When coronary blood flow is suddenly interrupted, myocardial contraction in the ischemic area becomes depressed within seconds. The biochemical mechanism of this ischemic dysfunction is not well understood. Our goal is to evaluate the role of depletion of specific high-energy phosphate compounds, tissue acidosis, and lactate accumulation in ischemic myocardial dysfunction. To do this, we will use 1H and 31P nuclear magnetic resonance (NMR) spectroscopic methods, coupled with simultaneous measurement of regional and global ventricular function and of regional myocardial blood flow, taking advantage of the exceptional facilities and personnel availabale at Yale for biologic NMR spectroscopy as well as the PI's unique background in cardiology, mathematics, computer science, and NMR. Dogs will be subjected to reversible ischemia using a balloon occluder around the left anterior descending coronary artery, while NMR spectra are collected using surface coils positioned over either the ischemic or the control regions of myocardium. In this way we hope to define a metabolic """"""""signature"""""""" of reversibly dysfunctional tissue. We will also study the effects both of reperfusion and of anti-ischemic and inotropic drug therapy. In the last 2 1/2 years of the project we will attempt to develop volume localization techniques to make it possible to perform NMR spectroscopy in the closed chest dog and in humans. We will apply this first to cardiomyopathy to verify the accuracy of the volume localization methods, and then to patients recovering from acute anterior myocardial infarction. Such information is potentially important in understanding the pathophysiology of human coronary artery disease, developing better cardiovascular diagnostic techniques, and designing new therapeutic agents for acute and chronic ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL001686-03
Application #
3082070
Study Section
Research Manpower Review Committee (MR)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zahler, R; Gilmore-Hebert, M; Sun, W et al. (1996) Na, K-ATPase isoform gene expression in normal and hypertrophied dog heart. Basic Res Cardiol 91:256-66
Zahler, R; Gilmore-Hebert, M; Baldwin, J C et al. (1993) Expression of alpha isoforms of the Na,K-ATPase in human heart. Biochim Biophys Acta 1149:189-94
Zahler, R; Ingwall, J S (1992) Estimation of heart mitochondrial creatine kinase flux using magnetization transfer NMR spectroscopy. Am J Physiol 262:H1022-8
Zahler, R; Barrett, E; Majumdar, S et al. (1992) Lactic acidosis: effect of treatment on intracellular pH and energetics in living rat heart. Am J Physiol 262:H1572-8
Zahler, R; Brines, M; Kashgarian, M et al. (1992) The cardiac conduction system in the rat expresses the alpha 2 and alpha 3 isoforms of the Na+,K(+)-ATPase. Proc Natl Acad Sci U S A 89:99-103
Zahler, R; Majumdar, S; Frederick, B et al. (1991) NMR determination of myocardial pH in vivo: separation of tissue inorganic phosphate from blood 2,3-DPG. Magn Reson Med 17:368-78