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In today's rapidly growing healthcare landscape, the role of Medical Affairs within pharmaceutical companies has transitioned from a traditional support function into a strategic one. Amidst acute challenges such as evolving globalization, digitization, and healthcare trends, effective talent development and professional standards in Medical Affairs emerge as a pivotal cornerstone to future-proof pharmaceutical companies. This article explores strategies, perspectives, and best practices for enhancing talent development with medical or natural sciences background in the field of Medical Affairs. From the historical development of Medical Affairs, we cover current challenges and provide a comprehensive approach to talent development strategies of next-generation talents in Medical Affairs. Drawing upon current literature and personal experiences, we discuss various aspects relevant for designing targeted training programs, fostering interdisciplinary collaboration, and enhancing both technical and soft skills essential for success in Medical Affairs roles. Furthermore, we highlight the significance of company-internal rotational programs in exposing talents to different facets of Medical Affairs. We advocate for a flexible and individualized approach to talent development, allowing next-generation talents to pursue personal interests and contribute to innovative projects. Overall, this article offers practical recommendations for pharmaceutical companies aiming to optimize their local talent development initiatives in Medical Affairs and align them with the evolving needs of the healthcare landscape.
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Indústria Farmacêutica , Humanos , Atenção à SaúdeRESUMO
The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.
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Insuficiência Cardíaca , Volume Sistólico , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Volume Sistólico/fisiologia , Medição de Risco , Função Ventricular Esquerda/fisiologiaRESUMO
AIMS: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). METHODS AND RESULTS: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. CONCLUSIONS: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF.
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Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Risco , Hemorragia , Anticoagulantes/uso terapêuticoRESUMO
Tissue engineering with human cardiac fibroblasts (CF) allows identifying novel mechanisms and anti-fibrotic drugs in the context of cardiac fibrosis. However, substantial knowledge on the influences of the used materials and tissue geometries on tissue properties and cell phenotypes is necessary to be able to choose an appropriate model for a specific research question. As there is a clear lack of information on how CF react to the mold architecture in engineered connective tissues (ECT), we first compared the effect of two mold geometries and materials with different hardnesses on the biomechanical properties of ECT. We could show that ECT, which formed around two distant poles (non-uniform model) were less stiff and more strain-resistant than ECT, which formed around a central rod (uniform model), independent of the materials used for poles and rods. Next, we investigated the cell state and could demonstrate that in the uniform versus non-uniform model, the embedded cells have a higher cell cycle activity and display a more pronounced myofibroblast phenotype. Differential gene expression analysis revealed that uniform ECT displayed a fibrosis-associated gene signature similar to the diseased heart. Furthermore, we were able to identify important relationships between cell and tissue characteristics, as well as between biomechanical tissue parameters by implementing cells from normal heart and end-stage heart failure explants from patients with ischemic or dilated cardiomyopathy. Finally, we show that the application of pro- and anti-fibrotic factors in the non-uniform and uniform model, respectively, is not sufficient to mimic the effect of the other geometry. Taken together, we demonstrate that modifying the mold geometry in tissue engineering with CF offers the possibility to compare different cellular phenotypes and biomechanical tissue properties.
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Fibroblastos , Miofibroblastos , Tecido Conjuntivo , Fibrose , Coração , Humanos , FenótipoRESUMO
Patients with heart failure are at a higher risk of cardiovascular events compared with the general population, particularly during domestic or international travel. Patients with heart failure should adhere to specific recommendations during travel to lower their risk of developing heart failure symptoms. In this Review, we aim to provide clinicians with a set of guidelines for patients with heart failure embarking on national or international travel. Considerations when choosing a travel destination include travel distance and time, the season upon arrival, air pollution levels, jet lag and altitude level because all these factors can increase the risk of symptom development in patients with heart failure. In particular, volume depletion is of major concern while travelling given that it can contribute to worsening heart failure symptoms. Pre-travel risk assessment should be performed by a clinician 4-6 weeks before departure, and patients should receive advice on potential travel-related illness and on strategies to prevent volume depletion. Oxygen supplementation might be useful for patients who are very symptomatic. Upon arrival at the destination, potential drug-induced photosensitivity (particularly in tropical destinations) and risks associated with the local cuisine require consideration. Special recommendations are needed for patients with cardiac implantable electronic devices or left ventricular assist devices as well as for those who have undergone major cardiac surgery.
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Cardiopatias , Insuficiência Cardíaca , Coração Auxiliar , Insuficiência Cardíaca/terapia , Humanos , Medição de Risco , Viagem , Doença Relacionada a ViagensRESUMO
BACKGROUND: Aging is associated with a progressive reduction in cellular function leading to poor health and loss of physical performance. Mitochondrial dysfunction is one of the hallmarks of aging; hence, interventions targeting mitochondrial dysfunction have the potential to provide preventive and therapeutic benefits to elderly individuals. Meta-analyses of age-related gene expression profiles showed that the expression of Ahnak1, a protein regulating several signal-transduction pathways including metabolic homeostasis, is increased with age, which is associated with low VO2MAX and poor muscle fitness. However, the role of Ahnak1 in the aging process remained unknown. Here, we investigated the age-related role of Ahnak1 in murine exercise capacity, mitochondrial function, and contractile function of cardiac and skeletal muscles. METHODS: We employed 15- to 16-month-old female and male Ahnak1-knockout (Ahnak1-KO) and wild-type (WT) mice and performed morphometric, biochemical, and bioenergetics assays to evaluate the effects of Ahnak1 on exercise capacity and mitochondrial morphology and function in cardiomyocytes and tibialis anterior (TA) muscle. A human left ventricular (LV) cardiomyocyte cell line (AC16) was used to investigate the direct role of Ahnak1 in cardiomyocytes. RESULTS: We found that the level of Ahnak1 protein is significantly up-regulated with age in the murine LV (1.9-fold) and TA (1.8-fold) tissues. The suppression of Ahnak1 was associated with improved exercise tolerance, as all aged adult Ahnak1-KO mice (100%) successfully completed the running programme, whereas approximately 31% male and 8% female WT mice could maintain the required running speed and distance. Transmission electron microscopic studies showed that LV and TA tissue specimens of aged adult Ahnak1-KO of both sexes have significantly more enlarged/elongated mitochondria and less small mitochondria compared with WT littermates (P < 0.01 and P < 0.001, respectively) at basal level. Further, we observed a shift in mitochondrial fission/fusion balance towards fusion in cardiomyocytes and TA muscle from aged adult Ahnak1-KO mice. The maximal and reserve respiratory capacities were significantly higher in cardiomyocytes from aged adult Ahnak1-KO mice compared with the WT counterparts (P < 0.05 and P < 0.01, respectively). Cardiomyocyte contractility and fatigue resistance of TA muscles were significantly increased in Ahnak1-KO mice of both sexes, compared with the WT groups. In vitro studies using AC16 cells have confirmed that the alteration of mitochondrial function is indeed a direct effect of Ahnak1. Finally, we presented Ahnak1 as a novel cardiac mitochondrial membrane-associated protein. CONCLUSIONS: Our data suggest that Ahnak1 is involved in age-related cardiac and skeletal muscle dysfunction and could therefore serve as a promising therapeutical target.
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Mitocôndrias , Músculo Esquelético , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Dinâmica Mitocondrial , Contração Muscular , Músculo Esquelético/metabolismoRESUMO
INTRODUCTION: Skeletal muscle wasting is a frequent clinical problem encountered in patients with chronic diseases. Increased levels of inflammatory markers play a role in the imbalance between muscle protein synthesis and degradation. Although testosterone has long been proposed as a treatment for patients with muscle wasting, undesirable side effects have raised concerns about prostatic hypertrophy in men as well as virilization in women. Selective androgen receptor modulators (SARMs) have demonstrated similar results like testosterone at improving lean body mass (LBM) with less side effects on androgen-dependent tissue. AREAS COVERED: This review outlines the ongoing clinical development in the field of SARMs and their effectiveness in improving body composition and physical function. The included articles were collected at pubmed.gov and analyzed integrally. EXPERT OPINION: There is an unmet clinical need for safe and effective anabolic compounds such as SARMs. Despite the effect on LBM shown by SARMs in phase II clinical trials, results on improved physical function and muscle strength are still lacking and long-term outcomes have to be assessed in these patients. Moreover, there is a need to determine the effect of resistance exercise training and protein intake associated with SARMs in the treatment of patients with muscle wasting.
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Anabolizantes/administração & dosagem , Atrofia Muscular/tratamento farmacológico , Receptores Androgênicos/efeitos dos fármacos , Anabolizantes/efeitos adversos , Anabolizantes/farmacologia , Animais , Desenvolvimento de Medicamentos , Humanos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Proteínas/administração & dosagem , Receptores Androgênicos/metabolismo , Treinamento Resistido/métodos , Testosterona/administração & dosagem , Testosterona/farmacologiaRESUMO
Numerous epidemiological, clinical, and animal studies showed that cardiac function and manifestation of cardiovascular diseases (CVDs) are different between males and females. The underlying reasons for these sex differences are definitely multifactorial, but major evidence points to a causal role of the sex steroid hormone 17ß-estradiol (E2) and its receptors (ER) in the physiology and pathophysiology of the heart. Interestingly, it has been shown that cardiac calcium (Ca2+) ion channels and mitochondrial function are regulated in a sex-specific manner. Accurate mitochondrial function and Ca2+ signaling are of utmost importance for adequate heart function and crucial to maintaining the cardiovascular health. Due to the highly sensitive nature of these processes in the heart, this review article highlights the current knowledge regarding sex dimorphisms in the heart implicating the importance of E2 and ERs in the regulation of cardiac mitochondrial function and Ca2+ ion channels, thus the contractility. In particular, we provide an overview of in-vitro and in-vivo studies using either E2 deficiency; ER deficiency or selective ER activation, which suggest that E2 and ERs are strongly involved in these processes. In this context, this review also discusses the divergent E2-responses resulting from the activation of different ER subtypes in these processes. Detailed understanding of the E2 and ER-mediated molecular and cellular mechanisms in the heart under physiological and pathological conditions may help to design more specifically targeted drugs for the management of CVDs in men and women.
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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.
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Estenose da Valva Aórtica/genética , Cardiomegalia/genética , Moléculas de Adesão Celular Neuronais/genética , Músculo Estriado/crescimento & desenvolvimento , Fatores de Crescimento Neural/genética , Animais , Estenose da Valva Aórtica/patologia , Cardiomegalia/patologia , Diferenciação Celular/genética , Modelos Animais de Doenças , Feminino , Humanos , Mutação com Perda de Função/genética , Masculino , Camundongos , Desenvolvimento Muscular/genética , Músculo Estriado/metabolismo , Músculo Estriado/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais/genética , Peixe-ZebraRESUMO
Aims: Sex differences in cardiac fibrosis point to the regulatory role of 17ß-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 (ERß). Methods and results: In 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 ERß-agonists (10-7 M) for 24 h, we identified ERα as repressive and ERß 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 ERß 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 ERß 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. Conclusion: The mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERß signaling in CFs.
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Colágeno Tipo III/metabolismo , Colágeno Tipo I/metabolismo , Estradiol/análogos & derivados , Estrogênios/farmacologia , Fibroblastos/efeitos dos fármacos , Cardiopatias/metabolismo , Miocárdio/metabolismo , Receptores de Estrogênio/efeitos dos fármacos , Idoso , Animais , Sítios de Ligação , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Modelos Animais de Doenças , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Cardiopatias/genética , Cardiopatias/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miocárdio/patologia , Fosforilação , Regiões Promotoras Genéticas , Ratos Wistar , Receptores de Estrogênio/metabolismo , Fatores Sexuais , Transdução de Sinais , Regulação para CimaRESUMO
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.
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Pesquisa Biomédica/métodos , Doenças Cardiovasculares , Sistema Cardiovascular , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Projetos de Pesquisa , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/terapia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Cromossomos Humanos X , Cromossomos Humanos Y , Feminino , Predisposição Genética para Doença , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Fenótipo , Gravidez , Prognóstico , Fatores de Risco , Caracteres Sexuais , Fatores SexuaisRESUMO
Epidemiological, clinical and animal studies revealed that sex differences exist in the manifestation and outcome of cardiovascular disease (CVD). The underlying molecular mechanisms implicated in these sex differences are not fully understood. The reasons for sex differences in CVD are definitely multifactorial, but major evidence points to the contribution of sex steroid hormone, 17ß-estradiol (E2), and its receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERß). In this review, we summarize past and present studies that implicate E2 and ER as important determinants of sexual dimorphism in the physiology and pathophysiology of the heart. In particular, we give an overview of studies aimed to reveal the role of E2 and ER in the physiology of the observed sex differences in CVD using ER knock-out mice. Finally, we discuss recent findings from novel transgenic mouse models, which have provided new information on the sexual dimorphic roles of ER specifically in cardiomyocytes under pathological conditions.
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Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Receptores de Estrogênio/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Estradiol/análise , Estradiol/genética , Estrogênios/análise , Estrogênios/genética , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Receptores de Estrogênio/análise , Receptores de Estrogênio/genética , Caracteres SexuaisRESUMO
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 17ß-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.
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Estradiol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Regulação da Expressão Gênica/genética , Contração Miocárdica/fisiologia , Cadeias Leves de Miosina/biossíntese , Animais , Western Blotting , Feminino , Imunofluorescência , Humanos , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Miócitos Cardíacos/metabolismo , Cadeias Leves de Miosina/genética , Reação em Cadeia da Polimerase , Técnicas do Sistema de Duplo-HíbridoRESUMO
BACKGROUND: Estrogen improves cardiac recovery after ischemia/reperfusion (I/R) by yet incompletely understood mechanisms. Mitochondria play a crucial role in I/R injury through cytochrome c-dependent apoptosis activation. We tested the hypothesis that 17ß-estradiol (E2) as well as a specific ERß agonist improve cardiac recovery through estrogen receptor (ER)ß-mediated mechanisms by reducing mitochondria-induced apoptosis and preserving mitochondrial integrity. METHODS: We randomized ovariectomized C57BL/6N mice 24h before I/R to pre-treatment with E2 or a specific ERß agonist (ERßA). Isolated hearts were perfused for 20min prior to 30min global ischemia followed by 40min reperfusion. RESULTS: Compared with controls, ERßA and E2 treated groups showed a significant improvement in cardiac recovery, i.e. an increase in left ventricular developed pressure, dP/dtmax and dP/dtmin. ERßA and E2 pre-treatment led to a significant reduction in apoptosis with decreased cytochrome c release from the mitochondria and increased mitochondrial levels of anti-apoptotic Bcl2 and ACAA2. Protein levels of mitochondrial translocase inner membrane (TIM23) and mitochondrial complex I of respiratory chain were increased by ERßA and E2 pre-treatment. Furthermore, we found a significant increase of myosin light chain 2 (MLC2) phosphorylation together with ERK1/2 activation in E2, but not in ERßA treated groups. CONCLUSIONS: Activation of ERß is essential for the improvement of cardiac recovery after I/R through the inhibition of apoptosis and preservation of mitochondrial integrity and can be a achieved by a specific ERß agonist. Furthermore, E2 modulates MLC2 activation after I/R independent of ERß.
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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.
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Caracteres Sexuais , Doença , Feminino , Humanos , Masculino , Medicina de Precisão , Fatores SexuaisRESUMO
ERß (oestrogen receptor ß) activation has been shown to be cardioprotective, but the cell types and mechanisms involved are not understood. To investigate whether ERß restricted to cardiomyocytes contributes to the observed cardioprotection, we tested the effects of cardiomyocyte-specific ERß-OE (ERß overexpression) on survival, cardiac remodelling and function after MI (myocardial infarction) and studied the molecular pathways potentially involved. Female and male mice with cardiomyocyte-specific ERß-OE and WT (wild-type) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ERß-OE mice showed improved survival (100% and 83% compared with 76% and 58% in WT females and males respectively). ERß-OE was associated with attenuated LV (left ventricular) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ERß-mediated myocardial protection. First, male and female ERß-OE mice had a lower reduction of SERCA2a (sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 2a) expression after MI, suggesting less reduction in diastolic Ca(2+)-reuptake into the sarcoplasmic reticulum post-MI. Secondly, male ERß-OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers collagen I and III, periostin and miR-21. Cardiomyocyte-specific ERß-OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca(2+) cycling in both sexes and a lower induction of cardiac fibrosis in males after MI.
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Receptor beta de Estrogênio/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores/metabolismo , Diástole/fisiologia , Receptor beta de Estrogênio/fisiologia , Feminino , Fibrose , Masculino , Camundongos Transgênicos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fatores Sexuais , Sístole/fisiologia , Ultrassonografia , Remodelação Ventricular/fisiologiaRESUMO
PURPOSE: Aging has severe implications for tissue damage and is a major risk factor for disease. However, the effects of aging on cardiac extracellular matrix (ECM) components in individuals free of cardiovascular disease are incompletely understood. We aimed at the characterization of the effects of aging on major ECM proteins in the heart of men and women. EXPERIMENTAL DESIGN: Left ventricular (LV) samples of nondiseased human hearts technically unusable for transplantation obtained from general organ donors (n = 31; age 17-68 years; 48% women) were used for protein isolation. We separated the group into 17-40 years (n = 7 men and 7 women) and 50-68 years (n = 9 men and 8 women). RESULTS: Analysis of ECM proteins demonstrated an age-dependent sex-specific regulation of collagen type I and III (interaction p < 0.05), type VI (interaction p = 0.01), tissue inhibitor of metalloproteinase 3 (interaction p < 0.05), SMAD2 (interaction p < 0.05), and SMAD3 (interaction p = 0.001). Overall, the levels of these proteins in younger individuals were lower in women than men, while in older individuals they were higher in women than men. CONCLUSIONS AND CLINICAL RELEVANCE: This age-mediated myocardial ECM remodeling might play a key role in the limited ability of the aging heart to adapt adequately to altered work load and to respond to tissue damage. Therapeutic agents that target ECM homeostasis represent promising prevention strategies.
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Envelhecimento/metabolismo , Doenças Cardiovasculares/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Miocárdio/metabolismo , Adolescente , Adulto , Idoso , Envelhecimento/patologia , Doenças Cardiovasculares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologiaRESUMO
AIMS: Women with aortic stenosis develop a more concentric form of LV hypertrophy than men. However, the molecular factors underlying sex differences in LV remodelling are incompletely understood. We took an unbiased approach to identify sex-specific patterns in gene expression and pathway regulation, and confirmed the most prominent findings in human hearts. METHODS AND RESULTS: Echocardiography was performed in 104 patients (53.8% women) with aortic stenosis before aortic valve replacement. LV mass, LV end-diastolic diameter, and relative wall thickness were included in a factor analysis to generate an index classifying LV remodelling as adaptive or maladaptive. Maladaptive remodelling was present in 64.6% of male and in 32.7% of female patients (P < 0.01). Genome-wide expression profiling of LV samples was performed in a representative subgroup of 19 patients (52.6% women) compared with samples from healthy controls (n = 18). Transcriptome characterization revealed that fibrosis-related genes/pathways were induced in male overloaded ventricles, while extracellular matrix-related and inflammatory genes/pathways were repressed in female overloaded ventricles (adjusted P < 0.05). We confirmed gene regulation by quantitative real-time reverse transcription-polymerase chain reaction and immunoblotting analysis, and we further demonstrate the relevance of our findings by histological documentation of higher fibrosis in men than in women. CONCLUSION: We conclude that in pressure overload distinct molecular processes are regulated between men and women. Maladaptive LV remodelling occurs more frequently in men and is associated with greater activation of profibrotic and inflammatory markers. Collectively, sex-specific regulation of these processes may contribute to sex differences in the progression to heart failure.
Assuntos
Estenose da Valva Aórtica/patologia , Hipertrofia Ventricular Esquerda/patologia , Remodelação Ventricular , Idoso , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/genética , Biópsia , Ecocardiografia , Feminino , Fibrose/diagnóstico por imagem , Fibrose/genética , Fibrose/patologia , Perfilação da Expressão Gênica , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Immunoblotting , Inflamação/diagnóstico por imagem , Inflamação/genética , Inflamação/patologia , Masculino , RNA/análise , Reação em Cadeia da Polimerase em Tempo Real , Fatores Sexuais , Análise Serial de Tecidos , Transcriptoma/genética , Remodelação Ventricular/genéticaRESUMO
OBJECTIVES: The purpose of this study was to test whether adaptive or maladaptive remodeling is associated with survival in women and men after aortic valve replacement (AVR). BACKGROUND: Women with isolated aortic valve stenosis (AS) develop more concentric left ventricular hypertrophy (LVH) than men in similar disease states. We recently reported less up-regulation of profibrotic genes at AVR and faster LVH regression post-operatively in women than in men, suggesting that there are sex differences in the adaptation to pressure overload and its regression. METHODS: The study cohort included 128 patients (age 70.0 ± 9.6 years, 49% women) undergoing AVR for AS. Echocardiography was obtained before and 4.0 ± 1.6 years after surgery. Factor analysis was used to classify LVH as adaptive (combining smaller left ventricular [LV] mass/diameters and greater relative wall thicknesses) or maladaptive. Myocardial tissue samples from the LV septum were obtained during AVR to analyze cardiac fibrosis and associated key molecular regulators. RESULTS: Before AVR, LVH was classified as adaptive in 62% of women and 45% of men (p < 0.050). Four years after AVR, adaptive LVH was observed in 75% of women and 49% of men (p < 0.031). At surgery, more cardiac fibrosis was present in men compared with women (p < 0.05). Higher levels of transforming growth factor beta 1 (p < 0.01), SMAD2 phosphorylation (p < 0.001), and periostin expression (p < 0.05) were found in men than in women. Women with maladaptive LVH had worse survival than women with adaptive LVH (p < 0.050), whereas the pattern of LVH did not affect survival in men (p < 0.307). CONCLUSIONS: Women more frequently exhibit adaptive LV remodeling with less fibrosis than men. Maladaptive LVH is associated with worse survival in women. Thus, sex should be considered as a strong modulating factor when management of patients with AS is discussed.
Assuntos
Estenose da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Hipertrofia Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/mortalidade , Biomarcadores/análise , Moléculas de Adesão Celular/análise , Análise Fatorial , Feminino , Fibrose , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/mortalidade , Masculino , Pessoa de Meia-Idade , Fosforilação , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Proteína Smad3/análise , Análise de Sobrevida , Fatores de Tempo , Fator de Crescimento Transformador beta1/análise , Resultado do Tratamento , UltrassonografiaRESUMO
Experimental studies showed that 17ß-estradiol (E2) and activated Estrogen Receptors (ER) protect the heart from ischemic injury. However, the underlying molecular mechanisms are not well understood. To investigate the role of ER-alpha (ERα) in cardiomyocytes in the setting of myocardial ischemia, we generated transgenic mice with cardiomyocyte-specific overexpression of ERα (ERα-OE) and subjected them to Myocardial Infarction (MI). At the basal level, female and male ERα-OE mice showed increased Left Ventricular (LV) mass, LV volume and cardiomyocyte length. Two weeks after MI, LV volume was significantly increased and LV wall thickness decreased in female and male WT-mice and male ERα-OE, but not in female ERα-OE mice. ERα-OE enhanced expression of angiogenesis and lymphangiogenesis markers (Vegf, Lyve-1), and neovascularization in the peri-infarct area in both sexes. However, attenuated level of fibrosis and higher phosphorylation of JNK signaling pathway could be detected only in female ERα-OE after MI. In conclusion, our study indicates that ERα protects female mouse cardiomyocytes from the sequelae of ischemia through induction of neovascularization in a paracrine fashion and impaired fibrosis, which together may contribute to the attenuation of cardiac remodelling.