title: Triiodothyronine increases myocardial function and pyruvate entry into the citric acid cycle after reperfusion in a model of infant cardiopulmonary bypass.
abstract: Triiodothyronine (T3) supplementation improves clinical outcomes in infants after cardiac surgery using cardiopulmonary bypass by unknown mechanisms. We utilized a translational model of infant cardiopulmonary bypass to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC), thereby providing the energy support for improved cardiac function after ischemia-reperfusion (I/R). Neonatal piglets received intracoronary [2-(13)Carbon((13)C)]pyruvate for 40 min (8 mM) during control aerobic conditions (control) or immediately after reperfusion (I/R) from global hypothermic ischemia. A third group (I/R-Tr) received T3 (1.2 μg/kg) during reperfusion. We assessed absolute CAC intermediate levels and flux parameters into the CAC through oxidative pyruvate decarboxylation (PDC) and anaplerotic carboxylation (PC) using [2-(13)C]pyruvate and isotopomer analysis by gas and liquid chromatography-mass spectrometry and (13)C-nuclear magnetic resonance spectroscopy. When compared with I/R, T3 (group I/R-Tr) increased cardiac power and oxygen consumption after I/R while elevating flux of both PDC and PC (∼4-fold). Although neither I/R nor I/R-Tr modified absolute CAC levels, T3 inhibited I/R-induced reductions in their molar percent enrichment. Furthermore, (13)C-labeling of CAC intermediates suggests that T3 may decrease entry of unlabeled carbons at the level of oxaloacetate through anaplerosis or exchange reaction with asparate. T3 markedly enhances PC and PDC fluxes, thereby providing potential substrate for elevated cardiac function after reperfusion. This T3-induced increase in pyruvate fluxes occurs with preservation of the CAC intermediate pool. Our labeling data raise the possibility that T3 reduces reliance on amino acids for anaplerosis after reperfusion.
authors.affiliation: Division of Cardiology, Department of Pediatrics, University of Washington, WA, USA.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Olson
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bouchard
authors.forename: Xue-Han
authors.initials: XH
authors.lastname: Ning
authors.forename: Nancy
authors.initials: N
authors.lastname: Isern
authors.forename: Christine Des
authors.initials: CD
authors.lastname: Rosiers
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D002315:Cardiopulmonary Bypass; D002952:Citric Acid Cycle; D003653:Decarboxylation; D006321:Heart / Q000502:physiology; D007036:Hypothermia, Induced; D008297:Male; D023421:Models, Animal; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D019289:Pyruvic Acid / Q000378:metabolism; D013552:Swine; D014284:Triiodothyronine / Q000378:metabolism* / Q000502:physiology
chemical_list: D014284:Triiodothyronine; D001224:Aspartic Acid; D019289:Pyruvic Acid