RESUMO
The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show long-term increased risk of cardiovascular disease and mortality is unknown. We aim to profile the urinary proteome in pregnant women with/without CV risk factors to identify proteins associated with postpartum RR. Our study included a prospective cohort of 32 healthy and 27 obese and/or hypertensive and/or diabetic pregnant women who underwent transthoracic echocardiography, pulse-wave-velocity, and urine collection at the 3rd trimester and 6 months postpartum. Shotgun HPLC-MS/MS profiled proteins. Generalized linear mixed-effects models were used to identify associations between urinary proteins and left ventricle mass (LVM), a surrogate of RR. An increase in arterial stiffness was documented from 3rd trimester to 6 months after delivery, being significantly elevated in women with CV risk factors. In addition, the presence of at least one CV risk factor was associated with worse LVM RR. We identified 6 and 11 proteins associated with high and low LVM regression, respectively. These proteins were functionally linked with insulin-like growth factor (IGF) transport and uptake regulation by IGF binding-proteins, platelet activation, signaling and aggregation and the immune system's activity. The concentration of IGF-1 in urine samples was associated with low LVM regression after delivery. Urinary proteome showed a predicting potential for identifying pregnant women with incomplete postpartum RR.
Assuntos
Período Pós-Parto , Proteoma , Remodelação Ventricular , Humanos , Feminino , Gravidez , Adulto , Proteoma/análise , Período Pós-Parto/urina , Estudos Prospectivos , Biomarcadores/urina , Rigidez Vascular , Ecocardiografia , Fatores de RiscoRESUMO
Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD-induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin-angiotensin-aldosterone system inhibitors, beta-blockers, diuretics and sodium-glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end-diastolic/end-systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre-clinical evaluation.
Assuntos
Remodelação Ventricular , Humanos , Remodelação Ventricular/fisiologia , Prognóstico , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/fisiopatologia , Europa (Continente) , Relevância ClínicaRESUMO
PURPOSE: This cohort study aimed to investigate the relationship between subjective (wellness and internal training load [ITL]) and objective (neuromuscular fatigue) monitoring markers and performance aspects (reception quality [RQ] and attack efficiency [AE]) in professional female volleyball players. METHODS: The study was conducted over an 8-week period during the final mesocycle of the competitive phase. A total of 24 training sessions and 10 matches were included in the analysis. Subjective measures of wellness and ITL were assessed, and neuromuscular fatigue was evaluated using countermovement-jump (CMJ) height. RQ and AE were determined based on game statistics. RESULTS: The study found a positive relationship between wellness and RQ, particularly affecting outside hitters and liberos. ITL showed a positive association with AE, primarily impacting outside hitters, opposite hitters, and middle blockers. Additionally, ITL demonstrated a negative correlation with RQ, mainly affecting outside hitters and liberos. CMJ performance was associated with AE, where a decrease in CMJ height was linked to reduced AE. CONCLUSIONS: The findings highlight the importance of considering players' wellness scores in training and match strategies for different positions. Careful management of training loads, considering both physical and technical demands, is crucial for optimizing performance outcomes. Monitoring neuromuscular fatigue, as indicated by CMJ performance, is particularly relevant for outside hitters, opposite hitters, and middle blockers involved in attack actions. Coaches, trainers, and sports practitioners can use these insights to develop position-specific training protocols and implement effective strategies for maintaining or improving performance metrics under various stressors.
Assuntos
Desempenho Atlético , Fadiga Muscular , Voleibol , Humanos , Feminino , Voleibol/fisiologia , Desempenho Atlético/fisiologia , Fadiga Muscular/fisiologia , Adulto Jovem , Condicionamento Físico Humano/métodos , Comportamento Competitivo/fisiologia , Adulto , Nível de Saúde , Estudos de CoortesRESUMO
Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.
Assuntos
Antineoplásicos , Neoplasias da Mama , Peptídeos , Receptores de Fatores de Crescimento de Fibroblastos , Rutênio , Feminino , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Concentração de Íons de Hidrogênio , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Rutênio/química , Rutênio/farmacologia , Rutênio/uso terapêuticoRESUMO
The consumption of non-sugar sweeteners (NSS) has increased during pregnancy. The European Food Safety Agency suggested that steviol glycosides, such as Rebaudioside A (RebA), the major sweetener component of stevia, are safe for humans up to a dose of 4 mg/kg body weight/day. However, the World Health Organization recommended in 2023 the restraint of using NSS, including stevia, at any life stage, highlighting the need to study NSS safety in early periods of development. We aimed to study the mitochondrial and cardiometabolic effects of long-term RebA consumption during the reproductive stage of the life cycle. Female rats were exposed to RebA (4 mg steviol equivalents/kg body weight/day) in the drinking water from 4 weeks before mating until weaning. Morphometry, food and water consumption, glucose and lipid homeostasis, heart structure, function, and mitochondrial function were assessed. RebA showed an atrophic effect in the heart, decreasing cardiomyocyte cross-sectional area and myocardial fibrosis without repercussions on cardiac function. Mitochondrial and myofilamentary functions were not altered. Glucose tolerance and insulin sensitivity were not affected, but fasting glycemia and total plasma cholesterol decreased. This work suggests that this RebA dose is safe for female consumption during the reproductive stage, from a cardiometabolic perspective. However, studies on the effects of RebA exposure on the offspring are mandatory.
RESUMO
Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.
Assuntos
Adaptação Fisiológica , Fatores de Risco de Doenças Cardíacas , Humanos , Feminino , Gravidez , Adulto , Função Ventricular Esquerda , Cardiomegalia/fisiopatologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/etiologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/sangue , Volume Sistólico , Terceiro Trimestre da Gravidez , Diabetes Gestacional/fisiopatologia , Complacência (Medida de Distensibilidade) , Primeiro Trimestre da Gravidez , Obesidade/fisiopatologia , Obesidade/complicações , Fatores de RiscoRESUMO
Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 µg/kg + 0.1 µg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients.
Assuntos
Insuficiência Cardíaca , Humanos , Ratos , Masculino , Animais , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Simendana/farmacologia , Ratos Endogâmicos WKY , Obesidade/complicações , Obesidade/tratamento farmacológico , Fibrose , Hipertrofia , MamíferosRESUMO
PURPOSE: The main objective of this study is to characterize and analyze modified peptides in DBS samples. This includes deciphering their specific PTMs and understanding their potential impact on the population or disease cohort under study. EXPERIMENTAL DESIGN: Using mass spectrometry-based proteomic approaches, we performed a comprehensive analysis of DBS samples. Our focus was on the identification and quantification of modified peptides. We also took advantage of recent advances in DBS mass spectrometry to ensure accurate detection and quantification. RESULTS: A comprehensive analysis identified 972 modified peptides in DBS samples. Of these, a subset of 211 peptides was consistently present in all samples, highlighting their potential biological importance and relevance. This indicates a diverse spectrum of PTMs in the proteome of DBS samples. CONCLUSIONS AND CLINICAL RELEVANCE: Integration of mass spectrometry and proteomics has revealed a broad spectrum of modified peptides in DBS samples and highlighted their importance in biological processes and disease progression. Accurate detection of these PTMs may be critical for risk stratification and disease management. This study improves the understanding of molecular mechanisms underlying biological processes and disease development, providing important insights for clinical applications.
Assuntos
Teste em Amostras de Sangue Seco , Espectrometria de Massas , Processamento de Proteína Pós-Traducional , Proteômica , Humanos , Proteômica/métodos , Teste em Amostras de Sangue Seco/métodos , Peptídeos/sangue , Peptídeos/análise , Proteoma/análiseRESUMO
INTRODUCTION AND OBJECTIVES: Echocardiography guidelines suggest normalizing left ventricular (LV) volumes and mass (LVM) to body size. During pregnancy, continuous weight variation impacts on body surface area (BSA) calculation, limiting the longitudinal analysis of cardiac remodeling (CR) and reverse remodeling (RR) variables. Our aim was to identify the most common indexing methodologies in the literature on pregnant populations through a systematic review; and, to compare four scaling methods: (i) none (absolute values); (ii) indexing to the BSA before pregnancy; (iii) allomeric indexing; and (iv) indexing to BSA measured at the same day of cardiac assessment, using an illustrative example. METHODS: We performed a systematic review of CR and RR during pregnancy and post-partum, using two databases. We included studies reporting longitudinal echocardiographic analysis of cardiac chamber volumes in humans. We used a prospective cohort study of healthy pregnant women who underwent four echocardiographic evaluations during pregnancy and postpartum, as an illustrative example. RESULTS: Twenty-seven studies were included, most studies indexed to BSA measured at each evaluation moment (n=21). Within-subjects design was the most reported to analyse longitudinal data (n=17). Indexation to the pre-pregnancy BSA or application of allometric indexes revealed a higher effect than BSA measured at each evaluation and an equal effect to not indexing using within-subjects design. The within-subjects designs also revealed a higher effect size value than the between-subjects design for longitudinal analysis of LVM adaptations during pregnancy and postpartum. CONCLUSION(S): This study concludes that indexation methods do not impact the clinical interpretation of longitudinal echocardiographic assessment but highlights the need to harmonize normalization procedures during pregnancy.
Assuntos
Ecocardiografia , Coração , Gravidez , Feminino , Humanos , Estudos Prospectivos , Ventrículos do Coração , Período Pós-PartoRESUMO
A man in his 60s presented to the emergency department with generalised abdominal pain and distention associated with the inability to pass stool or gas. The patient had undergone a laparoscopic partial right nephrectomy due to renal cell carcinoma a year ago. The workup diagnosis suggested an incarcerated incisional hernia. Surgical treatment was proposed. Intraoperatively, we found an ileocecal appendix with a macroscopically gangrenous appearance inside the hernia sac. An appendectomy was performed, and the hernia defect was closed using a tension repair. Amyand's hernia, a rare condition, is classically described as an inguinal hernia containing the appendix, but it can also refer to an incisional hernia containing the appendix. Amyand's hernia classification depends on the localisation of the hernia sac and its contents, including the presence or absence of appendix inflammation.This case report described a patient with Amyand's hernia, which was diagnosed intraoperatively. The treatment was also discussed including open appendectomy and primary repair of the defect using a tension repair approach.
Assuntos
Apendicite , Apêndice , Hérnia Inguinal , Hérnia Incisional , Masculino , Humanos , Apendicite/complicações , Apendicite/cirurgia , Apendicite/diagnóstico , Hérnia Incisional/complicações , Apêndice/cirurgia , Apêndice/patologia , Apendicectomia , Hérnia Inguinal/complicações , Hérnia Inguinal/diagnóstico , Hérnia Inguinal/cirurgiaRESUMO
While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF.
Assuntos
Insuficiência Cardíaca , Humanos , Doença Aguda , Prognóstico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Doença Crônica , Fatores de RiscoRESUMO
Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the Adenosine-L-Arginine-Nitric Oxide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research.
Assuntos
Doenças Cardiovasculares , Diabetes Gestacional , Obesidade Materna , Gravidez , Feminino , Humanos , Diabetes Gestacional/metabolismo , Placenta/metabolismo , Óxido Nítrico/metabolismo , Doenças Cardiovasculares/metabolismo , Obesidade Materna/complicações , Obesidade Materna/metabolismo , Arginina/metabolismoRESUMO
Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk of developing many chronic diseases in an early stage of life, including obesity, type 2 diabetes, and cardiovascular disease (CVD). CVD is the main cause of death worldwide among men and women, and it is manifested in a sex-divergent way. Maternal nutrition and MO during gestation could prompt CVD development in the offspring through adaptations of the offspring's cardiovascular system in the womb, including cardiac epigenetic and persistent metabolic programming of signaling pathways and modulation of mitochondrial metabolic function. Currently, despite diet supplementation, effective therapeutical solutions to prevent the deleterious cardiac offspring function programming by an obesogenic womb are lacking. In this review, we discuss the mechanisms by which an obesogenic intrauterine environment could program the offspring's cardiovascular metabolism in a sex-divergent way, with a special focus on cardiac mitochondrial function, and debate possible strategies to implement during MO pregnancy that could ameliorate, revert, or even prevent deleterious effects of MO on the offspring's cardiovascular system. The impact of maternal physical exercise during an obesogenic pregnancy, nutritional interventions, and supplementation on offspring's cardiac metabolism are discussed, highlighting changes that may be favorable to MO offspring's cardiovascular health, which might result in the attenuation or even prevention of the development of CVD in MO offspring. The objectives of this manuscript are to comprehensively examine the various aspects of MO during pregnancy and explore the underlying mechanisms that contribute to an increased CVD risk in the offspring. We review the current literature on MO and its impact on the offspring's cardiometabolic health. Furthermore, we discuss the potential long-term consequences for the offspring. Understanding the multifaceted effects of MO on the offspring's health is crucial for healthcare providers, researchers, and policymakers to develop effective strategies for prevention and intervention to improve care.
RESUMO
The mother represents one of the earliest sources of microorganisms to the child, influencing the acquisition and establishment of its microbiota in early life. However, the impact of the mother on the oral microbiota of the child from early life until adulthood remains to unveil. This narrative review aims to: i) explore the maternal influence on the oral microbiota of the child, ii) summarize the similarity between the oral microbiota of mother and child over time, iii) understand possible routes for vertical transmission, and iv) comprehend the clinical significance of this process for the child. We first describe the acquisition of the oral microbiota of the child and maternal factors related to this process. We compare the similarity between the oral microbiota of mother and child throughout time, while presenting possible routes for vertical transmission. Finally, we discuss the clinical relevance of the mother in the pathophysiological outcome of the child. Overall, maternal and non-maternal factors impact the oral microbiota of the child through several mechanisms, although the consequences in the long term are still unclear. More longitudinal research is needed to unveil the importance of early-life microbiota on the future health of the infant.
RESUMO
Background: Low levels of triiodothyronine (T3) are common in patients with heart failure (HF). Our aim was to evaluate the effects of supplementation with low and replacement doses of T3 in an animal model of HF with preserved ejection fraction (HFpEF). Methods: We evaluated four groups: ZSF1 Lean (n = 8, Lean-Ctrl), ZSF1 Obese (rat model of metabolic-induced HFpEF, n = 13, HFpEF), ZSF1 Obese treated with a replacement dose of T3 (n = 8, HFpEF-T3high), and ZSF1 Obese treated with a low-dose of T3 (n = 8, HFpEF-T3low). T3 was administered in drinking water from weeks 13 to 24. The animals underwent anthropometric and metabolic assessments, echocardiography, and peak effort testing with maximum O2 consumption (VO2max) determination at 22 weeks, and a terminal hemodynamic evaluation at 24 weeks. Afterwhile myocardial samples were collected for single cardiomyocyte evaluation and molecular studies. Results: HFpEF animals showed lower serum and myocardial thyroid hormone levels than Lean-Ctrl. Treatment with T3 did not normalize serum T3 levels, but increased myocardial T3 levels to normal levels in the HFpEF-T3high group. Body weight was significantly decreased in both the T3-treated groups, comparing with HFpEF. An improvement in glucose metabolism was observed only in HFpEF-T3high. Both the treated groups had improved diastolic and systolic function in vivo, as well as improved Ca2+ transients and sarcomere shortening and relaxation in vitro. Comparing with HFpEF animals, HFpEF-T3high had increased heart rate and a higher rate of premature ventricular contractions. Animals treated with T3 had higher myocardial expression of calcium transporter ryanodine receptor 2 (RYR2) and α-myosin heavy chain (MHC), with a lower expression of ß-MHC. VO2max was not influenced by treatment with T3. Myocardial fibrosis was reduced in both the treated groups. Three animals died in the HFpEF-T3high group. Conclusions: Treatment with T3 was shown to improve metabolic profile, myocardial calcium handling, and cardiac function. While the low dose was well-tolerated and safe, the replacement dose was associated with increased heart rate, and increased risk of arrhythmias and sudden death. Modulation of thyroid hormones may be a potential therapeutic target in HFpEF; however, it is important to take into account the narrow therapeutic window of T3 in this condition.
Assuntos
Insuficiência Cardíaca , Ratos , Animais , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Tri-Iodotironina/farmacologia , Tri-Iodotironina/uso terapêutico , Cálcio/metabolismo , Modelos Animais de Doenças , Obesidade/complicaçõesRESUMO
Metabolic syndrome (MetS), characterized by a set of conditions that include obesity, hypertension, and dyslipidemia, is associated with increased cardiovascular risk. Exercise training (EX) has been reported to improve MetS management, although the underlying metabolic adaptations that drive its benefits remain poorly understood. This work aims to characterize the molecular changes induced by EX in skeletal muscle in MetS, focusing on gastrocnemius metabolic remodelling. 1H NMR metabolomics and molecular assays were employed to assess the metabolic profile of skeletal muscle tissue from lean male ZSF1 rats (CTL), obese sedentary male ZSF1 rats (MetS-SED), and obese male ZF1 rats submitted to 4 weeks of treadmill EX (5 days/week, 60 min/day, 15 m/min) (MetS-EX). EX did not counteract the significant increase of body weight and circulating lipid profile, but had an anti-inflammatory effect and improved exercise capacity. The decreased gastrocnemius mass observed in MetS was paralleled with glycogen degradation into small glucose oligosaccharides, with the release of glucose-1-phosphate, and an increase in glucose-6-phosphate and glucose levels. Moreover, sedentary MetS animals' muscle exhibited lower AMPK expression levels and higher amino acids' metabolism such as glutamine and glutamate, compared to lean animals. In contrast, the EX group showed changes suggesting an increase in fatty acid oxidation and oxidative phosphorylation. Additionally, EX mitigated MetS-induced fiber atrophy and fibrosis in the gastrocnemius muscle. EX had a positive effect on gastrocnemius metabolism by enhancing oxidative metabolism and, consequently, reducing susceptibility to fatigue. These findings reinforce the importance of prescribing EX programs to patients with MetS.
Assuntos
Síndrome Metabólica , Ratos , Masculino , Animais , Síndrome Metabólica/terapia , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Músculo Esquelético/metabolismo , Glucose/metabolismo , Peso CorporalRESUMO
Heart failure (HF) is a debilitating disease with a significant clinical and economic impact worldwide. Multiple factors seem to increase the risk of developing HF, such as hypertension, obesity and diabetes. Since chronic inflammation plays a significant role in HF pathophysiology and gut dysbiosis is associated with low-grade chronic inflammation, the risk of cardiovascular diseases is likely modulated by the gut microbiome (GM). Considerable progress has been made in HF management. However, there is a need to find new strategies to reduce mortality and increase the quality of life, mainly of HFpEF patients, since its prevalence continues to rise. Recent studies validate that lifestyle changes, such as diet modulation, represent a potential therapeutic approach to improve several cardiometabolic diseases, although their effects on the GM and its indirect cardiac impact still warrant further research. Hence, in this paper, we aim to clarify the link between HF and the human microbiome.
Assuntos
Insuficiência Cardíaca , Microbiota , Humanos , Qualidade de Vida , Volume Sistólico , Dieta , Inflamação , PrognósticoRESUMO
INTRODUCTION: Heart failure (HF) is among the leading causes of morbidity and mortality worldwide. Several conditions trigger left ventricular chronic pressure or volume overload, hypertrophy, systolic and diastolic dysfunction, leading to cardiac remodeling and a rapid progression toward HF. Therapeutic interventions elicit reverse remodeling (RR), a highly variable myocardial response that ranges from none to total ventricular structural/functional recovery. However, HF patients present several comorbidities and medications that mask a comprehensive molecular knowledge of RR and hinder the identification of potential biomarkers of its progression or prognosis. Therefore, instead of using this heterogeneous population or even animal models to understand myocardial remodeling, we propose studying pregnancy-induced cardiovascular remodeling and postpartum-induced RR. OBJECTIVES: To assess cardiovascular functional and structural adaptations during pregnancy and in postpartum, characterizing the associated molecular changes; as well as to explore the impact of hypertension, obesity and diabetes on these processes. METHODS: We will perform echocardiography and assess endothelial function and arterial stiffness (EndoPAT® and pulse wave velocity, respectively) and assess potential markers of remodeling and RR using plasma and urine samples from pregnant women. To translate to a HF context, we will determine the impact of risk factors (hypertension, obesity and diabetes) by studying subgroups of pregnant women with these comorbidities. RESULTS: Not applicable. CONCLUSION: We are convinced that understanding the impact of these comorbidities in such a homogeneous population, such as pregnant women, provides a valuable model to unveil the most relevant pathologic and often masked signaling pathways underlying cardiac remodeling and incomplete RR in a heterogeneous population, such as HF patients. Moreover, we expect to identify potential novel biomarkers of RR progression/prognosis more easily.