Oxidative energy metabolism is essential for normal cardiac contractile function. Magnetic resonance spectroscopy (MRS) with phosphorus (31P) is uniquely able to noninvasively assess key metabolites, adenosine triphosphate (ATP) and phosphocreatine (PCr), in the heart. Patient MRS studies show reduced PCr and ATP: levels in myocardial infarction (MI). Human biopsy and autopsy data show that total myocardial creatine (CR=PCr+unphosphorylated creatine,Cr) is also reduced, while animal studies show that the rate of generating ATP from PCr via the creatine kinase reaction (CKR) is reduced in dysfunctional myocardium post-MI. These data together demonstrate that CKR metabolite levels and energy supply are compromised in these common disease states. Prior to the first funding period of this grant, studies of myocardial CR were possible only with invasive tissue biopsies. In the first funding period, we developed noninvasive water-referenced localized MRS using protons (1H) to quantify myocardial CR. We showed, for the first time, the noninvasive detection and quantification of CR in canine and human myocardium, and CR depletion in non-viable, infarcted tissue in patients with MI. Due to the higher 1H MRS sensitivity and much greater proton concentration of the CR moiety, CR MRS can provide a more than 20-fold gain in sensitivity relative to 31P studies of PCr. Therefore, in this competitive renewal, we plan first to advance quantitative 1H MRS of CR by reducing its motion sensitivity with constructive averaging techniques, and introduce CR imaging methods to reveal metabolic defects in patients with MI and delayed hyper-enhancing 1H MRI lesions. Second, we will extend this work by combining CR imaging with contrast-MRI to assess the metabolic viability of hyper-enhancing MRI lesions in acute MI and chronic follow-up. This will address the clinically-relevant question for contrast MRI, of whether such lesions initially include substantial amounts of metabolically viable tissue. Third, we have developed and tested a new fast 31P MRS method that provides CKR flux measures in scan times that are tolerable by patients. For the first time, we will discover the rate at which ATP energy is supplied via the CKR in human heart. We will apply this method to learn whether the CKR ATP supply increases to meet energy demand during stress, and whether it is altered in MI patients with dysfunction, and thereby provide new, fundamental information about myocardial energetics.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Diagnostic Radiology Study Section (RNM)
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Buxton, Denis B
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Johns Hopkins University
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Schär, Michael; Gabr, Refaat E; El-Sharkawy, AbdEl-Monem M et al. (2015) Two repetition time saturation transfer (TwiST) with spill-over correction to measure creatine kinase reaction rates in human hearts. J Cardiovasc Magn Reson 17:70
Bottomley, Paul A; Panjrath, Gurusher S; Lai, Shenghan et al. (2013) Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death. Sci Transl Med 5:215re3
Abraham, M Roselle; Bottomley, Paul A; Dimaano, Veronica Lea et al. (2013) Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy. Am J Cardiol 112:861-6
Hirsch, Glenn A; Bottomley, Paul A; Gerstenblith, Gary et al. (2012) Allopurinol acutely increases adenosine triphospate energy delivery in failing human hearts. J Am Coll Cardiol 59:802-8
Zhang, Yi; Gabr, Refaat E; Schär, Michael et al. (2012) Magnetic resonance Spectroscopy with Linear Algebraic Modeling (SLAM) for higher speed and sensitivity. J Magn Reson 218:66-76
Gabr, Refaat E; El-Sharkawy, Abdel-Monem M; Schar, Michael et al. (2011) High-energy phosphate transfer in human muscle: diffusion of phosphocreatine. Am J Physiol Cell Physiol 301:C234-41
Gabr, R E; El-Sharkawy, A M; Schar, M et al. (2011) Measuring energy diffusion: phosphocreatine in human skeletal muscle. Proc Int Soc Magn Reson Med Sci Meet Exhib Int Soc Magn Reson M 19:1140
Zhang, Y; Gabr, R E; Schär, M et al. (2011) Encoding of pre-selected compartments produces large SNR and speed advantages for P MRS. Proc Int Soc Magn Reson Med Sci Meet Exhib Int Soc Magn Reson M 19:1438
Schär, Michael; El-Sharkawy, Abdel-Monem M; Weiss, Robert G et al. (2010) Triple repetition time saturation transfer (TRiST) 31P spectroscopy for measuring human creatine kinase reaction kinetics. Magn Reson Med 63:1493-501
El-Sharkawy, AbdEl-Monem; Schär, Michael; Ouwerkerk, Ronald et al. (2009) Quantitative cardiac 31P spectroscopy at 3 Tesla using adiabatic pulses. Magn Reson Med 61:785-95

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