Revascularization reverses chronic ventricular dysfunction, a major determinant of survival, in some patients with coronary disease. Identification of chronically underperfused but viable (hibernating) myocardium is an important diagnostic goal. We have developed a method for detecting chronically hypoxic but viable myocardium noninvasively using 18F-fluoromisonidazole (FMISO) and positron emission tomography (PET). In pilot PET studies we have demonstrated FMISO trapping in humans with chronic ischemic heart disease, and in animal studies, that FMISO is a more sensitive indicator of ischemia than 18F-fluorodeoxyglucose (FDG).
The specific aims of this proposal are to: 1. Compare 18F-FMISO images to 18F-FDG uptake/myocardial blood flow (15O-water) mismatch images in patients with regional ventricular dysfunction before and after revascularization to establish the relative sensitivity/specificity of the two methods for predicting functional recovery. We hypothesize that FMISO will prove to be a sensitive indicator of myocardial viability and that reversal of chronic hypoxia will correlate with contractile improvement. 2. Develop and validate new positron labeled hypoxia tracers that exhibit more rapid oxygen-sensitive bioreduction and accelerated plasma clearance than FMISO, potentially allowing shorter imaging protocols and the detection of acute ischemia. We will synthesize and radiolabel new nitroimidazole analogues (among others, 4-methyl-2-nitroimidazole, 4-hydroxymethyl-2-nitroimidazole and 2-nitroimidazole-4-carboxylic acid) whose chemical characteristics appear favorable for hypoxia imaging. These compounds will be evaluated by biodistribution studies in rats and by oxygen-sensitivity studies in isolated adult rat myocytes. For the analogues with the greatest oxygen-sensitivity and fastest blood clearance, PET studies will be performed in a canine model of prolonged ischemia with reversible regional dysfunction. The ultimate goal of this project is to validate and optimize the use of hypoxia markers and PET for the noninvasive evaluation of patients with regional ventricular dysfunction who may benefit from revascularization.
| Bassingthwaighte, James B; Butterworth, Erik; Jardine, Bartholomew et al. (2012) Compartmental modeling in the analysis of biological systems. Methods Mol Biol 929:391-438 |
| Dash, Ranjan K; Bassingthwaighte, James B (2010) Erratum to: Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 38:1683-701 |
| Bassingthwaighte, James B; Raymond, Gary M; Butterworth, Erik et al. (2010) Multiscale modeling of metabolism, flows, and exchanges in heterogeneous organs. Ann N Y Acad Sci 1188:111-20 |
| Dash, Ranjan K; Bassingthwaighte, James B (2006) Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion. Ann Biomed Eng 34:1129-48 |
| Dash, Ranjan K; Bassingthwaighte, James B (2004) Blood HbO2 and HbCO2 dissociation curves at varied O2, CO2, pH, 2,3-DPG and temperature levels. Ann Biomed Eng 32:1676-93 |
| Kellen, Michael R; Bassingthwaighte, James B (2003) Transient transcapillary exchange of water driven by osmotic forces in the heart. Am J Physiol Heart Circ Physiol 285:H1317-31 |
| Kellen, Michael R; Bassingthwaighte, James B (2003) An integrative model of coupled water and solute exchange in the heart. Am J Physiol Heart Circ Physiol 285:H1303-16 |
| Wang, C Y; Bassingthwaighte, J B (2001) Capillary supply regions. Math Biosci 173:103-14 |
| Swanson, K R; True, L D; Lin, D W et al. (2001) A quantitative model for the dynamics of serum prostate-specific antigen as a marker for cancerous growth: an explanation for a medical anomaly. Am J Pathol 158:2195-9 |
| Swanson, K R; Alvord Jr, E C; Murray, J D (2000) A quantitative model for differential motility of gliomas in grey and white matter. Cell Prolif 33:317-29 |
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