Abstract

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:
Aim 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.
Aim 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 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050239-07
Application #
2771342
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1992-09-30
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Bahrainy, Samira; Levy, Wayne C; Busey, Janet M et al. (2016) Exercise training bradycardia is largely explained by reduced intrinsic heart rate. Int J Cardiol 222:213-216
Caldwell, James H; Link, Jeanne M; Levy, Wayne C et al. (2008) Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure. J Nucl Med 49:234-41
Mann, Gary N; Link, Jeanne M; Pham, Pam et al. (2006) [11C]metahydroxyephedrine and [18F]fluorodeoxyglucose positron emission tomography improve clinical decision making in suspected pheochromocytoma. Ann Surg Oncol 13:187-97
O'Sullivan, Finbarr (2006) Locally constrained mixture representation of dynamic imaging data from PET and MR studies. Biostatistics 7:318-38
Chen, Grace P; Tabibiazar, Ramin; Branch, Kelley R et al. (2005) Cardiac receptor physiology and imaging: an update. J Nucl Cardiol 12:714-30
Link, Jeanne M; Stratton, John R; Levy, Wayne et al. (2003) PET measures of pre- and post-synaptic cardiac beta adrenergic function. Nucl Med Biol 30:795-803
Tseng, H; Link, J M; Stratton, J R et al. (2001) Cardiac receptor physiology and its application to clinical imaging: present and future. J Nucl Cardiol 8:390-409
Link, J M; Synovec, R E (1999) Whole-column radioactivity detection: simultaneous separation and enhanced detectability. Anal Chem 71:2700-7
Tewson, T J; Krohn, K A (1998) PET radiopharmaceuticals: state-of-the-art and future prospects. Semin Nucl Med 28:221-34
Caldwell, J H; Kroll, K; Li, Z et al. (1998) Quantitation of presynaptic cardiac sympathetic function with carbon-11-meta-hydroxyephedrine. J Nucl Med 39:1327-34

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