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.
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.
|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|
|Purmal, Colin; Kucejova, Blanka; Sherry, A Dean et al. (2014) Propionate stimulates pyruvate oxidation in the presence of acetate. Am J Physiol Heart Circ Physiol 307:H1134-41|
|Comment, Arnaud; Merritt, Matthew E (2014) Hyperpolarized magnetic resonance as a sensitive detector of metabolic function. Biochemistry 53:7333-57|