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 ms; 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 mg/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,
Texas, USA).
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 %.
Figure 1. Effect of stimulation on
RR-interval. Top 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.
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