Abstract 13523: Extracorporeal Membrane Oxygenation Stimulates Myocardial Protein Synthesis without Altering Leucine Oxidation in Immature Swine in vivo
Introduction: Extracorporeal Membrane Oxygenation (ECMO) serves as a mechanical circulatory support bridge to recovery in children, allowing the heart to overcome severe insults such as ischemia/reperfusion injury. ECMO unloads the left ventricle, decreasing contractile work and oxygen consumption. Decreased loading can induce myocardial atrophy, which may affect recovery of function. The mechanisms leading to myocardial atrophy and dysfunction are unclear, but may relate to alterations in protein synthesis or degradation with increases in amino acid (AA) oxidation.
Hypothesis: We tested the hypothesis that ventricular unloading (ECMO) increases AA contribution to oxidative flux while decreasing AA protein incorporation.
Methods: We placed immature swine (7.8-14.5 kg, n=16) under general anesthesia and provided intracoronary infusion of 13C6, 15N L-leucine alone or with sodium 2-13C pyruvate after 8 hours of loaded (LOAD) or ECMO conditions (arterial pulse pressure: 26 ± 2.3 mmHg vs. 6 ± 1.1 mmHg (p<0.001). We determined substrate fractional contributions (FC) to the citric acid cycle (CAC) using 13C-NMR spectroscopy and glutamate isotopomer analyses, and CAC intermediate and leucine enrichment patterns and protein fractional synthesis rates (FSR) with GC-MS.
Results: ECMO did not alter total leucine FC (FCLeu LOAD 0.06±0.01 vs. FCLeu ECMO 0.08±0.02, p>0.2) or leucine FC relative to pyruvate (FCLeu/Pyr LOAD 0.09±0.02 vs. FCLeu/Pyr ECMO 0.12±0.02, p>0.3). ECMO decreased overall CAC intermediate enrichment, but did not alter anaplerotic entry into the CAC. FSR increased under ECMO (0.91%±0.04% vs. 0.63%±0.10%, p<0.05), but only in the absence of pyruvate. ECMO also increased mTOR phosphorylation (by immunoblot).
Conclusions: The early phase of ventricular unloading does not alter leucine oxidative contribution or apparent anaplerotic CAC entry from other AA. Surprisingly, ECMO preserves and may stimulate myocardial protein synthesis, possibly by activating the mTOR pathway. Activation of protein synthesis depends on substrate supply, as pyruvate inhibits leucine transmembrane transport in both LOAD and ECMO conditions. Thus, substrate can be used to manipulate protein synthesis during conditions promoting cardiac atrophy.
- © 2011 by American Heart Association, Inc.