Thyroid Regulation of Cardiac Metabolism
EMSL Project ID
21591
Abstract
Thyroid hormone deficiency occurs in adults and children after cardiopulmonary bypass (CPB), and can be responsible for acute and persistent decreases in cardiac performance during the critical postoperative period. Conceivably, post-CPB thyroid hormone deficiency contributes to diminished myocardial viability associated with "low cardiac output syndrome," particularly observed in children after surgery for congenital heart disease. Experimental and clinical data indicate that triiodothyronine supplementation or repletion produces profound effects on performance in the adult heart following CPB and cardiac surgery. Preliminary clinical data suggest that children respond similarly to triiodothyronine supplementation. However, thyroid hormone's operative mechanisms require elucidation. Recent studies indicate that postischemic or reperfusion-related alterations in myocardial oxidative phosphorylation and substrate utilization reduce efficiency of ATP production and utilization. Furthermore, postischemic cardiac contractile function can be improved through manipulation of substrate utilization pathways, such as inhibition of carnitine palimitoyl transferase. Data obtained in this laboratory during the first years of our NIH grant indicate that thyroid hormone modulates regulation of oxidative phosphorylation and controls substrate utilization and preference in the intact heart. Thus, cardiac dysfunction in vivo, which occurs after a reduction in blood supply to the heart and is linked to inefficient oxygen utilization, might be exacerbated by relative thyroid hormone deficiency in the postoperative period. The principal investigator has developed unique strategies for examining regulation of myocardial respiration and substrate utilization in the intact animal. The proposed research will address regulation of myocardial oxidative phosphorylation and substrate utilization at near maximal energy expenditure rates (induced by inotropic stimulation) in juvenile porcine hearts exposed to conditions of hypothermia, ischemia, and reperfusion. The degree and duration of hypothermia and reperfusion will emulate clinical conditions during CPB procedures in children. The applicant will perform experimental measurements using 13Carbon isotopomer analyses in conjunction with traditional measures of myocardial oxygen consumption and metabolic parameters. Although, the primary hypotheses for this study require experimentation in a neonatal pig model, some basic cell mechanisms require study in isolated working hearts, which are not subjected to systemic influence. The specific aims of this application will be directed towards testing three hypotheses in a neonatal pig heart model, and mice, and rats. 1. a. Determine if changes in substrate delivery ameliorate bioenergetic alterations caused by hypothermia/and or ischemia.
b. Determine if thyroid hormone deficiency caused by CPB exacerbates the defined bioenergetic abnormalities and if triiodothyronine repletion and improves efficiency of energy utilization and synthesis.
2. a. Determine if the acetyl-CoA delivery to the tricarboxylic acid cycle through the pyruvate dehydrogenase and acyl-CoA synthase pathways is limited or altered in vivo after cardiopulmonary bypass and circulatory arrest.
b. Determine if thyroid hormone deficiency caused by CPB alters substrate utilization and if triiodothyronine repletion reverses such alterations.
3. Determine the specific targets fro triiodothyronine (T3) regulation of myocardial substrate flux (mouse model)
a) evaluate insulin interaction with T3
b) determine if T3 moderates flux through substrate transporter localization
c) determine if T3 mediates flux through synthesis or degradation of specific enzymes.
Project Details
Project type
Capability Research
Start Date
2006-12-22
End Date
2007-07-18
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
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