Thyroid hormone (TH) deficiency occurs in adults and children after cardiopulmonary bypass (CPB), and can be responsible for acute and persistent decreases in myocardial performance during the critical postoperative period. Post-CPB thyroid hormone deficiency may contribute to diminished myocardial viability associated with low cardiac output syndrome. Experimental/clinical data indicate that triiodothyronine (T3) supplementation effects adult heart performance after CPB. Pilot clinical data suggest that children respond similarly to T3, but T3'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 use. Postischemic cardiac function can be improved through manipulation of substrate utilization pathways. Our data indicate that T3 modulates regulation of oxidative phosphorylation and substrate utilization in intact heart. Postischemic cardiac dysfunction in vivo, linked to inefficient O2 utilization, may be exacerbated by relative T3 deficiency. The PI has developed strategies to examine regulation of myocardial respiration and substrate utilization in the intact animal. The proposed research will address this regulation 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 will emulate clinical conditions during CPB in children. The PI will perform 31Phosphorous magnetic resonance spectroscopy and 13Carbon isotopomer analyses.
The specific aims are: 1a. Determine if conditions of hypothermic CPB and circulatory arrest decrease efficiency of energy use, reduce phosphorylation potential, and alter regulation of myocardial respiration in vivo. b. Determine if changes in substrate delivery ameliorate these bioenergetic alterations. c. Determine if thyroid hormone deficiency caused by CPB exacerbates the defined bioenergetic abnormalities, and T3 repletion improves the efficiency of energy utilization. 2.a. Determine if the acetyI-CoA delivery to the tricarboxylic acid cycle through the pyruvate dehydrogenase and acyI-CoA synthase pathways is altered in vivo after cardiopulmonary bypass and circulatory arrest. b. Determine if TH deficiency caused by CPB alters substrate utilization and triiodothyronine repletion reverses such alterations. ? ?
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