Mechanistic insights into sympathetic neuronal regeneration: Multitracer molecular imaging of catecholamine handling after cardiac transplantation

Paco E. Bravo, Riikka Lautamäki, Debra Carter, Daniel Holt, Stephan G. Nekolla, Robert F Dannals, Stuart D. Russell, Frank M. Bengel

Research output: Contribution to journalArticle

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. Methods and 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 (T1/2 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 (T1/2 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T1/2 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.

Original languageEnglish (US)
JournalCirculation: Cardiovascular Imaging
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Molecular Imaging
Heart Transplantation
Catecholamines
Regeneration
Epinephrine
Phenylephrine
Healthy Volunteers
Ventricular Septum
Ammonia
Positron-Emission Tomography
Heart Ventricles
3-hydroxyephedrine
Carbon
Pathology
Transplants

Keywords

  • catecholamines
  • heart transplantation
  • positron-emission tomography
  • regeneration
  • sympathetic nervous system

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Radiology Nuclear Medicine and imaging
  • Medicine(all)

Cite this

Mechanistic insights into sympathetic neuronal regeneration : Multitracer molecular imaging of catecholamine handling after cardiac transplantation. / Bravo, Paco E.; Lautamäki, Riikka; Carter, Debra; Holt, Daniel; Nekolla, Stephan G.; Dannals, Robert F; Russell, Stuart D.; Bengel, Frank M.

In: Circulation: Cardiovascular Imaging, Vol. 8, No. 8, 01.08.2015.

Research output: Contribution to journalArticle

Bravo, Paco E. ; Lautamäki, Riikka ; Carter, Debra ; Holt, Daniel ; Nekolla, Stephan G. ; Dannals, Robert F ; Russell, Stuart D. ; Bengel, Frank M. / Mechanistic insights into sympathetic neuronal regeneration : Multitracer molecular imaging of catecholamine handling after cardiac transplantation. In: Circulation: Cardiovascular Imaging. 2015 ; Vol. 8, No. 8.
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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. Methods and 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 (T1/2 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 (T1/2 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T1/2 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.",
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AU - Bravo, Paco E.

AU - Lautamäki, Riikka

AU - Carter, Debra

AU - Holt, Daniel

AU - Nekolla, Stephan G.

AU - Dannals, Robert F

AU - Russell, Stuart D.

AU - Bengel, Frank M.

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N2 - 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. Methods and 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 (T1/2 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 (T1/2 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T1/2 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.

AB - 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. Methods and 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 (T1/2 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 (T1/2 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T1/2 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.

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