Chronic cyclic vagus nerve stimulation has beneficial electrophysiological effects on healthy hearts in the absence of autonomic imbalance

Abstract

Cardiovascular disease degrades the regulatory function of the autonomic nervous system. Cyclic vagus nerve stimulation (VNS) is an already FDA-approved therapy for drug-resistant epilepsy and depression, and has been shown to normalize autonomic function and improve objective measures of heart function and subjective measures of heart failure symptoms. However, it remains unclear whether VNS may induce negative effects in patients with potentially healthy hearts where VNS can be used for epileptic patients. Hence, this study aims to investigate the effects of VNS on the hearts of healthy rats with normal autonomic balance. Sprague-Dawley rats were implanted with stimulators and randomized to either Sham or VNS groups. Rats in VNS group received 10 weeks of chronic intermittent VNS via stimulation of the right cervical vagus nerve. Echocardiography was performed at Baseline (prior to VNS), Week 2, and Week 9. After 10 weeks, high-resolution optical mapping was performed in ex vivo perfused hearts to evaluate the electrophysiological remodeling that occurs in the heart as a result of the VNS therapy. Chronic VNS modified the electrophysiological properties of healthy rat hearts by reducing the action potential duration at 50% (APD50) and 80% (APD80) repolarization. Chronic VNS also affected the restitution properties of the heart at the APD50 level and increased myocardial conduction velocity (CV). VNS did not induce any significant changes to ventricular ejection fraction (EF) and spatial dispersion of APD, thus indicating that VNS did not negatively affect cardiac function. VNS also reduced the susceptibility to ventricular arrhythmias (ventricular fibrillation [VF] and ventricular tachycardia [VT]) during ex vivo programmed electrical stimulation. In summary, chronic application of cyclic VNS induces changes to the electrophysiological properties of healthy rat hearts. The observed decrease in APD and increase in CV suggest that the beneficial effects of VNS do not require the presence of existing autonomic imbalance.

Keywords: Arrhythmias; autonomic nervous system; optical mapping; vagus nerve stimulation.

© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Figures

Figure 1

Effects of long‐term intermittent VNS on left ventricular (LV) function. Mean ejection fraction (EF) (%) measurements from Sham and VNS rats for Baseline, Week 2, and Week 9.

Figure 2

Representative left ventricular (LV) action potential duration (APD) maps at basic cycle length (BCL) = 200 msec and 100 msec. (A) Examples of APD 80 maps with action potential traces from pixels “” and “” for BCLs = 200 msec and 100 msec, respectively. (B) Examples of APD 50 maps with representative action potential traces from pixels “”and “”for Sham and VNS, respectively.

Figure 3

Effects of long‐term intermittent VNS on APD. (A) Mean APD 50 and APD 80 values for both Sham and VNS at different BCLs. Normalized (B) APD 80 and (C) APD 50 values to BCL 200. *, #Statistical significance (P < 0.05) between Sham and VNS for APD 80 and APD 50, respectively.

Figure 4

Effects of VNS on spatial dispersion of APD (μ). Mean μ values for (A) APD 80 and (B) APD 50 for BCLs = 200 msec and 100 msec.

Figure 5

Effects of VNS on conduction velocity (CV). (A) Mean CV values at different BCL values. (B) Representative examples of LV action potential activation maps for the epicardial surfaces of Sham and VNS rats at BCL = 100 msec. Isochrones for activation time maps are shown 3 msec apart. The red marker denotes pacing site. *Statistical significance (P < 0.05).

Figure 6

Quantification of the number of rats exhibiting ex vivo ventricular fibrillation (VF) and tachycardia (VT) episodes during programmed stimulation.