Sympathetic nerve damage and restoration after ischemia-reperfusion injury as assessed by (11)C-hydroxyephedrine.
OBJECTIVE
An altered state of the cardiac sympathetic nerves is an important prognostic factor in patients with coronary artery disease. The aim of this study was to investigate regional sympathetic nerve damage and restoration utilizing a rat model of myocardial transient ischemia and a catecholamine analog PET tracer, (11)C-hydroxyephedrine ((11)C-HED).


METHODS
Transient myocardial ischemia was induced by coronary occlusion for 20 min and reperfusion in male Wistar rats. Dual-tracer autoradiography was performed subacutely (7 days) and chronically (2 months) after ischemia, and in control rats without ischemia using (11)C-HED as a marker of sympathetic innervation and (201)TI for perfusion. Additional serial in vivo cardiac (11)C-HED and (18)F-FDG PET scans were performed in the subacute and chronic phases after ischemia.


RESULTS
After transient ischemia, the (11)C-HED uptake defect areas in both the subacute and chronic phases were clearly larger than the perfusion defect areas in the midventricular wall. The subacute (11)C-HED uptake defect showed a transmural pattern, whereas uptake recovered in the subepicardial portion in the chronic phase. Tyrosine hydroxylase antibody nerve staining confirmed regional denervation corresponding to areas of decreased (11)C-HED uptake. Serial in vivo PET imaging visualized reductions in the area of the (11)C-HED uptake defects in the chronic phase consistent with autoradiography and histology.


CONCLUSIONS
Higher susceptibility of sympathetic neurons compared to myocytes was confirmed by a larger (11)C-HED defect with a corresponding histologically identified region of denervation. Furthermore, partial reinnervation was observed in the chronic phase as shown by recovery of subepicardial (11)C-HED uptake.
Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.|Comprehensive Heart Failure Center, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.
Rudolf A
RA
Werner
Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.|Research Centre, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
Yoshifumi
Y
Maya
Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany.
Christoph
C
Rischpler
Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins University, Baltimore, MD, USA.
Mehrbod S
MS
Javadi
Department of Radiology, Hyogo College of Medicine, Hyogo, Japan.
Kazuhito
K
Fukushima
Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.
Constantin
C
Lapa
Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.|Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Ken
K
Herrmann
Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany. thiguchi@me.com.|Comprehensive Heart Failure Center, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany. thiguchi@me.com.
Takahiro
T
Higuchi
D000818:Animals; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging* / Q000473:pathology; D014018:Tissue Distribution
D019275:Radiopharmaceuticals; C065363:3-hydroxyephedrine; D004809:Ephedrine
11C-Hydroxyephedrine; Ischemia; Nerve sprout; Rat; Sympathetic nerve