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Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart.
Am J Physiol Heart Circ Physiol. 2018 04 01; 314(4):H704-H715.AJ

Abstract

The left ventricular working, crystalloid-perfused heart is used extensively to evaluate basic cardiac function, pathophysiology, and pharmacology. Crystalloid-perfused hearts may be limited by oxygen delivery, as adding oxygen carriers increases myoglobin oxygenation and improves myocardial function. However, whether decreased myoglobin oxygen saturation impacts oxidative phosphorylation (OxPhos) is unresolved, since myoglobin has a much lower affinity for oxygen than cytochrome c oxidase (COX). In the present study, a laboratory-based synthesis of an affordable perfluorocarbon (PFC) emulsion was developed to increase perfusate oxygen carrying capacity without impeding optical absorbance assessments. In left ventricular working hearts, along with conventional measurements of cardiac function and metabolic rate, myoglobin oxygenation and cytochrome redox state were monitored using a novel transmural illumination approach. Hearts were perfused with Krebs-Henseleit (KH) or KH supplemented with PFC, increasing perfusate oxygen carrying capacity by 3.6-fold. In KH-perfused hearts, myoglobin was deoxygenated, consistent with cytoplasmic hypoxia, and the mitochondrial cytochromes, including COX, exhibited a high reduction state, consistent with OxPhos hypoxia. PFC perfusate increased aortic output from 76 ± 6 to 142 ± 4 ml/min and increased oxygen consumption while also increasing myoglobin oxygenation and oxidizing the mitochondrial cytochromes. These results are consistent with limited delivery of oxygen to OxPhos resulting in an adapted lower cardiac performance with KH. Consistent with this, PFCs increased myocardial oxygenation, and cardiac work was higher over a wider range of perfusate Po2. In summary, heart mitochondria are limited by oxygen delivery with KH; supplementation of KH with PFC reverses mitochondrial hypoxia and improves cardiac performance, creating a more physiological tissue oxygen delivery. NEW & NOTEWORTHY Optical absorbance spectroscopy of intrinsic chromophores reveals that the commonly used crystalloid-perfused working heart is oxygen limited for oxidative phosphorylation and associated cardiac work. Oxygen-carrying perfluorocarbons increase myocardial oxygen delivery and improve cardiac function, providing a more physiological mitochondrial redox state and emphasizing cardiac work is modulated by myocardial oxygen delivery.

Authors+Show Affiliations

Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia.Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia.Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia.Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29127235

Citation

Kuzmiak-Glancy, Sarah, et al. "Cardiac Performance Is Limited By Oxygen Delivery to the Mitochondria in the Crystalloid-perfused Working Heart." American Journal of Physiology. Heart and Circulatory Physiology, vol. 314, no. 4, 2018, pp. H704-H715.
Kuzmiak-Glancy S, Covian R, Femnou AN, et al. Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. Am J Physiol Heart Circ Physiol. 2018;314(4):H704-H715.
Kuzmiak-Glancy, S., Covian, R., Femnou, A. N., Glancy, B., Jaimes, R., Wengrowski, A. M., Garrott, K., French, S. A., Balaban, R. S., & Kay, M. W. (2018). Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. American Journal of Physiology. Heart and Circulatory Physiology, 314(4), H704-H715. https://doi.org/10.1152/ajpheart.00321.2017
Kuzmiak-Glancy S, et al. Cardiac Performance Is Limited By Oxygen Delivery to the Mitochondria in the Crystalloid-perfused Working Heart. Am J Physiol Heart Circ Physiol. 2018 04 1;314(4):H704-H715. PubMed PMID: 29127235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. AU - Kuzmiak-Glancy,Sarah, AU - Covian,Raúl, AU - Femnou,Armel N, AU - Glancy,Brian, AU - Jaimes,Rafael,3rd AU - Wengrowski,Anastasia M, AU - Garrott,Kara, AU - French,Stephanie A, AU - Balaban,Robert S, AU - Kay,Matthew W, Y1 - 2017/11/10/ PY - 2017/11/12/pubmed PY - 2019/1/8/medline PY - 2017/11/12/entrez KW - cytochrome c oxidase KW - myoglobin oxygen saturation KW - oxidative phosphorylation KW - rabbit KW - rapid-scanning optical spectroscopy SP - H704 EP - H715 JF - American journal of physiology. Heart and circulatory physiology JO - Am. J. Physiol. Heart Circ. Physiol. VL - 314 IS - 4 N2 - The left ventricular working, crystalloid-perfused heart is used extensively to evaluate basic cardiac function, pathophysiology, and pharmacology. Crystalloid-perfused hearts may be limited by oxygen delivery, as adding oxygen carriers increases myoglobin oxygenation and improves myocardial function. However, whether decreased myoglobin oxygen saturation impacts oxidative phosphorylation (OxPhos) is unresolved, since myoglobin has a much lower affinity for oxygen than cytochrome c oxidase (COX). In the present study, a laboratory-based synthesis of an affordable perfluorocarbon (PFC) emulsion was developed to increase perfusate oxygen carrying capacity without impeding optical absorbance assessments. In left ventricular working hearts, along with conventional measurements of cardiac function and metabolic rate, myoglobin oxygenation and cytochrome redox state were monitored using a novel transmural illumination approach. Hearts were perfused with Krebs-Henseleit (KH) or KH supplemented with PFC, increasing perfusate oxygen carrying capacity by 3.6-fold. In KH-perfused hearts, myoglobin was deoxygenated, consistent with cytoplasmic hypoxia, and the mitochondrial cytochromes, including COX, exhibited a high reduction state, consistent with OxPhos hypoxia. PFC perfusate increased aortic output from 76 ± 6 to 142 ± 4 ml/min and increased oxygen consumption while also increasing myoglobin oxygenation and oxidizing the mitochondrial cytochromes. These results are consistent with limited delivery of oxygen to OxPhos resulting in an adapted lower cardiac performance with KH. Consistent with this, PFCs increased myocardial oxygenation, and cardiac work was higher over a wider range of perfusate Po2. In summary, heart mitochondria are limited by oxygen delivery with KH; supplementation of KH with PFC reverses mitochondrial hypoxia and improves cardiac performance, creating a more physiological tissue oxygen delivery. NEW & NOTEWORTHY Optical absorbance spectroscopy of intrinsic chromophores reveals that the commonly used crystalloid-perfused working heart is oxygen limited for oxidative phosphorylation and associated cardiac work. Oxygen-carrying perfluorocarbons increase myocardial oxygen delivery and improve cardiac function, providing a more physiological mitochondrial redox state and emphasizing cardiac work is modulated by myocardial oxygen delivery. SN - 1522-1539 UR - https://www.unboundmedicine.com/medline/citation/29127235/Cardiac_performance_is_limited_by_oxygen_delivery_to_the_mitochondria_in_the_crystalloid_perfused_working_heart_ L2 - http://www.physiology.org/doi/full/10.1152/ajpheart.00321.2017?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -