(32 - Saturday) Effects of kynurenine pathway blockade on myocardial and kidney mitochondrial respiration in a swine model of pediatric cardiopulmonary bypass with deep hypothermic circulatory arrest.
Associate Professor Children's Hospital Colorado/University of Colorado, United States
Abstract: Introduction/
Objectives: Cardiac surgery with cardiopulmonary bypass (CPB) results in mitochondrial dysfunction in multiple organs including the heart, brain, and kidneys. The etiology of this dysfunction is not well understood. Tryptophan catabolism through the kynurenine pathway (KP) is the sole source of de novo nicotinamide adenine dinucleotide (NAD) production, a key substrate for mitochondrial Complex I during respiration. We hypothesized that blockade of the KP with high dose intravenous linrodostat, a selective inhibitor of indoleamine 2,3-dioxygenase, would result in decreased tissue mitochondrial respiration and provide evidence to support de novo NAD production as a modulator of mitochondrial function/dysfunction following CPB.
Methods: Infant swine (7-10kg) underwent either CPB with 75min of deep hypothermic circulatory arrest (DHCA) followed by 6 hours of ICU care (n=4) or 12 hours of mechanical ventilation without CPB/DHCA (controls; n=2). Two of the CPB/DHCA animals received 75mg of intravenous linrodostat, divided equally between pre- and post-CPB doses. Following euthanasia, 10-15mg pieces of kidney cortex and left ventricle were collected and stored in BIOPS solution. Mitochondrial respiration was measured using a highâresolution respirometer (Oroboros O2k, Oroboros, Innsbruck, Austria).
Results: CPB/DHCA significantly increased mitochondrial respiration in the heart compared to mechanically ventilated controls, while kidney mitochondrial respiration was unchanged (Figure 1A and B). Linrodostat significantly decreased mitochondrial respiration in both the heart and kidney (Figure 1A and B). Upon addition of the Complex I inhibitor, rotenone, O2 flux of CPB/DHCA-exposed heart tissue became equivalent to controls, indicating that an increase in Complex I activity is the major mechanism of increased myocardial respiration after CPB/DHCA. The relative contribution of mitochondrial Complex II to maximal respiration (rotenone/uncoupled; r/u) varied by organ, with a markedly greater contribution of Complex II in the kidney compared to the heart (Figure 1C and D).
Conclusions: CPB/DHCA acutely increased myocardial mitochondrial respiration while not significantly affecting kidney respiration. The difference in myocardial respiration was largely attributable to an increase in Complex I activity. As hypothesized, blockade of the KP with intravenous linrodostat decreased respiration in both the heart and kidney, pointing to a central role for this pathway in the maintenance of mitochondrial function. Further research is needed to determine if the paradoxical increase in myocardial respiration is protective or harmful (via increased reactive oxygen species production) and if KP/NAD modulation represents a potential novel therapeutic strategy for postoperative organ protection.
