-50.4% vs 39.5%; P < 0.001. Of the 173,473 who received MCS (32% women), intra-aortic balloon pumps, percutaneous LVAD, extracorporeal membrane oxygenation, and ≥ 2 MCS devices were used in 92%, 4%, 1%, and 3%, respectively. Women were on average older (69 ± 12 vs 64 ± 13 years), of black race (10% vs 6%), and had more comorbidity (mean Charlson comorbidity index 5.0 ± 2.0 vs 4.5 ± 2.1). Women had higher in-hospital mortality than men (34% vs 29%, adjusted odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.16-1.23; P < 0.001) overall, in intra-aortic balloon pumps users (OR: 1.20 [95% CI: 1.16-1.23]; P < 0.001), and percutaneous LVAD users (OR: 1.75 [95% CI: 1.49-2.06]; P < 0.001), but not in extracorporeal membrane oxygenation or ≥ 2 MCS device users (P > 0.05). Women had higher use of palliative care, DNR status, and discharges to skilled nursing facilities. Conclusions: There are persistent sex disparities in the outcomes of AMI-CS admissions receiving MCS support. Women have higher in-hospital mortality, palliative care consultation, and use of DNR status.

Contexte: On dispose de peu de données quant à l'influence du sexe sur les résultats pour les patients qui reçoivent une assistance circulatoire mécanique (ACM) temporaire à la suite d'un infarctus aigu du myocarde accompagné d'un choc cardiogénique (IAM-CC). Méthodologie: Nous avons recensé dans l'échantillon national des patients hospitalisés (NIS, National Inpatient Sample) tous les patients admis à l'hôpital pour un IAM-CC qui ont reçu une ACM de 2005 à 2016. Les résultats d'intérêt comprenaient la mortalité hospitalière, l'état à la sortie, le recours aux soins palliatifs et à une ordonnance de non-réanimation (ONR), l'implantation d'un dispositif d'assistance ventriculaire gauche (DAVG) permanent et la transplantation cardiaque. Résultats: Chez les patients admis à l'hôpital pour un IAM-CC durant la période de 12 ans étudiée, l'ACM a été utilisée plus fréquemment chez les hommes que chez les femmes (50,4 % vs 39,5 %; p < 0,001). Sur les 173 473 patients qui ont reçu une ACM (dont 32 % étaient des femmes), les méthodes employées se répartissaient comme suit : ballon de contre-pulsion intra-aortique, 92 %; assistance ventriculaire gauche percutanée, 4 %; oxygénation extracorporelle par membrane, 1 %; et au moins 2 types d'ACM, 3 %. Les femmes étaient plus âgées en moyenne (69 ± 12 ans vs 64 ± 13 ans), étaient plus souvent de race noire (10 % vs 6 %) et présentaient un plus grand nombre d'affections concomitantes (indice de comorbidité de Charlson moyen de 5,0 ± 2,0 vs 4,5 ± 2,1). Le taux de mortalité hospitalière était plus élevé chez les femmes que chez les hommes (34 % vs 29 %, risque relatif approché [RRA] corrigé : 1,19; intervalle de confiance [IC] à 95 % : de 1,16 à 1,23; p < 0,001) dans l'ensemble, ainsi que chez les utilisateurs d'un ballon de contre-pulsion intra-aortique (RRA : 1,20 [IC à 95 % : de 1,16 à 1,23]; p < 0,001), et chez les utilisateurs d'un DAVG percutané (RRA : 1,75 [IC à 95 % : 1,49 à 2,06]; p < 0,001), mais pas chez les utilisateurs de l'oxygénation extracorporelle par membrane ni chez les utilisateurs d'au moins 2 types d'ACM (p > 0,05). Le recours aux soins palliatifs, l'établissement d'une ordonnance de non-réanimation et l'orientation vers un établissement de soins infirmiers spécialisés à la sortie de l'hôpital étaient plus fréquents chez les femmes. Conclusions: Il existe toujours des disparités entre les sexes à l'égard des résultats pour les patients admis à l'hôpital pour IAM-CC recevant une ACM. Le taux de mortalité hospitalière était plus élevé chez les femmes, et celles-ci avaient plus souvent recours à une consultation en soins palliatifs et à une ONR.

Sex Disparities in the Management and Outcomes of Cardiogenic Shock Complicating Acute Myocardial Infarction in the Young.

BACKGROUND: There are limited data on how sex influences the outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in young adults. METHODS: A retrospective cohort of AMI-CS admissions aged 18 to 55 years, during 2000 to 2017, was identified using the National Inpatient Sample. Use of coronary angiography, percutaneous coronary intervention, mechanical circulatory support and noncardiac interventions was identified. Outcomes of interest included in-hospital mortality, use of cardiac interventions, hospitalization costs, and length of stay. RESULTS: A total 90 648 AMI-CS admissions ≤55 years of age were included, of which 26% were women. Higher rates of CS were noted in men (2.2% in 2000 to 4.8% in 2017) compared with women (2.6% in 2000 to 4.0% in 2017; P<0.001). Compared with men, women with AMI-CS were more frequently of Black race, from a lower socioeconomic status, with higher comorbidity, and admitted to rural and small hospitals (all P<0.001). Women had lower rates of ST-segment elevation presentation (73.0% versus 78.7%), acute noncardiac organ failure, cardiac arrest (34.3% versus 35.7%), and received less-frequent coronary angiography (78.3% versus 81.4%), early coronary angiography (49.2% versus 54.1%), percutaneous coronary intervention (59.2% versus 64.0%), and mechanical circulatory support (50.3% versus 59.2%; all P<0.001). Female sex was an independent predictor of in-hospital mortality (23.0% versus 21.7%; adjusted odds ratio, 1.11 [95% CI, 1.07-1.16]; P<0.001). Women had lower hospitalization costs ($156 372±$198 452 versus $167 669±$208 577; P<0.001) but comparable lengths of stay compared with men. CONCLUSIONS: In young AMI-CS admissions, women are treated less aggressively and experience higher in-hospital mortality than men.

Reporting of sex as a variable in cardiovascular studies using cultured cells: A systematic review.

Reporting the sex of biological material is critical for transparency and reproducibility in science. This study examined the reporting of the sex of cells used in cardiovascular studies. Articles from 16 cardiovascular journals that publish peer-reviewed studies in cardiovascular physiology and pharmacology in the year 2018 were systematically reviewed using terms "cultured" and "cells." Data were collected on the sex of cells, the species from which the cells were isolated, and the type of cells, and summarized as a systematic review. Sex was reported in 88 (38.6%) of the 228 studies meeting inclusion criteria. Reporting rates varied with Circulation, Cardiovascular Research and American Journal of Physiology: Heart and Circulatory Physiology having the highest rates of sex reporting (>50%). A majority of the studies used cells from male (54.5%) or both male and female animals (32.9%). Humans (31.8%), rats (20.4%), and mice (43.8%) were the most common sources for cells. Cardiac myocytes were the most commonly used cell type (37.0%). Overall reporting of sex of experimental material remains below 50% and is inconsistent among journals. Sex chromosomes in cells have the potential to affect protein expression and molecular signaling pathways and should be consistently reported.

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation.

BACKGROUND: Estrogen may inhibit cell senescence that contributes to age-related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. METHODS: Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead-based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17ß-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. RESULTS: Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [-108 pg/mL (p = .008), -234 pg/mL (p = .0006), and -1374 pg/mL (p < .0001), respectively] than for tE2 [-76 pg/mL (p = .072), -105 pg/mL (p = .076), and -695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019). CONCLUSIONS: Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

Associations of pituitary-ovarian hormones and white matter hyperintensities in recently menopausal women using hormone therapy.

OBJECTIVE: Little is known about how menopausal hormone treatment (HT) may influence the development of white matter hyperintensities (WMHs) in the brain. This study evaluated the associations of changes in levels of pituitary-ovarian hormones during HT and changes in WMH. METHODS: Women (n = 78 adherent to treatment) enrolled in the Kronos Early Estrogen Prevention Study underwent brain magnetic resonance imaging, and blood collection before and after 48 months of randomization to 0.45 mg/d oral conjugated equine estrogen (oCEE) daily, 50 µg/d transdermal 17ß estradiol (tE2), or placebo pills and patches. Women in the active treatment groups also received oral 200 mg/d micronized progesterone the first 12 days of the month. Estradiol (E2), estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum by high sensitivity liquid chromatography/mass spectrometry at baseline and following 48 months of HT. Longitudinal change in WMH volume was determined from fluid-attenuated inversion recovery magnetic resonance imaging using a semiautomated image segmentation algorithm. RESULTS: Serum levels of FSH, LH, E1, or E2 did not associate with WMH volume at baseline. After 48 months of treatment, smaller increases in WMH associated with decreases in FSH from baseline in the tE2 group and increases in E1 in both tE2 and oCEE groups. Changes in LH did not associate with changes in WMH in any group. CONCLUSIONS: Circulating levels of pituitary-ovarian hormones associate with changes in WMH volume in recently menopausal women using HT. Whether these relationships would be influenced by different doses of tE2 or oCEE remains to be determined. : Video Summary:http://links.lww.com/MENO/A590.

Video Summary:http://links.lww.com/MENO/A590.

Aortic Hemodynamics and Cognitive Performance in Postmenopausal Women: Impact of Pregnancy History.

BACKGROUND: Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS: Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS: Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS: Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.