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Pyruvate augments mechanical function via activation of the pyruvate dehydrogenase complex in reperfused ischemic
Y Saiki1, G D Lopaschuk, K Dodge
1Division of Cardiovascular Surgery, University of Alberta, Edmonton, Alberta, T6G 2B7, Canada.
Insights
Pyruvate improves cardiac function in newborn rabbit hearts during reperfusion after ischemia. Supplementation activates pyruvate dehydrogenase complex (PDC) activity, enhancing mechanical performance and efficiency.
Area of Science:
- Cardiology
- Biochemistry
- Neonatal Physiology
Background:
- Ischemic adult hearts show reduced pyruvate oxidation and pyruvate dehydrogenase (PDH) activity, decreasing cardiac efficiency.
- Immature newborn hearts may experience amplified effects due to underdeveloped PDH pathways.
- This study investigates pyruvate's potential to enhance mechanical function in immature hearts during ischemia-reperfusion.
Purpose of the Study:
- To test the hypothesis that pyruvate augments mechanical function in immature hearts by activating the PDH complex (PDC) during reperfusion.
- To evaluate the impact of pyruvate supplementation on cardiac performance and PDC activity in neonatal rabbit hearts subjected to severe ischemia.
Main Methods:
- Isolated working hearts from 7-day-old rabbits were perfused with palmitate-containing Krebs solution.
- Pyruvate was administered either before or after a 30-minute normothermic global ischemia period.
- Cardiac function and PDC activity were measured and correlated throughout the protocol.
Main Results:
- Pyruvate addition before ischemia increased active PDC but did not improve function.
- During reperfusion, cardiac function was depressed; pyruvate significantly increased aortic flow, cardiac output, and developed pressure.
- Removing pyruvate led to decreased PDC activity and impaired cardiac function.
Conclusions:
- Pyruvate supplementation improves cardiac performance during reperfusion in neonatal rabbit hearts.
- This functional improvement is directly associated with the activation of the pyruvate dehydrogenase complex (PDC).
Background:
Reperfusion of ischemic adult hearts is associated with increased fatty acid oxidation, reduced pyruvate oxidation, and reduced pyruvate dehydrogenase (PDH) activity, leading to a decrease in cardiac efficiency. These effects may be amplified in newborn hearts because of the immaturity of their PDH pathway. We hypothesize that pyruvate can augment mechanical function in the immature heart by activating the PDH complex (PDC) during reperfusion in severely ischemic hearts.
Materials And Methods:
Seven-day old isolated working rabbit hearts (n = 12) were perfused with modified Krebs solution containing 0.4 mM palmitate. Pyruvate (5 mM) was added for a 10-min period either before or after a 30-min period of normothermic global ischemia. Cardiac functional indices before global ischemia and during reperfusion were correlated with active and total PDC activity measured in 28 additional hearts frozen at the various time points throughout the perfusion protocol.
Results:
Addition of pyruvate before ischemia increased the proportion of active PDC but did not affect any measured functional indices. During early reperfusion, aortic flow, cardiac output, and cardiac work were all significantly depressed compared to preischemic values. Addition of pyruvate significantly increased the proportion of active PDC and was also associated with a significant increase in aortic flow, cardiac work, and developed pressure. Removal of pyruvate from the perfusate resulted in a subsequent significant decrease in PDC activity and these functional parameters.
Conclusion:
During reperfusion of neonatal rabbit hearts, addition of pyruvate improves cardiac performance in association with activation of PDC.