Hypothermia improves resistance to ischemia in the cardioplegia-arrested heart. This adaptive process produces changes in specific signaling pathways for mitochondrial proteins and heat-shock response. To further test for hypothermic modulation of other signaling pathways such as apoptosis, we used various molecular techniques, including cDNA arrays. Isolated rabbit hearts were perfused and exposed to ischemic cardioplegic arrest for 2 h at 34 degrees C [ischemic group (I); n = 13] or at 30 degrees C before and during ischemia [hypothermic group (H); n = 12]. Developed pressure, the maximum first derivative of left ventricular pressure, oxygen consumption, and pressure-rate product (P < 0.05) recovery were superior in H compared with in I during reperfusion. mRNA expression for the mitochondrial proteins, adenine translocase and the beta-subunit of F1-ATPase, was preserved by hypothermia. cDNA arrays revealed that ischemia altered expression of 13 genes. Hypothermia modified this response to ischemia for eight genes, six related to apoptosis. A marked, near fivefold increase in transformation-related protein 53 in I was virtually abrogated in H. Hypothermia also increased expression for the anti-apoptotic Bcl-2 homologue Bcl-x relative to I but decreased expression for the proapoptotic Bcl-2 homologue bak. These data imply that hypothermia modifies signaling pathways for apoptosis and suggest possible mechanisms for hypothermia-induced myocardial protection.

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Background-MRI guidance of percutaneous transluminal balloon angioplasty (PTA) of aortic coarctation (CoA) would be desirable for continuous visualization of anatomy and to eliminate x-ray exposure. The aim of this study was (1) to determine the suitability of MRI-controlled PTA using the iron oxide-based contrast medium Resovist (ferucarbotran) for catheter visualization and (2) to subsequently apply this technique in a pilot study with patients with CoA. Methods and Results-The MRI contrast-to-noise ratio and artifact behavior of Resovist-treated balloon catheters was optimized in in vitro and animal experiments (pigs). In 5 patients, anatomy of the CoA was evaluated before and after intervention with high-resolution respiratory-navigated 3D MRI and multiphase cine MRI. Position monitoring of Resovist-treated catheters was realized with interactive real-time MRI. Aortic pressures were continuously recorded.Conventional catheterization was performed before and after MRI to confirm interventional success. During MRI, catheters filled with 25 mol of iron particles per milliliter of Resovist produced good signal contrast between catheters and their background anatomy but no image distortion due to susceptibility artifacts. All MRI procedures were performed successfully in the patient study. There was excellent agreement between the diameters of CoA and pressure gradients as measured during MRI and conventional catheterization. In 4 patients, PTA resulted in substantial widening of the CoA and a decrease in pressure gradients. In 1 patient, PTA was ineffective. Conclusions-The MRI method described represents a potential alternative to conventional x-ray fluoroscopy for catheter-based treatment of patients with CoA. (Circulation. 2006;113:1093-1100.)

Triiodothyronine (T(3)) exerts direct action on myocardial oxygen consumption (MVO(2)), although its immediate effects on substrate metabolism have not been elucidated. The hypothesis, that T(3) regulates substrate selection and flux, was tested in isovolumic rat hearts under four conditions: control, T(3) (10 nM), epinephrine (Epi), and T(3) and Epi (TE). Hearts were perfused with [1,3-(13)C]acetoacetic acid (AA, 0.17 mM), L-[3-(13)C]lactic acid (LAC, 1.2 mM), U-(13)C-labeled long-chain free fatty acids (FFA, 0.35 mM), and unlabeled D-glucose (5.5 mM) for 30 min. Fractional acetyl-CoA contribution to the tricarboxylic acid cycle (Fc) per substrate was determined using (13)C NMR and isotopomer analysis. Oxidative fluxes were calculated using Fc, the respiratory quotient, and MVO(2). T(3) increased (P < 0.05) Fc(FFA), decreased Fc(LAC), and increased absolute FFA oxidation from 0.58 +/- 0.03 to 0.68 +/- 0.03 micromol. min(-1). g dry wt(-1) (P < 0.05). Epi decreased Fc(FFA) and Fc(AA), although FFA flux increased from 0.58 +/- 0.03 to 0.75 +/- 0.09 micromol. min(-1). g dry wt(-1). T(3) moderated the change in Fc(FFA) induced by Epi. In summary, T(3) exerts direct action on substrate pathways and enhances FFA selection and oxidation, although the Epi effect dominates at a high work state.

Hypothermia before and/or during no-flow ischemia promotes cardiac functional recovery and maintains mRNA expression for stress proteins and mitochondrial membrane proteins (MMP) during reperfusion. Adaptation and protection may occur through cold-induced change in anaerobic metabolism. Accordingly, the principal objective of this study was to test the hypothesis that hypothermia preserves myocardial function during hypoxia and reoxygenation. Hypoxic conditions in these experiments were created by reducing O 2 concentration in perfusate, thereby maintaining or elevating coronary flow (CF). Isolated Langendorff-perfused rabbit hearts were subjected to perfusate (PO 2 ϭ 38 mmHg) with glucose (11.5 mM) and perfusion pressure (90 mmHg). The control (C) group was at 37°C for 30 min before and 45 min during hypoxia, whereas the hypothermia (H) group was at 29.5°C for 30 min before and 45 min during hypoxia. Reoxygenation occurred at 37°C for 45 min for both groups. CF increased during hypoxia. The H group markedly improved functional recovery during reoxygenation, including left ventricular developed pressure (DP), the product of DP and heart rate, dP/dt max, and O2 consumption (MVO2) (P Ͻ 0.05 vs. control). MVO 2 decreased during hypothermia. Lactate and CO 2 gradients across the coronary bed were the same in C and H groups during hypoxia, implying similar anaerobic metabolic rates. Hypothermia preserved MMP ␤F 1-ATPase mRNA levels but did not alter adenine nucleotide translocator-1 or heat shock protein-70 mRNA levels. In conclusion, hypothermia preserves cardiac function after hypoxia in the hypoxic high-CF model. Thus hypothermic protection does not occur exclusively through cold-induced alterations in anaerobic metabolism. lactate; mitochondrial membrane protein; myocardial ischemia; reperfusion EVALUATION OF HYPOTHERMIC myocardial protection has occurred predominantly in experimental models employing reductions in coronary flow to reduce oxygen supply. Exposure to mild or moderate hypothermic insult promotes cross-tolerance to variable forms of subsequent injury, particularly those produced by ischemia and/or reperfusion (19,21). A reduction in ATP utilization rate initiated by hypothermia persists during rewarming and plays a central role in preserving myocardial function after ischemia and reperfusion (20). Hypothermic ATP preservation may promote specific molecular responses observed during reperfusion in the isolated rabbit heart model, including stabilization of steady-state mRNA levels for nuclear-encoded mitochondrial membrane proteins, enhanced induction of the stress protein heat shock protein-70 (HSP70) (19,21,22) and promotion of signaling for antiapoptotic pathways (18).Hypothermia under no-flow conditions also reduces anaerobic ATP synthesis, thereby minimizing accumulation of glycolytic end products and raising myocardial pH (21). The anaerobic metabolites are known to exacerbate myocardial injury during reperfusion and to putatively regulate signaling for heat shock responses (15). Thus the hypoth...

Thyroid acting through ligand binding to nuclear receptors modifies myocardial respiratory kinetics and oxidative phosphorylation in the heart. Direct nongenomic action of thyroid hormone on high-energy phosphate concentrations and respiratory kinetics has never been proven in vivo but might be responsible for observed changes in oxygen utilization efficiency immediately after triiodothyronine (T3) administration. We tested the hypothesis that T3 directly and rapidly modifies myocardial high-energy phosphate concentrations and phosphorylation potential in vivo. Anesthetized sheep (age 28 -40 days) thyroidectomized shortly after birth (Thy) and euthyroid age-matched controls (Con) underwent median sternotomy and received T3 infusion (0.8 g/kg), followed by epinephrine infusion to increase myocardial oxygen consumption (MV O2).31 P magnetic resonance spectra were monitored via a surface coil over the left ventricle. T3 increased phosphocreatine (PCr)/ATP and decreased ADP in Thy animals without causing a change in MV O2. T3 produced no changes in high-energy phosphates in Con animals. T3 did not modify the PCr/ATP or ADP response to epinephrine and elevation in MV O2 in either group. Cardiac mitochondria isolated from Thy and Con animals showed no change in respiratory rate or ADP/ATP exchange efficiency after T3 incubation. T3 infusion in a hypothyroid state decreases ADP concentration, thereby altering the equilibrium between phosphorylation potential and myocardial respiratory rate. These T3-induced effects are not due to changes in ADP/ATP exchange efficiency through action at the adenine nucleotide translocator but may be due to T3 mediation of substrate utilization, confirmed in other models. adenine nucleotide translocator; myocardial energy metabolism; substrate oxidation THYROID HORMONE REGULATES myocardial metabolism at the transcriptional level through binding to nuclear receptors. Ligand-dependent binding of these receptors to thyroid receptor elements controls transcription of various target genes involved in contractile and metabolic processes (5, 16). Although these nuclear receptor-mediated processes have been investigated to some extent, thyroid hormone as its active component, triiodothyronine (T 3 ), also regulates cellular processes through direct binding to membranes or enzymes (2).The direct or nongenomic actions of T 3 on cardiac energy metabolism and high-energy phosphate kinetics remain somewhat obscure. In previous studies, we (20) demonstrated that T 3 directly regulates myocardial substrate oxidation in isolated, perfused hearts. The relationship between substrate oxidation and phosphorylation potential has been established in several cardiac models (23,43). An apparent equilibrium exists between mitochondrial NADH/NAD and cytosolic phosphorylation potential. Accordingly, we considered that T 3 could also elevate phosphorylation potential in vivo. Prior studies in sheep in vivo implicate the adenine nucleotide translocator (ANT), which facilitates ADP/ATP exchange across the mitochondri...

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