Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • COVID-19 submission information
    • Peer reviewer login
  • Alerts
  • Podcasts
  • Subscriptions

Iron bioavailability and cardiopulmonary function during ascent to very high altitude

David A. Holdsworth, Matthew C. Frise, Josh Bakker-Dyos, Christopher Boos, Keith L. Dorrington, David Woods, Adrian Mellor, Peter A. Robbins
European Respiratory Journal 2020 56: 1902285; DOI: 10.1183/13993003.02285-2019
David A. Holdsworth
1Dept of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
2Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: david.holdsworth@dpag.ox.ac.uk
Matthew C. Frise
1Dept of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Matthew C. Frise
Josh Bakker-Dyos
2Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher Boos
3Institute for Sport, Physical Activity and Leisure, Leeds Beckett University, Leeds, UK
4Dept of Postgraduate Medical Education, Bournemouth University, Bournemouth, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Keith L. Dorrington
1Dept of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Woods
2Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, UK
3Institute for Sport, Physical Activity and Leisure, Leeds Beckett University, Leeds, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adrian Mellor
2Royal Centre for Defence Medicine, Queen Elizabeth Hospital, Birmingham, UK
3Institute for Sport, Physical Activity and Leisure, Leeds Beckett University, Leeds, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter A. Robbins
1Dept of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Peter A. Robbins
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher SpO2 on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function. https://bit.ly/2VQX5fR

To the Editor:

More than one hundred million people reside worldwide at altitudes in excess of 2500 m above sea level. In the millions more who sojourn at high altitude for recreational, occupational or military pursuits, hypobaric hypoxia drives physiological changes affecting the pulmonary circulation, haematocrit and right ventricle (RV) [1]. Coincident with these, maximal left ventricular (LV) stroke volume (SV) falls [2], with a reduction of 20% reported after a 2-week stay at 4300 m [3]. A rise in heart rate (HR) compensates at rest and during submaximal exercise but is insufficient during maximal intensity exercise, constraining maximal cardiac output (CO). Previously, it was considered that a reduction in plasma volume or a direct effect of hypoxia on LV myocardial contractility were probably responsible [4]. More recently it has been suggested that increased RV afterload may be of greater importance [5].

Hypoxic pulmonary vasoconstriction (HPV) contributes significantly to increased RV work and pulmonary hypertension during alveolar hypoxia [6]. In healthy iron-replete individuals, intravenous (i.v.) iron attenuates HPV [7, 8], tending to reduce RV afterload. We hypothesised that i.v. iron would improve cardiopulmonary function during ascent to very high altitude through this action upon the pulmonary vasculature, with or without a direct effect on the heart.

We conducted a randomised, controlled, double-blind, clinical physiology study. 18 British Armed Forces personnel (17 male, 1 female) volunteered; one was excluded because of abnormal baseline iron indices. Participants were randomised to receive either 1 g ferric carboxymaltose (Ferinject), or saline control, as a single infusion. 2 weeks later, participants flew to Kathmandu, Nepal, at an altitude of 1400 m, were driven to 2600 m (day 4), trekked to 3800 m (day 5), 4100 m (day 7), and then 5100 m (day 10). Serial measurements of iron indices, peripheral oxyhaemoglobin saturation (SpO2), and transthoracic echocardiographic parameters (VividQ, GE, Boston, MA, USA) were recorded at rest.

Stroke volume was estimated by multiplying LV outflow tract (LVOT) velocity-time integral (VTI) by LVOT cross-sectional area, and CO by multiplying SV and HR. Both were then normalised to body surface area in m2 (BSA; Mosteller formula).

Right ventricular systolic pressure (RVSP) was estimated from the peak velocity of the tricuspid regurgitation jet [1, 5, 7–9]. The LV and RV indices of myocardial performance (LIMP and RIMP) and tricuspid annular planar systolic excursion (TAPSE) were measured. Pulmonary vascular resistance (PVR) was estimated using the Abbas method [9]. Between-group differences in responses were analysed using mixed-effects modelling (SPSS Statistics version 25, IBM). Ethical approval was given by the Ministry of Defence Research Ethics Committee, all participants provided written informed consent, and the study was registered with ClinicalTrials.gov (NCT03707249).

The groups were well matched at baseline. Comparisons for the iron group versus controls were as follows: mean±sd age 35.5±8.2 versus 36.1±7.7 years; body mass index 24.8±1.0 versus 24.6±2.0 kg·m−2; and BSA 2.02±0.06 versus 1.99±0.04 m2. No adverse infusion-related events occurred. One participant in the control group did not ascend beyond 4100 m due to severe gastrointestinal symptoms; all available data for this participant were included in the analysis.

Changes in iron indices, haematological parameters and cardiopulmonary variables are illustrated in figure 1. Ferritin and hepcidin were elevated in the iron group, with a corresponding reduction in the rise in both erythropoietin and soluble transferrin receptor (sTfR).

FIGURE 1
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1

Variation with altitude of iron indices, haematological parameters and cardiopulmonary physiological variables. Sea-level data were acquired immediately prior to infusion of iron or saline. Data are plotted as mean±sem. The p-values given are for the interaction between group and altitude, that is, whether iron administration altered the change from sea level to maximum altitude. SpO2: peripheral oxyhaemoglobin saturation; SVI: stroke volume index; TSat: transferrin saturation; Hb: haemoglobin concentration; sTfR: soluble transferrin receptor; CI: cardiac index; RIMP and LIMP: RV and LV indices of myocardial performance (combined measures of the efficiency of ventricular filling and ejection; higher values indicate more significant impairment); Epo: erythropoietin; RVSP: right ventricular systolic pressure; PVR: pulmonary vascular resistance; TAPSE: tricuspid annular planar systolic excursion.

The prior administration of iron significantly attenuated the progressive fall in SpO2 seen with increasing altitude (absolute difference in desaturation 5.5%, 95% CI 2.5–8.4%; p<0.001). Iron also abolished the normal fall in SV observed with increasing altitude. The mean between-group difference in the change in stroke volume index (SVI) was 6.2 mL·m−2 (95% CI 0.31–12.2 mL·m−2; p=0.039).

In the control group, LIMP, RIMP and TAPSE all worsened significantly with increasing altitude. LIMP rose by 0.08 (95% CI 0.003–0.16; p=0.043), RIMP rose by 0.31 (95% CI 0.24–0.38; p<0.001), and TAPSE fell by 0.55 cm (95% CI 0.27–0.83 cm; p<0.001). When comparing the iron group with controls, the degree of impairment in RIMP and TAPSE was reduced by 0.14 (95% CI 0.03–0.24; p=0.013) and 0.41 cm (95% CI 0.01–0.82 cm; p=0.045), respectively. However, the iron group showed no difference in the deterioration in LIMP (95% CI for between group difference −0.07–0.16; p=0.41) nor the rise in RVSP on ascent (95% CI −7.6–4.0 mmHg; p=0.51).

Interestingly, we found that iron supplementation was associated with augmented SV in the absence of a difference in RVSP. Had PVR remained similar in both groups, the higher SV of the iron group would be expected to have associated with a higher RVSP. In fact, RVSP responses were similar and there appeared to be a trend towards a lower PVR in the iron group, although this was not statistically significant (95% CI −0.58–0.23 Wood units; p=0.38). However, a strong negative correlation was evident between the change in SVI and the change in PVR (Pearson's r=−0.72; p=0.003), implying a close relationship between increased RV afterload and falling SV.

Reduced PVR might be a direct result of increased iron bioavailability, as previously described [7, 8], or may result from improved oxyhaemoglobin saturation. The latter would also act to reduce HPV as the result of a corresponding increase in mixed venous oxygen tension. The latter is a significant stimulus for HPV, albeit less so than alveolar oxygen tension [10]. Both mechanisms are biologically plausible, as is the putative mechanism for increased oxygenation in the iron group: that an iron-mediated reduction in HPV promotes ventilation/perfusion matching. The finding that RV, but not LV, function was enhanced in the group given iron also seems likely to reflect reduced RV work secondary to attenuated HPV and consequently reduced PVR.

An alternative explanation would be that iron acted to augment the ventilatory response to hypobaric hypoxia. We were not able to measure ventilation as part of the expedition. Whilst there is good reason to believe iron bioavailability might affect pulmonary ventilation via an action on the hypoxia inducible factor pathway within carotid body glomus cells [11], no human study has detected such a phenomenon [8, 12]. Moreover, the expected direction of effect is for iron to diminish alveolar ventilation rather than augment it.

The links between iron, erythropoiesis and oxygen homeostasis are complex [13]. Erythropoietin is under transcriptional regulation by both hypoxia and iron [12], so the attenuated erythropoietin rise in the iron group will reflect some combination of both a direct action of iron and improved renal oxygenation. The rise in sTfR, levels of which reflect the balance between iron supply and erythropoietic activity [14], was similarly attenuated in the iron group, reflecting some combination of greater iron bioavailability and lower stimulation of the bone marrow by erythropoietin. Both iron and hypoxia regulate expression of hepcidin, the key hormone regulating iron homeostasis; the effect of hypoxia is indirect, mediated downstream of marrow stimulation [13]. The effect of prior iron infusion on iron bioavailability in the present study was so marked that it lifted the heavy suppression of hepcidin seen at 5100 m in the control group.

A role for i.v. iron therapy is well established in chronic heart failure [15]. Our findings support the view that manipulation of iron bioavailability should be explored more broadly in conditions that feature increased PVR, ventilation/perfusion mismatch, or right heart dysfunction, including right heart failure, acute pulmonary embolism, high altitude pulmonary oedema, adult congenital heart disease, chronic thromboembolic pulmonary hypertension and COPD.

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-02285-2019.Shareable

Acknowledgement

We thank GE Healthcare for the loan of the Vivid q echocardiography machine.

Footnotes

  • This study was registered with ClinicalTrials.gov (NCT03707249). Data were collected as part of a British Military expedition. Although all data have not therefore been made available through an online repository, all reasonable requests for additional data and full data sharing will be considered. Where such data do not represent a security concern they will be granted.

  • Conflict of interest: D.A. Holdsworth has nothing to disclose.

  • Conflict of interest: M.C. Frise has nothing to disclose.

  • Conflict of interest: J. Bakker-Dyos has nothing to disclose.

  • Conflict of interest: C. Boos has nothing to disclose.

  • Conflict of interest: K.L. Dorrington has nothing to disclose.

  • Conflict of interest: D. Woods has nothing to disclose.

  • Conflict of interest: A. Mellor has nothing to disclose.

  • Conflict of interest: P.A. Robbins reports grants from Vifor Pharma, outside the submitted work.

  • Support statement: M.C. Frise was supported by a BHF Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington was supported by the Dunhill Medical Trust (R178/1110).

  • Received November 26, 2019.
  • Accepted April 17, 2020.
  • Copyright ©ERS 2020
http://creativecommons.org/licenses/by/4.0/

This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.

References

  1. ↵
    1. Naeije R
    . Pulmonary hypertension at high altitude. Eur Respir J 2019; 53: 1900985. doi:10.1183/13993003.00985-2019
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Bartsch P,
    2. Gibbs JS
    . Effect of altitude on the heart and the lungs. Circulation 2007; 116: 2191–2202. doi:10.1161/CIRCULATIONAHA.106.650796
    OpenUrlFREE Full Text
  3. ↵
    1. Saltin B,
    2. Grover RF,
    3. Blomqvist CG, et al.
    Maximal oxygen uptake and cardiac output after 2 weeks at 4,300 m. J Appl Physiol 1968; 25: 400–409. doi:10.1152/jappl.1968.25.4.400
    OpenUrl
  4. ↵
    1. Alexander JK,
    2. Grover RF
    . Mechanism of reduced cardiac stroke volume at high altitude. Clin Cardiol 1983; 6: 301–303. doi:10.1002/clc.4960060612
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Maufrais C,
    2. Rupp T,
    3. Bouzat P, et al.
    Heart mechanics at high altitude: 6 days on the top of Europe. Eur Heart J Cardiovasc Imaging 2017; 18: 1369–1377. doi:10.1093/ehjci/jew286
    OpenUrlPubMed
  6. ↵
    1. Groves BM,
    2. Reeves JT,
    3. Sutton JR, et al.
    Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen. J Appl Physiol 1987; 63: 521–530. doi:10.1152/jappl.1987.63.2.521
    OpenUrlPubMedWeb of Science
  7. ↵
    1. Smith TG,
    2. Talbot NP,
    3. Privat C, et al.
    Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA 2009; 302: 1444–1450. doi:10.1001/jama.2009.1404
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    1. Frise MC,
    2. Cheng HY,
    3. Nickol AH, et al.
    Clinical iron deficiency disturbs normal human responses to hypoxia. J Clin Invest 2016; 126: 2139–2150. doi:10.1172/JCI85715
    OpenUrlCrossRefPubMed
  9. ↵
    1. Abbas AE,
    2. Fortuin FD,
    3. Schiller NB, et al.
    A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003; 41: 1021–1027. doi:10.1016/S0735-1097(02)02973-X
    OpenUrlFREE Full Text
  10. ↵
    1. Marshall BE,
    2. Marshall C
    . A model for hypoxic constriction of the pulmonary circulation. J Appl Physiol 1988; 64: 68–77. doi:10.1152/jappl.1988.64.1.68
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    1. Cheng X,
    2. Prange-Barczynska M,
    3. Fielding JW, et al.
    Marked and rapid effects of pharmacological HIF-2alpha antagonism on hypoxic ventilatory control. J Clin Invest 2020; 130: 2237–2251.
    OpenUrl
  12. ↵
    1. Ren X,
    2. Dorrington KL,
    3. Maxwell PH, et al.
    Effects of desferrioxamine on serum erythropoietin and ventilatory sensitivity to hypoxia in humans. J Appl Physiol 2000; 89: 680–686. doi:10.1152/jappl.2000.89.2.680
    OpenUrlPubMedWeb of Science
  13. ↵
    1. Talbot NP,
    2. Smith TG,
    3. Lakhal-Littleton S, et al.
    Suppression of plasma hepcidin by venesection during steady-state hypoxia. Blood 2016; 127: 1206–1207. doi:10.1182/blood-2015-05-647404
    OpenUrlFREE Full Text
  14. ↵
    1. Skikne BS,
    2. Punnonen K,
    3. Caldron PH, et al.
    Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Hematol 2011; 86: 923–927. doi:10.1002/ajh.22108
    OpenUrlCrossRefPubMed
  15. ↵
    1. Ponikowski P,
    2. van Veldhuisen DJ,
    3. Comin-Colet J, et al.
    Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency. Eur Heart J 2015; 36: 657–668. doi:10.1093/eurheartj/ehu385
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
View this article with LENS
Vol 56 Issue 3 Table of Contents
European Respiratory Journal: 56 (3)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Iron bioavailability and cardiopulmonary function during ascent to very high altitude
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Iron bioavailability and cardiopulmonary function during ascent to very high altitude
David A. Holdsworth, Matthew C. Frise, Josh Bakker-Dyos, Christopher Boos, Keith L. Dorrington, David Woods, Adrian Mellor, Peter A. Robbins
European Respiratory Journal Sep 2020, 56 (3) 1902285; DOI: 10.1183/13993003.02285-2019

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Iron bioavailability and cardiopulmonary function during ascent to very high altitude
David A. Holdsworth, Matthew C. Frise, Josh Bakker-Dyos, Christopher Boos, Keith L. Dorrington, David Woods, Adrian Mellor, Peter A. Robbins
European Respiratory Journal Sep 2020, 56 (3) 1902285; DOI: 10.1183/13993003.02285-2019
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Shareable PDF
    • Acknowledgement
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Agora

  • Airway immune responses to COVID-19 vaccination in COPD patients
  • Wider access to rifapentine-based regimens is needed for TB care globally
  • Association between immunosuppressants and outcomes of COVID-19
Show more Agora

Research letters

  • Mitochondrial DNA as biomarker of survival in RA-ILD
  • Lung transplantation for cystic fibrosis before and after availability of elexacaftor/tezacaftor/ivacaftor
  • Elexacaftor-tezacaftor-ivacaftor and circulating neutrophil counts in CF
Show more Research letters

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Reviewers
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society