Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control

Abstract

Background

Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy.

Objective

To characterize heart rate (HR) responses (HRR) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart.

Methods

In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n = 8, "cardiac" configuration) or with electrode positions reversed (n = 8, "epilepsy" configuration). In awake state, HRR were determined for each combination of pulse frequency (2–20 Hz), intensity (0–3.5 mA) and pulse widths (130–750 μs) over 14 months.

Results

At low intensities and higher frequency VNS, HR increases during VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation are balanced, a null HRR is evoked [defined as "neural fulcrum"] during which HRR ≅ 0. As intensity increases further, HR is reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart.

Conclusions

VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

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