A technique for in vivo mapping of myocardial creatine kinase metabolism

Abstract

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.

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Figure 1: CrEST measurement in ex vivo noninfarcted myocardial tissue.
Figure 2: CrEST map of a noninfarcted ex vivo lamb myocardium measured at two separate time points (14 h and 62 h) following excision of the heart.
Figure 3: Ex vivo CrEST of noninfarcted and infarcted myocardial tissue from swine.
Figure 4: In vivo CrEST data from normal and infarcted swine or sheep myocardium.
Figure 5: CrEST maps of exercise-induced changes in skeletal muscle.

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Acknowledgements

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.

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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.

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Correspondence to Ravinder Reddy.

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Haris, M., Singh, A., Cai, K. et al. A technique for in vivo mapping of myocardial creatine kinase metabolism. Nat Med 20, 209–214 (2014). https://doi.org/10.1038/nm.3436

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