International Journal of Cardiology 176 (2014) 1030–1032

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International Journal of Cardiology

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Letter to the Editor

Application of vagus nerve stimulation from the onset of ventricularfibrillation to post-shock period improves defibrillation efficacy

Kittiya Thunsiri a,b, Krekwit Shinlapawittayatorn b,c,1, Kreokkiat Chinda b, Siripong Palee b, Sirirat Surinkaew b,Siriporn C. Chattipakorn b,d, Bruce H. KenKnight e, Nipon Chattipakorn b,c,⁎a Biomedical Engineering Center, Faculty of Engineering, Chiang Mai University, Chiang Mai, Thailandb Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailandc Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailandd Department of Oral Biology and Diagnostic Science, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailande Emerging Therapies, Cyberonics Inc, Houston, TX, USA

⁎ Corresponding author at: Cardiac ElectrophysiologyFaculty of Medicine, Chiang Mai University, Chiang Mai945 329; fax: +66 53 945 368.

E-mail address: nchattip@gmail.com (N. Chattipakorn1 These two authors contributed equally to this work.

http://dx.doi.org/10.1016/j.ijcard.2014.07.3020167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved

a r t i c l e i n f o

Article history:

Received 3 June 2014Accepted 26 July 2014Available online 15 August 2014

Keywords:Defibrillation thresholdVentricular fibrillationVagus nerve stimulation

The study has been approved by the Institutional Animal Care and UseCommittees of the Faculty of Medicine, Chiang Mai University. Allanimals were cared for according to the Guide for the Care and Use ofLaboratory Animals published by the US National Institutes of Health(NIH Publication No. 85-23, revised 1996). Thirteen anesthetized pigs(30–35 kg) were used in this study. In each pig, shocking electrodeswere placed at the right ventricular (RV) apex and the junction betweensuperior vena cava and right atrium. VF was induced by 60-Hz alternat-ing current delivered from an electrode at the tip of the RV catheter. De-

Sudden cardiac death remains a major unresolved clinical problemworldwide. Many of these deaths result from malignant ventriculararrhythmias, including ventricular fibrillation (VF) [1]. Although themost effective treatment for VF is electrical defibrillation, several studieshave suggested the potential for myocardial damage when high-energyshocks were applied during defibrillation [2]. Thus, the improvement ofdefibrillation efficacy has been extensively studied in an attempt tolower the shock strength required for successful defibrillation includingmodulation of the autonomic nervous system by vagus nerve stimula-tion (VNS). Although left cervical (LC) VNS has been used as a therapeu-tic tool for epilepsy and drug resistant depression, a previous study hasshown that VNS applied 8 s before the defibrillation onset coulddecrease the defibrillation energy [3]. Moreover, a growing number ofstudies have suggested that increased sympathetic activity [4] andrapid repetitive cardiac electrical activities occurring after defibrillation(post-shock activation) could be responsible for failed defibrillation[5–7]. Therefore, we hypothesized that by applying LC VNS continuous-ly beginning at the VF onset until the post-shock period could improve

Research and Training Center,50200, Thailand. Tel.: +66 53

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defibrillation efficacy by decreasing the defibrillation threshold (DFT).

fibrillation was attempted with biphasic truncated exponential shocksafter 10 s of VF. LC VNSwas applied at the onset of VF at 5 Hz and at du-rations of 10, 15, and 20 s. The DFT was determined at the beginning ofthe study and after LC VNS by the three reversal up–down protocol. Aminimumof 4minwas allowed to elapse between VF episodes. The sur-face ECGwasmonitored and recorded throughout the experiments. Pigswere randomly divided into 2 groups. Group 1 (n= 7) received 10 mA,5 HzVNS at different durations (10, 15 and 20 s). In group 2 (n=6), theeffective VNS parameter selected from group 1 was applied in the pres-ence of 3%Mepivacaine for blocking the effect of VNS. For the local nerveblock, the LC vagus nerve was caudally covered by the nerve cuff whichis the route for the administration of 3% Mepivacaine. Mepivacaine wasmaintained in the nerve cuff for the entire experiment.

In group 1, VNS (5Hz) significantly prolonged P–R and R–R intervals(approximately 17±2% change for P–R interval and 18±1% change forR–R interval at all durations) while caused no change in QRS complexand Q–T interval (Table 1). The delivered voltage and energy of theDFT were significantly decreased only at VNS durations of 15 and 20 s(Fig. 1A). In the present study, VNS parameter of 5 Hzwith 20 s durationwas selected for group 2 study. To verify if improved defibrillation effi-cacy was from VNS, sodium channel blocker Mepivacaine was used ingroup 2. Our results showed that VNS significantly prolonged P–R andR–R intervals, and Mepivacaine did not alter the P–R and R–R intervals(Table 1). Moreover, the beneficial effect of VNS on the DFT reductionwas abolished when the LC vagus nerve was locally blocked by 3%Mepivacaine (Fig. 1B).

The parasympathetic innervation of the heart is modulated throughthe vagus nerve. It is known that right VNS can cause bradycardia,

Table 1ECG parameters at baseline, and during VNS.

Frequency (Hz) Duration (s) Condition P–R interval (ms) R–R interval (ms) QRS complex (ms) Q–T interval (ms)

Group 15 10 Baseline 114 ± 28 662 ± 113 33 ± 17 334 ± 40

Stimulation 133 ± 23⁎ 781 ± 169⁎ 34 ± 16 329 ± 4215 Baseline 122 ± 37 705 ± 119 36 ± 17 349 ± 46

Stimulation 140 ± 23⁎ 840 ± 153⁎ 35 ± 15 345 ± 4420 Baseline 119 ± 40 698 ± 123 39 ± 18 337 ± 52

Stimulation 142 ± 29⁎ 824 ± 141⁎ 41 ± 18 337 ± 53

Group 2 (with 3% Mepivacaine local block)5 20 Baseline 93 ± 10 577 ± 96

Stimulation 117 ± 16⁎ 716 ± 11⁎

Block 93 ± 15 536 ± 69

⁎ P b 0.05 vs Baseline.

1031K. Thunsiri et al. / International Journal of Cardiology 176 (2014) 1030–1032

whereas left VNS induces AV block. Although LC VNS was performedin the present study, the prolonged R–R interval was shownwhen com-pared with the baseline. Based on the richly parasympathetic nerve in-nervation throughout all chambers of the swine heart [8], the prolongedR–R interval could be due to the direct transfer of the electrical stimula-tion to the SA node.

The effective VNSparameters in the present studywere 5Hzwith 15or 20 swhich are continuously VNS applied fromVF onset until 5 or 10 safter the defibrillation, suggesting that VNS applied long enough tocover the post-shock period significantly increased the defibrillation ef-ficacy as shown in Fig. 1A. The previous studies suggested that rapid car-diac electrical activities occurring after defibrillation (post-shockactivation) could be responsible for the failed defibrillation [5–7].Thus, the DFT reductionmight be explained by the cardiac electrophys-iological modulation by the VNS whichmodulated the cardiac electrical

A. VNS 5 Hz

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Del

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BL = Baseline (no VNS), VNS = Vagal Nerve Stimulation,5 Hz for 20 s, Block = VNS was blocked by 3% Mepivacaine, *P<0.05 vs BL

BL VNS Block BL VNS Block

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BL 10 15 20 BL 10 15 206

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Duration of stimulation (s)

** * *

B. VNS 5 Hz, 20 s in the presence of 3% Mepivacaine

Fig. 1. Effects of VNS frequencies and durations on delivered voltage and delivered energyof DFT.

activities during the post-shock period. Interestingly, the effect of para-sympathetic modulation observed in our present studywas also consis-tent with the previous experiment, which demonstrated thatparasympathomimetic drugs not only decreased the DFT but also in-creased ventricular fibrillation threshold (VFT) [9]. The increased VFToccurs via post-ganglionic efferent fibers which is a direct action ofVNS on the ventricle [9]. Furthermore, in the isolated innervated rabbitheart preparation [4], VNS has been shown to increase the VFT, makingVF harder to induce. In our experiment we also found that some of ouranimals failed to develop VF by the same amount of AC current afterVNS was applied (unpublished data).

To verify the roles of VNS in improved defibrillation efficacy,Mepivacaine was used for blocking nerve impulses via the vagusnerve. Prior to Mepivacaine application, VNS caused the prolongationof P–R and R–R intervals, and also reduced the DFT. After Mepivacainewas applied, VNS did not make any change on both P–R and R–R inter-vals and theDFT, comparedwith the baseline. This finding strongly con-firmed that the beneficial effects of VNS on the electrophysiologicalproperties of the heart were modulated through the vagus nerve. How-ever, the major limitation of this study is that the direct electrophysio-logical parameters such as the action potential duration and theeffective refractory period were not measured. Future studies are need-ed to investigate whether these parameters were modulated by VNS.

Funding sources

This study was supported by the Thailand Research Fund TRF-CHEResearch Grant for New Scholars MRG5580125 (KS), BRG5780016(SC), RTA5580006 (NC), and the ChiangMai University Excellent CenterAward (NC).

Conflict of interest

The authors report no relationships that could be construed as aconflict of interest.

References

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