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.
