Clinical implications of cardiac hyperpolarized magnetic resonance imaging
Oliver J Rider, Damian J Tyler, Oliver J Rider, Damian J Tyler
Abstract
Alterations in cardiac metabolism are now considered a cause, rather than a result, of cardiac disease. Although magnetic resonance spectroscopy has allowed investigation of myocardial energetics, the inherently low sensitivity of the technique has limited its clinical application in the study of cardiac metabolism. The development of a novel hyperpolarization technique, based on the process of dynamic nuclear polarization, when combined with the metabolic tracers [1-(13)C] and [2-(13)C] pyruvate, has resulted in significant advances in the understanding of real time myocardial metabolism in the normal and diseased heart in vivo. This review focuses on the changes in myocardial substrate selection and downstream metabolism of hyperpolarized 13C labelled pyruvate that have been shown in diabetes, ischaemic heart disease, cardiac hypertrophy and heart failure in animal models of disease and how these could translate into clinical practice with the advent of clinical grade hyperpolarizer systems.
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References
- Evans RD, Clarke K. Myocardial substrate metabolism in heart disease. Front Biosci. 2012;4:556–80.
- Kolwicz SC Jr, Tian R. Glucose metabolism and cardiac hypertrophy. Cardiovasc Res. 2011;90(2):194–201. doi: 10.1093/cvr/cvr071.
- Rider OJ. et al.Myocardial substrate metabolism in obesity. Int J Obes (Lond) 2013;37(7):972–9. doi: 10.1038/ijo.2012.170.
- Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85(3):1093–129. doi: 10.1152/physrev.00006.2004.
- Neubauer S. The failing heart–an engine out of fuel. N Engl J Med. 2007;356(11):1140–51. doi: 10.1056/NEJMra063052.
- Lee L. et al.Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112(21):3280–8. doi: 10.1161/CIRCULATIONAHA.105.551457.
- Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev. 2005;4 CD003614.
- Hale SL. et al.Late sodium current inhibition as a new cardioprotective approach. J Mol Cell Cardiol. 2008;44(6):954–67. doi: 10.1016/j.yjmcc.2008.03.019.
- Obrzut S. et al.Imaging and modeling of myocardial metabolism. J Cardiovasc Transl Res. 2010;3(4):384–96. doi: 10.1007/s12265-010-9170-1.
- Karamitsos TD. et al.The role of cardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol. 2009;54(15):1407–24. doi: 10.1016/j.jacc.2009.04.094.
- Lamb HJ. et al.Metabolic response of normal human myocardium to high-dose atropine-dobutamine stress studied by 31P-MRS. Circulation. 1997;96(9):2969–77. doi: 10.1161/01.CIR.96.9.2969.
- Neubauer S. et al.Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96(7):2190–6. doi: 10.1161/01.CIR.96.7.2190.
- Dobbins RL, Malloy CR. Measuring in-vivo metabolism using nuclear magnetic resonance. Curr Opin Clin Nutr Metab Care. 2003;6(5):501–9. doi: 10.1097/00075197-200309000-00003.
- Gallagher FA. et al.Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature. 2008;453(7197):940–3. doi: 10.1038/nature07017.
- Schroeder MA. et vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci U S A. 2008;105(33):12051–6. doi: 10.1073/pnas.0805953105.
- Ardenkjaer-Larsen JH. et al.Dynamic nuclear polarization polarizer for sterile use intent. NMR Biomed. 2011;24(8):927–32. doi: 10.1002/nbm.1682.
- Viale A. et al.Hyperpolarized agents for advanced MRI investigations. Q J Nucl Med Mol Imaging. 2009;53(6):604–17.
- Fain SB. et al.Functional lung imaging using hyperpolarized gas MRI. J Magn Reson Imaging. 2007;25(5):910–23. doi: 10.1002/jmri.20876.
- Bhattacharya P, Ross BD, Bunger R. Cardiovascular applications of hyperpolarized contrast media and metabolic tracers. Exp Biol Med (Maywood) 2009;234(12):1395–416. doi: 10.3181/0904-MR-135.
- Ardenkjaer-Larsen JH. et al.Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR. Proc Natl Acad Sci USA. 2003;100(18):10158–63. doi: 10.1073/pnas.1733835100.
- Golman K, in ’t Zandt R, Thaning M. Real-time metabolic imaging. Proc Natl Acad Sci USA. 2006;103(30):11270–5. doi: 10.1073/pnas.0601319103.
- Merritt ME. et al.Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc Natl Acad Sci USA. 2007;104(50):19773–7. doi: 10.1073/pnas.0706235104.
- Schroeder MA. et al.Measuring intracellular pH in the heart using hyperpolarized carbon dioxide and bicarbonate: a 13C and 31P magnetic resonance spectroscopy study. Cardiovasc Res. 2010;86(1):82–91. doi: 10.1093/cvr/cvp396.
- Golman K. et al.Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Magn Reson Med. 2008;59(5):1005–13. doi: 10.1002/mrm.21460.
- Dodd MS. et vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart. Cardiovasc Res. 2012;95(1):69–76. doi: 10.1093/cvr/cvs164.
- Atherton HJ. et al.Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. Circulation. 2011;123(22):2552–61. doi: 10.1161/CIRCULATIONAHA.110.011387.
- Oliver MF, Opie LH. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet. 1994;343(8890):155–8. doi: 10.1016/S0140-6736(94)90939-3.
- Vik-Mo H, Mjos OD. Influence of free fatty acids on myocardial oxygen consumption and ischemic injury. Am J Cardiol. 1981;48(2):361–5. doi: 10.1016/0002-9149(81)90621-4.
- Barak C. et al.Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart. J Cardiovasc Pharmacol. 1998;31(3):336–44. doi: 10.1097/00005344-199803000-00002.
- Kudej RK. et al.Brief increase in carbohydrate oxidation after reperfusion reverses myocardial stunning in conscious pigs. Circulation. 2002;106(22):2836–41. doi: 10.1161/01.CIR.0000039326.87475.98.
- Merritt ME. et al.Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized (CO2)-C-13 and (HCO3-)-C-13. Magn Reson Med. 2008;60(5):1029–36. doi: 10.1002/mrm.21760.
- Ball DR, Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1- C]pyruvate. NMR Biomed. 2013. Jun 14. doi: 10.1002/nbm.2972.
- Lau AZ. et al.Reproducibility study for free-breathing measurements of pyruvate metabolism using hyperpolarized (13) C in the heart. Magn Reson Med. 2013;69(4):1063–71. doi: 10.1002/mrm.24342.
- Shaw LJ. et al.Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation. 2008;117(10):1283–91. doi: 10.1161/CIRCULATIONAHA.107.743963.
- Pagley PR. et al.Improved outcome after coronary bypass surgery in patients with ischemic cardiomyopathy and residual myocardial viability. Circulation. 1997;96(3):793–800. doi: 10.1161/01.CIR.96.3.793.
- Wijns W, Vatner SF, Camici PG. Hibernating myocardium. N Engl J Med. 1998;339(3):173–81. doi: 10.1056/NEJM199807163390307.
- Lau AZ. et al.Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart. Magn Reson Med. 2010;64(5):1323–31. doi: 10.1002/mrm.22525.
- Bonow RO. et al.Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. 2011;364(17):1617–25. doi: 10.1056/NEJMoa1100358.
- Garlick PB, Radda GK, Seeley PJ. Studies of acidosis in the ischaemic heart by phosphorus nuclear magnetic resonance. Biochem J. 1979;184(3):547–54.
- Vaughan-Jones RD, Spitzer KW, Swietach P. Intracellular pH regulation in heart. J Mol Cell Cardiol. 2009;46(3):318–31. doi: 10.1016/j.yjmcc.2008.10.024.
- Opie LH. Myocardial ischemia–metabolic pathways and implications of increased glycolysis. Cardiovasc Drugs Ther. 1990;4(Suppl 4):777–90.
- Bing OH, Brooks WW, Messer JV. Heart muscle viability following hypoxia: protective effect of acidosis. Science. 1973;180(4092):1297–8. doi: 10.1126/science.180.4092.1297.
- Frohlich O, Wallert MA. Methods of measuring intracellular pH in the heart. Cardiovasc Res. 1995;29(2):194–202.
- Hoult DI. et al.Observation of tissue metabolites using 31P nuclear magnetic resonance. Nature. 1974;252(5481):285–7. doi: 10.1038/252285a0.
- Katz LA. et al.Intracellular pH and inorganic phosphate content of heart in vivo: a 31P-NMR study. Am J Physiol. 1988;255(1 Pt 2):H189–96.
- Schroeder MA. et al.Real-time assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy. FASEB J. 2009;23(8):2529–38. doi: 10.1096/fj.09-129171.
- Atherton HJ, Investigating the Metabolic Effects of Heart Failure Progression using Hyperpolarized Magnetic Resonance. Proc. Intl. Soc. Mag. Reson. Med. 18. 2010.
- Schroeder MA. et al.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(2):130–40. doi: 10.1093/eurjhf/hfs192.
- Kurhanewicz J. et al.Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia. 2011;13(2):81–97.
- Nelson SJ. et al.Strategies for rapid in vivo H-1 and hyperpolarized C-13 MR spectroscopic imaging. J Magn Reson. 2013;229:187–97.
- Schroeder MA. et al.Hyperpolarized magnetic resonance A novel technique for the In vivo assessment of cardiovascular disease. Circulation. 2011;124(14):1580–94. doi: 10.1161/CIRCULATIONAHA.111.024919.
- Schillinger W. et al.Intracoronary pyruvate in cardiogenic shock as an adjunctive therapy to catecholamines and intra-aortic balloon pump shows beneficial effects on hemodynamics. Clin Res Cardiol. 2011;100(5):433–8. doi: 10.1007/s00392-010-0261-4.
- Hermann HP. et al.Improved systolic and diastolic myocardial function with intracoronary pyruvate in patients with congestive heart failure. Eur J Heart Fail. 2004;6(2):213–8. doi: 10.1016/j.ejheart.2003.10.001.
- Hermann HP. et al.Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet. 1999;353(9161):1321–3. doi: 10.1016/S0140-6736(98)06423-X.
- Petkova I. et al.Sodium pyruvate infusions in patients with alcoholic liver disease. Preliminary report. Acta Physiol Pharmacol Bulg. 2000;25(3–4):103–8.
- UCSF Prostate Cancer News Release. 2010. Available from: .
- Nelson SJ. et al.Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci Transl Med. 2013;5(198):198. ra108.
- Gallagher FA. et al.Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors. Proc Natl Acad Sci USA. 2009;106(47):19801–6. doi: 10.1073/pnas.0911447106.
- Gallagher FA. et al.Detection of tumor glutamate metabolism In vivo using C-13 magnetic resonance spectroscopy and hyperpolarized [1-C-13]glutamate. Magn Reson Med. 2011;66(1):18–23. doi: 10.1002/mrm.22851.
- Ball DR, Hyperpolarized butyrate: A metabolic probe of short chain fatty acid metabolism in the heart. Magn Reson Med. 2013. doi: 10.1002/mrm.24849.
- Jensen PR. et al.Tissue-specific short chain fatty acid metabolism and slow metabolic recovery after ischemia from hyperpolarized NMR in vivo. J Biol Chem. 2009;284(52):36077–82. doi: 10.1074/jbc.M109.066407.
- Allouche-Arnon H. et vivo magnetic resonance imaging of glucose - initial experience. Contrast Media Mol Imaging. 2013;8(1):72–82.
- Bohndiek SE. et al.Hyperpolarized [1-C-13]-ascorbic and dehydroascorbic acid: vitamin C as a probe for imaging redox status in vivo. J Am Chem Soc. 2011;133(30):11795–801. doi: 10.1021/ja2045925.
- Hu S. et vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-C-13]alanine. Magn Reson Imaging. 2011;29(8):1035–40. doi: 10.1016/j.mri.2011.07.001.
- Keshari KR. et al.Hyperpolarized C-13 dehydroascorbate as an endogenous redox sensor for in vivo metabolic imaging. Proc Natl Acad Sci U S A. 2011;108(46):18606–11. doi: 10.1073/pnas.1106920108.
- Mayer D. et al.Application of hyperpolarized [1-13C]lactate for the in vivo investigation of cardiac metabolism. NMR Biomed. 2012;25(10):1119–24. doi: 10.1002/nbm.2778.
- Golman K. et al.Molecular imaging with endogenous substances. Proc Natl Acad Sci U S A. 2003;100(18):10435–9. doi: 10.1073/pnas.1733836100.
- Golman K. et al.Parahydrogen-induced polarization in imaging: subsecond (13)C angiography. Magn Reson Med. 2001;46(1):1–5. doi: 10.1002/mrm.1152.
- Svensson J. et al.Hyperpolarized 13C MR angiography using trueFISP. Magn Reson Med. 2003;50(2):256–62. doi: 10.1002/mrm.10530.
- Olsson LE. et coronary angiography in pigs with intraarterial injections of a hyperpolarized 13C substance. Magn Reson Med. 2006;55(4):731–7. doi: 10.1002/mrm.20847.
- Ishii M. et al.Hyperpolarized 13C MRI of the pulmonary vasculature and parenchyma. Magn Reson Med. 2007;57(3):459–63. doi: 10.1002/mrm.21168.
- Buckert D. et al.Intermediate-term prognostic value of reversible perfusion deficit diagnosed by adenosine CMR: a prospective follow-up study in a consecutive patient population. JACC Cardiovasc Imaging. 2013;6(1):56–63. doi: 10.1016/j.jcmg.2012.08.011.
- Schwitter J. Myocardial perfusion imaging by cardiac magnetic resonance. J Nucl Cardiol. 2006;13(6):841–54. doi: 10.1016/j.nuclcard.2006.09.008.
- Mansson S. et al.13C imaging-a new diagnostic platform. Eur Radiol. 2006;16(1):57–67. doi: 10.1007/s00330-005-2806-x.
- Johansson E. et al.Perfusion assessment with bolus differentiation: a technique applicable to hyperpolarized tracers. Magn Reson Med. 2004;52(5):1043–51. doi: 10.1002/mrm.20247.
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