Abstract
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Objectives Disorders of sympathetic nervous system was recognized as key underlying pathophysiology after myocardial ischemia reperfusion (IR). Norepinephrine transporter (NET) is located in the noradrenergic neurons and is responsible for the synaptic reuptake of extracellular norepinephrine. In this study, a novel PET tracer [11C]Me@HAPTHI with high affinity and selectivity to the NET was used to characterize sympathetic denervation and innervation after myocardial ischemia.
Methods Myocardial uptake of [11C]Me@HAPTHI was compared [11C]-mHED which is taken up by sympathetic nerve terminals through the NET using PET/CT. In vivo dynamic [11C]Me@HAPTHI (acquisition time: 26 minutes, started from 4 minutes after injection) and 18F-FDG (acquisition time: 40 minutes, started from 20 minutes after injection) gated PET imaging and ex-vivo autoradiography was performed to determine rat myocardial sympathetic nerve denervation and viability at subacute and chronic phases (1day, 3days, 1week, 4 weeks) following transient ischemia of 20 minutes. Tracer’s biodistribution and kinetics was analysed. Specificity of tracers was evaluated by PET imaging with NET blocking agent Nisoxetine (2mg/kg). Immunohistochemical stains of H&E and Tetrazolium chloride (TTC) assay were used to determine myocardial defect area and remote region. As a novel biomarker of cardiac sympathetic denervation, neurotrimin was evaluated in the plasma. Region-of-interest analysis was used to determine uptake ratios for the ischemic region related to the remote area.
Results Significant myocardial uptake of [11C]Me@HAPTHI compared with [11C]mHED PET was observed (Fig.A). After transient ischemia, reduced [11C]Me@HAPTHI uptake was detected from day 1 to 4 weeks, which was confirmed by increased uptake ratio of ischemic area to the non-ischemic area (Fig. A), and increased uptake ratio of non-ischemic area to the blood pool (Fig.D). Representative time-course PET/CT images are shown in figure A. Correspondingly, in autoradiography, decreased uptake in the ischemia region with myocardial injury was observed, which was determined by histology (Fig.A,D); moreover, innervation in the heart was confirmed during the time course (Fig.C). Slight reduced apical 18F-FDG uptake was observed in the left ventricle indicating reduced myocardial viability with corresponding sympathetic nerve denervation in the heart indicating by [11C]Me@HAPTHI uptake in the ischemic region. (Fig.B). In the kinetics analysis, the ratio of myocardium to blood radioactivity was reduced by the pre-injection of blockers (Fig. D) confirming the high specificity of cardiac uptake.
Conclusions [11C]Me@HAPTHI PET can be used for specific imaging and quantitative method for cardiac adrenergic nerve function with high specific myocardial uptake through NET. It enable in vivo monitoring dynamic repair process after transient ischemia. Further therapeutic studies with remote ischemic conditioning will be conducted at left limb of rats to achieve protection against IR injury and evaluated by [11C]Me@HAPTHI PET scan.