Cardiovascular Applications of Hyperpolarized MRI

Many applications of MRI are limited by an inherently low sensitivity. Previous attempts to overcome this insensitivity have focused on the use of MRI systems with stronger magnetic fields. However, the gains that can be achieved in this way are relatively small and increasing the magnetic field invariably leads to greater technical challenges. More recently, the development of a range of techniques, which can be gathered under the umbrella term of “hyperpolarization,” has offered potential solutions to the low sensitivity. Hyperpolarization techniques have been demonstrated to temporarily increase the signal available in an MRI experiment by as much as 100,000-fold. This article outlines the main hyperpolarization techniques that have been proposed and explains how they can increase MRI signals. With particular emphasis on the emerging technique of dynamic nuclear polarization, the existing preclinical cardiovascular applications are reviewed and the potential for clinical translation is discussed

In Vivo Carbon-13 Dynamic MRS and MRSI of Normal and Fasted Rat Liver with Hyperpolarized 13C-Pyruvate

BACKGROUND: The use of in vivo (13)C nuclear magnetic resonance spectroscopy in probing metabolic pathways to study normal metabolism and characterize disease physiology has been limited by its low sensitivity. However, recent technological advances have enabled greater than 50,000-fold enhancement of liquid-state polarization of metabolically active (13)C substrates, allowing for rapid assessment of (13)C metabolism in vivo. The present study applied hyperpolarized (13)C magnetic resonance spectroscopy to the investigation of liver metabolism, demonstrating for the first time the feasibility of applying this technology to detect differences in liver metabolic states. PROCEDURES: [1-(13)C]pyruvate was hyperpolarized with a dynamic nuclear polarization instrument and injected into normal and fasted rats. The uptake of pyruvate and its conversion to the metabolic products lactate and alanine were observed with slice-localized dynamic magnetic resonance spectroscopy and 3D magnetic resonance spectroscopic imaging (3D-MRSI). RESULTS: Significant differences in lactate to alanine ratio (P < 0.01) between normal and fasted rat liver slice dynamic spectra were observed. 3D-MRSI localized to the fasted livers demonstrated significantly decreased (13)C-alanine levels (P < 0.01) compared to normal. CONCLUSIONS: This study presents the initial demonstration of characterizing metabolic state differences in the liver with hyperpolarized (13)C spectroscopy and shows the ability to detect physiological perturbations in alanine aminotransferase activity, which is an encouraging result for future liver disease investigations with hyperpolarized magnetic resonance technology

Hyperpolarized Long-T1 Silicon Nanoparticles for Magnetic Resonance Imaging

Silicon nanoparticles are experimentally investigated as a potential hyperpolarized, targetable MRI imaging agent. Nuclear T_1 times at room temperature for a variety of Si nanoparticles are found to be remarkably long (10^2 to 10^4 s) - roughly consistent with predictions of a core-shell diffusion model - allowing them to be transported, administered and imaged on practical time scales without significant loss of polarization. We also report surface functionalization of Si nanoparticles, comparable to approaches used in other biologically targeted nanoparticle systems.Comment: supporting material here: http://marcuslab.harvard.edu/Aptekar_hyper1_sup.pd

An Experimental Investigation of Colonel Blotto Games

"This article examines behavior in the two-player, constant-sum Colonel Blotto game with asymmetric resources in which players maximize the expected number of battlefields won. The experimental results support all major theoretical predictions. In the auction treatment, where winning a battlefield is deterministic, disadvantaged players use a 'guerilla warfare' strategy which stochastically allocates zero resources to a subset of battlefields. Advantaged players employ a 'stochastic complete coverage' strategy, allocating random, but positive, resource levels across the battlefields. In the lottery treatment, where winning a battlefield is probabilistic, both players divide their resources equally across all battlefields." (author's abstract)"Dieser Artikel untersucht das Verhalten von Individuen in einem 'constant-sum Colonel Blotto'-Spiel zwischen zwei Spielern, bei dem die Spieler mit unterschiedlichen Ressourcen ausgestattet sind und die erwartete Anzahl gewonnener Schlachtfelder maximieren. Die experimentellen Ergebnisse bestätigen alle wichtigen theoretischen Vorhersagen. Im Durchgang, in dem wie in einer Auktion der Sieg in einem Schlachtfeld deterministisch ist, wenden die Spieler, die sich im Nachteil befinden, eine 'Guerillataktik' an, und verteilen ihre Ressourcen stochastisch auf eine Teilmenge der Schlachtfelder. Spieler mit einem Vorteil verwenden eine Strategie der 'stochastischen vollständigen Abdeckung', indem sie zufällig eine positive Ressourcenmenge auf allen Schlachtfeldern positionieren. Im Durchgang, in dem sich der Gewinn eines Schlachtfeldes probabilistisch wie in einer Lotterie bestimmt, teilen beide Spieler ihre Ressourcen gleichmäßig auf alle Schlachtfelder auf." (Autorenreferat

Measuring intracellular pH in the heart using hyperpolarized carbon dioxide and bicarbonate: a 13C and 31P magnetic resonance spectroscopy study

AIMS: Technological limitations have restricted in vivo assessment of intracellular pH (pH(i)) in the myocardium. The aim of this study was to evaluate the potential of hyperpolarized [1-(13)C]pyruvate, coupled with (13)C magnetic resonance spectroscopy (MRS), to measure pH(i) in the healthy and diseased heart. METHODS AND RESULTS: Hyperpolarized [1-(13)C]pyruvate was infused into isolated rat hearts before and immediately after ischaemia, and the formation of (13)CO(2) and H(13)CO(3)(-) was monitored using (13)C MRS. The HCO(3)(-)/CO(2) ratio was used in the Henderson-Hasselbalch equation to estimate pH(i). We tested the validity of this approach by comparing (13)C-based pH(i) measurements with (31)P MRS measurements of pH(i). There was good agreement between the pH(i) measured using (13)C and (31)P MRS in control hearts, being 7.12 +/- 0.10 and 7.07 +/- 0.02, respectively. In reperfused hearts, (13)C and (31)P measurements of pH(i) also agreed, although (13)C equilibration limited observation of myocardial recovery from acidosis. In hearts pre-treated with the carbonic anhydrase (CA) inhibitor, 6-ethoxyzolamide, the (13)C measurement underestimated the (31)P-measured pH(i) by 0.80 pH units. Mathematical modelling predicted that the validity of measuring pH(i) from the H(13)CO(3)(-)/(13)CO(2) ratio depended on CA activity, and may give an incorrect measure of pH(i) under conditions in which CA was inhibited, such as in acidosis. Hyperpolarized [1-(13)C]pyruvate was also infused into healthy living rats, where in vivo pH(i) from the H(13)CO(3)(-)/(13)CO(2) ratio was measured to be 7.20 +/- 0.03. CONCLUSION: Metabolically generated (13)CO(2) and H(13)CO(3)(-) can be used as a marker of cardiac pH(i) in vivo, provided that CA activity is at normal levels

Search for heavy neutrinos mixing with tau neutrinos

We report on a search for heavy neutrinos (\nus) produced in the decay D_s\to \tau \nus at the SPS proton target followed by the decay \nudecay in the NOMAD detector. Both decays are expected to occur if \nus is a component of $\nu_{\tau}$.\ From the analysis of the data collected during the 1996-1998 runs with $4.1\times10^{19}$ protons on target, a single candidate event consistent with background expectations was found. This allows to derive an upper limit on the mixing strength between the heavy neutrino and the tau neutrino in the \nus mass range from 10 to 190 $\rm MeV$. Windows between the SN1987a and Big Bang Nucleosynthesis lower limits and our result are still open for future experimental searches. The results obtained are used to constrain an interpretation of the time anomaly observed in the KARMEN1 detector.\Comment: 20 pages, 7 figures, a few comments adde

Systematic NMR Analysis of Stable Isotope Labeled Metabolite Mixtures in Plant and Animal Systems: Coarse Grained Views of Metabolic Pathways

BACKGROUND: Metabolic phenotyping has become an important 'bird's-eye-view' technology which can be applied to higher organisms, such as model plant and animal systems in the post-genomics and proteomics era. Although genotyping technology has expanded greatly over the past decade, metabolic phenotyping has languished due to the difficulty of 'top-down' chemical analyses. Here, we describe a systematic NMR methodology for stable isotope-labeling and analysis of metabolite mixtures in plant and animal systems. METHODOLOGY/PRINCIPAL FINDINGS: The analysis method includes a stable isotope labeling technique for use in living organisms; a systematic method for simultaneously identifying a large number of metabolites by using a newly developed HSQC-based metabolite chemical shift database combined with heteronuclear multidimensional NMR spectroscopy; Principal Components Analysis; and a visualization method using a coarse-grained overview of the metabolic system. The database contains more than 1000 (1)H and (13)C chemical shifts corresponding to 142 metabolites measured under identical physicochemical conditions. Using the stable isotope labeling technique in Arabidopsis T87 cultured cells and Bombyx mori, we systematically detected >450 HSQC peaks in each (13)C-HSQC spectrum derived from model plant, Arabidopsis T87 cultured cells and the invertebrate animal model Bombyx mori. Furthermore, for the first time, efficient (13)C labeling has allowed reliable signal assignment using analytical separation techniques such as 3D HCCH-COSY spectra in higher organism extracts. CONCLUSIONS/SIGNIFICANCE: Overall physiological changes could be detected and categorized in relation to a critical developmental phase change in B. mori by coarse-grained representations in which the organization of metabolic pathways related to a specific developmental phase was visualized on the basis of constituent changes of 56 identified metabolites. Based on the observed intensities of (13)C atoms of given metabolites on development-dependent changes in the 56 identified (13)C-HSQC signals, we have determined the changes in metabolic networks that are associated with energy and nitrogen metabolism