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Interplay of hypoxia-inducible factors and oxygen therapy in cardiovascular medicine

Nature Reviews Cardiology volume 20, pages 723–737 (2023)Cite this article

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Abstract

Mammals have evolved to adapt to differences in oxygen availability. Although systemic oxygen homeostasis relies on respiratory and circulatory responses, cellular adaptation to hypoxia involves the transcription factor hypoxia-inducible factor (HIF). Given that many cardiovascular diseases involve some degree of systemic or local tissue hypoxia, oxygen therapy has been used liberally over many decades for the treatment of cardiovascular disorders. However, preclinical research has revealed the detrimental effects of excessive use of oxygen therapy, including the generation of toxic oxygen radicals or attenuation of endogenous protection by HIFs. In addition, investigators in clinical trials conducted in the past decade have questioned the excessive use of oxygen therapy and have identified specific cardiovascular diseases in which a more conservative approach to oxygen therapy could be beneficial compared with a more liberal approach. In this Review, we provide numerous perspectives on systemic and molecular oxygen homeostasis and the pathophysiological consequences of excessive oxygen use. In addition, we provide an overview of findings from clinical studies on oxygen therapy for myocardial ischaemia, cardiac arrest, heart failure and cardiac surgery. These clinical studies have prompted a shift from liberal oxygen supplementation to a more conservative and vigilant approach to oxygen therapy. Furthermore, we discuss the alternative therapeutic strategies that target oxygen-sensing pathways, including various preconditioning approaches and pharmacological HIF activators, that can be used regardless of the level of oxygen therapy that a patient is already receiving.

Key points

  • Patients with cardiovascular disease frequently experience hypoxia, which can be systemic or localized.

  • Hypoxia causes the stabilization of hypoxia-inducible factor (HIF) transcription factors, which promote adaptive responses to limited oxygen availability, precondition the heart and increase resistance to acute ischaemia.

  • In the past 12 decades, oxygen therapy has been used extensively in patients with cardiovascular disease to treat or prevent hypoxia but often leads to unintended high oxygen levels (hyperoxia).

  • Hyperoxia is associated with the excessive production of reactive oxygen species and also dampens endogenous adaptive responses to hypoxia, including HIF stabilization, thereby exacerbating organ injury.

  • The findings from several clinical trials from the past 10 years support a more conservative and vigilant approach to oxygen therapy in specific cardiovascular disease contexts, including myocardial infarction, cardiac arrest, heart failure or cardiac surgery.

  • Alternative approaches targeting oxygen-sensing pathways include preconditioning approaches or newly developed pharmacological agents that promote the stabilization of HIFs; these therapeutic interventions are being developed for the treatment of cardiovascular disease and can be applied independently of the level of oxygen therapy that a patient is receiving.

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Fig. 1: Responses of HIFs to hypoxia or hyperoxia.
Fig. 2: Pathophysiological effects of hyperoxia on the cardiovascular system.
Fig. 3: Oxygen targets during cardiovascular disease and acute illness.
Fig. 4: Molecular mechanisms of preconditioning, postconditioning and RIPC for cardioprotection.

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Acknowledgements

The authors were awarded the following grants: the Natural Science Foundation of Hunan Province Grant (2018JJ3736), Hunan Youth Talents Program (2021RC3034) and the 2022 International Anaesthesia Research Society Mentored Research Award to W.R.; the American Thoracic Society Unrestricted Grant, American Heart Association Career Development Award (19CDA34660279), American Lung Association Catalyst Award (CA-622265), the Center for Clinical and Translational Sciences McGovern Medical School Pilot Award (1UL1TR003167–01) and the Parker B. Francis Fellowship to X.Y.; National Institute of Health grants (R01HL154720, R01DK122796, R01DK109574, R01HL133900) and the Department of Defense Grant (W81XWH2110032) to H.K.E.

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  1. These authors contributed equally: Yafen Liang, Wei Ruan.

Authors and Affiliations

  1. Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA

    Yafen Liang, Wei Ruan, Yandong Jiang, Xiaoyi Yuan & Holger K. Eltzschig

  2. Department of Cardiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA

    Richard Smalling

  3. Outcomes Research Consortium, Cleveland, OH, USA

    Holger K. Eltzschig

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Contributions

Y.L. and H.K.E. researched data for the article. Y.L., Y.J., X.Y. and H.K.E. contributed to the discussion of its content. Y.L., W.R., Y.J., X.Y. and H.K.E. wrote the manuscript, and all the authors contributed to reviewing and editing the manuscript before submission.

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Correspondence to Yafen Liang.

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X.Y. and H.K.E. have received a sponsored research contract from Akebia Therapeutics. The other authors declare no competing interests.

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Liang, Y., Ruan, W., Jiang, Y. et al. Interplay of hypoxia-inducible factors and oxygen therapy in cardiovascular medicine. Nat Rev Cardiol 20, 723–737 (2023). https://doi.org/10.1038/s41569-023-00886-y

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