Angus Z. Lau

Hyperpolarized (13)C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart.

Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized 13C magnetic resonance (MR), in which 13C‐labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non‐invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non‐invasive hyperpolarized [13C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.

Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and pH, using hyperpolarized [1,2-(13)C2]pyruvate in vivo.

13C MR spectroscopy studies performed on hearts ex vivo and in vivo following perfusion of prepolarized [1‐13C]pyruvate have shown that changes in pyruvate dehydrogenase (PDH) flux may be monitored non‐invasively. However, to allow investigation of Krebs cycle metabolism, the 13C label must be placed on the C2 position of pyruvate. Thus, the utilization of either C1 or C2 labeled prepolarized pyruvate as a tracer can only afford a partial view of cardiac pyruvate metabolism in health and disease. If the prepolarized pyruvate molecules were labeled at both C1 and C2 positions, then it would be possible to observe the downstream metabolites that were the results of both PDH flux (13CO2 and H13CO3‐) and Krebs cycle flux ([5‐13C]glutamate) with a single dose of the agent. Cardiac pH could also be monitored in the same experiment, but adequate SNR of the 13CO2 resonance may be difficult to obtain in vivo. Using an interleaved selective RF pulse acquisition scheme to improve 13CO2 detection, the feasibility of using dual‐labeled hyperpolarized [1,2‐13C2]pyruvate as a substrate for dynamic cardiac metabolic MRS studies to allow simultaneous investigation of PDH flux, Krebs cycle flux and pH, was demonstrated in vivo. Copyright

Spectral–spatial excitation for rapid imaging of DNP compounds

Dynamic nuclear polarization and dissolution offer the exciting possibility of imaging biochemical reactions in vivo, including some of the key enzymatic reactions involved in cellular metabolism. The development of new pulse sequence strategies has been motivated by demanding applications, such as the imaging of hyperpolarized metabolite distributions in the heart. In this article, the key considerations surrounding the application of spectral–spatial imaging pulse sequences for hyperpolarized 13C metabolic imaging in cardiac and cancer applications are explored. Spiral pulse sequences for multislice imaging of [1‐13C]pyruvate in the heart were developed, as well as time‐resolved, three‐dimensional, echo‐planar imaging sequences for the imaging of [1‐13C]pyruvate–lactate exchange in cancer. The advantages and challenges associated with these sequences were determined by testing in pig and rat models. Copyright

Accelerated human cardiac diffusion tensor imaging using simultaneous multislice imaging

To demonstrate the feasibility of accelerating measurements of cardiac fiber structure using simultaneous multislice (SMS) imaging.

Robust and high resolution hyperpolarized metabolic imaging of the rat heart at 7 T with 3D spectral-spatial EPI.

Hyperpolarized metabolic imaging has the potential to revolutionize the diagnosis and management of diseases where metabolism is dysregulated, such as heart disease. We investigated the feasibility of imaging rodent myocardial metabolism at high resolution at 7 T.

Cardiac perfusion imaging using hyperpolarized (13) c urea using flow sensitizing gradients.

To demonstrate the feasibility of imaging the first passage of a bolus of hyperpolarized 13C urea through the rodent heart using flow‐sensitizing gradients to reduce signal from the blood pool.

Simultaneous assessment of cardiac metabolism and perfusion using copolarized [1-13 C]pyruvate and 13 C-urea.

To demonstrate the feasibility of imaging a bolus of co‐polarized [1‐13C]pyruvate and 13C‐urea to simultaneously assess both metabolism and perfusion in the rodent heart.

Multichannel receiver coils for improved coverage in cardiac metabolic imaging using prepolarized 13C substrates

MR imaging using hyperpolarized 13C substrates has become a promising tool to study real‐time cardiac‐metabolism in vivo. For such fast imaging of nonrecoverable prepolarized magnetization it is important to optimize the RF‐coils to obtain the best signal‐to‐noise ratio possible, given the required coverage. In this work, three different receiver‐coil configurations were computed in pig and human models. The sensitivity maps were demonstrated in phantoms and in vivo experiments performed in pigs. Signal‐to‐noise ratio in the posterior heart was increased up to 80% with the best multichannel coil as expected. These new coil configurations will allow imaging of the different metabolite signals even in the posterior regions of the myocardium, which is not possible with a single‐channel surface‐coil. Magn Reson Med, 2013.

Mapping of intracellular pH in the in vivo rodent heart using hyperpolarized [1-13C]pyruvate

To demonstrate the feasibility of mapping intracellular pH within the in vivo rodent heart. Alterations in cardiac acid‐base balance can lead to acute contractile depression and alterations in Ca2+ signaling. The transient reduction in adenosine triphosphate (ATP) consumption and cardiac contractility may be initially beneficial; however, sustained pH changes can be maladaptive, leading to myocardial damage and electrical arrhythmias.

Hyperpolarized [1,4-13C2]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis

Objectives The aim of this study was to determine if hyperpolarized [1,4–13C2]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI). Background MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4–13C2]fumarate to [1,4–13C2]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4–13C2]malate imaging could measure necrosis after MI. Methods Isolated perfused hearts were given hyperpolarized [1,4–13C2]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4–13C2]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI. Results In isolated hearts, [1,4–13C2]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4–13C2]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R2 = 0.904). In vivo, the quantity of [1,4–13C2]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post-infarct. [1,4–13C2]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4–13C2]malate was not visible in control hearts. Conclusions Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients.