Heart Metabolomics during ventricular unloading
EMSL Project ID
25391
Abstract
Extracorporeal membrane oxygenation (ECMO) remains the primary method of long term support after myocardial stunning after cardiac surgery in this age group. 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. Nutritional and/or insulin therapy has been considered as a general therapy, but do not alter overall net protein turnover in these patients. Substantial abnormalities in hormonal balance, such as decreases in circulating levels of thyroid hormones, occur during both shorter term cardiopulmonary bypass (CPB) and longer term ECMO. We have identified thyroid hormone as an important modifier of cardiac metabolism in the developing heart. These modifications occur through transcriptional pathways involving nuclear receptors, and more direct pathways, that promote change in substrate utilization. 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 promote anaplerosis and improve cardiac function after CPB in immature pigs. We have linked this improvement in function to pyruvate entry into the citric acid cycle, which occurs through both carboxylation and decarboxylation. These findings suggest that appropriate substrate supplementation can improve functional recovery in the short term. We will test the primary hypothesis that mechanocirculatory support for the developing heart alters myocardial substrate utilization and protein synthesis. Additionally, some of these hypotheses will be explored using transgenic mouse models in the working heart. SPECIFIC AIMS: 1) DETERMINE that conditions of cardiopulmonary bypass and ischemia, emulating clinical conditions, alter substrate utilization and protein synthesis in the developing heart after reperfusion 2) CONFIRM that ventricular unloading with mechanical circulatory support alters substrate utilization and protein synthesis in the heart.
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-05-23
End Date
2010-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Olson A, DR Ledee, PhD, K Iwamoto, M Kajimoto, CM O'Kelly-Priddy, NG Isern, and MA Portman. 2012. "C-Myc Induced Compensated Cardiac Hypertrophy Increases Free Fatty Acid Utilization for the Citric Acid Cycle." Journal of Molecular and Cellular Cardiology.
Superior Cardiac Function Via Anaplerotic Pyruvate in the Immature Swine Heart After Cardiopulmonary Bypass and Reperfusion AARON K. OLSON1,5, OUTI M. HYYTI1,2,5, GORDON A. COHEN3,5, XUE-HAN NING1,5, MARTIN SADILEK4, NANCY ISERN6 AND MICHAEL A. PORTMAN1,5 Division of Cardiology, Department of Pediatrics1, Department of Radiology2, Division of Pediatric Cardiovascular Surgery, Department of Surgery3 , Department of Chemistry4, University of Washington, Children’s Hospital and Regional Medical Center5, Seattle WA, 98195; Pacific Northwest National Laboratory, Richland WA, 993926