American Journal of Physiology - Heart and Circulatory Physiology
American Journal of Physiology - Heart and Circulatory Physiology
5 years ago

Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart.

Armel N Femnou, Brian Glancy, Anastasia M Wengrowski, Sarah Kuzmiak-Glancy, Stephanie French, Robert S Balaban, Matthew W Kay, Rafael Jaimes, Raul Covian, Kara Garrott
The left ventricular (LV) 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 LV 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 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; supplementing KH with PFC reverses mitochondrial hypoxia and improves cardiac performance, creating a more physiological tissue oxygen delivery.

Publisher URL: http://doi.org/10.1152/ajpheart.00321.2017

DOI: 10.1152/ajpheart.00321.2017

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