Abstract 20262: In vivo [R)-[11C]Rolipram Positron Emission Tomography Imaging Detects Increased Phosphodiesterase-4 in Normally-Perfused Rat Myocardial Regions 8–12 Weeks Following Myocardial Infarction
Sympathetic hyperactivity in heart failure is associated with changes in the noradrenergic signal transduction at the level of the beta adrenergic receptor (beta-AR) and intracellular second messenger cAMP. Cardiac cAMP-specific phosphodiesterase-4 (PDE4) enzymes are regulated by cAMP levels, with changes reported in cardiac diseases. PDE4 enzymes are evaluated 8–12 weeks post-infarct in the current study using (R)-[11C]rolipram and positron emission tomography. Sprague-Dawley rats underwent left anterior descending coronary artery ligations (n=8) or sham surgeries (n=4). Cardiac function was evaluated by echocardiography. Animals were injected with [13N]NH3 (2.9–4.6 mCi iv) at 8–12 weeks and scanned for 30 min, prior to a 60 min (R)-[11C]rolipram scan (0.5–1.2 mCi iv, cold mass <0.2 μg/kg). Myocardial blood flow (MBF) and (R)-[11C]rolipram distribution volumes (DVs) were calculated using FlowQuant© software, with perfusion defect defined as the region with MBF <75% maximum. Left ventricle segments with maximal tracer uptake were compared between MI and sham rats. PDE4A, B and D expression and cAMP-hydrolyzing activity were evaluated with immunohistochemistry and enzyme activity assays. Infarcted rats displayed an MBF defect covering 26–49% of the left ventricle, with a 20% decrease in cardiac ejection fraction compared to controls. Segments displaying no perfusion defect showed a 15% increase (p = 0.01) in (R)-[11C]rolipram DV, while the MBF was unaffected (sham: 3.0 ± 0.3; MI: 2.9 ± 0.3 mL/min/g; p = 0.2) suggesting enhanced PDE4 binding. Unchanged PDE4 activity and expression emphasizes the use of a non-invasive assay that measures PDE4 in its physiological setting. (R)-[11C]rolipram imaging in the non-infarcted area 8–12 weeks post LAD-ligation detects increased PDE4 binding despite normal perfusion, without corresponding alteration in enzyme expression and activity in vitro measurements, warranting further studies.
- © 2010 by American Heart Association, Inc.