Bioelectronic block of stellate ganglia mitigates pacing-induced heterogeneous release of catecholamine and neuropeptide Y in the infarcted pig heart.

Abstract

The sympathetic nervous system modulates cardiac contractile and electrophysiological function and contributes to adverse remodelling following myocardial infarction (MI). Axonal modulation therapy (AMT), directed at the sympathetic chain, blocks efferent sympathetic outflow to the heart and is a strategy to transiently and controllably mitigate chronic MI-associated sympatho-excitation. In porcine models, we evaluated scalable AMT, directed at the paravertebral chain, in blocking reflex-mediated pacing-induced sympatho-excitation post-MI. The level of sympatho-excitation was assessed by dynamic interstitial measurement of noradrenaline (NA) and neuropeptide Y (NPY). In anaesthetized normal (n = 5) and age-matched pigs 6 weeks post-MI induction (n = 10), we electrically stimulated the right sympathetic chain and determined levels of direct current block applied at the T1-T2 level sufficient to reduce the evoked changes in heart rate and/or contractility by 25-75%. Reflex-mediated neural release of NA and NPY into the interstitial space during programmed pacing (PP) was assessed using fast-scanning cyclic voltammetry and capacitive immunoprobes. Normal animals demonstrated homogeneous NA and NPY release profiles during PP. In contrast, for MI animals PP evoked differential NA and NPY release in remote and MI border zones of the left ventricle. Right-sided AMT mitigated NA and NPY pacing-induced release in the remote left ventricle with a positive correlation to increasing AMT levels. Pacing-induced NA and NPY release in the MI border zone was not mitigated by AMT. Differential effects of AMT on NA and NPY may underlie the anti-arrhythmic effects of partial stellate ganglion block in the setting of chronic MI. KEY POINTS: Programmed cardiac pacing evokes homogeneous noradrenaline (NA) and neuropeptide Y (NPY) release in equivalent areas (e.g. medial and lateral aspects) of the normal left ventricle. Programmed cardiac pacing evokes differential NA and NPY release in remote and border zones of the infarcted left ventricle. Axonal modulation therapy (AMT), using a graded direct current block applied to the stellate ganglia, can proportionally modulate cardiac sympathetic reflexes. Unilateral AMT mitigates NA and NPY release in remote left ventricular tissue, with release negatively correlated to increasing AMT levels. Heterogeneities in NA and NPY between the border and remote tissues are reduced by progressive AMT.