Vol 31, No 2 (2024)
Original Article
Published online: 2023-10-16

open access

Page views 1134
Article views/downloads 453
Get Citation

Connect on Social Media

Connect on Social Media

Intravenous iron supplementation improves energy metabolism of exercising skeletal muscles without effect on either oxidative stress or inflammation in male patients with heart failure with reduced ejection fraction

Marcin D. Drozd12, Michał Tkaczyszyn12, Monika Kasztura3, Kinga Węgrzynowska-Teodorczyk45, Irena Flinta5, Waldemar Banasiak5, Piotr Ponikowski12, Ewa A. Jankowska12
Pubmed: 37853824
Cardiol J 2024;31(2):300-308.

Abstract

Background: Skeletal muscle dysfunction is a feature of heart failure (HF). Iron deficiency (ID) is prevalent in patients with HF associated with exercise intolerance and poor quality of life. Intravenous iron in iron deficient patients with HF has attenuated HF symptoms, however the pathomechanisms remain unclear. The aim of study was to assess whether intravenous iron supplementation as compared to placebo improves energy metabolism of skeletal muscles in patients with HF.

Methods: Men with heart failure with reduced ejection fraction (HFrEF) and ID were randomised in 1:1 ratio to either intravenous ferric carboxymaltose (IV FCM) or placebo. In vivo reduction of lactates by exercising skeletal muscles of forearm was analyzed. A change in lactate production between week 0 and 24 was considered as a primary endpoint of the  study.

Results: There were two study arms: the placebo and the IV FCM (12 and 11 male patients with HFrEF). At baseline, there were no differences between these two study arms. IV FCM therapy as compared to placebo reduced the exertional production of lactates in exercising skeletal muscles. These effects were accompanied by a significant increase in both serum ferritin and transferrin saturation in the IV FCM arm which was not demonstrated in the placebo arm.

Conclusions: Intravenous iron supplementation in iron deficient men with HFrEF improves the functioning of skeletal muscles via an improvement in energy metabolism in exercising skeletal muscles, limiting the contribution of anaerobic reactions generating ATP as reflected by a lower in vivo lactate production in exercising muscles in patients with repleted iron stores.

Article available in PDF format

View PDF Download PDF file

References

  1. Lena A, Anker MS, Springer J. Muscle wasting and sarcopenia in heart failure-the current state of science. Int J Mol Sci. 2020; 21(18).
  2. Suzuki T, Palus S, Springer J. Skeletal muscle wasting in chronic heart failure. ESC Heart Fail. 2018; 5(6): 1099–1107.
  3. Coats AJ. The "muscle hypothesis" of chronic heart failure. J Mol Cell Cardiol. 1996; 28(11): 2255–2262.
  4. Hirai D, Musch T, Poole D. Exercise training in chronic heart failure: improving skeletal muscle O2transport and utilization. Am J Physiol-Hear Circ Physiol. 2015; 309(9): H1419–H1439.
  5. Jankowska EA, Malyszko J, Ardehali H, et al. Iron status in patients with chronic heart failure. Eur Heart J. 2013; 34(11): 827–834.
  6. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J. 2013; 165(4): 575–582.e3.
  7. von Haehling S, Jankowska EA, van Veldhuisen DJ, et al. Iron deficiency and cardiovascular disease. Nat Rev Cardiol. 2015; 12(11): 659–669.
  8. Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013; 34(11): 816–829.
  9. Jankowska EA, Kirwan BA, Kosiborod M, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study. Eur Heart J. 2021; 42(31): 3011–3020.
  10. Ponikowski P, van Veldhuisen DJ, 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(11): 657–668.
  11. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361(25): 2436–2448.
  12. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016; 18(7): 786–795.
  13. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020; 396(10266): 1895–1904.
  14. Kobak KA, Radwańska M, Dzięgała M, et al. Structural and functional abnormalities in iron-depleted heart. Heart Fail Rev. 2019; 24(2): 269–277.
  15. Stugiewicz M, Tkaczyszyn M, Kasztura M, et al. The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications. Eur J Heart Fail. 2016; 18(7): 762–773.
  16. Dziegala M, Josiak K, Kasztura M, et al. Iron deficiency as energetic insult to skeletal muscle in chronic diseases. J Cachexia Sarcopenia Muscle. 2018; 9(5): 802–815.
  17. Kobak K, Kasztura M, Dziegala M, et al. Iron limitation promotes the atrophy of skeletal myocytes, whereas iron supplementation prevents this process in the hypoxic conditions. Int J Mol Med. 2018; 41(5): 2678–2686.
  18. Kasztura M, Dzięgała M, Kobak K, et al. Both iron excess and iron depletion impair viability of rat H9C2 cardiomyocytes and L6G8C5 myocytes. Kardiol Pol. 2017; 75(3): 267–275.
  19. Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of iron isomaltoside on skeletal muscle energetics in patients with chronic heart failure and iron deficiency. Circulation. 2019; 139(21): 2386–2398.
  20. Members AF, McMurray JJV, Adamopoulos S, et al. et al.. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Hear J. 2012; 33: 1787–1847.
  21. Scott AC, Wensel R, Davos CH, et al. Skeletal muscle reflex in heart failure patients: role of hydrogen. Circulation. 2003; 107(2): 300–306.
  22. Giannitsi S, Bougiakli M, Bechlioulis A, et al. 6-minute walking test: a useful tool in the management of heart failure patients. Ther Adv Cardiovasc Dis. 2019; 13: 1753944719870084.
  23. Faggiano P, D'Aloia A, Gualeni A, et al. The 6 minute walking test in chronic heart failure: indications, interpretation and limitations from a review of the literature. Eur J Heart Fail. 2004; 6(6): 687–691.
  24. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130(6): 461–470.
  25. Comin-Colet J, Lainscak M, Dickstein K, et al. The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study. Eur Heart J. 2013; 34(1): 30–38.
  26. Filippatos G, Ponikowski P, Farmakis D, et al. Association between hemoglobin levels and efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency: an AFFIRM-AHF subgroup analysis. Circulation. 2023; 147(22): 1640–1653.
  27. Filippatos G, Farmakis D, Colet JC, et al. Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial. Eur J Heart Fail. 2013; 15(11): 1267–1276.
  28. Kobak KA, Franczuk P, Schubert J, et al. Primary human cardiomyocytes and cardiofibroblasts treated with sera from myocarditis patients exhibit an increased iron demand and complex changes in the gene expression. Cells. 2021; 10(4).
  29. Dziegala M, Kobak KA, Kasztura M, et al. Iron depletion affects genes encoding mitochondrial electron transport chain and genes of non-oxidative metabolism, pyruvate kinase and lactate dehydrogenase, in primary human cardiac myocytes cultured upon mechanical stretch. Cells. 2018; 7(10).
  30. Dziegala M, Kasztura M, Kobak K, et al. Influence of the availability of iron during hypoxia on the genes associated with apoptotic activity and local iron metabolism in rat H9C2 cardiomyocytes and L6G8C5 skeletal myocytes. Mol Med Rep. 2016; 14(4): 3969–3977.
  31. Hoes MF, Grote Beverborg N, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018; 20(5): 910–919.