PMID- 29127235 OWN - NLM STAT- MEDLINE DCOM- 20190107 LR - 20200930 IS - 1522-1539 (Electronic) IS - 0363-6135 (Print) IS - 0363-6135 (Linking) VI - 314 IP - 4 DP - 2018 Apr 1 TI - Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. PG - H704-H715 LID - 10.1152/ajpheart.00321.2017 [doi] AB - 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 Po(2). 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. FAU - Kuzmiak-Glancy, Sarah AU - Kuzmiak-Glancy S AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Covian, Raul AU - Covian R AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Femnou, Armel N AU - Femnou AN AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Glancy, Brian AU - Glancy B AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Jaimes, Rafael 3rd AU - Jaimes R 3rd AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. FAU - Wengrowski, Anastasia M AU - Wengrowski AM AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. FAU - Garrott, Kara AU - Garrott K AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. FAU - French, Stephanie A AU - French SA AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Balaban, Robert S AU - Balaban RS AD - Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland. FAU - Kay, Matthew W AU - Kay MW AD - Department of Biomedical Engineering, The George Washington University , Washington, District of Columbia. LA - eng GR - R01 HL095828/HL/NHLBI NIH HHS/United States GR - R21 HL132618/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20171110 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (Crystalloid Solutions) RN - 0 (Emulsions) RN - 0 (Fluorocarbons) RN - 0 (Krebs-Henseleit solution) RN - 0 (Myoglobin) RN - 023C2WHX2V (Tromethamine) RN - 9007-43-6 (Cytochromes c) RN - IY9XDZ35W2 (Glucose) RN - S88TT14065 (Oxygen) SB - IM CIN - Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H776-H779. PMID: 29351474 MH - Animals MH - Crystalloid Solutions/chemical synthesis/*pharmacology MH - Cytochromes c/metabolism MH - Emulsions MH - Fluorocarbons/chemical synthesis/*pharmacology MH - Glucose/pharmacology MH - Heart/*drug effects/physiology MH - Isolated Heart Preparation MH - Mitochondria, Heart/*drug effects/metabolism MH - Myocardial Contraction/*drug effects MH - Myoglobin/metabolism MH - Oxidation-Reduction MH - Oxidative Phosphorylation/drug effects MH - Oxygen/*metabolism MH - Oxygen Consumption/*drug effects MH - Perfusion/*methods MH - Rabbits MH - Tromethamine/pharmacology MH - Ventricular Function, Left/*drug effects PMC - PMC5966767 OTO - NOTNLM OT - cytochrome c oxidase OT - myoglobin oxygen saturation OT - oxidative phosphorylation OT - rabbit OT - rapid-scanning optical spectroscopy EDAT- 2017/11/12 06:00 MHDA- 2019/01/08 06:00 PMCR- 2019/04/01 CRDT- 2017/11/12 06:00 PHST- 2017/11/12 06:00 [pubmed] PHST- 2019/01/08 06:00 [medline] PHST- 2017/11/12 06:00 [entrez] PHST- 2019/04/01 00:00 [pmc-release] AID - ajpheart.00321.2017 [pii] AID - H-00321-2017 [pii] AID - 10.1152/ajpheart.00321.2017 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H704-H715. doi: 10.1152/ajpheart.00321.2017. Epub 2017 Nov 10.