Cardiac Metabolism and Protein Synthesis during Extracorporeal Life Support
EMSL Project ID
46708
Abstract
Mechanical Circulatory Support (MCS) in the form of cardiopulmonary bypass (CPB) is commonly used for infants and children. Extracorporeal life support (ECLS) also a form of MCS remains the primary method of long term support after myocardial stunning caused by cardiac surgery in this age group. ECLS provides a bridge to recovery in these young patients. However, ventricular unloading with ECLS also promotes cardiac atrophy. Therefore, this ther-apy can be counterproductive in initiating reparative processes leading to restoration of normal cardiac function. Nutritional and/or insulin therapy has been considered as a therapy, but do not alter overall energy balance in ECLS patients. Substantial abnormalities in hormonal homeosta-sis, such as decreases in circulating levels of thyroid hormone (TH), occur during ECLS. We have identified TH as an important modifier of cardiac metabolism in the developing heart. These modifications occur through transcriptional pathways involving nuclear receptors, and more direct post-transcriptional and post-translational mechanisms, which control substrate utili-zation. Disruptions in TH homeostasis can alter substrate utilization and deplete citric acid cy-cle (CAC) intermediates, possibly effecting net protein turnover. Additionally, we have noted that pyruvate supplementation can improve cardiac function after CPB in immature pigs. TH sup-plementation under CPB promotes pyruvate entry into the citric acid cycle, and promotes me-tabolite conversion to amino acids. Thus, appropriate substrate supplementation may improve protein synthesis and functional recovery after protracted ECLS. However, the mechanisms controlling protein synthesis lack clarity. We will study ECLS in the immature pig, an appropriate translational model for children undergoing these procedures. We will test the primary hypothe-ses: 1) impaired substrate utilization during ventricular unloading (ECLS)) causes dysfunction of the immature heart; 2) Targeted metabolic interventions in combination with TH supplementa-tion will minimize the adverse effects of ECLS and thereby improve longer term functional re-covery and survival. As promoted in the EMSL Proposal Call Focus, we will use multidiscipli-nary EMSL capabilities (LC-NMR, LC-MS, GC-MS) in conjunction with our complex operative model to study this problem. EMSL capabilities, including newly purchased ARRA LC-MS and LC-NMR-MS, will provide a comprehensive integrated approach to studying cardiac metabolism and protein synthesis in a true translational model. Techniques and methodologies developed for this proposal will have broad application to cellular metabolic network analysis, addressing the 'analysis and reconstruction of intercellular and intracellular networks' component of the EMSL Biological Interactions and Dynamics Science Theme. Specific Aims 1. Determine if metabolic abnormalities, leading to cardiac dysfunction and atrophy can be treated by supplementing the CAC with pyruvate via two distinct pathways: carboxylation and decarboxylation. Determine if pyruvate combined with TH supplementation (T3): a) accelerates flux through these pyruvate pathways, b) reduces oxidation of amino acids, c) stimulates transamination to amino acids and d) improves cardiac function and protein synthesis after a prolonged period of ventricular unloading. Explore the mechanisms involved in altering protein synthesis including regulation of signaling cascades by phosphorylation. 2. Determine if supplementation of medium chain fatty acids with and/or without TH maintains citric acid cycle intermediates, inhibits oxidation of amino acids, and promotes protein synthesis during unloading by mechanical circulatory support.
Project Details
Project type
Exploratory Research
Start Date
2011-12-20
End Date
2013-02-12
Status
Closed
Released Data Link
Team
Principal Investigator
Related Publications
Kajimoto M, CM O'Kelly-Priddy, DR Ledee, C Xu, NG Isern, A Olson, and MA Portman. 2013. "Extracorporeal membrane oxygenation promotes long chain fatty acid oxidation in the immature swine heart in vivo." Journal of Molecular and Cellular Cardiology 62:144-152. doi:10.1016/j.yjmcc.2013.05.014
Kajimoto M, CM Priddy, D Ledee, C Xu, NG Isern, A Olson, C Des Rosiers, and MA Portman. 2013. "Myocardial Reloading after Extracorporeal Membrane Oxygenation Alters Substrate Metabolism While Promoting Protein Synthesis." Journal of the American Heart Association 2(4):Article No. e000106. doi:10.1161/JAHA.113.000106
Kajimoto M, DB Atkinson, DR Ledee, EB Kayser, PG Morgan, MM Sedensky, NG Isern, C Des Rosiers, and MA Portman. 2014. "Propofol Compared to Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex in Vivo ." Journal of Cerebral Blood Flow and Metabolism. doi:10.1038/jcbfm.2013.229
Ledee D, MA Portman, M Kajimoto, NG Isern, and A Olson. 2013. "THYROID HORMONE REVERSES AGING-INDUCED MYOCARDIAL FATTY ACID OXIDATION DEFECTS AND IMPROVES THE RESPONSE TO ACUTELY INCREASED AFTERLOAD." PLoS One 8(6):e65532. doi:10.1371/journal.pone.0065532
Olson A, B Bouchard, XH Ning, NG Isern, C Des Rosiers, and MA Portman. 2012. "TRIIODOTHYRONINE INCREASES MYOCARDIAL FUNCTION AND PYRUVATE ENTRY INTO THE CITRIC ACID CYCLE AFTER REPERFUSION IN A MODEL OF INFANT CARDIOPULMONARY BYPASS ." American Journal of Physiology. Heart and Circulatory Physiology 302(5):H1086-H1093.
Olson A, D Ledee, K Iwamoto, M Kajimoto, CM O'Kelly-Priddy, NG Isern, and MA Portman. 2013. "C-Myc Induced Compensated Cardiac Hypertrophy Increases Free Fatty Acid Utilization for the Citric Acid Cycle." Journal of Molecular and Cellular Cardiology 55:156-164. doi:10.1016/j.yjmcc.2012.07.005
Priddy, MD CM, M Kajimoto, D Ledee, B Bouchard, NG Isern, A Olson, C Des Rosiers, and MA Portman. 2013. "Myocardial Oxidative Metabolism and Protein Synthesis during Mechanical Circulatory Support by Extracorporeal Membrane Oxygenation." American Journal of Physiology. Heart and Circulatory Physiology 304(3):H406-H414. doi:10.1152/ajpheart.00672.2012