Elsevier

Autonomic Neuroscience

Volume 186, December 2014, Pages 38-44
Autonomic Neuroscience

Chronic spinal cord stimulation modifies intrinsic cardiac synaptic efficacy in the suppression of atrial fibrillation

https://doi.org/10.1016/j.autneu.2014.09.017Get rights and content

Highlights

  • Spinal cord stimulation (SCS) suppresses neurally induced atrial fibrillation (AF).

  • Effectiveness of SCS in AF suppression increases with time.

  • SCS minimally impacts active and passive properties of individual intrinsic cardiac neurons.

  • SCS modifies synaptic efficacy of the IC network.

  • SCS differentially impacts the neurotransmission to the accommodating sub-population of IC neurons.

Abstract

We sought to determine whether spinal cord stimulation (SCS) therapy, when applied chronically to canines, imparts long-lasting cardio-protective effects on neurogenic atrial tachyarrhythmia induction and, if so, whether its effects can be attributable to i) changes in intrinsic cardiac (IC) neuronal transmembrane properties vs ii) modification of their interneuronal stochastic interactivity that initiates such pathology. Data derived from canines subjected to long-term SCS [(group 1: studied after 3–4 weeks SCS; n = 5) (group 2: studied after 5 weeks SCS; n = 11)] were compared to data derived from 10 control animals (including 4 sham SCS electrode implantations). During terminal studies conducted under anesthesia, chronotropic and inotropic responses to vagal nerve or stellate ganglion stimulation were similar in all 3 groups. Chronic SCS suppressed atrial tachyarrhythmia induction evoked by mediastinal nerve stimulation. When induced, arrhythmia durations were shortened (controls: median of 27 s; SCS 3–4 weeks: median of 16 s; SCS 5 weeks: median of 7 s). Phasic and accommodating right atrial neuronal somata displayed similar passive and active membrane properties in vitro, whether derived from sham or either chronic SCS group. Synaptic efficacy was differentially enhanced in accommodating (not phasic) IC neurons by chronic SCS. Taken together these data indicate that chronic SCS therapy modifies IC neuronal stochastic inter-connectivity in atrial fibrillation suppression by altering synaptic function without directly targeting the transmembrane properties of individual IC neuronal somata.

Introduction

Clinical evidence indicates that symptoms associated with chronic refractory angina of cardiac origin can be alleviated by delivering high frequency, low intensity electrical stimuli to the dorsal aspect of the thoracic spinal cord–spinal cord stimulation (SCS) therapy (Eliasson et al., 1996, Mannheimer et al., 2002). It is known that the myocardium state is transduced by cardiac sensory neurites that are associated with somata nexus points throughout the cardiac nervous system, including intrathoracic ganglia and central loci (Armour and Kember, 2004, Longhurst et al., 2001, Tjen-A-Looi et al., 1997, Zucker et al., 2012). All of these populations directly and indirectly influence the behavior of intrinsic cardiac neurons, including intrinsic cardiac local circuit neurons (Ardell, 2004, Armour, 2008).

Excessive activation of selective neuronal inputs to the intrinsic cardiac nervous system (ICNS) – for instance by select mediastinal nerve stimulation – consistently initiates atrial tachyarrhythmias in the canine model (Armour et al., 2005, Cardinal et al., 2010). It is also known that SCS, when applied acutely, modifies the behavior of select populations of intrinsic cardiac neurons, in particular its local circuit neuronal population (Armour et al., 2002, Foreman et al., 2000), to obtund atrial tachyarrhythmias of neuronal origin (Cardinal et al., 2006). Recent evidence indicates that the efficacy of acute SCS may reside primarily in its capacity to stabilize ICNS local circuit neurons in the presence of such excessive and heterogeneous neuronal inputs (Gibbons et al., 2012).

While the cardiac nervous system is optimized to respond to every day stressors (heat, exercise, emotion, orthostatic), it can be critically disrupted by cardiac pathology such as myocardial ischemia, myocardial infarction, heart failure and chronic arrhythmias (Ajijola et al., 2013, Dell'Italia, 2011, Kember et al., 2013, Nakahara et al., 2010, Zucker et al., 2012). In contradistinction to global and non-specific effects of pharmacological management of such pathologies (Brunton et al., 2010), chronic neuromodulation based approaches offer the opportunity to target relevant elements of the cardiac nervous system and, as a consequence, influence the cardiomyocytes they regulate (Liu et al., 2012, Lopshire and Zipes, 2012, Schwartz, 2012). What remains to be determined is the short versus long term effects of such therapy in the context of specific cardiac pathologies.

It is known that long-term application of SCS prevents the development of a tachypacing-induced atrial fibrillation (Bernstein et al., 2012), an effect that has been proposed to depend on electrophysiological remodeling of cardiac myocyte ionic channels (Lopshire et al., 2009). However, based on our prior work (Beaumont et al., 2013, Cardinal et al., 2006, Gibbons et al., 2012), it is likely that the intrinsic cardiac nervous system, especially its local circuit neurons (Gibbons et al., 2012), represent a major target for this reduced arrhythmia potential. It remains to be established whether chronic SCS therapy imparts long-term effects on the intrinsic cardiac nervous system. It also remains to be established whether chronic SCS therapy: 1) targets the function of individual neurons within the intrinsic cardiac nervous system such that their membrane excitability to neuronal inputs becomes modified (Cardinal et al., 2004) vs 2) suppressing the stochastic network hyper-interactivity that occurs among populations of intrinsic cardiac local circuit neurons in the induction of atrial arrhythmias (Beaumont et al., 2013) vs 3) a combination of both processes.

In order to understand these core issues, chronic SCS (3–4 weeks vs 5 weeks) was applied in normal canines to determine the impact of this therapy on the capacity of the intrinsic cardiac nervous system to initiate atrial tachyarrhythmias. By these means, we found that the primary target of chronic SCS therapy in atrial arrhythmia treatment resides in its capacity to regulate intrinsic cardiac neuronal network excitability, rather than solely targeting and remodeling the function of individual intrinsic cardiac neurons. If such a thesis is sustained it implies that suppression of hyper-excited, stochastic interactions within this target organ's nervous system that lead to pathology represents a potential target for anti-arrhythmia therapy.

Section snippets

Animals

Experiments were approved by the Animal Research Ethics Committee of the Sacré-Coeur Hospital Research Centre and were in accordance with the Guide for the Care and Use of Laboratory Animals, Eighth Edition, National Academy Press, Washington DC, 2010. Three groups of canines were studied: i) 5 canines were subjected to continuous spinal cord stimulation for 21–27 days (3–4 weeks); ii) 11 canines were subjected to continuous SCS for 33–35 days (5 weeks); and iii) 10 control animals were studied

Vagosympathetic complex or stellate ganglion stimulation (Fig. 1)

Heart rate decrements in response to right or left vagus nerve stimulation were similar in control and chronic SCS treated animals. Heart rate, LV chamber pressure and dP/dtmax enhancement responses to right or left stellate ganglion stimulation were also similar among groups.

Mediastinal nerve stimulation induction of atrial tachyarrhythmias

In the anesthetized control animals (n = 10), 4 of which had chronically implanted spinal cord electrodes that were not activated, focal electrical stimuli delivered individually to multiple mediastinal nerves reproducibly

Discussion

The main findings derived from this study indicate that long-term SCS therapy imparts sustained cardioprotection with regard to the induction of atrial tachyarrhythmias in response to excessive, asymmetric activation of the intrinsic cardiac nervous system (ICNS) and that the efficacy of that arrhythmia stabilization increases with duration of treatment. Moreover, the chronic effects that SCS imparts to the intrinsic cardiac nervous system are not primarily associated with any modification of

Author contributions

JLA, RC and JAA contributed to the conception and design of experiments. EB, MV and FS performed experiments and analyzed the data. JLA, RC, EB and JAA drafted, edited and revised the manuscript. All authors approved the final version of the manuscript.

Funding

This work was supported by grants from the Canadian Institutes of Health Research (MOP-11252 to R.C., F.M.S.), the National Institutes of Health (RO1 HL71830 to JLA), and St. Jude Medical/Advanced Neuromodulation Systems.

Conflict of interest

None.

Acknowledgments

The authors wish to thank Ms. Caroline Bouchard for her expert technical assistance in the performance of the experiments.

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