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Regional ¹¹C-Hydroxyephedrine Retention in Hibernating Myocardium: Chronic Inhomogeneity of Sympathetic Innervation in the Absence of Infarction

¹ Department of Medicine, SUNY at Buffalo, VA Western New York Health Care System, Buffalo, New York
² Cardiac PET Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
³ Department of Nuclear Medicine, SUNY at Buffalo, Buffalo, New York
⁴ Department of Physiology/Biophysics, SUNY at Buffalo, Buffalo, New York

We have previously shown that ex vivo counting of ¹³¹I-metaiodobenzylguanidine can identify regional reductions in sympathetic norepinephrine uptake in pigs with hibernating myocardium. However, nonneuronal uptake limited relative differences between regions and would preclude accurate assessment with conventional imaging. We therefore hypothesized that the superior specificity of the positron-emitting isotope ¹¹C-hydroxyephedrine (HED) would facilitate the imaging of regional differences, and we designed this study to determine whether altered uptake of norepinephrine by sympathetic nerves in viable, dysfunctional myocardium can be imaged in vivo and to determine the temporal progression and stability of sympathetic dysinnervation in hibernating myocardium. Methods: Pigs (n = 15) were chronically instrumented with a 1.5-mm stenosis of the left anterior descending coronary artery, a procedure that we have previously shown to produce viable chronically dysfunctional myocardium with reduced resting flow, or hibernating myocardium, after 3 mo. Physiologic studies and HED PET were performed 1–5 mo later with the animals in the closed-chest sedated state. One animal with a myocardial infarct was analyzed separately. Results: After 3 mo, anterior hypokinesis developed (wall thickening, 32% ± 4% vs. 60% ± 4%, P < 0.001), with reductions in resting flow (subendocardial flow, 0.81 ± 0.11 vs. 1.20 ± 0.18 mL/min/g, P < 0.05) and a critical reduction in subendocardial flow reserve (subendocardial adenosine flow, 0.53 ± 0.20 vs. 3.96 ± 0.43 mL/min/g, P < 0.001). Extensive defects in HED uptake were found for hibernating myocardium, with regional retention 50% lower than that in normally perfused remote myocardium (0.035 ± 0.002 vs. 0.066 ± 0.002 min^–1, P < 0.001). Relative HED uptake (left anterior descending coronary artery/remote) was lower in chronically instrumented animals than in control animals (n = 4, P < 0.001) and animals studied 1 mo after instrumentation (n = 2, P < 0.05). The regional reduction in sympathetic nerve function was persistent and unaltered for at least 2 mo after the development of hibernating myocardium. Conclusion: Hibernating myocardium is associated with persistent reductions in regional uptake of norepinephrine by sympathetic nerves. The inhomogeneity in sympathetic innervation in viable dysfunctional myocardium is similar to that occurring after myocardial infarction and may contribute to arrhythmic death in patients with ischemic cardiomyopathy.

Key Words: hibernation • isotopes • myocardial stunning • sympathetic nervous system

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