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

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 16s; SCS 5 weeks: median of 7s). 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.

Keywords: Atrial tachyarrhythmia; Heart; Intrinsic cardiac neurons; Neuromodulation; Spinal cord stimulation.

Figure 1

Chronic SCS does not functionally remodel chronotropic or inotropic responses to sympathetic or parasympathetic efferent neuronal stimulation. Percent change in heart rate (panels A–C) or left ventricular dp/dt _max (panel D) in response to right (panel A) or left (panel B) cervical vagosympathetic vs right (RSG) or left (LSG) stellate ganglia (panels C–D) stimulation in sham controls versus animals with 3–4 versus 5 weeks of chronic SCS. Data are expressed as mean ± SD.

Figure 2

Chronic SCS suppresses atrial tachyarrhythmias of neural origin. A. In a control (sham SCS) preparation, delivering 3 stimuli (current intensity: 2 mA; vertical arrows) to a mediastinal nerve first prolonged atrial cycle length (CL) that rapidly transitioned to an atrial arrhythmia episode that lasted for 58 s before converting spontaneously to sinus rhythm (SR). B. In an animal exposed to 5 weeks of SCS, sinus CL prolongation was elicited during mediastinal nerve stimulation - with no accompanying AT episode. Abbreviations: Aeg = atrial electrogram; cycle length = atrial electrical cycle duration; ECG = electrocardiogram; mA = current.

Figure 3

A. Cumulative indices of atrial tachyarrhythmias (AT) induced in the three groups, as engendered with increasing mediastinal nerve stimulus strengths (1, 2, and 5 mA). Controls: AT incidence increased from 20% at 1 mA (6/30) to 46% at 2 mA (14/30) and to 66% at 5 mA (20/30). Incidences decreased following 3–4 weeks (cross-hatched bar: 5 preparations) and even more following 5 weeks (filled bar: 11 preparations) of SCS. B. The durations of ATs induced among controls (25 episodes) (median values of 27s) were reduced to 16s (SCS 3–4 weeks) and 7s (SCS 5 weeks) (p<.001, group differences demonstrated by Kruskal-Wallis one-way analysis of variance for independent samples) by SCS.

Figure 4

IC soma excitability, as assessed by transient depolarizing currents, and stratification into phasic versus accommodating neuron types dependent upon evoked responses (A) was unaltered by chronic SCS (B). Numbers in parentheses indicate number of neurons. nA=nanoampere.

Figure 5

IC neuronal response (i.e. soma action potential generation) to stimulation of adjacent intra-ganglionic axonal inputs. Control and chronic SCS derived IC somata responses to 2–20 Hz stimuli (0.5 ms duration; current 2x threshold) were grouped based on classification as phasic or accommodating as described in Figure 4. Synaptic efficacy, as defined by % action potential output/stimulus pulse input frequency, was differentially enhanced in accommodating IC neurons in chronic SCS. * p<0.04 between treatment group (control vrs SCS); # p<0.008 phasic vs accommodating IC neurons.