Female Hearts Research Articles

Abstract 11219: Female Patients Attending Female Cardiologist-Led Heart Clinic in Iraq: Clinical Landscape and Echocardiographic Data

Introduction: In Iraq, traditional and tribal rules prevent many women from having access to healthcare unless being managed exclusively by female doctors. So, lack of female cardiologists (FC) in Iraq deprived many women from proper cardiovascular care.Considering the absent Women′s Heart Clinics in Iraq and lack of data on female cardiac patients,we sought to provide data regarding demographic and echocardiographic characteristics of women attending a female cardiologist-led heart clinic (FC-LHC) in a first report from Iraq Methods: Women who attended a FC-LHC were included, clinical and echocardiographic characteristics were recorded. Results: n=213, mean age (46.5±16.6)year.Hypertension (HT) and dyslipidemia were most reported risk factors.History of gestational HT was most common sex-specific risk factor (figA).Women′s comorbidities differs with their social status as HT, DM, IHD and dyslipidemia were highest in widowed women (91.3%, 43.5%, 21.7% and 39.1% respectively). Consuming fast food≥4/week was highest in divorced (33.3%) and single women (23.1%). OCP was used by 5.2% of women; in general and 10.3% of married women at reproductive age; in particular. Prevalence of DM,IHD and LV dysfunction differs according to women′s education (figB). Palpitation (46.5%) and dyspnoea (30%) were most common presentations. Cardio-Obstetric and Cardio-Oncology services were offered in 5.2% and 5.6% respectively (figC). LV diastolic dysfunction and mitral regurgitation were most common echocardiographic abnormalities (figD). Conclusion: Younger women<65 years were more frequently attending FC-LHC.Prior history of gestational HT was the commonest sex-specific cardiovascular risk factor. Increasing diversity in cardiology workforce and establishing Women′s Heart Clinics that include FC are crucial in Iraq to promote focused cardiovascular care and education and to provide data for sex-specific research in cardiovascular management and outcomes

Abstract 13201: Sex Difference Following Cardiac-Targeted Irradiation in Mice

Introduction: Acute exposure of the heart to ionizing radiation (IR) can damage myocardium, coronary arteries, valves, and pericardium. Long term sequelae include fibrosis, heart failure, arrhythmias and sudden death. We previously reported a protective effect of the oxetanyl sulfoxide radiation mitigator MMS350 in mice treated acutely with 20 Gy total body IR. Here, we assess the long-term effects of cardiac targeted irradiation (CTI) and MMS350 treatment on cardiac structure and function. Methods: Ten week-old C57BL/6J mice (50% male) were exposed to 20 Gy CTI with (+R+D, n=20) or without (+R-D, n=20) MMS350 using an Xstrahl Small Animal Radiation Research Platform and followed for 9 months (mo); a parallel cohort was not irradiated (-R+D, n=10; -R-D, n=10). MMS350 was given in drinking water (0.087 mg/ml) for 10 days before to 9 mo after CTI with one IV injection (20 mg/kg) 30 minutes prior to CTI. Echocardiography (echo) was performed at baseline, 3, 6 and 9 mo. At euthanasia, heart weight (HW), lung weight (LW), body weight (BW) and histology were assessed. Results: CTI led to radiation dermatitis in 3 female mice requiring euthanasia. MMS350 treatment had no significant effect on any parameters. 9 mo after CTI, HW/BW was increased in male but not female mice, while LW/BW was increased in both sexes (Fig 1A-D). Echo showed a significant increase in EDV with CTI in male (p=0.006) but not female mice (Fig 1E-F), along with a trend towards a decrease in EF in male (79±3 vs 86±2%, p=0.11) but not female mice (85±1 vs 86±1%, p=0.59). Trichrome staining demonstrated fibrosis in both male and female hearts (Fig 1G-N). Conclusions: High dose CTI led to cardiac hypertrophy and ventricular dilation after 9 mo in male but not female mice. Both sexes developed cardiac fibrosis and lung congestion. Thus, sex may influence radiation-induced cardiac pathology through currently unknown mechanisms and may have important implications for radiotherapy of thoracic tumors in humans.

ПОЛОВЫЕ РАЗЛИЧИЯ В СОДЕРЖАНИИ СТЕРОИДНЫХ ГОРМОНОВ В МИТОХОНДРИЯХ КЛЕТОК СЕРДЦА НА ЭТАПАХ РАЗВИТИЯ МЕЛАНОМЫ В16/F10, СОПРЯЖЕННОЙ С ХРОНИЧЕСКОЙ НЕЙРОГЕННОЙ БОЛЬЮ

Aim - an analysis of levels of steroid hormones in heart cell mitochondria at the stages of B16/F10 melanoma development in combination with chronic neurogenic pain in male and female C57BL/6 mice. The study included male and female C57BL/6 mice (n=336). Experimental groups were: intact animals (♂ n=21; ♀ n=21); controls (♂ n=21; ♀ n=21) with a model of chronic neurogenic pain (CNP); the comparison group (♂ n=63; ♀ n=63) with melanomas (B16/ F10); the main group (♂ n=63; ♀ n=63) (CNP+B16/F10) with melanoma transplanted 3 weeks after the CNP model creation. Levels of estradiol (pg/g protein), estrone (pg/g protein), progesterone (ng/g protein), total testosterone (ng/g protein), and free testosterone (pg/g protein) were determined by ELISA in mitochondrial samples. In animals with CNP, changes in levels of steroid hormones were detected only in heart mitochondria of female mice: estradiol was reduced by 4.6 times, estrone by 2.2 times, progesterone by 1.8 times (p˂0.05), and total testosterone by 2.4 times compared with intact values. Melanoma growth (3 weeks) in females downregulated levels of estradiol by 1.7 times (p˂0.05), estrone by 1.8 times (p˂0.05), progesterone by 2.1 times, and total testosterone by 2.3 times compared with intact values. In males, only total testosterone decreased by 2.1 times during the same period. Melanoma growth in presence of CNP (3 weeks) in females decreased levels of estradiol by 1.6 times (p˂0.05) compared with control val- ues, while males showed reduced levels of estradiol and total and free testosterone by 1.3 times (p˂0.05), 1.9 times (p˂0.05) and 2.7 times, respectively, as well as elevated levels of estrone by 1.6 times (p˂0.05). CNP and the growth of B16/F10 melanoma to a greater extent weaken the heart of females due to the involvement of a wider spectrum of hormones and a decrease in their levels in the heart mitochondria, compared to males. When CNP was combined with B16/F10 melanoma, a more significant hormonal imbalance was determined in males than in females.

Sex differences exist in adult heart group 2 innate lymphoid cells

BackgroundGroup 2 innate lymphoid cells (ILC2s) are the most dominant ILCs in heart tissue, and sex-related differences exist in mouse lung ILC2 phenotypes and functions; however, it is still unclear whether there are sex differences in heart ILC2s.ResultsCompared with age-matched wild-type (WT) male mice, 8-week-old but not 3-week-old WT female mice harbored an obviously greater percentage and number of heart ILC2s in homeostasis. However, the percentage of killer-cell lectin-like receptor G1 (Klrg1)− ILC2s was higher, but the Klrg1+ ILC2s were lower in female mice than in male mice in both heart tissues of 3- and 8-week-old mice. Eight-week-old Rag2−/− mice also showed sex differences similar to those of age-matched WT mice. Regarding surface marker expression, compared to age-matched male mice, WT female mice showed higher expression of CD90.2 and Ki67 and lower expression of Klrg1 and Sca-1 in heart total ILC2s. There was no sex difference in IL-4 and IL-5 secretion by male and female mouse heart ILC2s. Increased IL-33 mRNA levels within the heart tissues were also found in female mice compared with male mice. By reanalyzing published single-cell RNA sequencing data, we found 2 differentially expressed genes between female and male mouse heart ILC2s. Gene set variation analysis revealed that the glycine, serine and threonine metabolism pathway was upregulated in female heart ILC2s. Subcluster analysis revealed that one cluster of heart ILC2s with relatively lower expression of Semaphorin 4a and thioredoxin interacting protein but higher expression of hypoxia-inducible lipid droplet-associated.ConclusionsThese results revealed greater numbers of ILC2s, higher expression of CD90.2, reduced Klrg1 and Sca-1 expression in the hearts of female mice than in male mice and no sex difference in IL-4 and IL-5 production in male and female mouse heart ILC2s. These sex differences in heart ILC2s might be due to the heterogeneity of IL-33 within the heart tissue.

Potential role of the apelin-APJ pathway in sex-related differential cardiotoxicity induced by doxorubicin in mice.

Preclinical and clinical findings suggest sexual dimorphism in cardiotoxicity induced by a chemotherapeutic drug, doxorubicin (DOX). However, molecular alterations leading to sex-related differential vulnerability of heart to DOX toxicity are not fully explored. In the present study, RNA sequencing in hearts of B6C3F1 mice indicated more differentially expressed genes in males than females (224 vs. 19; ≥1.5-fold, False Discovery Rate [FDR] < 0.05) at 1week after receiving 24 mg/kg total cumulative DOX dose that induced cardiac lesions only in males. Pathway analysis further revealed probable inactivation of cardiac apelin fibroblast signaling pathway (p = 0.00004) only in DOX-treated male mice that showed ≥1.25-fold downregulation in the transcript and protein levels of the apelin receptor, APJ. In hearts of DOX-treated females, the transcript levels of apelin (1.24-fold) and APJ (1.47-fold) were significantly (p < 0.05) increased compared to saline-treated controls. Sex-related differential DOX effect was also observed on molecular targets downstream of the apelin-APJ pathway in cardiac fibroblasts and cardiomyocytes. In cardiac fibroblasts, upregulation of Tgf-β2, Ctgf, Sphk1, Serpine1, and Timp1 (fibrosis; FDR < 0.05) in DOX-treated males and upregulation of only Tgf-β2 and Timp1 (p < 0.05) in females suggested a greater DOX toxicity in hearts of males than females. Additionally, Ryr2 and Serca2 (calcium handling; FDR < 0.05) were downregulated in conjunction with 1.35-fold upregulation of Casp12 (sarcoplasmic reticulum-mediated apoptosis; FDR < 0.05) in DOX-treated male mice. Drug effect on the transcript level of these genes was less severe in female hearts. Collectively, these data suggest a likely role of the apelin-APJ axis in sex-related differential DOX-induced cardiotoxicity in our mouse model.

Female donor hearts can improve survival for male pediatric heart transplant recipients.

Both gender- and weight-matching between donor and recipient are thought to impact survival in pediatric heart transplantation, with clinical dogma holding that male donor hearts and "ideal" weight-matching yield superior survival. The composite impacts of gender and weight on post-transplant survival (PTS) are understudied. All pediatric (age <18) heart recipients between 1989 and 2021 with the complete recipient and donor gender and weight data were identified in the United Network for Organ Sharing database. Patients were grouped by recipient-donor gender (M & F) and donor-to-recipient weight ratio (DRWR; undersized [<0.8], ideal-sized [0.8-1.5], oversized [>1.5]). A total of 10697 patients were identified. Among male recipients, PTS was greatest with oversized DRWR from either male or female donors (median 22.4 and 20.6 years; p < .001 vs. others) and lowest for undersized DRWR from either male or female donors (median 13.4 and 13.2 years; p < .001 vs. others). The majority (64%) of male recipients received ideal-sized DRWR, among which female donor hearts yielded superior survival to males (median 18.9 vs. 17.4 years, p=.014). No differences in PTS existed for female recipients on the basis of gender-match, DRWR, and gender/DRWR together (all p > .1). When considered together, gender and DRWR pairings impact PTS in male-but not female-pediatric heart transplant recipients. For males receiving ideal-sized DRWR organs (most common pairing, >60%), male recipients achieve superior survival when female donor hearts are transplanted. These findings suggest that if weight is being used for size-matching, donor gender should also be considered, particularly for male recipients.

Acute Toxicity LD50 Fraction Ethyl Acetate Aquilaria malaccensis, Ficus benjamina, Mikania micrantha, and Fraction Water Cinnamomum burmanii in Mus Musculus

Research on the acute toxicity of LD50 had been carried out on the ethyl acetate fraction of Gaharu leaves (Aquilaria malaccensis), beringin leaves (Ficus benjamina), sembung rambat leaves (Mikania micrantha), and kayu manis cortex (Cinnamomum burmanii) water fraction the base of use as traditional treatment by the Suku Anak Dalam (SAD) empirically obtained from ancestors. This research methodwas experimental and it used male and female mice. The control group was given a 1% NaCMC doses of 625 mg/kg body weight, 1,250 mg/kg body weight, 2,500 mg/kg body weight, and 5,000 mg/kg body weight. The test preparation was administered orally once per day. The Thomson-Weil method was used for the measurement of LD50 values. The weight ratio of organs was applied for heart, liver, lungs, kidneys, and stomach. The results showed that the LD50 value for male mice was 2454mg/kg body weight; 2454mg/kg body weight; 1546 mg/kg body weight and 2065mg/kg body weight respectfully. The LD50 value for female mice was a pseudo LD50. The value of the organ weight ratio in each sample showed P&lt;0.05 values that were obtained in gaharu leaves in the liver and kidney organs (male); heart in females. Beringin leaves value P&lt;0.05 lung organs (male). Sembung rambat leaves P&lt;0.05 values of the heart, liver, and stomach organs (male); heart and stomach (female). Cinnamomum cortex value P&lt;0.05 liver and stomach organs (male). The conclusions showed that the LD50 value of the ethyl acetate fraction of gaharu leaf, sembung rambat leaf, beringin leaf, and kayu manis cortex in male mice was slightly toxic, while in female mice it could not be counted.

The interplay of sex-specific electrophysiology and repolarization heterogeneity governs ventricular arrhythmia sustainability in women

Abstract Background The role of sex-specific electrophysiology in the development of lethal ventricular arrhythmia is poorly understood. Since female ventricles have a longer action potential duration (APD) than male ventricles, we hypothesized that female hearts are more vulnerable to sustained ventricular arrhythmia in the presence of known arrhythmogenic substrates. Purpose To determine if prolonged APD in females leads to sustained ventricular arrhythmia in the presence of left ventricular (LV) hypertrophy, diffuse fibrosis, and repolarization heterogeneity. Methods Magnetic resonance imaging (MRI) data were used to develop computational biventricular models of two aortic stenosis patients (male, 54 years; female, 64 years) before (LV hypertrophy) and 3 months after (regressed LV hypertrophy) aortic valve replacement (AVR). These patients were chosen since they exhibit reduced LV mass, less fibrosis, and no ventricular arrhythmias after AVR. The models were assigned sex-specific cellular electrophysiology and an apicobasal repolarization gradient derived from human data. Simulations of apical pacing with a cycle length (CL) of 750 ms were performed while APD at 90% repolarization (APD90) and repolarization time (activation time + APD90) were calculated. Reentrant arrhythmia was induced by rapidly pacing the LV with a 2 mm wide apicobasal line electrode at CL≤265 ms. The simulations were repeated in the presence of diffuse myocardial fibrosis derived from the MRI patient data, and repeated again with an apicobasal repolarization gradient reduced by ≈35%. Ventricular mass was calculated as the product of model volume and myocardial density. Results In hypertrophic ventricles with default apicobasal repolarization gradient, rapid pacing led to reentry that lasted longer in the female (&amp;gt;25 s) than in the male (1.0 s) ventricles. The duration of reentry increased in the presence of fibrosis in the male ventricles (male: 6.6 s; female &amp;gt;25 s) and decreased in the female ventricles when the apicobasal repolarization gradient was reduced (Figure). Sustained reentry (&amp;gt;25 s) was not observed in the ventricles with regressed hypertrophy, regardless of the presence of fibrosis or repolarization gradient. Average APD90 was longer in the female ventricles both before (male: 267±35 ms; female: 318±34 ms) and after (male: 272±35 ms; female: 328±38 ms) AVR. The female heart had lower myocardial mass than the male heart both before (280 vs. 406 g) and after AVR (227 vs. 310 g). Conclusion Longer APD and steeper apicobasal repolarization gradients in hypertrophic female ventricles resulted in sustained arrhythmia, despite their lower mass when compared to males. The absence of sustained reentry in the post-AVR models indicates a potential electrophysiological benefit of AVR and encourages future clinical studies to quantify sex-specific differences in spatial repolarization heterogeneity. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation program under the ERA-NET co-fund action No. 680969 with ANR (ERA-CVD SICVALVES) and Agence Nationale de la Recherche

Mechanism(s) for age-related sex differences in diet-induced cardiomyopathy: role of RNA methylation

Abstract Background/Introduction Age and sexual dimorphism contribute to the differential cardiometabolic dysfunctions associated with diet-induced obesity. However, the underlying mechanisms remain elusive. RNA modifications via RNA m6A methylation, is an emerging mediator of RNA stability, translation and localization responsible for regulation of multiple biological functions. RNA m6A modifications are regulated by “writers”, “erasers” and “readers”. The role of RNA methylation machinery genes in the heart is largely unexplored, and may provide insight into the influence of age and sex on cardiometabolic dysfunction. Purpose We aim to determine differential RNA methylation changes within the heart in a diet-induced cardiomyopathy mouse model, stratified according to age and sex. Methods Male and female C57BL/6 mice (6–8wk-old) were fed normal chow (NC) or high-fat/high-sucrose (HFHS) diet for 1 or 4 months. Echocardiographic measurements were performed at 1 and 4 months according to the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines. At study endpoint, glucose and insulin tolerance testing was conducted by injecting mice intraperitoneally with 2g/kg glucose or 0.6U/kg insulin, and monitoring blood glucose levels over a 2 hour period. RNA from heart tissue was subjected to quantitative PCR for RNA methylation machinery genes (FTO, ALKBH5, METTL3, METTL4, METTL14, YTHDF1 and YTHDF2). PPIA was used to normalise qPCR data. Results Both male and female mice showed evidence of age- and diet-induced metabolic dysfunction, however, males and females showed markedly different metabolic impairments. For example, glucose tolerance was exacerbated by 4 months of HFHS diet in males but not females; and only females showed impaired insulin tolerance. Echocardiography showed that males had systolic (stoke volume, cardiac output) and diastolic (E/A ratio) dysfunction after 4 months of HFHS diet, while females were unperturbed. We identified that METTL3 and METTL14, the “writers” of m6A methylation, were consistently increased in male mouse hearts at 1 vs 4 months of age but were unchanged or decreased in females, irrespective of diet. Conversely, YTHDF1, a “reader”, was unchanged in male mouse hearts at 1 vs. 4 months of age but was significantly increased in female hearts. Conclusion Our study confirms that markedly different cardiometabolic impairments occur in male versus female mice in response to long-term HFHS diet. Despite significant metabolic impairment in both sexes, cardiac dysfunction was only evident in males. RNA methylation machinery genes were differentially expressed in mouse hearts according to age and sex, suggesting that RNA methylation may be involved in age-related sexual dimorphism in cardiometabolic impairments. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Heart Foundation

Impact of co-morbidities on survival after heart transplant in females of childbearing age: analysis of the International Society for Heart and Lung Transplantation (ISHLT) Registry

Abstract Background Data on life expectancy specific to female heart transplant (HT) recipients of reproductive age are lacking, but are needed to inform shared decision making at the time of pre-conception counseling. We analyzed the ISHLT registry for post-transplant survival and studied the impact of co-morbidities in women of childbearing age. Methods Female HT recipients reported to the ISHLT registry who were aged 15–45 yrs at time of HT were included in this retrospective analysis. Primary outcome was post-transplant survival. Secondary outcomes included the impact of co-morbidities on conditional survival at 5, 10 and 15 years. Results Of 121,501 HT recipients (Jan 1992–June 2018), 30,179 (24.8%) were women. 9,229 (7.6%) were 15–45 yrs at time of HT. Overall median post-transplant survival was 15.2 yrs. Diabetes mellitus (DM) and/or severe chronic kidney disease (CKD) at HT adversely impacted long-term survival (Figure 1). Co-morbidities including cardiac allograft vasculopathy (CAV), DM and CKD negatively impacted 5yr and 10yr conditional survival, individually as well as a combination (Figure 2). 15yr conditional survival confirmed the negative impact of DM and CKD, while CAV did not reach statistical significance. Conclusion Female HT recipients of childbearing age have favorable survival post-HT. Conditional survival at 5 and 10 yrs is negatively impacted by CAV, DM and CKD. The quantification of survival outcomes after heart transplant in women of childbearing age may improve counseling as part of pre-conception informed decision making. Funding Acknowledgement Type of funding sources: None.

Assessing sex-based differences in postsurgical clinical outcomes after use of del Nido cardioplegia.

del Nido cardioplegia is used to pharmacologically arrest the heart during cardiac surgery and decrease reperfusion- and ischaemia-related myocardial injury. Studies have demonstrated the physiological differences between male and female hearts, potentially related to cardiac size or myocyte calcium handling; we aimed to assess for between-sex differences in clinical outcomes after receipt of del Nido cardioplegia. Patients who underwent coronary artery bypass or coronary artery bypass graft/valve surgery at our institution using del Nido cardioplegia (January 2014 to December 2019) were included (n = 2118). Clinical data were collected retrospectively. After the creation of a propensity-matched cohort (n = 1252), multivariable logistic regression was used to analyse binary postoperative outcomes, and a Gamma model was used for a continuous postoperative outcome. Our primary end-point was a composite end-point comprised of 30-day mortality and/or need for a post-bypass mechanical support device. The final cohort included 459 females and 793 males (matched up to 1:2, all standardized mean differences &lt;0.1). Multivariable logistic regression showed that biological sex was not associated with the composite primary end-point (odds ratio = 0.898, P = 0.779). A Gamma model indicated that there were no sex-related differences in vasoactive-inotropic scores reflecting vasopressor and inotrope usage at the time of patient operating room exit (exp[est] = 1.394, P = 0.189). Our findings showed no significant between-sex differences in clinical outcomes after receiving del Nido cardioplegia, suggesting adequate myocardial protection as currently administered. Further research is warranted to elicit if there are sex-based differences between cardioplegic solutions. 26 May 2021 (AAAR8359).

Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice

Cardiovascular diseases (CVD) are predominantly an aging disease. Important sex-specific differences exist and the mechanism(s) by which this sex-by-age interaction influences CVD development and progression remains elusive. Accordingly, it is still unknown whether cell senescence, a main feature of cardiac male aging, is a significant feature also of the female aged mouse heart and whether senolytics, senescence-clearing compounds, promote myocardial repair and regeneration after myocardial infarction (MI) in aged female mice. To this aim, the combination of two senolytics, dasatinib and quercetin (D+Q) or just their vehicle was administered to 22–24 months old C57BL/6 female mice after MI. D+Q improved global left ventricle function and myocardial performance after MI whereby female cardiac aging is characterized by accumulation of cardiac senescent cells that are further increased by MI. Despite their terminal differentiation nature, also cardiomyocytes acquire a senescent phenotype with age in females. D+Q removed senescent cardiac non-myocyte and myocyte cells ameliorating cardiac remodeling and regeneration. Senolytics removed aged dysfunctional cardiac stem/progenitor cells (CSCs), relieving healthy CSCs with normal proliferative and cardiomyogenic differentiation potential. In conclusions, cardiac senescent cells accumulate in the aged female hearts. Removing senescent cells is a key therapeutic target for efficient repair of the aged female heart.

Sexual Dimorphism in the Expression of Cytochrome P450 Enzymes in Rat Heart, Liver, Kidney, Lung, Brain, and Small Intestine.

Cytochrome P450 (P450) enzymes are monooxygenases that are expressed hepatically and extrahepatically and play an essential role in xenobiotic metabolism. Substantial scientific evidence indicates sex-specific differences between males and females in disease patterns and drug responses, which could be attributed, even partly, to differences in the expression and/or activity levels of P450 enzymes in different organs. In this study, we compared the mRNA and protein expression of P450 enzymes in different organs of male and female Sprague-Dawley rats by real-time polymerase chain reaction and western blot techniques. We found significant sex- and organ-specific differences in several enzymes. Hepatic Cyp2c11, Cyp2c13, and Cyp4a2 showed male-specific expression, whereas Cyp2c12 showed female-specific expression. Cyp2e1 and Cyp4f enzymes demonstrated higher expression in the female heart and kidneys compared with males; however, they showed no significant sexual dimorphism in the liver. Male rats showed higher hepatic and renal Cyp1b1 levels. All assessed enzymes were found in the liver, but some were not expressed in other organs. At the protein expression level, CYP1A2, CYP3A, and CYP4A1 demonstrated higher expression levels in the females in several organs, including the liver. Elucidating sex-specific differences in P450 enzyme levels could help better understand differences in disease pathogeneses and drug responses between males and females and thus improve treatment strategies. SIGNIFICANCE STATEMENT: This study characterized the differences in the mRNA and protein expression levels of different cytochrome P450 (P450) enzymes between male and female rats in the heart, liver, lung, kidney, brain, and small intestine. It demonstrated unique sex-specific differences in the different organs. This study is considered a big step towards elucidating sex-specific differences in P450 enzyme levels, which is largely important for achieving a better understanding of the differences between males and females in the disease's processes and treatment outcomes.

The impact of physical activity on female futsal players' heart rates, PO2 concentration, and level of exceptional endurance

Finding the finest strategies and techniques to help develop the unique endurance of futsal players, as well as attaining the proper functional adaptation, are key goals of the research. In order to establish some physiological factors and the unique endurance of futsal players, the researchers chose to use playing activities. In terms of the research problem: The research problem includes two main axes: the first one is the low stamina of the players, which is one of the obstacles that futsal players suffer from. Concerning the second axis, the challenge lies in identifying the most effective training regimens and strategies for enhancing individual endurance. The two researchers talked about how practicing sports can improve a player's heart rate, PO2 concentration, and level of endurance. One of the research's goals was to 1- Determine how playing exercises affected some physiological characteristics and futsal players' unique endurance (strength endurance, speed endurance, performance endurance). 2- Determining the difference in some physiological characteristics and the unique endurance of the female futsal players between the two groups. A pre- and post-test, two experimental groups, an experimental design with two groups, and data collection techniques such tools, devices, measurements, and a qualification method were all used by the researcher. The statistical approach was adopted by the researcher (SPSS).

Cardiac magnetic resonance defines mechanisms of sex-based differences in outcomes following cardiac resynchronization therapy.

BackgroundMechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood.ObjectiveTo use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type.Materials and methodsIn a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis.ResultsAmong 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67).ConclusionCMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.

217.3: Differences in Short-term and Medium-term Prognosis Between Female and Male Heart Transplant Recipients: Analysis of More Than 20 Years in a Single Center in Argentina

217.3: Differences in Short-term and Medium-term Prognosis Between Female and Male Heart Transplant Recipients: Analysis of More Than 20 Years in a Single Center in Argentina

The female syndecan-4-/- heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels.

Background: In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4−/− mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle (tibialis anterior, TA) of female syndecan-4−/− mice. To determine if the differences seen in Akt signaling are sex specific, we have presently investigated Akt signaling in the cardiac muscle of sedentary and exercised female syndecan-4−/− mice. To get deeper insight into the female syndecan-4−/− heart, alterations in cardiomyocyte size, a wide variety of different extracellular matrix components, well-known syndecan-4 binding partners and associated signaling pathways have also been investigated. Methods: Left ventricles (LVs) from sedentary and exercise trained female syndecan-4−/− and WT mice were analyzed by immunoblotting and real-time PCR. Cardiomyocyte size and phosphorylated Ser473-Akt were analyzed in isolated adult cardiomyocytes from female syndecan-4−/− and WT mice by confocal imaging. LV and skeletal muscle (TA) from sedentary male syndecan-4−/− and WT mice were immunoblotted with Akt antibodies for comparison. Glucose levels were measured by a glucometer, and fasting blood serum insulin and C-peptide levels were measured by ELISA. Results: Compared to female WT hearts, sedentary female syndecan-4−/− LV cardiomyocytes were smaller and hearts had higher levels of pSer473-Akt and its downstream target pSer9-GSK-3β. The pSer473-Akt inhibitory phosphatase PHLPP1/SCOP was lowered, which may be in response to the elevated serum insulin levels found in the female syndecan-4−/− mice. We also observed lowered levels of pThr308-Akt/Akt and GLUT4 in the female syndecan-4−/− heart and an increased LRP6 level after exercise. Otherwise, few alterations were found. The pThr308-Akt and pSer473-Akt levels were unaltered in the cardiac and skeletal muscles of sedentary male syndecan-4−/− mice. Conclusion: Our data indicate smaller cardiomyocytes, an elevated insulin/pSer473-Akt/pSer9-GSK-3β signaling pathway, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels in the female syndecan-4−/− heart. In contrast, cardiomyocyte size, and Akt signaling were unaltered in both cardiac and skeletal muscles from male syndecan-4−/− mice, suggesting important sex differences.

Impact of aging on mitochondrial respiration in various organs

Mitochondria are considered central regulator of the aging process; however, majority of studies dealing with the impact of age on mitochondrial oxygen consumption focused on skeletal muscle concluding (although not uniformly) a general declining trend with advancing age. In addition, gender related differences in mitochondrial respiration have not been satisfactorily described yet. The aim of the present study was to evaluate mitochondrial oxygen consumption in various organs of aging male and female Fischer 344 rats at the ages of 6, 12 and 24 months. Mitochondrial respiration of homogenized (skeletal muscle, left and right heart ventricle, hippocampus, cerebellum, kidney cortex), gently mechanically permeabilized (liver) tissue or intact cells (platelets) was determined using high-resolution respirometry (oxygraphs O2k, Oroboros, Austria). The pattern of age-related changes differed in each tissue: in the skeletal muscle and kidney cortex of both sexes and in female heart, parameters of mitochondrial respiration significantly declined with age. Resting respiration of intact platelets displayed an increasing trend and it did not correlate with skeletal muscle respiratory states. In the heart of male rats and brain tissues of both sexes, respiratory states remained relatively stable over analyzed age categories with few exceptions of lower mitochondrial oxygen consumption at the age of 24 months. In the liver, OXPHOS capacity was higher in females than in males with either no difference between the ages of 6 and 24 months or even significant increase at the age of 24 months in the male rats. In conclusion, the results of our study indicate that the concept of general pattern of age-dependent decline in mitochondrial oxygen consumption across different organs and tissues could be misleading. Also, the statement of higher mitochondrial respiration in females seems to be conflicting, since the gender-related differences may vary with the tissue studied, combination of substrates used and might be better detectable at younger ages than in old animals.

Proteogenomics reveals sex-biased aging genes and coordinated splicing in cardiac aging.

The risks of heart diseases are significantly modulated by age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here, we used RNA sequencing and mass spectrometry to compare gene expression in female and male young adult (4 mo) and early aging (20 mo) mouse hearts, identifying thousands of age- and sex-dependent gene expression signatures. Sexually dimorphic cardiac genes are broadly distributed, functioning in mitochondrial metabolism, translation, and other processes. In parallel, we found over 800 genes with differential aging response between male and female, including genes in cAMP and PKA signaling. Analysis of the sex-adjusted aging cardiac transcriptome revealed a widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the impact of the splicing events on cardiac proteoform composition, we applied an RNA-guided proteomics computational pipeline to analyze the mass spectrometry data and detected hundreds of putative splice variant proteins that have the potential to rewire the cardiac proteome. Taken together, the results here suggest that cardiac aging is associated with 1) widespread sex-biased aging genes and 2) a rewiring of RNA splicing programs, including sex- and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes contribute to the emerging evidence for considerable sexual dimorphism in the cardiac aging process that should be considered in the search for disease mechanisms.NEW & NOTEWORTHY Han et al. used proteogenomics to compare male and female mouse hearts at 4 and 20 mo. Sex-biased cardiac genes function in mitochondrial metabolism, translation, autophagy, and other processes. Hundreds of cardiac genes show sex-by-age interactions, that is, sex-biased aging genes. Cardiac aging is accompanied with a remodeling of exon usage in functionally coordinated genes, concomitant with differential expression of RNA-binding proteins and splice factors. These features represent an underinvestigated aspect of cardiac aging that may be relevant to the search for disease mechanisms.

Sex-dependent transcription of cardiac electrophysiology and links to acetylation modifiers based on the GTEx database.

Development of safer drugs based on epigenetic modifiers, e.g., histone deacetylase inhibitors (HDACi), requires better understanding of their effects on cardiac electrophysiology. Using RNAseq data from the genotype-tissue-expression database (GTEx), we created models that link the abundance of acetylation enzymes (HDAC/SIRT/HATs), and the gene expression of ion channels (IC) via select cardiac transcription factors (TFs) in male and female adult human hearts (left ventricle, LV). Gene expression data (transcripts per million, TPM) from GTEx donors (21–70 y.o.) were filtered, normalized and transformed to Euclidian space to allow quantitative comparisons in 84 female and 158 male LVs. Sex-specific partial least-square (PLS) regression models, linking gene expression data for HDAC/SIRT/HATs to TFs and to ICs gene expression, revealed tight co-regulation of cardiac ion channels by HDAC/SIRT/HATs, with stronger clustering in the male LV. Co-regulation of genes encoding excitatory and inhibitory processes in cardiac tissue by the acetylation modifiers may help explain their predominantly net-neutral effects on cardiac electrophysiology. ATP1A1, encoding for the Na/K pump, represented an outlier—with orthogonal regulation by the acetylation modifiers to most of the ICs. The HDAC/SIRT/HAT effects were mediated by strong (+) TF regulators of ICs, e.g., MEF2A and TBX5, in both sexes. Furthermore, for male hearts, PLS models revealed a stronger (+/-) mediatory role on ICs for NKX25 and TGF1B/KLF4, respectively, while RUNX1 exhibited larger (-) TF effects on ICs in females. Male-trained PLS models of HDAC/SIRT/HAT effects on ICs underestimated the effects on some ICs in females. Insights from the GTEx dataset about the co-expression and transcriptional co-regulation of acetylation-modifying enzymes, transcription factors and key cardiac ion channels in a sex-specific manner can help inform safer drug design.