Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice.

Aging presumably initiates shifts in substrate oxidation mediated in part by changes in insulin sensitivity. Similar shifts occur with cardiac hypertrophy and may contribute to contractile dysfunction. We tested the hypothesis that aging modifies substrate utilization and alters insulin sensitivity in mouse heart when provided multiple substrates.

Superior cardiac function via anaplerotic pyruvate in the immature swine heart after cardiopulmonary bypass and reperfusion.

Pyruvate produces inotropic responses in the adult reperfused heart. Pyruvate oxidation and anaplerotic entry into the tricarboxylic acid (TCA) cycle via carboxylation are linked to the stimulation of contractile function. The goals of this study were to determine if these metabolic pathways operate and are maintained in the developing myocardium after reperfusion.

Cardioselective dominant-negative thyroid hormone receptor (Delta337T) modulates myocardial metabolism and contractile efficiency.

Dominant-negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRbeta(1) mutation Delta337T.

Moderate hypothermia (30 degrees C) maintains myocardial integrity and modifies response of cell survival proteins after reperfusion.

Hypothermia preserves myocardial function, promotes signaling for cell survival, and inhibits apoptotic pathways during 45-min reperfusion. We tested the hypothesis that signaling at the transcriptional level is followed by corresponding proteomic response and maintenance of structural integrity after 3-h reperfusion. Isolated hearts were Langendorff perfused and exposed to mild (I group; n = 6, 34 degrees C) or moderate (H group; n = 6, 30 degrees C) hypothermia during 120-min total ischemia with cardioplegic arrest and 180-min 37 degrees C reperfusion.

Time-courses of perfusion and phosphocreatine in rat leg during low-level exercise and recovery.

Purpose: To develop a noninvasive protocol for measuring local perfusion and metabolic demand in muscle tissue with sufficient sensitivity and time resolution to monitor kinetics at the onset of low-level exercise and during recovery.

Materials And Methods: Capillary-level perfusion, the critical factor that determines oxygen and substrate delivery to active muscle, was measured by an arterial spin labeling (ASL) technique optimized for skeletal muscle. Phosphocreatine (PCr) kinetics, which signal the flux of oxidative phosphorylation, were measured by (31)P MR spectroscopy.

Nonlinear magnetic field gradients can reduce SAR in flow-driven arterial spin labeling measurements.

This work describes how custom-built gradient coils, designed to generate magnetic fields with amplitudes that vary nonlinearly with position, can be used to reduce the potential for unsafe tissue heating during flow-driven arterial spin labeling processes. A model was developed to allow detailed analysis of the adiabatic excitation process used for flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS) an arterial spin labeling method developed specifically for use in skeletal muscle. The model predicted that, by adjusting the amplitude of the gradient field, the specific absorption rate could be reduced by more than a factor of 6 while still achieving effective labeling.

Molecular mechanisms of cross-talk between thyroid hormone and peroxisome proliferator activated receptors: focus on the heart.

Thyroid hormone receptors (TR) and peroxisome proliferator activated receptors (PPAR) regulate cardiac metabolism. Numerous studies have examined TR and PPAR function since PPAR was first discovered in the early 1990s, however few have evaluated TR and PPAR interactions. Although ligands for these members of the nuclear steroid receptor family are under evaluation for treatment of congestive heart failure and various metabolic diseases, their interactions have not been investigated in detail in heart.

Short-cycle hypoxia in the intact heart: hypoxia-inducible factor 1alpha signaling and the relationship to injury threshold.

Hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptionally activates multiple genes, which regulate metabolic cardioprotective and cross-adaptive mechanisms. Hypoxia and several other stimuli induce the HIF-1alpha signaling cascade, although little data exist regarding the stress threshold for activation in heart. We tested the hypothesis that relatively mild short-cycle hypoxia, which produces minimal cardiac dysfunction and no sustained or major disruption in energy state, can induce HIF-1alpha activation.

Thyroid hormone controls myocardial substrate metabolism through nuclear receptor-mediated and rapid posttranscriptional mechanisms.

Thyroid hormone regulates metabolism through transcriptional and posttranscriptional mechanisms. The integration of these mechanisms in heart is poorly understood. Therefore, we investigated control of substrate flux into the citric acid cycle (CAC) by thyroid hormone using retrogradely perfused isolated hearts (n = 20) from control (C) and age-matched thyroidectomized rats (T).

Gradient-enhanced FAWSETS perfusion measurements.

This work describes the use of custom-built gradients to enhance skeletal muscle perfusion measurements acquired with a previously described arterial spin labeling technique known as FAWSETS (flow-driven arterial water stimulation with elimination of tissue signal). Custom-built gradients provide active control of the static magnetic field gradient on which FAWSETS relies for labeling. This allows selective, 180 degrees modulations of the phase of the perfusion component of the signal.

FAWSETS perfusion measurements in exercising skeletal muscle.

Arterial spin labeling (ASL) techniques are now recognized as valid tools for providing accurate measurements of cerebral and cardiac perfusion. The labeling process used with most ASL techniques creates two problems, magnetization transfer (MT) effects and arterial transit time effects, that require compensation. The compensation process limits time resolution and hinders absolute quantification.

Validation and advantages of FAWSETS perfusion measurements in skeletal muscle.

This work discusses the strengths, limitations and validity of a novel arterial spin labeling technique when used specifically to measure perfusion in limb skeletal muscle. The technique, flow-driven arterial water stimulation with elimination of tissue signal (FAWSETS), offers several advantages over existing arterial spin labeling techniques. The primary goal of this study was to determine the perfusion signal response to changes in net hind limb flow that were independently verifiable.

Hypothermia preserves myocardial function and mitochondrial protein gene expression during hypoxia.

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.

Hypothermic protection of the ischemic heart via alterations in apoptotic pathways as assessed by gene array analysis.

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.