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Interval hypoxic conditioning: systemic and molecular mechanisms, possibilities of use in clinical practice

Authors: Buziashvili Yu.I., Koksheneva I.V., Turakhonov T.K., Dzhalilov M.A.

Company: Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, Russian Federation

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Type:  Reviews


DOI: https://doi.org/10.24022/1997-3187-2026-20-2-208-220

For citation: Buziashvili Yu.I., Koksheneva I.V., Turakhonov T.K., Dzhalilov M.A. Interval hypoxic conditioning: systemic and molecular mechanisms, possibilities of use in clinical practice. Creative Cardiology. 2026; 20 (2): 208–220 (in Russ.). DOI: 10.24022/1997-3187- 2026-20-2-208-220

Received / Accepted:  12.01.2026 / 29.01.2026

Keywords: interval hypoxic conditioning adaptive mechanisms in hypoxia hypoxic therapy in the treatment of cardiovascular diseases



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Abstract

The intermittent hypoxic conditioning approach is based on alternating exposure to hypoxic and normo-/hyperoxic conditions, facilitating adaptation to reduced oxygen availability. This technique, originally used in sports and altitude medicine, has shown promise in the treatment and rehabilitation of a variety of diseases.

This review presents data from studies investigating the protective role of intermittent hypoxic conditioning and its underlying mechanisms, demonstrating its potential in protecting organs and treating a wide range of diseases. The adaptive mechanisms induced by hypoxic conditioning include a number of processes, such as improved mitochondrial function, decreased oxidative stress, inflammation, and apoptosis, as well as increased expression of hypoxic genes, improving metabolic status.

The potential beneficial effects of hypoxic conditioning have been demonstrated in many areas, showing clinical efficacy: for example, lowering blood pressure in patients with hypertension, reducing coronary artery symptoms in patients with stable coronary artery disease, promoting faster and more complete recovery after coronary artery bypass grafting, preserving cognitive function in the elderly, promoting weight loss in overweight individuals.

Given that intermittent hypoxic conditioning promotes beneficial physiological responses in many organs and systems, this review aims to draw attention to the potential for clinical application of interval hypoxic conditioning as a multi-organ protective strategy.

References

  1. Luks A.M., Hackett P.H. Medical conditions and high-altitude travel. New Eng. J. Medicine. 2022; 386 (4): 364–373. DOI: 10.1056/NEJMra2104829.
  2. Buziashvili Yu.I., Koksheneva I.V., Tugeeva E.F. et al. Do genetic factors affect the development of hyperlactataemia after cardiac surgery? The Bulletin of Bakoulev Center. Cardiovascular Diseases. 2020; 21 (4): 388–397 (in Russ.). DOI: 10.24022/1810-0694-2020-21-4-388-397.
  3. Kupryashov A.A., Rivnyak M.I. Hypoxia and iron deficiency: synergistic effects on the body. Clinical Physiology of Circulation. 2022; 19 (1): 57–69 (in Russ.). DOI: 10.24022/1814-6910-2022-19-1-57-69.
  4. Tokmakova K.A., Kupryashov A.A., Zhemarina D.Sh. et al. Mechanisms and prognosis of tissue hypoxia development in patients with late thrombocytopenia after surgery with artificial circulation. The Bulletin of Bakoulev Center. Cardiovascular Diseases. 2024; 25 (S3): 144 (in Russ.).
  5. Trembach N.V., Trembach I.A., Zabolotskikh I.B. Peripheral chemoreception in chronic heart failure: approaches to study and clinical significance. Clinical Physiology of Circulation. 2024; 21 (3): 182–200 (in Russ.). DOI: 10.24022/1814-6910-2024-21-3-182-200.
  6. Schito L., Semenza G.L. Hypoxia-inducible factors: Master regulators of cancer progression. Trends in Cancer. 2016; 2 (12): 758–770. DOI: 10.1016/j.trecan.2016.10.016.
  7. Panza G.S., Alex R.M., Yokhana S.S. et al. Increased oxidative stress, loop gain and the arousal threshold are clinical predictors of increased apnea severity following exposure to intermittent hypoxia. Nature and Science of Sleep. 2019; 11: 265–279. DOI: 10.2147/NSS.S228100.
  8. Glazachev O., Kopylov P., Susta D. et al. Adaptations following an intermittent hypoxia-hyperoxia training in coronary artery disease patients: A controlled study. Clinical Cardiology. 2017; 40 (6): 370–376 (in Russ.). DOI: 10.1002/clc.22670.
  9. Burtscher J., Romani M., Bernardo G. et al. Boosting mitochondrial health to counteract neurodegeneration. Progress in Neurobiology. 2022; 215: 102289. DOI: 10.1016/j.pneurobio.2022.102289.
  10. Gibson O.R., Taylor L., Watt P.W., Maxwell N.S. Cross-adaptation: Heat and cold adaptation to improve physiological and cellular responses to hypoxia. Sports Medicine. 2017; 47 (9): 1751–1768. DOI: 10.1007/s40279-017-0717-z.
  11. Burtscher J., Mallet R.T., Pialoux V. et al. Adaptive responses to hypoxia and/or hyperoxia in humans. Antioxidants & Redox Signaling. 2022; 37 (13–15): 887–912. DOI: 10.1089/ars.2021.0280.
  12. Burtscher J., Hohenauer E., Burtscher M. et al. Environmental and behavioral regulation of HIF-mitochondria crosstalk. Free Radical Biology & Medicine. 2023; 206: 63–73. DOI: 10.1016/j.freeradbiomed.2023.06.015.
  13. Smith K.A., Waypa G.B., Schumacker P.T. Redox signaling during hypoxia in mammalian cells. Redox Biology. 2017; 13: 228–234. DOI: 10.1016/j.redox.2017.05.020.
  14. Taylor C.T., Scholz C.C. The effect of HIF on metabolism and immunity. Nature Reviews Nephrology. 2022; 18 (9): 573–587. DOI: 10.1038/s41581-022-00587-8.
  15. Cartwright I.M., Colgan S.P. The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution. Frontiers in Immunology. 2023; 14: 1124774. DOI: 10.3389/fimmu.2023.1124774.
  16. Li G., Guan Y., Gu Y. et al. Intermittent hypoxic conditioning restores neurological dysfunction of mice induced by long-term hypoxia. CNS Neuroscience & Therapeutics. 2023; 29 (1): 202–215. DOI: 10.1111/cns.13996.
  17. Panza G.S., Puri S., Lin H.o-S. et al. Daily exposure to mild intermittent hypoxia reduces blood pressure in male OSA patients with hypertension. American Journal of Respiratory and Critical Care Medicine. 2022; 205 (8): 949–958. DOI: 10.1164/rccm.202108-1808OC.
  18. Glazachev O.S., Kryzhanovskaya S.Yu., Zapara M.A. et al. Safety and efficacy of intermittent hypoxia conditioning as a new rehabilitation/secondary prevention strategy for patients with cardiovascular diseases: A systematic review and meta-analysis. Current Cardiology Reviews. 2021; 17 (6): e051121193317. DOI: 10.2174/1573403X17666210514005235.
  19. Manukhina E.B., Belkina L.M., Terekhina O.L. et al. Normobaric, intermittent hypoxia conditioning is cardio- and vasoprotective in rats. Experimental Biology and Medicine. 2013; 238 (12): 1413–1420. DOI: 10.1177/1535370213508718.
  20. Bestavashvili A., Glazachev O., Bestavashvili A. et al. The effects of intermittent hypoxic–hyperoxic exposures on lipid profile and inflammation in patients with metabolic syndrome. Frontiers in Cardiovascular Medicine. 2021; 8: 700826. DOI: 10.3389/fcvm.2021.700826.
  21. Jarrard C.P., Nagel M.J., Stray-Gundersen S. et al. Hypoxic preconditioning attenuates ischemia-reperfusion injury in young healthy adults. Journal of Applied Physiology. 2021; 130 (3): 846–852. DOI: 10.1152/japplphysiol.00772.2020.
  22. Stray-Gundersen S., Massoudian S.D., Wojan F. et al. Hypoxic preconditioning reduces endothelial ischemia-reperfusion injury in older adults. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. 2022; 323 (5): R832–R838. DOI: 10.1152/ajpregu.00200.2022.
  23. Ryou M.G., Sun J., Oguayo K.N. et al. Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion. Experimental Biology and Medicine. 2008; 233 (6): 766–774. DOI: 10.3181/0710-RM-282.
  24. Golukhova E., Sigaev I., Keren M. et al. Early and Long-Term Results of Simultaneous and Staged Revascularization of Coronary and Carotid Arteries. Pathophysiology. 2024; 31 (2): 210–224. DOI: 10.3390/pathophysiology31020017.
  25. Tobin B., Costalat G., Renshaw G.M. Intermittent not continuous hypoxia provoked haematological adaptations in healthy seniors: Hypoxic pattern may hold the key. European Journal of Applied Physiology. 2020; 120 (3): 707–718. DOI: 10.1007/s00421-020-04310-y.
  26. Tobin B., Costalat G., Renshaw G.M.C. Pre-acclimation to altitude in young adults: Choosing a hypoxic pattern at sea level which provokes significant haematological adaptations. European Journal of Applied Physiology. 2022; 122 (2): 395–407. DOI: 10.1007/s00421-021-04837-8.
  27. Etulain J., Negrotto S., Carestia A. et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thrombosis and Haemostasis. 2012; 107 (01): 99–110. DOI: 10.1160/TH11-06-0443.
  28. Ehrenreich H., Garcia-Agudo L.F., Steixner-Kumar A.A. et al. Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance. Molecular Psychiatry. 2022; 27 (5): 2372–2379. DOI: 10.1038/s41380-022-01551-5.
  29. Raberin A., Burtscher J., Connes P., Millet G.P. Hypoxia and hemorheological properties in older individuals. Ageing Research Reviews. 2022; 79: 101650. DOI: 10.1016/j.arr.2022.101650.
  30. Siebenmann C., Robach P., Lundby C. Regulation of blood volume in lowlanders exposed to high altitude. Journal of Applied Physiology. 2017; 123 (4): 957–966. DOI: 10.1152/japplphysiol.00118.2017.
  31. Pernett F., Schagatay F., Vildevi C., Schagatay E. Spleen contraction during sudden eupneic hypoxia elevates hemoglobin concentration. Frontiers in Physiology. 2021; 12: 729123. DOI: 10.3389/fphys.2021.729123.
  32. Schlittler M., Gatterer H., Turner R. et al. Regulation of plasma volume in male lowlanders during 4 days of exposure to hypobaric hypoxia equivalent to 3500 m altitude. Journal of Physiology. 2021; 599 (4): 1083–1096. DOI: 10.1113/JP280601.
  33. Lee P., Chandel N.S., Simon M.C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nature Reviews Molecular Cell Biology. 2020; 21 (5): 268–283. DOI: 10.1038/s41580-020-0227-y.
  34. Pesta D., Heieis J., Hand O. et al. Case report: Muscle wasting during severe sustained hypoxia in two professional mountaineers. Medicine and Science in Sports and Exercise. 2023; 55 (3): 335–341. DOI: 10.1249/MSS.0000000000003060.
  35. Netzer N., Gatterer H., Faulhaber M. et al. Hypoxia, oxidative stress and fat. Biomolecules. 2015; 5 (2): 1143–1150. DOI: 10.3390/biom5021143.
  36. Soo J., Raman A., Lawler N.G. et al. The role of exercise and hypoxia on glucose transport and regulation. European Journal of Applied Physiology. 2023; 123 (6): 1147–1165. DOI: 10.1007/s00421-023-05135-1.
  37. Mackenzie R., Maxwell N., Castle P. et al. Acute hypoxia and exercise improve insulin sensitivity (S(I)2*) in individuals with type 2 diabetes. Diabetes Metabolism Research and Reviews. 2011; 27 (1): 94–101. DOI: 10.1002/dmrr.1156.
  38. Midha A.D., Zhou Y., Queliconi B.B. et al. Organ-specific fuel rewiring in acute and chronic hypoxia redistributes glucose and fatty acid metabolism. Cell Metabolism. 2023; 35 (3): 504–516. DOI: 10.1016/j.cmet.2023.02.007.
  39. Rybnikova E., Glushchenko T., Tyulkova E. et al. Mild hypobaric hypoxia preconditioning up-regulates expression of transcription factors c-Fos and NGFI-A in rat neocortex and hippocampus. Neuroscience Research. 2009; 65: 360–366. DOI: 10.1016/j.neures.2009.08.013.
  40. Aboouf M.A., Thiersch M., Soliz J. et al. The brain at high altitude: From molecular signaling to cognitive performance. International Journal of Molecular Sciences. 2023; 24 (12): 10179. DOI: 10.3390/ijms241210179.
  41. Carr J.M.J.R., Caldwell H.G., Ainslie P.N. Cerebral blood flow, cerebrovascular reactivity and their influence on ventilatory sensitivity. Experimental Physiology. 2021; 106 (7): 1425–1448. DOI: 10.1113/EP089446.
  42. Bailey D.M., Bain A.R., Hoiland R.L. et al. Hypoxemia increases blood-brain barrier permeability during extreme apnea in humans. Journal of Cerebral Blood Flow and Metabolism. 2022; 42 (6): 1120–1135. DOI: 10.1177/0271678X221075967.
  43. Manukhina E.B., Downey H.F., Shi X., Mallet R.T. Intermittent hypoxia training protects cerebrovascular function in Alzheimer’s disease. Experimental Biology and Medicine. 2016; 241 (12): 1351–1363. DOI: 10.1177/1535370216649060.
  44. Guan Y., Liu J., Gu Y., Ji X. Effects of hypoxia on cerebral microvascular angiogenesis: Benefits or damages? Aging and Disease. 2023; 14 (2): 370–385. DOI: 10.14336/AD.2022.0902.
  45. Bayer U., Likar R., Pinter G. et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimer’s & Dementia. 2017; 3: 114–122. DOI: 10.1016/j.trci.2017.01.002.
  46. Serebrovska Z.O., Xi L., Tumanovska L.V. et al. Response of circulating inflammatory markers to intermittent hypoxia-hyperoxia training in healthy elderly people and patients with mild cognitive impairment. Life. 2022; 12 (3): 432. DOI: 10.3390/life12030432.
  47. Behrendt T., Bielitzki R., Behrens M. et al. Effects of intermittent hypoxia-hyperoxia on performance- and health-related outcomes in humans: A systematic review. Sports Medicine Open. 2022; 8 (1): 70. DOI: 10.1186/s40798-022-00450-x.
  48. Scott B.R., Slattery K.M., Sculley D.V. et al. Acute physiological responses to moderate-load resistance exercise in hypoxia. Journal of Strength and Conditioning Research. 2017; 31: 1973–1981. DOI: 10.1519/JSC.0000000000001649.
  49. Spaulding H.R., Yan Z. AMPK and the adaptation to exercise. Annual Review of Physiology. 2022; 84 (1): 209–227. DOI: 10.1146/annurev-physiol-060721-095517.
  50. Lestón Pinilla L., Ugun-Klusek A., Rutella S., De Girolamo L.A. Hypoxia signaling in Parkinson’s disease: There is use in asking “What HIF?”. Biology. 2021; 10: 723. DOI: 10.3390/biology10080723.
  51. Burtscher J., Maglione V., Di Pardo A. et al. A rationale for hypoxic and chemical conditioning in Huntington’s disease. International Journal of Molecular Sciences. 2021; 22 (2): 582. DOI: 10.3390/ijms22020582.
  52. Tan A.Q., Barth S., Trumbower R.D. Acute intermittent hypoxia as a potential adjuvant to improve walking following spinal cord injury: Evidence, challenges, and future directions. Current Physical Medicine and Rehabilitation Reports. 2020; 8 (3): 188–198. DOI: 10.1007/s40141-020-00270-8.
  53. Hayes H.B., Jayaraman A., Herrmann M. et al. Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology. 2014; 82 (2): 104–113. DOI: 10.1212/01.WNL.0000437416.34298.43.
  54. Savla J.J., Levine B.D., Sadek H.A. The Effect of Hypoxia on Cardiovascular Disease: Friend or Foe? High Altitude Medicine & Biology. 2018; 19: 124–130. DOI: 10.1089/ham.2018.0044.
  55. Dzhitava T.G., Shamsiev G.A., Abdulloev O.K. et al. Determining factors of early rehabilitation of patients after open heart surgery. Grudnaya i Serdechno-Sosudistaya Khirurgiya. 2024; 66 (1): 99–112 (in Russ.). DOI: 10.24022/0236-2791-2024-66-1-99-112.

About Authors

  • Yuri I. Buziashvili, Dr. Med. Sci., Professor, Academician of the Russian Academy of Sciences, Head of the Clinical Diagnostic Department; ORCID
  • Inna V. Koksheneva, Dr. Med. Sci., Senior Researcher; ORCID
  • Temur K. Turakhonov, Cand. Med. Sci., Cardiologist; ORCID
  • Murad A. Jalilov, Cand. Med. Sci., Cardiologist

Chief Editor

Elena Z. Golukhova, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, Director of Bakoulev National Medical Research Center for Cardiovascular Surgery


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