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Heart Cycle Length Modulation by Electrical
Neurostimulation in the High Right Human
Atrium
Antje Pohl1, Barbara Bellmann2, Nima Hatam3, Patrick Schauerte4, and Steffen Leonhardt1
1Chair for Medical Information Technology, RWTH Aachen University, Aachen, Germany
2Dept. for Cardiology at the Charité Berlin, Campus Benjamin Franklin, Berlin, Germany
3Dept. of Cardiovascular and Thoracic Surgery, University Hospital Aachen, Aachen, Germany
4Praxis Kardiologie Berlin, Berlin, Germany
Email: pohl@hia.rwth-aachen.de
Abstract—Today, high resting heart rates are known to be
an independent risk factor for a higher overall mortality,
irrespective of underlying coronary diseases. Neuro-
stimulation is a fast growing, wide spread approach to treat
various disorders by electrical stimulation of specific nerve
cells. We present a technique of intracardiac
neurostimulation to the parasympathetic tone in the high
right human atrium in the sinoatrial node area.
Investigations include recording the decreasing effects of
heart rate, the anatomical endocardial visualization of the
right atrium, and developing gradient maps with
parasympathetic and sympathetic nerve bundles. During an
ablation procedure within the sinus rhythm, patients are
stimulated with a bipolar electrode catheter which can be
detected by an electroanatomical navigation system. Sinus
cycle length and corresponding ventricular heart rate are
recorded before, during and after stimulation and show a
direct correlation with the start and end of stimulation.
Index Terms—Electrical neurostimulation, modulation of
heart rate, intracardiac electrograms, heart rate reduction
I. INTRODUCTION
Depending on (among other factors) physical
constitution and age, healthy men have a resting heart
rate of about 1 – 1.3 Hz, which corresponds to 60 – 80
beats per minute (bpm). Modulation of heart rate is
regulated by the autonomous nervous system, which
consists of two subcomponents, i.e. the sympathetic and
parasympathetic nervous systems. Both these systems act
as antagonists: for example, in terms of cardiology, the
sympathetic nervous system increases heart rate (positive
chronotopic effect) whereas the parasympathetic system
decreases heart rate in case of regeneration (negative
chronotopic effect).
As an independent risk factor, high resting heart rates
can lead to a higher overall mortality even in healthy
persons [1]. However, especially individuals with
coronary artery diseases, such as heart insufficiency, have
an increased mortality rate due to their increased
sympathetic tone [2]. For example, Jouven et al.
demonstrated that individuals suffering from myocardial
infarction have relatively high cardiovascular mortality
rates [3].
In most cases, pharmacological approaches to decrease
relatively high heart rates are achieved with beta blockers.
Beta blockers inhibit the binding of adrenaline to the beta
receptors, which are also part of the cells in the heart. The
heart beat within sinus rhythm is generated in the
sinoatrial node, which is localized in the high right atrium
near the vena cava (Fig. 1; left side). The specialized
nerve cells forming the sinoatrial node have no constant
resting membrane potential. Diastolic depolarization of
these pacemaker cells leads to the pulse generating
automaticity of the heart. A typical action potential from
the sinoatrial node area is shown on the right side of Fig.
1. As beta blockers cannot exclusively target the sinus
node but also decrease blood pressure, this is a major
disadvantage. One approach consists of pharmacological
blockade of the if-channel, with, for example, Ivabradine.
The rhythmical activity of the heart is produced
according to intrinsic and spontaneous depolarizing ion
currents. The hyperpolarizing-activated if-current plays
an important role in this process. Because if is not
exclusively expressed in the sinoatrial node,
physiological effects on the atria may take place or visual
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of Life Sciences and Technologies Vol. 1, No. 4, December 2013
2013 Engineering and Technology Publishing 223
doi: 10.12720/jolst.1.4.223-227
Manuscript received September 6 2013; revised November 27, 2013.,
Figure 1. Left side: Schematic drawing of the human heart; marker is
in the high right atrium. Right side: Extracted intracardiac electrogram
(IEGM) excitation from the sinoatrial node area.
disorders caused by the central nervous system may
sometimes occur. Besides, as a matter of principle, no
medication can ever provide dynamic modulation of the
heart rate.
The selective electrical neurostimulation, also called
neuromodulation, of the autonomous nervous system is a
fast-growing research area which already has widespread
application. For instance, stimulation of specific points in
the spinal cord is used to relieve pain associated with
chronic reflex sympathetic dystrophy syndrome [4]. Deep
brain stimulation is under investigation for the treatment
of epilepsy [5] and psychiatric disorders [6]. Also, via
sacral nerve stimulation lower urinary tract dysfunctions
can be improved [7]. The feasibility of chronic
parasympathetic stimulation for ventricular rate control
during atrial fibrillation has been demonstrated in an
animal model and was shown to be safe, effective and
well tolerated even on the long term [8].
The current project aims to develop a technique of
intracardiac electrical neuromodulation to selectively
increase the parasympathetic tone in the sinoatrial node
area, with the objective to decrease high resting heart
rates. Therefore, during standard procedure of ablation
procedures in humans suffering from atrial fibrillation,
the sinoatrial node area in the high right atrium was
stimulated within the sinus rhythm. We present the design
of the study and show the results during intracardiac
neurostimulation.
II. METHODOLOGY
To investigate the principle of intracardiac
neurostimulation to decrease high resting heart rates, this
study included patients undergoing a standard procedure
of ablation. Patients are under deep sedation with
continuous surveillance of blood pressure, heart rate and
oxygen saturation. A multipolar steerable mapping
catheter (Thermocool Catheter, Biosense Webster Corp.,
USA) for radio frequency ablation is guided to the right
atrium through the femoral vein. The catheter tip is
located with a 3D electroanatomical navigation system
(Carto, Biosense Webster Corp., USA). This allows each
stimulation point to be recorded. Extrapolation of the
space between these stimulation points provides a
reconstruction of endocardial maps allowing detailed
investigation of the anatomical position of the
parasympathetic nerves in relation to the sinoatrial node.
A. Specific Medical Circumstances
In this complicated procedure, it is important to apply
appropriate trigger signals, because stimulation during the
vulnerable phase can cause atrial fibrillation. Therefore,
to exclusively address the parasympathetic nervous
system, stimulation is performed in the absolute
refractory period of the atrium, whilst the cells cannot be
excited. As trigger signal the intracardiac electrogram
(IEGM) is detected with an electrode catheter (Fig. 2).
The IEGM (blue solid line) represents the excitation of
the sinoatrial node area, as the signal correlates with the
start of the P-wave which is the first wave during cardiac
action (Fig. 2: ECG lead Einthoven I; black dashed line)
Figure 2.
ECG lead Einthoven I (black dashed line) and corresponding
intracardiac electrogram (IEGM; blue solid line) in the human sinoatrial
node area.
Figure 3.
Schematic of the setup for the human intracardiac neuromo-
dulation of heart rate with an ablation generator, a sense/trigger unit, the
HF stimulator with isolation unit for the generation of high frequency
stimulation bursts and Carto mapping for visualization of stimulated
areas in the high right human atrium.
Because neurostimulation will shorten the myocardial
ERP, the duration of stimulation bursts must be
significantly below the ERP minus an average latency
interval of 20 – 40 ms to the local atrial myocardial
excitation. Accordingly, stimulation burst periods should
last for 40 – 80 ms. Therefore, the frequency of the
neurostimulation bursts is optimally higher than in cases
of continuous stimulation. Low frequency stimulation
would not emit effective energy to the nerve cells. For
this reason, the stimulation burst frequency was chosen to
be 200 Hz. To evaluate the effect on local neurostimu-
lation, the sinus cycle length is measured before, during
and after the stimulation period. According to these
recordings in correlation with the strength of the negative
chronotopic effect, gradient maps of the functional
formation of nerve fibers in the sinoatrial node area have
been established.
B. Neurostimulation Setup for a Study Case
Fig. 3 shows the setup for the study on human
intracardiac neuromodulation. In human studies, only
technical equipment that has been approved for clinical
trials is used. Therefore, the IEGM trigger signal,
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of Life Sciences and Technologies Vol. 1, No. 4, December 2013
2013 Engineering and Technology Publishing 224
equal to the atrial excitation. The atrial myocardial
effective refractory period (ERP), ensures not to indicate
atrial fibrillation and to stimulate nerve cells in
musculature, takes more than 150 ms.
detected with the electrode catheter, is passed through the
ablation generator and the electrophysiological recording
system, to a sense/trigger stimulator (UHS 3000,
Biotronik, Germany) with a sense sensitivity of 1 mV.
For the high frequency stimulation bursts another
stimulation system (HF stimulator) is needed (Bloom
DTU 215B, Electrophysiology Stimulator, Fischer
Medical Technologies LLC, USA), providing symmetric
biphasic rectangular stimulation bursts. With a delay of
25 ms, IEGM synchronized high frequency pulses of 200
Hz with a duration of 50 ms at a maximum of 2 V are
generated. Passing an isolation unit (Remote Stimulus
Isolation Unit, Fischer Medical Technologies LLC, USA)
driven with 9 V batteries for maximum patient safety and
isolation, and a catheter input module synchronizing and
connecting signals, the stimulation bursts are transferred
back to the electrode catheter. The bursts have been
emitted bipolar between the first two electrodes at the
catheter tip. For 3D visualization map of the region of
interest (ROI) the signals are connected to the navigation
system. Measuring the cycle length and heart rate
indicates whether the reaction of the parasympathetic
tone has been achieved.
III. RESULTS
Fig. 4 shows a recording of a short episode of intra-
cardiac neurostimulation. It can be seen that directly after
the first IEGM excitation (blue solid line) the ECG
Einthoven lead I (black dashed line) shows the normal
cardiac cycle. The stimulation period started at 6.7 s
(green dotted bar). Therefore, immediately after the
second IEGM excitation, the stimulation is clearly seen to
start.
A representative plot of a complete neurostimulation
episode is shown in Fig. 5. At the top, the ECG
Einthoven lead I as gold standard is shown in correlation
with the middle display with the IEGM taken from the
sinoatrial node area. Heart rate in bpm is recorded in the
lower picture. The vertical green dotted bar at 6.7 s
indicates the start of the stimulation episode and the
active period of stimulation bursts is shown in the middle
picture. The second vertical bar at 51 s denotes the end of
stimulation. In the lower picture, a 20 % decrease in heart
rate can be seen. Although the given heart rate was
relatively low before stimulation (60 – 65 bpm), the
stimulation effect can be clearly seen. After the end of
stimulation the heart rate increases immediately within 10
s.
Figure 5. Upper picture: ECG lead Einthoven I as gold standard. Middle picture: Correlated IEGM from the electrode catheter (Map/Stim-Catheter).
Lower picture: Heart rate in bpm during neurostimulation. Vertical green bars indicate the start and end of intracardiac neurostimulation.
The resulting gradient map of this patient is shown in
Fig. 6. The right-hand side presents a 3D visualization of
the patient’s right atrium in frontal plane view can be
seen and the left-hand side shows the right atrium in
posterior view. The shape of the atrium depends on the
number of sampling points which have been made at the
beginning of the standard procedure. Interpolation of the
sampling points result in the presented views. Also the
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Figure 4. ECG Einthoven lead I (black dashed line) and corresponding
intracardiac electrogram (IEGM; blue solid line) taken from the elec-
trode catheter. Stimulation period started at 6.7 s (green dotted bar) and
can be seen in the IEGM signal as the electrode catheter is used for
signal detection and stimulation.
venae cavae and the pulmonary artery can be seen. Round
markers indicate the points of stimulation. A color map is
correlated with the decrease or increase in heart cycle
length.
Heart cycle length is measured by detection of RR
intervals in the ECG Einthoven lead I, averaged every
10 R-peaks. The cycle length at the very start of the
stimulation period was recorded with 970 ms, equivalent
to 61.9 bpm. Heart cycle length measurement over the
last 10 stimulation bursts shows an increase to 10950 ms,
equivalent to 54.8 bpm. In this case the strongest increase
in heart cycle length was +134 ms and the correlated area
is marked in the red-orange area (ROI 1) on the left
display. This is the sinoatrial node area, where we
expected to observe the most significant decrease in heart
rate. The surrounding area shows a minor increase in
cycle length (green). In the upper part of that picture, an
area (ROI 2) occurs where a slight decrease in heart cycle
length or an increase in heart rate can be detected
according to a bundle of sympathetic nerves.
IV. CONCLUSION
Based on these result, it can be seen that the principle
of heart rate reduction, respectively the increase in heart
cycle length, through electrical neurostimulation of the
parasympathetic tone in the sinoatrial node area is an
appropriate approach. Not only was a decrease in heart
rate shown, but even a slight increase in heart rate could
be detected. After termination of the stimulation, the
negative chronotopic effect ends immediately.
With respect to pharmacological approaches, the direct
control (within a few seconds) of heart rate is a major
advantage of this approach. Nevertheless, transferability
has to be demonstrated in future studies, as well as
identification of the best stimulation parameters, such as
burst stimulation frequency, stimulation patterns (e.g.
monophasic or biphasic), for maximum outcome at low
energy consumption. Integrated into modified pace-
makers, the neurostimulation modality is easily accessed
for patients and might be a major step in the therapy of
patients with chronic heart failure.
ACKNOWLEDGMENT
The authors thank the German Research Foundation
(DFG) for supporting this project (Grant Nos. DFG LE
817/10-1 and SCHA 790/3-1).
We also sincerely thank Ms. Carola Hausdorf, Dept. of
Cardiology, Pneumology, Angiology and Intensive Care
Medicine, University Hospital Aachen, Aachen, Germany,
for her assistance.
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Antje Pohl (née Schommartz) was born in
Essen, Germany, in 1981. She received the
Dipl.-Ing. degree, studying electrical
engineering and information technology with
specialization in medical engineering, from
Ruhr University Bochum, Bochum, Germany,
in 2009.
She is currently working as a Research
Assistant towards the Ph.D. degree at the
Philips Chair for Medical Information
Technology, RWTH Aachen University, Aachen, Germany. Her
research interests are focused on high frequency cardiac
neuromodulation, modeling physiological systems and capacitive ECG
measurement systems.
Mrs. Pohl is Graduate Student Member of the IEEE, and member of the
VDE and the DGBMT.
Barbara Bellmann was born in Hagen,
Germany, in 1984. After completing her study
in the human medicine at the University of
Bonn 2010, she worked as a resident physician
in the department for cardiology, RWTH
Aachen University, Aachen, Germany till
August 2013.
Currently she is working in the Department of
Cardiology at the Charité Berlin (Campus
Benjamin Franklin). Her research interests are
focused on high frequency cardiac
neuromodulation. She earned her doctorate 2010 on the subject
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of Life Sciences and Technologies Vol. 1, No. 4, December 2013
2013 Engineering and Technology Publishing 226
Figure 6. Plot in frontal and posterior view of the patient’s right atrium.
Markers indicate the points of stimulation. The color map shows the
increase (ROI 1) or decrease (ROI 2) in heart cycle length according to
parasympathetic or sympathetic nervous tissue during intracardiac
neurostimulation.
“Comparison of cryoballoon and radiofrequency ablation of pulmonary
veins in 40 patients with paroxysmal atrial fibrillation a case control
study” at the University of Bonn.
Dr. Bellmann is member of the DGK (Deutsche Kardiologische
Gesellschaft).
Nima Hatam was born in Mönchen-gladbach,
Germany, in 1978. He received his M.D. degree
in medicine from the RWTH Aachen University,
Aachen, Germany.
He is a consultant cardiac surgeon since 2011 at
RWTH Aachen University Hospital, Aachen,
Germany. His research interests are focused on
echocardiography and electrotherapy of the
heart.
Dr. Hatam is a member of the DGTHG,
DEGUM and EACVI.
Patrick Schauerte was born in Olsberg,
Germany, in 1966. He received the M.D. degree
in medicine from the Rheinische Friedrich-
Wilhelms University, Bonn, Germany, in 1991.
From 2004 - 2013, he was a Professor of internal medicine at RWTH
Aachen University Hospital, Aachen, Germany. He is with the Praxis
Kardiologie Berlin, Berlin, Germany, since 2013. Prof. Schauerte is
member of AFNET (The German Competence Network on Atrial
Fibrillation) and the DGK.
Steffen Leonhardt was born in Frankfurt,
Germany, in 1961. He received the M.S. degree in
Computer Engineering from the State University
of New York, Buffalo, and the Dipl.-Ing. degree in
Electrical Engineering, the Dr. Ing. degree in
Control Engineering from Technical University of
Darmstadt, Darmstadt, and the M.D. degree in
Medicine from Goethe University, Frankfurt. He
is the Head of the Philips Chair for Medical
Information Technology, RWTH Aachen University, Aachen, since
2003. His current research interests include physiological measurement
techniques, personal health care systems, and feedback control systems
in medicine.
Prof. Leonhardt is Senior Member of the IEEE (EMBS and CSS), VDE,
DGBMT and GMA.
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of Life Sciences and Technologies Vol. 1, No. 4, December 2013
2013 Engineering and Technology Publishing 227
