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1.
Br J Anaesth ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34872717

RESUMO

BACKGROUND: Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS: We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L-1). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS: Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L-1) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L-1), adjusted mean difference (10.98 g L-1; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION: A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION: ISRCTN13721808 (www.isrctn.com).

2.
Aerosp Med Hum Perform ; 92(8): 633-641, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34503616

RESUMO

AbstractBACKGROUND: Members of the public will soon be taking commercial suborbital spaceflights with significant Gx (chest-to-back) acceleration potentially reaching up to 6 Gx. Pulmonary physiology is gravity-dependent and is likely to be affected, which may have clinical implications for medically susceptible individuals.METHODS: During 2-min centrifuge exposures ranging up to 6 Gx, 11 healthy subjects were studied using advanced respiratory techniques. These sustained exposures were intended to allow characterization of the underlying pulmonary response and did not replicate actual suborbital G profiles. Regional distribution of ventilation in the lungs was determined using electrical impedance tomography. Neural respiratory drive (from diaphragm electromyography) and work of breathing (from transdiaphragmatic pressures) were obtained via nasoesophageal catheters. Arterial blood gases were measured in a subset of subjects. Measurements were conducted while breathing air and breathing 15 oxygen to simulate anticipated cabin pressurization conditions.RESULTS: Acceleration caused hypoxemia that worsened with increasing magnitude and duration of Gx. Minimum arterial oxygen saturation at 6 Gx was 86 1 breathing air and 79 1 breathing 15 oxygen. With increasing Gx the alveolar-arterial (A-a) oxygen gradient widened progressively and the relative distribution of ventilation reversed from posterior to anterior lung regions with substantial gas-trapping anteriorly. Severe breathlessness accompanied large progressive increases in work of breathing and neural respiratory drive.DISCUSSION: Sustained high-G acceleration at magnitudes relevant to suborbital flight profoundly affects respiratory physiology. These effects may become clinically important in the most medically susceptible passengers, in whom the potential role of centrifuge-based preflight evaluation requires further investigation.Pollock RD, Jolley CJ, Abid N, Couper JH, Estrada-Petrocelli L, Hodkinson PD, Leonhardt S, Mago-Elliott S, Menden T, Rafferty G, Richmond G, Robbins PA, Ritchie GAD, Segal MJ, Stevenson AT, Tank HD, Smith TG. Pulmonary effects of sustained periods of high-G acceleration relevant to suborbital spaceflight. Aerosp Med Hum Perform. 2021; 92(7):633641.


Assuntos
Medicina Aeroespacial , Voo Espacial , Aceleração , Centrifugação , Gravitação , Humanos
4.
Kidney Int ; 100(3): 559-569, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33991530

RESUMO

The hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and reticuloendothelial system, respective sites of iron absorption and recycling. Ferroportin is also abundant in the kidney, where it has been implicated in tubular iron reabsorption. However, it remains unknown whether endogenous hepcidin regulates ferroportin-mediated iron reabsorption under physiological conditions, and whether such regulation is important for kidney and/or systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible kidney-tubule specific knock-in of fpnC326Y, which encodes a hepcidin-resistant ferroportin termed FPNC326Y. Under conditions of normal iron availability, female mice harboring this allele had consistently decreased kidney iron but only transiently increased systemic iron indices. Under conditions of excess iron availability, male and female mice harboring this allele had milder kidney iron overload, but greater systemic iron overload relative to controls. Additionally, despite comparable systemic iron overload, kidney iron overload occurred in wild type mice fed an iron-loaded diet but not in hemochromatosis mice harboring a ubiquitous knock-in of fpnC326Y. Thus, our study demonstrates that endogenous hepcidin controls ferroportin-mediated tubular iron reabsorption under physiological conditions. It also shows that such control is important for both kidney and systemic iron homeostasis in the context of iron overload.


Assuntos
Hepcidinas , Sobrecarga de Ferro , Animais , Proteínas de Transporte de Cátions , Feminino , Hepcidinas/genética , Ferro , Rim , Masculino , Camundongos
6.
ERJ Open Res ; 7(2)2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33898618

RESUMO

Background: Multiple-breath washout techniques are increasingly used to assess lung function. The principal statistic obtained is the lung clearance index (LCI), but values obtained for LCI using the nitrogen (N2)-washout technique are higher than those obtained using an exogenous tracer gas such as sulfur hexafluoride. This study explored whether the pure oxygen (O2) used for the N2 washout could underlie these higher values. Methods: A model of a homogenous, reciprocally ventilated acinus was constructed. Perfusion was kept constant, and ventilation adjusted by varying the swept volume during the breathing cycle. The blood supplying the acinus had a standard mixed-venous composition. Carbon dioxide and O2 exchange between the blood and acinar gas proceeded to equilibrium. The model was initialised with either air or air plus tracer gas as the inspirate. Washouts were conducted with pure O2 for the N2 washout or with air for the tracer gas washout. Results: At normal ventilation/perfusion (V'/Q') ratios, the rate of washout of N2 and exogenous tracer gas was almost indistinguishable. At low V'/Q', the N2 washout lagged the tracer gas washout. At very low V'/Q', N2 became trapped in the acinus. Under low V'/Q' conditions, breathing pure O2 introduced a marked asymmetry between the inspiratory and expiratory gas flow rates that was not present when breathing air. Discussion: The use of pure O2 to washout N2 increases O2 uptake in low V'/Q' units. This generates a background gas flow into the acinus that opposes flow out of the acinus during expiration, and so delays the washout of N2.

7.
Sci Rep ; 11(1): 5252, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664377

RESUMO

Respiratory approaches to determining cardiac output in humans are securely rooted in mass balance and therefore potentially highly accurate. To address existing limitations in the gas analysis, we developed an in-airway analyser based on laser absorption spectroscopy to provide analyses every 10 ms. The technique for estimating cardiac output requires both a relatively soluble and insoluble tracer gas, and we employed acetylene and methane for these, respectively. A multipass cell was used to provide sufficient measurement sensitivity to enable analysis directly within the main gas stream, thus avoiding errors introduced by sidestream gas analysis. To assess performance, measurements of cardiac output were made during both rest and exercise on five successive days in each of six volunteers. The measurements were extremely repeatable (coefficient of variation ~ 7%). This new measurement technology provides a stable foundation against which the algorithm to calculate cardiac output can be further developed.

8.
Front Physiol ; 12: 571137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33737880

RESUMO

Concern is often voiced over the ongoing loss of atmospheric O2. This loss, which is caused by fossil-fuel burning but also influenced by other processes, is likely to continue at least for the next few centuries. We argue that this loss is quite well understood, and the eventual decrease is bounded by the fossil-fuel resource base. Because the atmospheric O2 reservoir is so large, the predicted relative drop in O2 is very small even for extreme scenarios of future fossil-fuel usage which produce increases in atmospheric CO2 sufficient to cause catastrophic climate changes. At sea level, the ultimate drop in oxygen partial pressure will be less than 2.5 mm Hg out of a baseline of 159 mmHg. The drop by year 2300 is likely to be between 0.5 and 1.3 mmHg. The implications for normal human health is negligible because respiratory O2 consumption in healthy individuals is only weakly dependent on ambient partial pressure, especially at sea level. The impacts on top athlete performance, on disease, on reproduction, and on cognition, will also be very small. For people living at higher elevations, the implications of this loss will be even smaller, because of a counteracting increase in barometric pressure at higher elevations due to global warming.

9.
Ann Am Thorac Soc ; 18(6): 981-988, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33735594

RESUMO

Rationale: Iron deficiency, in the absence of anemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin concentrations. The safety and benefit of parenteral iron replacement in this patient population is unclear. Objectives: To evaluate the safety and efficacy of parenteral iron replacement in PAH. Methods: In two randomized, double-blind, placebo-controlled 12-week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject) (1,000 mg or 15 mg/kg if weight <66.7 kg) or saline as placebo, and 17 patients in China received iron dextran (Cosmofer) (20 mg iron/kg body weight) or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by a serum ferritin <37 µg/L or iron <10.3 µmol/L or transferrin saturations <16.4%. Results: Both iron treatments were well tolerated and improved iron status. Analyzed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6-minute walk test) or cardiopulmonary hemodynamics, as assessed by right heart catheterization, cardiac magnetic resonance, or plasma NT-proBNP (N-terminal-pro hormone brain natriuretic peptide) at 12 weeks. Conclusions: Iron repletion by administration of a slow-release iron preparation as a single infusion to patients with PAH with iron deficiency without overt anemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).


Assuntos
Anemia Ferropriva , Hipertensão Arterial Pulmonar , Anemia Ferropriva/tratamento farmacológico , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Hipertensão Pulmonar Primária Familiar , Humanos , Ferro , Resultado do Tratamento
10.
J Appl Physiol (1985) ; 130(5): 1383-1397, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33475459

RESUMO

Many models of the body's gas stores have been generated for specific purposes. Here, we seek to produce a more general purpose model that: 1) is relevant for both respiratory (CO2 and O2) and inert gases; 2) is based firmly on anatomy and not arbitrary compartments; 3) can be scaled to individuals; and 4) incorporates arterial and venous circulatory delays as well as tissue volumes so that it can reflect rapid transients with greater precision. First, a "standard man" of 11 compartments was produced, based on data compiled by the International Radiation Protection Commission. Each compartment was supplied via its own parallel circulation, the arterial and venous volumes of which were based on reported tissue blood volumes together with data from a detailed anatomical model for the large arteries and veins. A previously published model was used for the blood gas chemistry of CO2 and O2. It was not permissible ethically to insert pulmonary artery catheters into healthy volunteers for model validation. Therefore, validation was undertaken by comparing model predictions with previously published data and by comparing model predictions with experimental data for transients in gas exchange at the mouth following changes in alveolar gas composition. Overall, model transients were fastest for O2, intermediate for CO2, and slowest for N2. There was good agreement between model estimates and experimentally measured data. Potential applications of the model include estimation of closed-loop gain for the ventilatory chemoreflexes and improving the precision associated with multibreath washout testing and respiratory measurement of cardiac output.NEW & NOTEWORTHY A model for the body gas stores has been generated that is applicable to both respiratory gases (CO2 and O2) and inert gases. It is based on anatomical details for organ volumes and blood contents together with anatomical details of the large arteries. It can be scaled to the body size and composition of different individuals. The model enables mixed venous gas compositions to be predicted from the systemic arterial compositions.


Assuntos
Dióxido de Carbono , Oxigênio , Débito Cardíaco , Humanos , Pulmão , Masculino , Gases Nobres , Troca Gasosa Pulmonar
11.
J Appl Physiol (1985) ; 129(6): 1277, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33280555
12.
BMJ Open Respir Res ; 7(1)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32565444

RESUMO

BACKGROUND: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (mean±SD: age 69±8 years, haemoglobin 144.8±13.2 g/L, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3%±15.2%; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO2) at rest after 1 week. The secondary endpoints included daily SpO2, overnight SpO2, exercise SpO2, 6 min walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures, and exacerbation frequency. RESULTS: SpO2 was unchanged 1 week after FCM administration (difference between groups 0.8%, 95% CI -0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6 min walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after 1 week (p=0.009). Modified MRC Dyspnoea Scale score was also significantly lower after FCM, and fewer participants reported scores ≥2 in the FCM group, compared with placebo (33.3% vs 66.7%, p=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs 8.3%, p<0.001). CONCLUSIONS: FCM did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well tolerated and produced improvements in exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies. TRIAL REGISTRATION NUMBER: ISRCTN09143837.


Assuntos
Dispneia/reabilitação , Tolerância ao Exercício/efeitos dos fármacos , Compostos Férricos/administração & dosagem , Maltose/análogos & derivados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração Intravenosa , Idoso , Método Duplo-Cego , Feminino , Hemoglobinas/análise , Humanos , Masculino , Maltose/administração & dosagem , Pessoa de Meia-Idade , Oxigênio/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Teste de Caminhada
13.
Blood ; 136(13): 1549-1557, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32542311

RESUMO

In the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling, respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harboring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores and hemoglobin, and markedly increased FPN in the liver, but not in the placenta. Thus, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is not actively regulated by fetal liver HAMP under normal physiological conditions.


Assuntos
Hepcidinas/metabolismo , Ferro/metabolismo , Fígado/embriologia , Animais , Proteínas de Transporte de Cátions/metabolismo , Feminino , Hemoglobinas/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Gravidez
14.
J Breath Res ; 14(4): 047102, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32531773

RESUMO

The fraction of exhaled nitric oxide (FENO) is an important biomarker for the diagnosis and management of asthma and other pulmonary diseases associated with airway inflammation. In this study we report on a novel method for accurate, highly time-resolved, real time detection of FENO at the mouth. The experimental arrangement is based on a combination of optical sensors for the determination of the temporal profile of exhaled NO and CO2 concentrations. Breath CO2 and exhalation flow are measured at the mouth using diode laser absorption spectroscopy (at 2 µm) and differential pressure sensing, respectively. NO is determined in a sidestream configuration using a quantum cascade laser based, cavity-enhanced absorption cell (at 5.2 µm) which simultaneously measures sidestream CO2. The at-mouth and sidestream CO2 measurements are used to enable the deconvolution of the sidestream NO measurement back to the at-mouth location. All measurements have a time resolution of 0.1 s, limited by the requirement of a reasonable limit of detection for the NO measurement, which on this timescale is 4.7 ppb (2 σ). Using this methodology, NO expirograms (FENOgrams) were measured and compared for eight healthy volunteers. The FENOgrams appear to differ qualitatively between individuals and the hope is that the dynamic information encoded in these FENOgrams will provide valuable additional insight into the location of the inflammation in the airways and potentially predict a response to therapy. A validation of the measurements at low-time resolution is provided by checking that results from previous studies that used a two-compartment model of NO production can be reproduced using our technology.


Assuntos
Testes Respiratórios/métodos , Fenômenos Ópticos , Análise Espectral/métodos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
BMJ Open Respir Res ; 7(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32161066

RESUMO

INTRODUCTION: In asthma, lung function measures are often discordant with clinical features such as disease activity or control. METHODS: We investigated a novel technique that provides a measure (σCL) of unevenness (inhomogeneity) in lung inflation/deflation. In particular, we compared σCL with FEV1% predicted (FEV1%pred) as measures of disease activity in the asthmatic lung. RESULTS: σCL correlated modestly with FEV1%pred. However, σCL is not simply a proxy for FEV1%pred as the effects of salbutamol on the two parameters were unrelated. Importantly, σCL reflected disease control better than FEV1. DISCUSSION: We conclude that σCL shows promise as an objective measure of disease activity in asthma.


Assuntos
Asma/fisiopatologia , Volume Expiratório Forçado , Pulmão/fisiopatologia , Troca Gasosa Pulmonar , Índice de Gravidade de Doença , Adulto , Idoso , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria/métodos
17.
N Engl J Med ; 382(9): 835-844, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32101665

RESUMO

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).


Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento/genética , Hipoglicemia/genética , Fator 1 Induzível por Hipóxia/deficiência , Mitocôndrias/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Expressão Gênica , Crescimento/genética , Humanos , Masculino , Metaboloma/genética , Metaboloma/fisiologia , Síndrome , Adulto Jovem
18.
J Clin Invest ; 130(5): 2237-2251, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31999648

RESUMO

Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1ß, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1ß. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.


Assuntos
Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Hipóxia/metabolismo , Indanos/farmacologia , Mutação de Sentido Incorreto , Sulfonas/farmacologia , Substituição de Aminoácidos , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/patologia , Camundongos , Camundongos Mutantes
19.
Front Cardiovasc Med ; 7: 616920, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33553263

RESUMO

Iron deficiency is the most prevalent micronutrient disorder globally. When severe, iron deficiency leads to anemia, which can be deleterious to cardiac function. Given the central role of iron and oxygen in cardiac biology, multiple pathways are expected to be altered in iron-deficiency anemia, and identifying these requires an unbiased approach. To investigate these changes, gene expression and metabolism were studied in mice weaned onto an iron-deficient diet for 6 weeks. Whole-exome transcriptomics (RNAseq) identified over 1,500 differentially expressed genes (DEGs), of which 22% were upregulated and 78% were downregulated in the iron-deficient group, relative to control animals on an iron-adjusted diet. The major biological pathways affected were oxidative phosphorylation and pyruvate metabolism, as well as cardiac contraction and responses related to environmental stress. Cardiac metabolism was studied functionally using in vitro and in vivo methodologies. Spectrometric measurement of the activity of the four electron transport chain complexes in total cardiac lysates showed that the activities of Complexes I and IV were reduced in the hearts of iron-deficient animals. Pyruvate metabolism was assessed in vivo using hyperpolarized 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate. Hearts from iron-deficient and anemic animals showed significantly decreased flux through pyruvate dehydrogenase and increased lactic acid production, consistent with tissue hypoxia and induction of genes coding for glycolytic enzymes and H+-monocarboxylate transport-4. Our results show that iron-deficiency anemia results in a metabolic remodeling toward a glycolytic, lactic acid-producing phenotype, a hallmark of hypoxia.

20.
Physiol Rep ; 7(13): e14164, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31270967

RESUMO

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V ˙ O 2 m a x ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V ˙ O 2 m a x remained unaffected in the iron-replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.


Assuntos
Pressão Sanguínea , Exercício Físico , Hipertensão Pulmonar/tratamento farmacológico , Ferro/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão Pulmonar/prevenção & controle , Injeções Intravenosas , Ferro/administração & dosagem , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Artéria Pulmonar/fisiologia
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