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Control of Heart Rate with Vagus Nerve Stimulation
H.P.J. Buschman1, C.J. Storm2, D.J. Duncker3, P.D. Verdouw3, P. van der Kemp4,
H.E. van der Aa1,5
1Twente Institute for Neuromodulation (TWIN), Medisch Spectrum Twente, Enschede,
2Department of Cardiology, Medisch Centrum Rijnmond-Zuid, Rotterdam,
3Experimental Cardiology, Thoraxcenter, Erasmus University, Rotterdam,
4Foundation for Aviation Medicine Research, Oegstgeest,
5Department of Neurosurgery, Medisch Spectrum Twente, Enschede, The Netherlands,
Abstract
Electrical stimulation of the vagus nerve can change
heart rate in animals and humans. We investigated if a
clinical implantable lead system that is used in chronic
cervical vagus nerve stimulation (VNS) for treatment of
epilepsy can be used for control of the heart rate.
Experiments were carried out in three pigs under general
anaesthesia. The right and left vagus nerves in the neck
region were exposed by dissection, and bipolar multiturn,
helical leads were wrapped round the vagus nerves.
Stimulation was applied by an external device with multi
variable settings. Measurements were performed under
normal sinus rhythm and during isoprenaline induced
tachycardia.
VNS under optimal pacing conditions increased
RR-intervals by ~40%, irrespective of the duration of the
RR-interval preceding NVS. The effect on heart rate was
established within 5 seconds after the onset of stimulation
and was reversible.
We conclude that a helical lead for nerve stimulation can
be used effectively to decrease heart rate. Fully
implantable vagus nerve stimulation devices may be used
for nonpharmacological treatment of illnesses in which
tachycardia result in deterioration of cardiac function.
1. Introduction
Electrical stimulation of the vagus nerve (VNS) has been
shown to influence heart rate in animals and humans [1-4].
In animals reductions in heart rate vary from 20% to 80 %
[1]. In humans few studies have investigated cardiac
effects as a result of stimulation of parasympathetic nerves
[2-4].
In this study we investigated the use of a commercially
available helical coiled lead for vagus nerve stimulation to
control heart rate [5]. In addition we determined the
optimal stimulus characteristics, and investigated whether
left, right and left + right vagus nerve stimulation gave
similar results.
2. Methods
2.1. Animal Care
All experiments were performed in accordance with the
Guiding Principles for Research Involving Animals and
Human Beings as approved by Council of the American
Physiological Society and under the regulations of the
Animal Care Committee of the Erasmus University,
Rotterdam, The Netherlands.
2.2. Surgical Procedure
After an overnight fast, crossbred Landrace × Yorkshire
pigs of either sex (weight 21 to 26 kg, n = 3) were sedated
with ketamine (20 to 25 mg/kg IM), anesthetized with
sodium pentobarbital (20 mg/kg IV), intubated, and
connected to a respirator for intermittent positive pressure
ventilation with a mixture of oxygen and nitrogen.
Respiratory rate and tidal volume were set to keep arterial
blood gases within the normal range.
Catheters were positioned in the superior caval vein for the
continuous administration of sodium pentobarbital (10 to
15 mg ⋅ kg-1 ⋅ h-1) and saline. In the descending aorta, a
fluid-filled catheter was placed to monitor aortic blood
pressure. Through a carotid artery, a manometer-tipped
catheter (B. Braun Medical BV) was inserted into the left
ventricle for measurement of pressure.
After the administration of pancuronium bromide (4 mg)
the left and right cervical vagus nerves were dissected free
in a similar way as described for electrode placement for
vagus nerve stimulation electrode placement in patients
with refractory epilepsy [6]. At least 4 cm of the nerve was
completely freed from its surrounding tissues. Depending
on the size of the exposed nerves, either 2 mm or 3 mm
diameter helical electrodes (NeuroCybernetic electrode
model 300, Cyberonics, Inc., TX, USA) were wrapped
around the nerve trunks. This lead is a bipolar, multi-turn
silicone helix with a platinum band on the inner turn of one
helix. During the experiment the wound was kept moist
using physiological saline.
2.3. Experimental Protocol
After a 10-minute stabilization period, baseline heart rate
measurements were obtained. Then, following a protocol
the left and right vagus nerves were randomly stimulated.
Stimulation was applied with an EMG Electronic
Stimulator (model SEM-4201, Nihon-Kohden, Tokyo,
Japan). Stimulation parameters were: stimulation
frequency 10-100 Hz; pulse duration 100-700 µs; delay
after R-top 0-0.5 msec; stimulation current 0.5-14 mA.
Measurements were performed both at cardiac rest rates
(100-120 min-1) and at increased rates (200-220 min-1)
during isoprenaline infusion (2 µg/min).
2.4. Data analysis
Data were recorded using a digital ECG storage system
and analyzed using LabVIEW (Development System
Version 4.0.1, National Instruments Corporation, Austin,
Tex as , U SA ).
3. Results
Cardiac rates at rest periods (baseline rates) with and
without isoprenaline infusion in repeated experiments
were respectively 120 ± 4 min-1 (N=7) and 202 ± 6 min-1
(N=7). After stopping the infusion of isoprenaline the heart
rate decreased to control rates within 30 minutes.
VNS under optimal conditions (100 Hz, 5 mA, 0.2 msec,
70 msec delay) in an ECG-triggered pacing mode
increased RR-intervals by more than 40 %.
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
100
110
120
130
140
150
RR-interval (% of control)
Current (mA)
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
100
110
120
130
140
150
RR-interval (% of control)
Current (mA)
Figure 1. Effect of stimulation on RR-interval. To p Effect
at baseline rates. Bottom Effect at isoprenaline-infusion
increased rates. Solid circles: left vagus nerve stimulation;
open circles: right vagus nerve stimulation. Experimental
conditions: 30 Hz, 0.5 msec, pulse delay 70 msec. The
RR-interval was averaged over 5-7 heart beats.
Figure 1 shows the effect of stimulation current on the
RR-interval for both left- and right-sided vagus nerve
stimulation at near optimum stimulation conditions. The
upper graph shows the results for vagus nerve stimulation
at normal cardiac rates, and the lower graph for rates
increased as a result of isoprenaline infusion. The
RR-interval is represented as the fraction of the control
value without vagal nerve stimulation. These graphs
illustrate that the RR-interval increases almost linearly
with increasing stimulation current, and percentage-wise
the effects are similar during basal heart rate and during
isoprenaline-induced tachycardia, i.e. no statistically
significant differences were found between the effects on
RR-interval observed at normal rates and the RR-interval
at high rates. The absolute effect of vagus nerve
stimulation on RR-interval at normal rates (not shown),
however, was statistically significant lower than the effect
at isoprenaline-induced increased rates for all applied
stimulation currents. In the lower graph from visual
inspection it seems that the maximum effect (about 35 %
increase in RR-interval) is reached at a stimulation current
of about 3 mA, after which the effect stabilizes.
Furthermore, the lower graph shows that stimulation of the
left and right vagus nerves have similar slowing effects on
heart rate. The maximum vagus nerve stimulation induced
effect on RR-interval is reached within 5 seconds (5 ± 2;
mean ± SD), and is the same for left + right-sided
stimulation. Blood pressure and left ventricular pressure
remained unchanged during VNS.
4. Summary and Conclusions
In this study we have carried out experiments to
determine the effect of cervical electrical vagus nerve
stimulation on heart rate of pigs using an implantable
multiturn helical lead [5]. We looked at effects on heart
rate when the vagus nerve including the cardiac branches
were stimulated, and identified the optimal stimulation
parameters for control of heart rate. Our results show that
the heart rate can be reduced significantly (> 40%). This
was achieved at electrical stimulation energies that are
similar to those used in VNS for treatment of epilepsy [7].
Moreover, our results indicate that the effect of VNS on
heart rate is rapid and can be administered to control heart
rate on specific moments in time.
Although most VNS research for control of heart rate has
been performed in animal studies the consistency of the
results obtained in preliminary human studies suggests that
this technique may be used in human. This potentially
opens up the possibility to implant a device which, in
contrast to a cardiac pacemaker, lowers the heart rate, and
may be particularly beneficial for terminating specific
paroxysmal arrhythmia or the nonpharmacological
treatment of chronic heart failure [8].
We conclude that stimulation of the vagus nerve with a
commercially available NVS-electrode for chronic
treatment of epilepsy can effectively lower the heart rate in
pigs both during basal heart rate and pharmacological
induced tachycardia. Further studies are needed to
determine whether this technique is effective in humans
where chronic intermittent lowering of sinus rate is
desirable.
References
[1] Armour JA, Randall WC, Sinha S. Localized
myocardial response to stimulation of small cardiac
branches of the vagus. Am J Physiol 1975;228:141-8.
[2] Thompson GW, Levett JM, Miller SM, et al.
Bradycardia induced by intravascular versus direct
stimulation of the vagus nerve. Ann Thorac Surg
1998;65:637-642.
[3] Asconape JJ, Moore DD, Zipes DP, et al. Bradycardia
and asystole with the use of vagus nerve stimulation for the
treatment of epilepsy: a rare complication of intraoperative
device testing. Epilepsia 1999;40:1452-1454.
[4] Schimmel LJJC, Buschman HPJ, Hageman G, et al.
Intraoperative and postoperative bradycardia with the use
of vagus nerve stimulation [Abstract]. Epilepsia 2000;41(5
Suppl): 43S
[5] Brent Tarver W, et al. Clinical experience with a
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[6] Reid SA. Surgical technique for implantation of the
neurocybernetic prosthesis. Epilepsia 1990;31:S38-39
[7] Rutecki P. Anatomical, physiological, and theoretical
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stimulation. Epilepsia 1990;31(Suppl 2):S1-6
[8] Morillo CA, Klein GJ, Thakur RK, et al. Mechanism
of ‘inappropriate’ sinus tachycardia: role of
sympathovagal balance. Circulation 1994;90:873-877