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

Abstract

Key points: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained.

Abstract: 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. The objective of this work was to characterize heart rate (HR) responses (HRRs) 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. 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, HRRs 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. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR ≈ 0. As intensity increased further, HR was 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 the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Keywords: cardiac afferent; neural fulcrum; neurocardiology; parasympathetic; vagus nerve stimulation.

Figure 1. Chronotropic responses evoked during right cervical VNS in a conscious animal

Frequency (10 Hz) and pulse width (500 μs) were held constant; duty cycle was 17.5% with a 14 s on‐phase. Current intensities were 0.25 mA (A), 1.00 mA (B), 1.75 mA (C) and 3.00 mA (D).

Figure 2. Chronotropic topographic response surface as a function of RCV VNS intensity (mA), frequency (Hz) and pulse width

Animals were awake and standing quietly in Pavlov stand. VNS delivered at 17.5% duty cycle (14 s on‐phase). Bipolar electrodes were chronically implanted anode cephalad to cathode (n = 8). Pulse widths were 130 μs (A), 250 μs (B), 500 μs (C) and 750 μs (D). Heart rate depicted as percentage change from baseline during the on‐phase of VNS with magnitude indicated by colour scale.

Figure 3. Chronotropic topographic response surface as a function of LCV VNS intensity (mA), frequency (Hz) and pulse width

Animals were standing quietly in Pavlov stand. VNS delivered at 17.5% duty cycle. Bipolar electrodes were chronically implanted anode cephalad to cathode (n = 8). Pulse widths were 130 μs (A), 250 μs (B), 500 μs (C) and 750 μs (D).

Figure 4. Bradycardia threshold to RCV VNS as function of frequency, pulse width and electrode orientation

A, electrodes chronically implanted with anode cephalad to cathode (n = 8). B, electrodes chronically implanted with cathode cephalad to anode (n = 8). Pulse widths were 130 μs (PW130), 250 μs (PW250), 500 μs (PW500) or 750 μs (PW750). ^* P < 0.0005 PW130 vs. all other pulse widths; ^† P < 0.003 PW250 vs. PW500 or PW750.

Figure 5. Time domain analysis of HRV in animals (n = 8) in response to cyclic RCV delivered at the neural fulcrum (grey bars) vs. the same animals with sham VNS (black bars)

Data are subdivided into 6 h time segments starting at 18.00 h. Shown are heart rate (A), and indices of heart rate variability including pNN50 (%) (B), SDNN (C) and RMSSD (D). ‡ P ≤ 0.040 vs. 18.00–00.00 h; ^* P ≤ 0.010 vs. 18.00–00.00 h; and ^† P ≤ 0.001 vs. 00.00–06.00 h.

Figure 6. Chronotropic topographic response surface as a function of RCV (A and B) or LCV VNS (C and D) intensity (mA), frequency (Hz) and pulse width

Bipolar electrodes were chronically implanted cathode cephalad to anode (n = 8). Other details as described in Fig. 2.

Figure 7. Chronotropic response to RCV VNS (n = 8) prior to and 30 min following either β‐adrenergic blockade (metoprolol, 1 mg kg⁻¹; A) or β‐adrenergic and muscarinic blockade (glycopyrrolate, 0.4 mg; B)

For chronic pharmacological treatment (n = 8), animals were administered for 2 weeks twice daily (PO) metoprolol (12.25 mg) or combination therapy with metoprolol, enalapril (2.5 mg) and ivabradine (5 mg). C, average data for the untreated condition (control), then following either metoprolol or combination therapy treatments with enalapril, metoprolol and ivabradine. ^* P < 0.002 vs. control; ^† P < 0.0001 metoprolol vs. metoprolol+glycopyrrolate.

Figure 8. Anaesthesia alters the chronotropic response to cervical VNS

A and C reflect chronotropic responses to VNS with electrode bipole in cathode cephalad to anode orientation (n = 8); B and D reflect response surfaces with anode cephalad to cathode orientation (n = 8). While the response surfaces are similar including a tachycardia phase at low level intensity transitioning to bradycardia at higher intensities, there are quantitative differences including an enhanced bradycardia to higher intensity stimulations with the bipole in the anode cephalad to cathode orientation. Autonomic nerves intact in both states. ^* P < 0.0004 awake vs. anaesthetized.

Figure 9. Evoked changes in chronotropic (A and B), left ventricular inotropic (C and D) and lusitropic (E and F) function in response right (left panels) and left (right panels) cervical VNS prior to and following cervical vagus transections rostral to stimulating electrode

Animals were anaesthetized throughout. VNS delivered at 500 μs pulse width and a 17.5% duty cycle with a 14 s on‐phase. Responses reflect percentage change from baseline during VNS as a function of stimulus frequency. ^* P < 0.001 vs. intact.

Figure 10. Clinical relevance of the VNS neural fulcrum

The chronotropic response surface is replotted from Fig. 2 C, but with the addition of specific points operationally used in three recent clinical trials for HFrEF: NECTAR‐HF (Zannad et al. 2015), INOVATE‐HF (Gold et al. 2016) and ANTHEM‐HF (Premchand et al. 2014, 2016). Yellow‐shaded region on response surface is approximately the neural fulcrum.