Measurement of in vivo flux using 13C labeled substrates, fast dissolution dynamic nuclear polarization (fd- DNP), and magnetic resonance imaging (MRI) is one of the most promising new technologies for molecular imaging in vivo. Almost all research in DNP to this point has focused on the use of [1-13C]pyruvate as the imaging substrate. While initial results have demonstrated the fantastic potential of the methodology, the inherent limitation of pyruvate is that it probes a limited number of pathways. Extension of the methodology to study other pathways such as b-oxidation or anaplerosis would dramatically expand the scope of its utilization. Our target of study is the perfused heart from the C57BL/6J (B6) mouse (control) and an aortic band model of pressure overload. We hypothesize that LVH will lead to increased [13C]bicarbonate production following injection of [1-13C]pyruvate, and that a propionate challenge will further increase the amount of HP bicarbonate that is observable. These hypotheses will be tested in the perfused mouse heart using a HyperSense DNP polarizer and a custom built 10 mm, 13C-optimized cryoprobe. The increase in sensitivity over standard isotopomer analysis using this suite of equipment will be on the order of 100000 to 140000 times. Relevance Left ventricular hypertrophy is a common malady associated with diabetes and obesity. LVH can under common circumstances progress to heart failure (HF), a common cause of mortality in the US and developed world. LVH is commonly associated with a change in myocardial energetics, where the heart is thought to preferentially oxidize glucose as compared to its normal substrate of choice, fatty acids. Development of a molecular imaging technique that could detect the onset of changes in energetics in vivo or possibly monitor the effects of the emerging """"""""metabolic therapies"""""""" would constitute a major development in healthcare. This proposal is focused on identifying a reliable biomarker of substrate preference in the myocardium. We hypothesize that [13C]bicarbonate could serve as such a marker following injection of hyperpolarized [1- 13C]pyruvate.

Public Health Relevance

In this R21, we hypothesize that [13C]bicarbonate production from injected, hyperpolarized [1-13C]pyruvate will be diagnostic of metabolic changes associated with left ventricular hypertrophy. In addition, we hypothesize that a propionate challenge will amplify this effect, increasing the diagnostic capability of a hyperpolarized exam. These protocols will be tested with a rigorous set of control experiments to confirm their validity and the outcome of this grant should be an algorithm for hyperpolarized imaging that could be useful both for diagnosis and design of treatment plans involving metabolic therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB016197-01A1
Application #
8702686
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Liu, Guoying
Project Start
2014-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Walker, Christopher M; Merritt, Matthew; Wang, Jian-Xiong et al. (2016) Use of a Multi-compartment Dynamic Single Enzyme Phantom for Studies of Hyperpolarized Magnetic Resonance Agents. J Vis Exp :e53607
Wang, Jian-Xiong; Merritt, Matthew E; Sherry, Dean et al. (2016) A general chemical shift decomposition method for hyperpolarized (13) C metabolite magnetic resonance imaging. Magn Reson Chem 54:665-73
Marco-Rius, Irene; Cao, Peng; von Morze, Cornelius et al. (2016) Multiband spectral-spatial RF excitation for hyperpolarized [2-(13) C]dihydroxyacetone (13) C-MR metabolism studies. Magn Reson Med :
Bastiaansen, Jessica A M; Merritt, Matthew E; Comment, Arnaud (2016) Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-(13)C]butyrate and [1-(13)C]pyruvate. Sci Rep 6:25573
Khemtong, Chalermchai; Carpenter, Nicholas R; Lumata, Lloyd L et al. (2015) Hyperpolarized 13C NMR detects rapid drug-induced changes in cardiac metabolism. Magn Reson Med 74:312-9
Burgess, Shawn C; Merritt, Mathew E; Jones, John G et al. (2015) Limitations of detection of anaplerosis and pyruvate cycling from metabolism of [1-(13)C] acetate. Nat Med 21:108-9
Lumata, Lloyd L; Martin, Richard; Jindal, Ashish K et al. (2015) Development and performance of a 129-GHz dynamic nuclear polarizer in an ultra-wide bore superconducting magnet. MAGMA 28:195-205
Lumata, Lloyd; Yang, Chendong; Ragavan, Mukundan et al. (2015) Hyperpolarized (13)C Magnetic Resonance and Its Use in Metabolic Assessment of Cultured Cells and Perfused Organs. Methods Enzymol 561:73-106
Moreno, Karlos X; Moore, Christopher L; Burgess, Shawn C et al. (2015) Production of hyperpolarized (13)CO2 from [1-(13)C]pyruvate in perfused liver does reflect total anaplerosis but is not a reliable biomarker of glucose production. Metabolomics 11:1144-1156
Comment, Arnaud; Merritt, Matthew E (2014) Hyperpolarized magnetic resonance as a sensitive detector of metabolic function. Biochemistry 53:7333-57

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