ATP derived from the conversion of phosphocreatine to creatine by creatine kinase provides an essential chemical energy source that governs myocardial contraction. Here, we demonstrate that the exchange of amine protons from creatine with protons in bulk water can be exploited to image creatine through chemical exchange saturation transfer (CrEST) in myocardial tissue. We show that CrEST provides about two orders of magnitude higher sensitivity compared to 1H magnetic resonance spectroscopy. Results of CrEST studies from ex vivo myocardial tissue strongly correlate with results from 1H and 31P magnetic resonance spectroscopy and biochemical analysis. We demonstrate the feasibility of CrEST measurement in healthy and infarcted myocardium in animal models in vivo on a 3-T clinical scanner. As proof of principle, we show the conversion of phosphocreatine to creatine by spatiotemporal mapping of creatine changes in the exercised human calf muscle. We also discuss the potential utility of CrEST in studying myocardial disorders.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & Magnetization transfer contrast in MR imaging of the heart. Radiology 180, 671–675 (1991).

  2. 2.

    , & Assessment of myocardial viability by MRI. J. Magn. Reson. Imaging 10, 418–422 (1999).

  3. 3.

    , & Cardiovascular magnetic resonance in patients with myocardial infarction: current and emerging applications. J. Am. Coll. Cardiol. 55, 1–16 (2009).

  4. 4.

    et al. Delayed contrast-enhanced magnetic resonance imaging for the prediction of regional functional improvement after acute myocardial infarction. J. Am. Coll. Cardiol. 42, 895–901 (2003).

  5. 5.

    & Assessment of cardiac ischaemia and viability: role of cardiovascular magnetic resonance. Eur. Heart J. 32, 799–809 (2011).

  6. 6.

    et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N. Engl. J. Med. 343, 1445–1453 (2000).

  7. 7.

    et al. Metabolic imaging using F18-fluorodeoxyglucose to assess myocardial viability. Int. J. Card. Imaging 13, 145–155, discussion 157–160 (1997).

  8. 8.

    et al. Acute myocardial infarction: myocardial viability assessment in patients early thereafter comparison of contrast-enhanced MR imaging with resting 201Tl SPECT. Single photon emission computed tomography. Radiology 226, 138–144 (2003).

  9. 9.

    & Thallium 201 for assessment of myocardial viability. Semin. Nucl. Med. 21, 230–241 (1991).

  10. 10.

    & Assessment of myocardial viability: guide to prognosis and clinical management. Eur. Heart J. 21, 961–963 (2000).

  11. 11.

    , , , & Effect of mitochondrial viability and metabolism on technetium-99m-sestamibi myocardial retention. Eur. J. Nucl. Med. 20, 20–25 (1993).

  12. 12.

    , , & Failing energetics in failing hearts. Curr. Cardiol. Rep. 2, 212–217 (2000).

  13. 13.

    , & Pathobiology of acute myocardial ischemia: metabolic, functional and ultrastructural studies. Am. J. Cardiol. 52, 72A–81A (1983).

  14. 14.

    & Non-invasive magnetic-resonance detection of creatine depletion in non-viable infarcted myocardium. Lancet 351, 714–718 (1998).

  15. 15.

    et al. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with 31P-SLOOP magnetic resonance spectroscopy. J. Am. Coll. Cardiol. 40, 1267–1274 (2002).

  16. 16.

    et al. Absolute quantification of high energy phosphate metabolites in normal, hypertrophied and failing human myocardium. MAGMA 11, 73–74 (2000).

  17. 17.

    et al. Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J. Am. Coll. Cardiol. 42, 1587–1593 (2003).

  18. 18.

    et al. Decreased high-energy phosphate ratios in the myocardium of men with diabetes mellitus type I. J. Cardiovasc. Magn. Reson. 4, 493–502 (2002).

  19. 19.

    , & Human cardiac high-energy phosphate metabolite concentrations by 1D-resolved NMR spectroscopy. Magn. Reson. Med. 35, 664–670 (1996).

  20. 20.

    et al. Profound bioenergetic abnormalities in peri-infarct myocardial regions. Am. J. Physiol. Heart Circ. Physiol. 291, H648–H657 (2006).

  21. 21.

    , , , & Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat. Med. 9, 1085–1090 (2003).

  22. 22.

    , , , & MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST). Proc. Natl. Acad. Sci. USA 104, 4359–4364 (2007).

  23. 23.

    , , & Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc. Natl. Acad. Sci. USA 105, 2266–2270 (2008).

  24. 24.

    et al. Artificial reporter gene providing MRI contrast based on proton exchange. Nat. Biotechnol. 25, 217–219 (2007).

  25. 25.

    , , , & In vivo mapping of brain myo-inositol. Neuroimage 54, 2079–2085 (2011).

  26. 26.

    et al. Magnetic resonance imaging of glutamate. Nat. Med. 18, 302–306 (2012).

  27. 27.

    et al. Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI. NMR Biomed. 25, 1305–1309 (2012).

  28. 28.

    , , & 1H NMR of intact muscle at 11 T. FEBS Lett. 165, 231–237 (1984).

  29. 29.

    Comparison of methanol and perchloric acid extraction procedures for analysis of nucleotides by isotachophoresis. J. Chromatogr. A 374, 162–169 (1986).

  30. 30.

    et al. Regional absolute quantification of the neurochemical profile of the canine brain: investigation by proton nuclear magnetic resonance spectroscopy and tissue extraction. Appl. Magn. Reson. 38, 65–74 (2010).

  31. 31.

    & Noninvasive localized MR quantification of creatine kinase metabolites in normal and infarcted canine myocardium. Radiology 219, 411–418 (2001).

  32. 32.

    , , , & High-throughput screening of chemical exchange saturation transfer MR contrast agents. Contrast Media Mol. Imaging 5, 162–170 (2010).

  33. 33.

    et al. Regional biochemical remodeling in non-infarcted tissue of rat heart post-myocardial infarction. J. Mol. Cell. Cardiol. 28, 1531–1538 (1996).

  34. 34.

    , & Total creatine in muscle: imaging and quantification with proton MR spectroscopy. Radiology 204, 403–410 (1997).

  35. 35.

    , & Influence of phosphagen concentration on phosphocreatine breakdown kinetics. Data from human gastrocnemius muscle. J. Appl. Physiol. 105, 158–164 (2008).

  36. 36.

    et al. “Keyhole” method for accelerating imaging of contrast agent uptake. J. Magn. Reson. Imaging 3, 671–675 (1993).

  37. 37.

    & k-space weighted image contrast (KWIC) for contrast manipulation in projection reconstruction MRI. Magn. Reson. Med. 44, 825–832 (2000).

  38. 38.

    et al. Hyperpolarized magnetic resonance: a novel technique for the in vivo assessment of cardiovascular disease. Circulation 124, 1580–1594 (2011).

  39. 39.

    et al. Metabolic response of normal human myocardium to high-dose atropine-dobutamine stress studied by 31P-MRS. Circulation 96, 2969–2977 (1997).

  40. 40.

    Spatial localization in NMR spectroscopy in vivo. Ann. NY Acad. Sci. 508, 333–348 (1987).

Download references


This work was supported by National Institutes of Health grants P41 EB015893, P41 EB015893S1 and R21DA032256-01 and a pilot grant from the Translational Biomedical Imaging Center of the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania. The authors acknowledge W. Liu and S. Pickup for technical assistance in using the 9.4-T NMR spectrometer, K. Nath for assistance with biochemical analysis and D. Reddy for help with regulatory protocol.

Author information

Author notes

    • Mohammad Haris
    •  & Anup Singh

    These authors contributed equally to this work.


  1. Center for Magnetic Resonance and Optical Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Mohammad Haris
    • , Anup Singh
    • , Kejia Cai
    • , Feliks Kogan
    • , Catherine DeBrosse
    • , Walter R T Witschey
    • , Hari Hariharan
    •  & Ravinder Reddy
  2. Gorman Cardiovascular Research Group, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Jeremy McGarvey
    • , Gerald A Zsido
    • , Walter R T Witschey
    • , Kevin Koomalsingh
    • , James J Pilla
    • , Joseph H Gorman
    •  & Robert C Gorman
  3. Department of Medicine, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, USA.

    • Julio A Chirinos
  4. Department of Medicine, Cardiovascular Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Julio A Chirinos
    •  & Victor A Ferrari


  1. Search for Mohammad Haris in:

  2. Search for Anup Singh in:

  3. Search for Kejia Cai in:

  4. Search for Feliks Kogan in:

  5. Search for Jeremy McGarvey in:

  6. Search for Catherine DeBrosse in:

  7. Search for Gerald A Zsido in:

  8. Search for Walter R T Witschey in:

  9. Search for Kevin Koomalsingh in:

  10. Search for James J Pilla in:

  11. Search for Julio A Chirinos in:

  12. Search for Victor A Ferrari in:

  13. Search for Joseph H Gorman in:

  14. Search for Hari Hariharan in:

  15. Search for Robert C Gorman in:

  16. Search for Ravinder Reddy in:


M.H. and A.S. designed and performed experiments, analyzed data and wrote the manuscript; K.C. provided technical support with animal studies and helped with manuscript editing; F.K. performed experiments and helped with human subject scanning and manuscript editing; J.M. helped with animal handling and manuscript editing; C.D. helped with human subject scanning; G.A.Z. helped with animal handling and scanning; W.R.T.W. provided technical support with animal imaging; and K.K. and J.J.P. helped with animal handling and preparation for imaging. J.A.C., V.A.F. and J.H.G. advised on cardiovascular imaging aspects and contributed to manuscript editing; H.H. provided pulse sequence design and technical guidance and contributed to the manuscript writing; R.C.G. helped with animal experimental design and contributed to manuscript editing; and R.R. conceived of and designed the study and contributed to manuscript writing and editing.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ravinder Reddy.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Discussion and Supplementary Methods

About this article

Publication history






Further reading