Adaptive Cardiac Metabolism Under Chronic Hypoxia: Mechanism and Clinical Implications

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Feb 19

PMID 33604337

Citations 14

Authors

Zhanhao Su

Yiwei Liu

Hao Zhang

Affiliations

Soon will be listed here.

Abstract

Chronic hypoxia is an essential component in many cardiac diseases. The heart consumes a substantial amount of energy and it is important to maintain the balance of energy supply and demand when oxygen is limited. Previous studies showed that the heart switches from fatty acid to glucose to maintain metabolic efficiency in the adaptation to chronic hypoxia. However, the underlying mechanism of this adaptive cardiac metabolism remains to be fully characterized. Moreover, how the altered cardiac metabolism affects the heart function in patients with chronic hypoxia has not been discussed in the current literature. In this review, we summarized new findings from animal and human studies to illustrate the mechanism underlying the adaptive cardiac metabolism under chronic hypoxia. Clinical focus is given to certain patients that are subject to the impact of chronic hypoxia, and potential treatment strategies that modulate cardiac metabolism and may improve the heart function in these patients are also summarized.

Citing Articles

PGRMC2 is a pressure-volume regulator critical for myocardial responses to stress in mice.

Amirrad F, La V, Ohadi S, Albotaif M, Webster S, Pru J Nat Commun. 2025; 16(1):2422.

PMID: 40069180 PMC: 11897200. DOI: 10.1038/s41467-025-57707-8.

Cardiomyocytes in Hypoxia: Cellular Responses and Implications for Cell-Based Cardiac Regenerative Therapies.

Dwyer K, Snyder C, Coulombe K Bioengineering (Basel). 2025; 12(2).

PMID: 40001674 PMC: 11851968. DOI: 10.3390/bioengineering12020154.

Effects of a Three-Day vs. Six-Day Exposure to Normobaric Hypoxia on the Cardiopulmonary Function of Rats.

Bambor C, Daunheimer S, Raffort C, Koedel J, Salameh A, Rassler B Curr Issues Mol Biol. 2025; 47(2).

PMID: 39996846 PMC: 11854188. DOI: 10.3390/cimb47020125.

Association of electrocardiogram features with risk of obstructed sleep apnea: a population-based cohort study.

Wu C, Huang J, Huang M, Tan Y, Chen C, Zheng M Sleep Breath. 2025; 29(1):96.

PMID: 39934598 DOI: 10.1007/s11325-025-03266-7.

Prolonged Hypoxia in Rat Living Myocardial Slices Affects Function, Expression, and Structure.

Waleczek F, Cipriano G, Haas J, Garg A, Pfanne A, Just A Int J Mol Sci. 2025; 26(1.

PMID: 39796086 PMC: 11720517. DOI: 10.3390/ijms26010218.

References

Hochachka P, Clark C, Holden J, Stanley C, Ugurbil K, Menon R . 31P magnetic resonance spectroscopy of the Sherpa heart: a phosphocreatine/adenosine triphosphate signature of metabolic defense against hypobaric hypoxia. Proc Natl Acad Sci U S A. 1996; 93(3):1215-20. PMC: 40059. DOI: 10.1073/pnas.93.3.1215. View

Soccio R, Chen E, Lazar M . Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 2014; 20(4):573-91. PMC: 4192012. DOI: 10.1016/j.cmet.2014.08.005. View

Ge R, Simonson T, Cooksey R, Tanna U, Qin G, Huff C . Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. Mol Genet Metab. 2012; 106(2):244-7. PMC: 3437309. DOI: 10.1016/j.ymgme.2012.03.003. View

Lee D, Pagire H, Pagire S, Bae E, Dighe M, Kim M . Discovery of Novel Pyruvate Dehydrogenase Kinase 4 Inhibitors for Potential Oral Treatment of Metabolic Diseases. J Med Chem. 2019; 62(2):575-588. DOI: 10.1021/acs.jmedchem.8b01168. View

Clarke G, Solis-Herrera C, Molina-Wilkins M, Martinez S, Merovci A, Cersosimo E . Pioglitazone Improves Left Ventricular Diastolic Function in Subjects With Diabetes. Diabetes Care. 2017; 40(11):1530-1536. PMC: 5652586. DOI: 10.2337/dc17-0078. View

Boudina S, Abel E . Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in diabetes. Physiology (Bethesda). 2006; 21:250-8. DOI: 10.1152/physiol.00008.2006. View

Horscroft J, Burgess S, Hu Y, Murray A . Altered Oxygen Utilisation in Rat Left Ventricle and Soleus after 14 Days, but Not 2 Days, of Environmental Hypoxia. PLoS One. 2015; 10(9):e0138564. PMC: 4577132. DOI: 10.1371/journal.pone.0138564. View

Ryan S . Mechanisms of cardiovascular disease in obstructive sleep apnoea. J Thorac Dis. 2019; 10(Suppl 34):S4201-S4211. PMC: 6321896. DOI: 10.21037/jtd.2018.08.56. View

Kinota F, Droma Y, Kobayashi N, Horiuchi T, Kitaguchi Y, Yasuo M . The Contribution of Genetic Variants of the Peroxisome Proliferator-Activated Receptor-Alpha Gene to High-Altitude Hypoxia Adaptation in Sherpa Highlanders. High Alt Med Biol. 2018; 24(3):186-192. PMC: 10516232. DOI: 10.1089/ham.2018.0052. View

10.

Larsen S, Nielsen J, Hansen C, Nielsen L, Wibrand F, Stride N . Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol. 2012; 590(14):3349-60. PMC: 3459047. DOI: 10.1113/jphysiol.2012.230185. View

11.

Doronzo G, Russo I, Mattiello L, Riganti C, Anfossi G, Trovati M . Insulin activates hypoxia-inducible factor-1alpha in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impairment in insulin resistance owing to defects in insulin signalling. Diabetologia. 2006; 49(5):1049-63. DOI: 10.1007/s00125-006-0156-0. View

12.

Calmettes G, Deschodt-Arsac V, Thiaudiere E, Muller B, Diolez P . Modular control analysis of effects of chronic hypoxia on mouse heart. Am J Physiol Regul Integr Comp Physiol. 2008; 295(6):R1891-7. DOI: 10.1152/ajpregu.90548.2008. View

13.

Bertero E, Maack C . Metabolic remodelling in heart failure. Nat Rev Cardiol. 2018; 15(8):457-470. DOI: 10.1038/s41569-018-0044-6. View

14.

Bigham A, Lee F . Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev. 2014; 28(20):2189-204. PMC: 4201282. DOI: 10.1101/gad.250167.114. View

15.

Singh R, Cummings E, Pantos C, Singh J . Protein kinase C and cardiac dysfunction: a review. Heart Fail Rev. 2017; 22(6):843-859. PMC: 5635086. DOI: 10.1007/s10741-017-9634-3. View

16.

Kemp G, Rajagopalan B, Taylor D, Radda G, Haworth S . Magnetic resonance spectroscopy in congenital heart disease. Heart. 1996; 75(6):614-9. PMC: 484387. DOI: 10.1136/hrt.75.6.614. View

17.

Hochachka P, Lutz P . Mechanism, origin, and evolution of anoxia tolerance in animals. Comp Biochem Physiol B Biochem Mol Biol. 2001; 130(4):435-59. DOI: 10.1016/s1096-4959(01)00408-0. View

18.

Ferrannini E, Mark M, Mayoux E . CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016; 39(7):1108-14. DOI: 10.2337/dc16-0330. View

19.

Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi J . Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics. PLoS One. 2010; 5(2):e9306. PMC: 2823784. DOI: 10.1371/journal.pone.0009306. View

20.

Nouette-Gaulain K, Malgat M, Rocher C, Savineau J, Marthan R, Mazat J . Time course of differential mitochondrial energy metabolism adaptation to chronic hypoxia in right and left ventricles. Cardiovasc Res. 2005; 66(1):132-40. DOI: 10.1016/j.cardiores.2004.12.023. View