Application of hyperpolarized magnetic resonance in the study of cardiac metabolism

The application of magnetic resonance (MR) for metabolic imaging and spectroscopy has been limited by the intrinsically low sensitivity and natural abundance of 13C. Recently a method has been developed in which solid-state, dynamically polarized MR-active nuclei can be dissolved to obtain a solution polarized in excess of 20%. When used in concert with MR spectroscopy, this method of hyperpolarization provides the MR signal necessary to detect low-abundance molecules, enabling visualization of the substrate uptake and in vivo metabolism in real time. This study utilized hyperpolarized [1- 13C]pyruvate as a metabolic tracer to monitor cardiac metabolism in healthy rats in vivo. The conversion of [1- 13C]pyruvate to [1- 13C]lactate, [1- 13C]alanine and bicarbonate (H 13CO 3-) was observed with high signal-to-noise ratio at 1 s temporal resolution. The acquired spectra demonstrated that injection of hyperpolarized [1- 13C]pyruvate elicited a consistent metabolic response in vivo and displayed instantaneous information regarding the evolution of the metabolite pools of each product of pyruvate. We have demonstrated the feasibility of applying hyperpolarized MR to the study of cardiac metabolism, with a view to detecting the alterations in substrate utilization that occur in heart disease. © 2008 Springer-Verlag

The effect of hyperpolarized tracer concentration on myocardial uptake and metabolism.

Hyperpolarized (13)C-labeled substrates directly provide a source of magnetic resonance (MR) signal to observe the substrates' real-time uptake and enzymatic conversion. The aim of this study was to optimize the concentration of hyperpolarized [1-(13)C]pyruvate infused as a metabolic tracer, by observing the mitochondrial conversion of pyruvate to H(13)CO(3)(-) in heart tissue. Hyperpolarized pyruvate was infused into rats at concentrations between 20 mM and 80 mM and the relationships between [1-(13)C]lactate, [1-(13)C]alanine, and H(13)CO(3)(-) production and the infused pyruvate concentration were investigated. H(13)CO(3)(-) production reached saturation above 40 mM infused pyruvate concentration, indicating that hyperpolarized MR experiments performed at this concentration maximize the H(13)CO(3)(-) signal with minimal alterations to in vivo substrate composition. Additionally, the linear dependence of alanine production on pyruvate concentration confirmed that hyperpolarized MR methods in the heart reveal enzyme activity, rather than cellular uptake. H(13)CO(3)(-) production demonstrated evidence of sigmoidal enzyme kinetics, a reflection of the allosteric nature of the pyruvate dehydrogenase (PDH) enzyme complex. This protocol could be useful to optimize the infused concentration of other hyperpolarized metabolites in different organs, to ensure adequate MR signal with minimum metabolic perturbation

Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T.

The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra- and inter-subject variability, as well as intra- and inter-observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 +/- 0.38 and for scan 2 was 2.14 +/- 0.46, showing no significant difference between scans. Intra-subject variability was 0.43 +/- 0.35 (percentage difference 20%) and the inter-subject coefficient of variation was 18%. The intra-observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 +/- 0.24 with no significant difference between analyses. The inter-observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra-class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias

Human hippocampal energy metabolism is impaired during cognitive activity in a lipid infusion model of insulin resistance

Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin‐mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin‐dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin‐dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin‐signaled GLUT4 transport. We studied hippocampal high‐energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood–brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. 31Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)‐to‐adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity

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Neuronal glucose uptake was thought to be independent of insulin, being facilitated by glucose transporters GLUT1 and GLUT3, which do not require insulin signaling. However, it is now known that components of the insulin-mediated glucose uptake pathway, including neuronal insulin synthesis and the insulin-dependent glucose transporter GLUT4, are present in brain tissue, particularly in the hippocampus. There is considerable recent evidence that insulin signaling is crucial to optimal hippocampal function. The physiological basis, however, is not clear. We propose that while noninsulin-dependent GLUT1 and GLUT3 transport is adequate for resting needs, the surge in energy use during sustained cognitive activity requires the additional induction of insulin-signaled GLUT4 transport. We studied hippocampal high-energy phosphate metabolism in eight healthy volunteers, using a lipid infusion protocol to inhibit insulin signaling. Contrary to conventional wisdom, it is now known that free fatty acids do cross the blood-brain barrier in significant amounts. Energy metabolism within the hippocampus was assessed during standardized cognitive activity. (31)Phosphorus magnetic resonance spectroscopy was used to determine the phosphocreatine (PCr)-to-adenosine triphosphate (ATP) ratio. This ratio reflects cellular energy production in relation to concurrent cellular energy expenditure. With lipid infusion, the ratio was significantly reduced during cognitive activity (PCr/ATP 1.0 ± 0.4 compared with 1.4 ± 0.4 before infusion, P = 0.01). Without lipid infusion, there was no reduction in the ratio during cognitive activity (PCr/ATP 1.5 ± 0.3 compared with 1.4 ± 0.4, P = 0.57). This provides supporting evidence for a physiological role for insulin signaling in facilitating increased neuronal glucose uptake during sustained cognitive activity. Loss of this response, as may occur in type 2 diabetes, would lead to insufficient neuronal energy availability during cognitive activity