Mechanistic Insights into Sympathetic Neuronal Regeneration

Abstract

T he sympathetic nervous system plays a key role in maintaining the homeostasis and integrity of the cardiovascular system. It is impaired in the natural course of various cardiovascular diseases, where imbalance contributes to electromechanical instability and progression of heart failure.1-3 Regeneration of impaired innervation, however, may also occur. See Clinical PerspectiveThe transplanted heart is a unique model in this regard. After transplantation, the heart becomes denervated because of surgical disruption of the extracardiac sympathetic nerve fibers at the base of the heart. However, this process is not complete as the intrinsic cardiac network or ganglia of the transplanted heart has the potential to function independently in the absence of central neuronal inputs. 4 Various studies have shown that the intrinsic cardiac nervous system becomes partly reinnervated by extracardiac sympathetic efferent neurons with time after transplantation. [5][6][7][8] This has been associated with improved left ventricular (LV) performance and exercise capacity after heart transplantation 9 and with improved regulation of myocardial perfusion 10 and substrate utilization.11 Studies evaluating the presence, extent, and functional consequences of restored extracardiac sympathetic innervation, however, have typically used only a single tracer to determine catecholamine uptake and washout. This provides only a snapshot of nerve terminal integrity and does 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 (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 rein...

Cardiac neuroanatomy - Imaging nerves to define functional control

“…110–115 Bravo et al used three different C-11 labeled catecholamines to identify neurotransmitter metabolites involved in vesicular storage, transport and degradation in the sympathetic nerve terminal and outlined the dynamic regeneration process of sympathetic nerve function in the transplanted heart. 116 In studies of m IBG, the radiotracer is injected and the mean counts per pixel in the heart are compared to those of the mediastinum to generate a heart/mediastinal (H/M) uptake ratio. Quantification of the H/M ratio has resulted in the identification of cutoffs that have been associated with disease progression and response to therapy.…”

Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging

“…[ 11 C]-EPI produces clear images due to rapid blood clearance and very slow myocardial clearance (half-time, ~10 h) [14]. Stable retention in the myocardium indicates efficient vesicular uptake and protection of [ 11 C]-EPI from intraneuronal metabolism [21•]. As such, the [ 11 C]-EPI RI is higher than that observed for [ 11 C]-HED in humans [14, 21•].…”

“…Stable retention in the myocardium indicates efficient vesicular uptake and protection of [ 11 C]-EPI from intraneuronal metabolism [21•]. As such, the [ 11 C]-EPI RI is higher than that observed for [ 11 C]-HED in humans [14, 21•]. However, peripheral metabolism of [ 11 C]-EPI necessitates the need for metabolite correction even for simple RI calculations.…”

“…Since all aspects of the uptake-1 mechanism (e.g., uptake, storage, metabolism) are disturbed following transplant surgery, investigators have used transplant patients to evaluate the specificity of presynaptic SNS PET tracers to each of these mechanisms early after surgery. As such, the specificity of [ 11 C]-HED, [ 11 C]-EPI, and [ 11 C]-PHEN for NE uptake, storage, and metabolism, respectively, has been evaluated and confirmed by this model [14, 18, 21•]. Recently, Bravo et al [21•] evaluated posttransplant reinnervation at the subcellular level by simultaneously assessing the uptake index of these three tracers in transplant patients and normal controls.…”

“…As such, the specificity of [ 11 C]-HED, [ 11 C]-EPI, and [ 11 C]-PHEN for NE uptake, storage, and metabolism, respectively, has been evaluated and confirmed by this model [14, 18, 21•]. Recently, Bravo et al [21•] evaluated posttransplant reinnervation at the subcellular level by simultaneously assessing the uptake index of these three tracers in transplant patients and normal controls. These investigators showed that [ 11 C]-PHEN wash greatly influenced by the overlap area of [ 11 C]-HED and [ 11 C]-EPI, suggesting that [ 11 C]-PHEN metabolism to MAO is largely dependent on intact uptake and vesicular storage, as originally suggested by Raffel et al in seminal [ 11 C]-PHEN studies [22].…”