Oxidative energy metabolism is essential for normal cardiac contractile function. Phosphorus (31P) magnetic resonance spectroscopy (MRS) is unique in its ability to provide noninvasive access to key metabolites such as adenosine triphosphate (ATP) and phosphocreatine (PCr) in the heart. Patient MRS studies show reduced levels of PCr and ATP in myocardial infarction, and altered PCr/ATP ratios in heart failure that correlate with clinical severity. Biopsy and autopsy date demonstrate that total myocardial creatine (CR, however, have been limited by the invasive nature of existing techniques. But CR can be observed in vivo by proton MRS. Moreover, due to the higher 1H MRS sensitivity and the extraordinarily greater proton concentration of the CR N-CH3 moiety, CR MRS can potentially provide a more than 20 fold gain in signal-to-noise relative to 31P studies of PCr. Thus 1H MRS of CR MRS offers a new, sensitive, window for quantifying, mapping, and even imaging, an important myocardial energy metabolite. We have demonstrated CR detection and mapping in normal human heart and CR reductions in human myocardial infarction in our preliminary 1H MRS work. Here, the development and validation of 1H MRS as a tool for quantifying regional myocardial CR in the human heart is proposed using phantom, MRS, and biopsy studies of canine myocardium, as well as noninvasive human MRS studies. The use of CR MRS for differentiating infarcted myocardium from noninfarcted myocardium will be assessed via quantitative MRS and tissue assays in a well-defined canine model of infarction, and by MRS studies of patients with myocardial infarction. The hypothesis that myocardial CR and PCr levels in the CK reaction are reduced in the failing human heart in proportion to the severity of heart failure will be tested with noninvasive1H and 31P MRS studies of patients with heart failure. The development of a new, sensitive, noninvasive method for quantifying myocardial energy metabolism would significantly advance our understanding of the role of energy deprivation in heart disease, and potentially provide us with a new probe for assessing cardiac tissue viability.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056882-02
Application #
2702347
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1997-05-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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