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.
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