Hyperpolarized 13C Metabolic MRI of the Human Heart: Initial Experience
Charles H Cunningham, Justin Y C Lau, Albert P Chen, Benjamin J Geraghty, William J Perks, Idan Roifman, Graham A Wright, Kim A Connelly, Charles H Cunningham, Justin Y C Lau, Albert P Chen, Benjamin J Geraghty, William J Perks, Idan Roifman, Graham A Wright, Kim A Connelly
Abstract
Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism.
Objective: To demonstrate the first hyperpolarized 13C metabolic magnetic resonance imaging of the human heart.
Methods and results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1-13C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1-13C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1-13C]lactate signal appeared both within the chambers and in the myocardium. The mean 13C image signal:noise ratio was 115 for [1-13C]pyruvate, 56 for 13C-bicarbonate, and 53 for [1-13C]lactate.
Conclusions: These results represent the first 13C images of the human heart. The appearance of 13C-bicarbonate signal after administration of hyperpolarized [1-13C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology.
Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02648009.
Keywords: heart failure; magnetic resonance imaging; metabolic imaging; metabolism; mitochondria.
© 2016 The Authors.
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References
- Stanley WC, Chandler MP. Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev. 2002;7:115–130.
- Ashrafian H, Frenneaux MP, Opie LH. Metabolic mechanisms in heart failure. Circulation. 2007;116:434–448. doi: 10.1161/CIRCULATIONAHA.107.702795.
- Ardehali H, Sabbah HN, Burke MA, Sarma S, Liu PP, Cleland JG, Maggioni A, Fonarow GC, Abel ED, Campia U, Gheorghiade M. Targeting myocardial substrate metabolism in heart failure: potential for new therapies. Eur J Heart Fail. 2012;14:120–129. doi: 10.1093/eurjhf/hfr173.
- Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013;113:709–724. doi: 10.1161/CIRCRESAHA.113.300376.
- Garlick PB, Radda GK, Seeley PJ. Phosphorus NMR studies on perfused heart. Biochem Biophys Res Commun. 1977;74:1256–1262.
- Bailey IA, Gadian DG, Matthews PM, Radda GK, Seeley PJ. Studies of metabolism in the isolated, perfused rat heart using 13C NMR. FEBS Lett. 1981;123:315–318.
- Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH, Servin R, Thaning M, Golman K. Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proc Natl Acad Sci U S A. 2003;100:10158–10163. doi: 10.1073/pnas.1733835100.
- Merritt ME, Harrison C, Storey C, Jeffrey FM, Sherry AD, Malloy CR. Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc Natl Acad Sci U S A. 2007;104:19773–19777. doi: 10.1073/pnas.0706235104.
- Golman K, Petersson JS, Magnusson P, Johansson E, Akeson P, Chai CM, Hansson G, Månsson S. Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Magn Reson Med. 2008;59:1005–1013. doi: 10.1002/mrm.21460.
- Schroeder MA, Cochlin LE, Heather LC, Clarke K, Radda GK, Tyler DJ. In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci U S A. 2008;105:12051–12056. doi: 10.1073/pnas.0805953105.
- Schroeder MA, Clarke K, Neubauer S, Tyler DJ. Hyperpolarized magnetic resonance: a novel technique for the in vivo assessment of cardiovascular disease. Circulation. 2011;124:1580–1594. doi: 10.1161/CIRCULATIONAHA.111.024919.
- Lau AZ, Chen AP, Barry J, Graham JJ, Dominguez-Viqueira W, Ghugre NR, Wright GA, Cunningham CH. Reproducibility study for free-breathing measurements of pyruvate metabolism using hyperpolarized (13) C in the heart. Magn Reson Med. 2013;69:1063–1071. doi: 10.1002/mrm.24342.
- Schroeder MA, Lau AZ, Chen AP, Gu Y, Nagendran J, Barry J, Hu X, Dyck JR, Tyler DJ, Clarke K, Connelly KA, Wright GA, Cunningham CH. Hyperpolarized (13)C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart. Eur J Heart Fail. 2013;15:130–140. doi: 10.1093/eurjhf/hfs192.
- Le Page LM, Rider OJ, Lewis AJ, Ball V, Clarke K, Johansson E, Carr CA, Heather LC, Tyler DJ. Increasing pyruvate dehydrogenase flux as a treatment for diabetic cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study. Diabetes. 2015;64:2735–2743. doi: 10.2337/db14-1560.
- Lau AZ, Chen AP, Ghugre NR, Ramanan V, Lam WW, Connelly KA, Wright GA, Cunningham CH. Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart. Magn Reson Med. 2010;64:1323–1331. doi: 10.1002/mrm.22525.
- Tropp J, Calderon P, Carvajal L, Robb F, Larson PEZ, Shin P, Vigneron DB, Nelson SJ. Proceedings of the 20th Annual Meeting of ISMRM. Melbourne, Australia: 2012. A carbon receive array of 8 elements, interoperable with proton scanning, for human temporal lobe. Abstract 2658.
- Ardenkjaer-Larsen JH, Leach AM, Clarke N, Urbahn J, Anderson D, Skloss TW. Dynamic nuclear polarization polarizer for sterile use intent. NMR Biomed. 2011;24:927–932.
- Witney TH, Kettunen MI, Brindle KM. Kinetic modeling of hyperpolarized 13C label exchange between pyruvate and lactate in tumor cells. J Biol Chem. 2011;286:24572–24580. doi: 10.1074/jbc.M111.237727.
- Rider OJ, Tyler DJ. Clinical implications of cardiac hyperpolarized magnetic resonance imaging. J Cardiovasc Magn Reson. 2013;15:93. doi: 10.1186/1532-429X-15-93.
- Taegtmeyer H, McNulty P, Young ME. Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation. 2002;105:1727–1733.
- Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, Boudina S, Abel ED. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes. 2004;53:2366–2374.
- Lewis AJ, Neubauer S, Tyler DJ, Rider OJ. Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy. Expert Opin Ther Targets. 2016;20:755–766. doi: 10.1517/14728222.2016.1126248.
Source: PubMed