Scintigraphic and electrophysiological evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application.

Abstract

Epicardial phenol application or transmural myocardial infarction in dogs produces sympathetic denervation of myocardium apical to the site of the intervention. Because efferent denervation is probably postganglionic, reinnervation most likely occurs but has not been shown. We investigated whether '23I-labeled metaiodobenzylguanidine (MIBG), a norepinephrine analogue taken up by sympathetic nerve terminals, could provide a scintigraphic image that would detect apical sympathetic denervation and possible reinnervation. Dogs underwent MIBG scintigraphic imaging at various times after phenol application or transmural myocardial infarction. The results of MIBG scintigraphy were correlated with electrophysiological responses obtained during ansae subclaviae and norepinephrine stimulation to establish the presence of neural denervation and reinnervation. Apical defects in the MIBG scan, which were associated with either normal perfusion by thallium or a smaller-sized defect, were found consistently in dogs that had apical sympathetic innervation. MIBG scintigraphic images returned to normal after 14 weeks (mean) at a time when reinnervation was shown to have occurred. Thus, the results of MIBG scintigraphy correlated accurately with the presence of denervation and reinnervation established by neuroelectrophysiological testing. Supersensitive refractory period shortening in response to norepinephrine infusion was present after denervation and persisted for more than 3 weeks after scintigraphic and electrophysiological evidence of reinnervation. Conclusions are that 1) MIBG can be used noninvasively to determine the presence of regional myocardial elferent sympathetic denervation and subsequent reinnervation, 2) reinnervation occurs after phenol application or transmural myocardial infarction, and 3) denervation supersensitivity persists even after reinnervation occurs.

Heterogeneous Sympathetic Innervation Influences Local Myocardial Repolarization in Normally Perfused Rabbit Hearts

“…Previous studies of MIBG uptake in the phenol model have shown that the reduction in uptake is due to an absence of sympathetic nerve terminals, or denervation. 8,14 A gradient in MIBG uptake was found, ranging from a severe reduction, relative to the unaffected area, to a mild reduction. As discussed below, the local repolarization responses were different within the different regions of MIBG uptake.…”

“…1,2 Heterogeneity in the spatial distribution and activity of sympathetic innervation is also thought to contribute to the potential for fatal arrhythmia, possibly through effects on reentry. 3,4 Recently, several investigations have suggested a relationship between regional neuronal dysfunction and ventricular arrhythmia in humans 5,6 and animals 7,8 in the absence of infarction or perfusion abnormalities. Denervation supersensitivity to circulating catecholamines has been implicated in the pathogenesis of these arrhythmias.…”

“…Phenol causes necrosis to a depth of 0.25 mm on the epicardium and interrupts both afferent and efferent sympathetic fibers, denervating myocardium downstream from the injured area. 8 Sympathetic innervation was measured from 3D reconstructions of serial autoradiographs of metaiodobenzylguanidine (MIBG) to map sympathetic nerves and sestamibi (MIBI) to map perfusion. Scintigraphic results were compared with activation recovery intervals (ARIs) 9,10 measured simultaneously at 64 epicardial sites.…”

Cardiac autonomic imaging with SPECT tracers

“…The rationale for SPECT is that the presence of regional autonomic tracer defects, particularly if tracer uptake is relatively preserved on a separately obtained standard rest perfusion image, i.e., an autonomic/perfusion mismatch, may indicate potential for electrical heterogeneity and denervation supersensitivity, pre-disposing to potentially lethal arrhythmias. 56,57 While there is no officially established method for scoring SPECT 123 I-mIBG images, analysis can be performed similar to the conventional 17-segment method used for MPI, with generation of a summed score. 37,58 However, a key difference for 123 I-mIBG images is that when there is globally decreased uptake, homogeneous tracer uptake cannot be scored as normal as, unlike the custom for perfusion images, one cannot assume a ''normal'' region.…”

“…133 MI causes sympathetic denervation beyond the infarcted area. 56,[134][135][136][137] Injury to sympathetic innervation may persist after myocyte recovery, resulting in areas of autonomic/perfusion mismatch, possibly pre-disposing to post-MI arrhythmias. 57,[138][139][140] Tomoda et al 141 showed that 3-4 weeks after nonST segment elevation MI, 123 I-mIBG defects may be present without Tl-201 perfusion defects.…”