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Iron deficiency augments hypoxic pulmonary arterial pressure in healthy individuals and exacerbates pulmonary arterial hypertension (PAH) in patients, even without anemia. Conversely, iron supplementation has been shown to be beneficial in both settings. The mechanisms underlying the effects of iron availability are not known, due to lack of understanding of how cells of the pulmonary vasculature respond to changes in iron levels. The iron export protein ferroportin (FPN) and its antagonist peptide hepcidin control systemic iron levels by regulating release from the gut and spleen, the sites of absorption and recycling, respectively. We found FPN to be present in pulmonary arterial smooth muscle cells (PASMCs) and regulated by hepcidin cell autonomously. To interrogate the importance of this regulation, we generated mice with smooth muscle-specific knock in of the hepcidin-resistant isoform fpn C326Y. While retaining normal systemic iron levels, this model developed PAH and right heart failure as a consequence of intracellular iron deficiency and increased expression of the vasoconstrictor endothelin-1 (ET-1) within PASMCs. PAH was prevented and reversed by i.v. iron and by the ET receptor antagonist BQ-123. The regulation of ET-1 by iron was also demonstrated in healthy humans exposed to hypoxia and in PASMCs from PAH patients with mutations in bone morphogenetic protein receptor type II. Such mutations were further associated with dysregulation of the HAMP/FPN axis in PASMCs. This study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function. It offers a mechanistic underpinning for the known effects of iron availability in humans.

Busana et al . ( doi.org/10.1152/japplphysiol.00871.2020 ) published 5 patients with COVID-19 in whom the fraction of non-aerated lung tissue had been quantified by computed tomography. They assumed that shunt flow fraction was proportional to the non-aerated lung fraction, and, by randomly generating 10 6 different bimodal distributions for the ventilation-perfusion ( V ˙ / Q ˙ ) ratios in the lung, specified as sets of paired values V ˙ i , Q ˙ i , sought to identify as solutions those that generated the observed arterial partial pressures of CO 2 and O 2 (Pa CO2 and Pa O2 ). Our study sought to develop a direct method of calculation to replace the approach of randomly generating different distributions, and so provide more accurate solutions that were within the measurement error of the blood-gas data. For the one patient in whom Busana et al . did not find solutions, we demonstrated that the assumed shunt flow fraction led to a non-shunt blood flow that was too low to support the required gas exchange. For the other four patients, we found precise solutions (prediction error < 1x10 -3 mmHg for both Pa CO2 and Pa O2 ), with distributions qualitatively similar to those of Busana et al . These distributions were extremely wide and unlikely to be physically realisable, because they predict the maintenance of very large concentration gradients in regions of the lung where convection is slow. We consider that these wide distributions arise because the assumed value for shunt flow is too low in these patients, and we discuss possible reasons why the assumption relating to shunt flow fraction may break down in COVID-19 pneumonia.

The indigenous people of the Tibetan Plateau have been the subject of much recent interest because of their unique genetic adaptations to high altitude. Recent studies have demonstrated that the Tibetan EPAS1 haplotype is involved in high altitude-adaptation and originated in an archaic Denisovan-related population. We sequenced the whole-genomes of 27 Tibetans and conducted analyses to infer a detailed history of demography and natural selection of this population. We detected evidence of population structure between the ancestral Han and Tibetan subpopulations as early as 44 to 58 thousand years ago, but with high rates of gene flow until approximately 9 thousand years ago. The CMS test ranked EPAS1 and EGLN1 as the top two positive selection candidates, and in addition identified PTGIS, VDR, and KCTD12 as new candidate genes. The advantageous Tibetan EPAS1 haplotype shared many variants with the Denisovan genome, with an ancient gene tree divergence between the Tibetan and Denisovan haplotypes of about 1 million years ago. With the exception of EPAS1, we observed no evidence of positive selection on Denisovan-like haplotypes.

Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion ofFpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes ofFpnknockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain. Many proteins inside cells require iron to work properly, and so this mineral is an essential part of the diets of most mammals. However, because too much iron in the body is also bad for health, mammals possess several proteins whose role is to maintain the balance of iron. Two proteins in particular, called hepcidin and ferroportin, are thought to be important in this process. Some ferroportin is found in the cells that line the gut (where iron is absorbed into the body) and is required to release this iron into the bloodstream. It is also found in the spleen, which is where iron is removed from old red blood cells so that it can be recycled. The liver produces hepcidin to control when ferroportin is active in the gut and spleen. Both hepcidin and ferroportin are also found in heart cells. In 2015, a study reported that that heart ferroportin plays an important role in heart activity. However, it was not clear what role hepcidin plays in this organ. Now, Lakhal-Littleton et al. – including many of the researchers from the previous work – have genetically engineered mice such that they specifically lacked heart hepcidin, or had a version of ferroportin in their heart that does not respond to hepcidin. The experiments show that these changes caused fatal heart failure in the mice because ferroportin releases iron from heart cells in an uncontrolled manner. Lakhal-Littleton et al. were able to prevent heart failure by injecting the animals with iron directly into the bloodstream. These findings show that hepcidin produced outside the liver has a role in controlling the levels of iron in the body’s organs. Other organs such as the brain, kidney and placenta all have their own forms of hepcidin and ferroportin; further work could investigate the roles of these proteins. Finally, another challenge for the future will be to test whether new drugs that are being developed to block or mimic hepcidin from the liver have the potential to treat heart conditions in humans.

By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.

Jonathan Flint, Richard Mott and colleagues employ low-coverage (0.15×) sequencing and their new imputation method STITCH to perform genome-wide association analysis for complex traits in an outbred mouse population. They find >250 QTLs for 92 phenotypes and obtain gene-level mapping resolution for around 20% of the loci. Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

Computed cardiopulmonography (CCP) is a technique that measures lung volumes (functional residual capacity and deadspace) together with novel parameters reflecting lung inhomogeneities (non‐uniformities in lung inflation and deadspace path length). First, highly precise measurements of gas exchange are made during a nitrogen washout with a purpose‐built molecular flow sensor. Second, an individual's lung physiology is then described by personalising the parameters of a bespoke cardio‐respiratory model obtained by fitting the model to the data. The present study examines the effects of participants’ physical characteristics on these parameter values, and from this also provides preliminary estimates for normal ranges. Data from 92 healthy individuals (27% female, age 40 ± 19 (mean ± SD) years, height 1.75 ± 0.09 m, mass 74 ± 14 kg) were used. A prediction equation for each CCP parameter was written as: y = α + βln(age) + γln(height) + δln(BMI) + ε(is_Female) + error, where BMI is body mass index. Non‐significant terms (P > 0.1) were removed sequentially to identify just the significant characteristics. Physical characteristics exerted a large influence on volume‐related CCP parameters. In contrast, only age had a significant influence on inhomogeneity‐related CCP parameters. The prediction equations, together with their mean squared errors, were used to calculate z‐scores for CCP data from three previously published studies in asthma, chronic obstructive pulmonary disease, and early cystic fibrosis. Values for these z‐scores often lay beyond those commonly used to define a normal range (±1.65). In conclusion, reference values for inhomogeneity‐based CCP parameters may only need correcting for age, and often appear as abnormal in airways disease. What is the central question of this study? Computed cardiopulmonography (CCP) is a technique that measures lung volumes together with novel parameters reflecting inhomogeneities in lung structure/function: what is the effect of a healthy person's physical characteristics on these parameters? What is the main finding and its importance? CCP parameters relating to inhomogeneity were influenced only by age, and not by height, body mass index or sex. Based on these data, z‐scores calculated for CCP parameters in patients with airways disease were commonly abnormal, suggesting CCP may be more sensitive than the established clinical techniques for detecting airways disease.

Following acute COVID‐19 infection, unvaccinated patients have been reported to exhibit elevated alveolar deadspace (̇VD,alv/̇VT) and intrapulmonary shunt (̇Qs/̇QT) fractions. However, as there is uncertainty surrounding the upper limits of normal for ̇VD,alv/̇VT and ̇Qs/̇QT, we sought to replicate the findings from a separate, previously reported cohort of COVID‐19 patients that also included a healthy control group never infected with COVID‐19. Data from 81 participants, classified into four different groups based on the severity of prior COVID‐19 infection, were used. All participants had arterial blood‐gas samples drawn while highly precise measurements of their respiratory gas exchange were made. The gas exchange data were used to estimate alveolar PCO2 ${P_{{\\mathrm{C}}{{\\mathrm{O}}_2}}}$and PO2 ${P_{{{\\mathrm{O}}_2}}}$ , and the differences between these values and the corresponding arterial blood‐gas values provided the alveolar–arterial gradients from which ̇VD,alv/̇VT and ̇Qs/̇QT were calculated. Mean ̇VD,alv/̇VT was 0.115 ± 0.062 and mean ̇Qs/̇QT was 0.014 ± 0.011. No significant differences between the groups, including the uninfected control group, were detected for either ̇VD,alv/̇VT or ̇Qs/̇QT, although if severity was instead treated as an interval measure, then a small increase in ̇Qs/̇QT with severity (P = 0.00934) could be detected. Many participants, including controls, exceeded the originally proposed upper limit of normal for ̇VD,alv/̇VT, whereas no participant exceeded the originally proposed upper limit for ̇Qs/̇QT. We conclude that prior infection with COVID‐19 had no effect on ̇VD,alv/̇VT and little effect on ̇Qs/̇QT, and that the supposedly high values of ̇VD,alv/̇VT are within the normal range. What is the central question of this study? Using a three‐compartment lung model to evaluate gas exchange in patients following recovery from COVID‐19 and in uninfected control participants, does prior infection with COVID‐19 affect gas exchange efficiency? What is the main finding and its importance? There was no difference between patients and controls for alveolar deadspace fraction, and any elevation in shunt fraction was minor. Measured values for alveolar deadspace fraction were ∼10‐fold greater than those for intrapulmonary shunt fraction, and this appears to reflect normal physiology rather than any effect of COVID‐19.

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case–control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31 P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.