Modulations of myocardial energy metabolism via xanthine oxidase inhibition, Sca-1+ stem cell treatment and PPAR-delta gene ablation

Phosphorous-31 magnetic resonance spectroscopy (MRS) is a versatile tool for studying myocardial energy metabolism. Along the pathways to heart failure the myocardium progressively decreases phosphocreatine (PCr), ATP and its PCr/ATP ratio. The work in this dissertation is directed toward understanding novel modulations in myocardial energy metabolism by xanthine oxidase inhibition (XOI), cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta (PPAR-delta) ablation and Sca-1+ stem cell treatment in postinfarction left ventricular remodeling. Moreover, a novel technique for myocardial MRS in mice is designed, fabricated and applied.; In regard to XOI, this work examines the effects of acute allopurinol and febuxostat infusion on myocardial PCr/ATP, free ADP and mitochondria oxidative phosphorylation in a normal open-chest canine model at basal and high cardiac workstates. Measurements include hemodynamics (invasive catheters), myocardial high energy phosphates (MRS), myocardial perfusion (radioactive microspheres) and myocardial oxygen consumption (blood gases).; Combined with the increasing popularity of transgenic mice as disease models, in vivo cardiac MRS provides a unique opportunity to nondestructively probe the mechanisms of left ventricular dysfunction in the failing heart. Current in vivo mouse cardiac MRS methods require relatively long acquisition times ranging one-half to 3 hours. This arm of work encompasses (1) engineering of an NMR surface coil design with an open-chest surgery that permits 12 minute cardiac NMR spectrum acquisition from the whole heart without the possibility of skeletal muscle contamination; and (2) its application to examining mouse models of postinfarction LV remodeling with Sca-1+ stem cell therapy and PPAR-delta gene ablation.