title: Mechanistic Insights into Sympathetic Neuronal Regeneration: Multitracer Molecular Imaging of Catecholamine Handling After Cardiac Transplantation.
abstract: BACKGROUND
  Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated.
  
  
  RESULTS
  Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N-13 ammonia. Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T(1/2) 49±6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24±19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8±7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T(1/2) 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T(1/2) 36±8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation.
  
  
  CONCLUSIONS
  Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation.
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Paco E
authors.initials: PE
authors.lastname: Bravo
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Riikka
authors.initials: R
authors.lastname: Lautamäki
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Debra
authors.initials: D
authors.lastname: Carter
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Nekolla
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.).
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Russell
authors.affiliation: From the Division of Nuclear Medicine (P.E.B., R.L., D.P.H., R.F.D., F.M.B.) and Division of Cardiology (D.C., S.D.R.), Johns Hopkins University, Baltimore, MD; Division of Cardiology, University of Washington, Seattle (P.E.B.); Heart Center and Turku PET Centre, Turku University Hospital, Turku, Finland (R.L.); Department of Nuclear Medicine, Technical University of Munich, Munich, Germany (S.G.N.); and Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany (F.M.B.). bengel.frank@mh-hannover.de.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002395:Catecholamines / Q000493:pharmacokinetics; D004809:Ephedrine / Q000031:analogs & derivatives; D004837:Epinephrine / Q000031:analogs & derivatives; D005260:Female; D006321:Heart / Q000294:innervation*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D055414:Myocardial Perfusion Imaging; D009416:Nerve Regeneration; D010656:Phenylephrine; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D017729:Presynaptic Terminals / Q000000981:diagnostic imaging / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D002395:Catecholamines; D019275:Radiopharmaceuticals; D010656:Phenylephrine; C065363:3-hydroxyephedrine; D004809:Ephedrine; D004837:Epinephrine
keywords: catecholamines; heart transplantation; positron-emission tomography; regeneration; sympathetic nervous system