Intermittent electrical stimulation of the right cervical vagus nerve in salt-sensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology

Elizabeth M Annoni, Xueyi Xie, Steven W Lee, Imad Libbus, Bruce H KenKnight, John W Osborn, Elena G Tolkacheva, Elizabeth M Annoni, Xueyi Xie, Steven W Lee, Imad Libbus, Bruce H KenKnight, John W Osborn, Elena G Tolkacheva

Abstract

Hypertension (HTN) is the single greatest risk factor for potentially fatal cardiovascular diseases. One cause of HTN is inappropriately increased sympathetic nervous system activity, suggesting that restoring the autonomic nervous balance may be an effective means of HTN treatment. Here, we studied the potential of vagus nerve stimulation (VNS) to treat chronic HTN and cardiac arrhythmias through stimulation of the right cervical vagus nerve in hypertensive rats. Dahl salt-sensitive rats (n = 12) were given a high salt diet to induce HTN. After 6 weeks, rats were randomized into two groups: HTN-Sham and HTN-VNS, in which VNS was provided to HTN-VNS group for 4 weeks. In vivo blood pressure and electrocardiogram activities were monitored continuously by an implantable telemetry system. After 10 weeks, rats were euthanized and their hearts were extracted for ex vivo electrophysiological studies using high-resolution optical mapping. Six weeks of high salt diet significantly increased both mean arterial pressure (MAP) and pulse pressure, demonstrating successful induction of HTN in all rats. After 4 weeks of VNS treatment, the increase in MAP and the number of arrhythmia episodes in HTN-VNS rats was significantly attenuated when compared to those observed in HTN-Sham rats. VNS treatment also induced changes in electrophysiological properties of the heart, such as reduction in action potential duration (APD) during rapid drive pacing, slope of APD restitution, spatial dispersion of APD, and increase in conduction velocity of impulse propagation. Overall, these results provide further evidence for the therapeutic efficacy of VNS in HTN and HTN-related heart diseases.

Keywords: Arrhythmia; hypertension; optical mapping; vagus nerve stimulation.

© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Figures

Figure 1
Figure 1
(A) Experimental design timeline. HTN was induced through 6 weeks of high salt diet (8% NaCl). DSI transmitters and VNS devices were implanted during Week 5. Rats were randomly divided into two groups: HTN-Sham (n = 6) with nonfunction VNS stimulators and HTN-VNS (n = 6) with functional stimulators. VNS therapy was turned on at Week 6, and ECG and blood pressure were monitored in both groups. (B) Sample ECG (top) and arterial blood pressure (bottom) recordings from DSI telemetric devices. Insert: MAP is calculated using SBP and DBP measured from the blood pressure recordings.
Figure 2
Figure 2
Relative change of 24-h mean data for (A) MAP; (B) PP; and (C) HR with respect to baseline data (Week 0) for both HTN-Sham and HTN-VNS rats. † indicates statistical significance (P < 0.05) with respect to Week 6; # indicates statistical significance (P < 0.05) between HTN-VNS and HTN-Sham.
Figure 3
Figure 3
(A, B) ΔMAP and (C, D) ΔHR during the day (6 AM–6 PM) (panels A and C) and night (6 PM-6 AM) (panels B and D) for the HTN-Sham and HTN-VNS rats. # indicates statistical significance (P < 0.05) between HTN-VNS and HTN-Sham.
Figure 4
Figure 4
(A) Examples of episodes of PVC (left) and other arrhythmias (atrial fibrillation and skipped beats, right) from HTN-Sham rat at Week 6. (B) Mean number of episodes of PVCs and other arrhythmias for Week 6 and Week 10 for HTN-Sham and HTN-VNS rats. † indicates statistical significance (P < 0.05) between Week 6 and Week 10.
Figure 5
Figure 5
(A) Representative examples of 2D APD80 maps calculated at BCL = 200 ms for RV and LV of HTN-VNS and HTN-Sham hearts. (B) Single pixel action potential traces taken from RV (●) and LV (■) data from panel A for HTN-VNS (solid line) and HTN-Sham (dashed line) hearts. (C) Mean APD80 as a function of BCL for RV and LV of HTN-VNS (n = 5) and HTN-Sham (n = 5) hearts. (D) Mean Smax values for RV and LV of all HTN-VNS and HTN-Sham hearts. # indicates statistical significance (P < 0.05) between HTN-VNS and HTN-Sham.
Figure 6
Figure 6
(A) APD heterogeneity index μ and (C) mean CV as a function of BCL for RV and LV of HTN-VNS and HTN-Sham hearts. (B) Representative examples of activation time maps calculated at BCL = 180 ms. # indicates statistical significance (P < 0.05) between HTN-VNS and HTN-Sham.
Figure 7
Figure 7
Dynamics of ex vivo arrhythmias. (A) Representative example of 2D DF map from RV of HTN-VNS and HTN-Sham hearts (top) and single pixel sample traces of VT (●) and VF (■) (bottom). (B) Maximum DF as a function of number of DF domains from all arrhythmic episodes in HTN-VNS and HTN-Sham hearts. # indicates statistical significance (P < 0.05) between HTN-VNS and HTN-Sham. (C) Snapshot of representative examples of phase movies during arrhythmia for HTN-VNS and HTN-Sham hearts (see supplemental material for movies).

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