Extracorporeal membrane oxygenation (ECMO) remains the primary method of long term support after myocardial stunning caused by cardiac surgery in infants and children. ECMO often provides a bridge to recovery in these young patients. However, ventricular unloading as occurs with ECMO also promotes cardiac atrophy. Therefore, this therapy can be counterproductive in initiating reparative processes leading to restoration of normal cardiac function. Substantial abnormalities in hormonal homeostasis, such as decreases in circulating levels of thyroid hormones, occur during both shorter term cardiopulmonary bypass (CPB) and longer term ECMO. Disruptions in thyroid hormone homeostasis can alter substrate utilization, deplete citric acid cycle intermediates, possibly effecting net protein turnover. Additionally, we have noted that pyruvate supplementation can improve cardiac function after CPB in immature pigs. Thyroid hormone supplementation promotes pyruvate entry into the citric acid cycle, and promotes citric acid cycle intermediate conversion to amino acids. These findings suggest that appropriate substrate supplementation can improve protein synthesis and functional recovery after protracted mechanical circulatory support. We will study a prolonged period of mechanical circulatory support (ECMO) in the immature pig, an appropriate translational model for children undergoing these procedures. We will test the primary hypothesis: in the developing heart cardiac dysfunction due to ventricular unloading (ECMO)-is a consequence of impaired substrate utilization due at least in part to disruptions of thyroid hormone homeostasis. Targeted metabolic interventions in combination with thyroid hormone supplementation will minimize the adverse effects of ECMO and thereby improve longer term functional recovery and survival. Using NMR and GC-MS, we will determine if metabolic abnormalities, which lead to cardiac dysfunction and atrophy can be treated by supplementing the citric acid cycle with pyruvate. We will determine if pyruvate combined with thyroid hormone supplementation (T3) a) accelerates pyruvate flux, 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. We will also determine if supplementation of medium chain fatty acids with and/or without thyroid hormone similarly supports the heart.

Public Health Relevance

Infants and children are often supported by a bypass pump during or after heart repair. This study will determine hormone and nutritional strategies to support the immature heart while supported by this type of mechanical circulation. In particular, we will examine how thyroid hormone influences how the heart generates and uses important energy molecules.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060666-14
Application #
8494667
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schramm, Charlene A
Project Start
1998-09-30
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$460,638
Indirect Cost
$223,839
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Ledee, Dolena R; Kajimoto, Masaki; O'Kelly Priddy, Colleen M et al. (2015) Pyruvate modifies metabolic flux and nutrient sensing during extracorporeal membrane oxygenation in an immature swine model. Am J Physiol Heart Circ Physiol 309:H137-46
Higdon, Roger; Earl, Rachel K; Stanberry, Larissa et al. (2015) The promise of multi-omics and clinical data integration to identify and target personalized healthcare approaches in autism spectrum disorders. OMICS 19:197-208
Kajimoto, Masaki; Ledee, Dolena R; Olson, Aaron K et al. (2015) Differential effects of octanoate and heptanoate on myocardial metabolism during extracorporeal membrane oxygenation in an infant swine model. Am J Physiol Heart Circ Physiol 309:H1157-65
Ning, Xue-Han; Villet, Outi M; Ge, Ming et al. (2015) Optimal protective hypothermia in arrested mammalian hearts. Ther Hypothermia Temp Manag 5:40-7
Kajimoto, Masaki; Priddy, Colleen M O'Kelly; Ledee, Dolena R et al. (2014) Effects of continuous triiodothyronine infusion on the tricarboxylic acid cycle in the normal immature swine heart under extracorporeal membrane oxygenation in vivo. Am J Physiol Heart Circ Physiol 306:H1164-70
Kajimoto, Masaki; Ledee, Dolena R; Xu, Chun et al. (2014) Triiodothyronine activates lactate oxidation without impairing fatty acid oxidation and improves weaning from extracorporeal membrane oxygenation. Circ J 78:2867-75
Kajimoto, Masaki; Ledee, Dolena R; Xu, Chun et al. (2014) Triiodothyronine Activates Lactate Oxidation Without Impairing Fatty Acid Oxidation and Improves Weaning From Extracorporeal Membrane Oxygenation. Circ J :
Kajimoto, Masaki; Atkinson, Douglas B; Ledee, Dolena R et al. (2014) Propofol compared with isoflurane inhibits mitochondrial metabolism in immature swine cerebral cortex. J Cereb Blood Flow Metab 34:514-21
Files, Matthew D; Kajimoto, Masaki; O'Kelly Priddy, Colleen M et al. (2014) Triiodothyronine facilitates weaning from extracorporeal membrane oxygenation by improved mitochondrial substrate utilization. J Am Heart Assoc 3:e000680
Priddy, Colleen M O'Kelly; Kajimoto, Masaki; Ledee, Dolena R et al. (2013) Myocardial oxidative metabolism and protein synthesis during mechanical circulatory support by extracorporeal membrane oxygenation. Am J Physiol Heart Circ Physiol 304:H406-14

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