Atrial overdrive pacing in patients with sleep apnea with implanted pacemaker.

Abstract

Atrial overdrive pacing markedly improved sleep-disordered breathing in a recent study.
Using a single-blind, randomized, crossover design, we aimed to reproduce these findings and investigate the possible underlying mechanisms.
Twenty ambulatory patients with an implanted pacemaker or cardioverter defibrillator were studied by polysomnography on 3 consecutive nights in a randomized, single-blind, crossover study in which devices were programmed for nonpacing or for overdrive pacing at 7 or 15 beats/minute faster than the mean nocturnal heart rate. Ventilation and biomarkers (urinary norepinephrine excretion, amino-terminal portion of the precursor of brain natriuretic peptide, or NT-proBNP, were also evaluated.
Neither the primary endpoint apnea-hypopnea index, nor the apnea index, oxygen desaturation, ventilation, or biomarkers were affected by the nocturnal atrial overdrive pacing. A small, clinically insignificant, rate-dependent reduction in the hypopnea index was evoked by pacing (nonpacing, 13.4 +/- 1.4; pacing 7, 12.9 +/- 1.4; pacing 15, 10.9 +/- 1.0; p < 0.01, analysis of variance).
The lack of effect on the apnea-hypopnea index means that atrial overdrive pacing is inappropriate for treating sleep-disordered breathing.

Full text

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Atrial overdrive pacing in sleep apnea patients with implanted
pacemaker
Lars Lüthje, MD; Christina Unterberg-Buchwald MD; Dani Dajani; Dirk
Vollmann, MD; Gerd Hasenfuß, MD; Stefan Andreas, MD
Department of Cardiology and Pneumology, Georg-August-Universität, Göttingen,
Germany
Address for correspondence:
Prof. Dr. S. Andreas
Herzzentrum Göttingen
Abteilung Kardiologie und Pneumologie
Georg-August-Universität Göttingen Tel: +49 551 39-8921
Robert-Koch-Str. 40 Fax: +49 551 39-14370
37075 Göttingen E-Mail: sandreas@med.uni-goettingen.de
Support:
This investigator initiated study was supported by the Medtronic Inc., Minneapolis,
USA
Running head: Pacing in sleep apnea
Descriptor number: 17
Word count: 2469
This article has an online data supplement, which is accessible from this issue's table
of content online at www.atsjournals.org

AJRCCM Articles in Press. Published on March 4, 2005 as doi:10.1164/rccm.200409-1258OC
Copyright (C) 2005 by the American Thoracic Society.

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Abstract
Rationale: Atrial overdrive pacing markedly improved sleep disordered breathing in a
recent study.
Objectives: Using a single blinded, randomized, crossover design, we aimed to
reproduce these findings and investigate the possible underlying mechanisms.
Methods: Twenty ambulatory patients with an implanted pacemaker or cardioverter
defibrillator were studied by polysomnography on three consecutive nights in a
randomized single-blind crossover study in which devices were programmed for non-
pacing, or for overdrive pacing at 7 or 15 beats per minute faster than the mean
nocturnal heart rate. Ventilation (Respitrace) and biomarkers (urinary norepinephrine
excretion, aminoterminal portion of the precursor of brain natriuretic peptide (NT-
proBNP)) were also evaluated.
Measurements and Main Results: Neither the primary endpoint apnea-hypopnea
index, nor the apnea index, oxygen desaturation, ventilation or biomarkers were
affected by the nocturnal atrial overdrive pacing. A small, clinically insignificant rate-
dependent reduction in the hypopnea index was evoked by pacing (non-pacing: 13.4
± 1.4; pacing 7: 12.9 ± 1.4; pacing 15: 10.9 ± 1.0; p ANOVA < 0.01).
Conclusions: The lack of effect on the apnea-hypopnea index means that atrial
overdrive pacing is inappropriate for treating sleep disordered breathing.
Word count: 183
Key words: sleep apnea, pacing, randomized trial

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Introduction
Obstructive sleep apnea (OSA) has a high prevalence within the general population
that will rise further given the obesity epidemic at hand [1]. OSA is associated with
arterial hypertension and increased cardiovascular morbidity [2-4]. Continuous
positive airway pressure (CPAP) is an effective therapy for OSA. However, CPAP
therapy is often difficult to tolerate and patients frequently stop using it because of
discomfort. The nasal mask interface may cause pressure sores, claustrophobia,
nasal congestion, and other side effects that lead to suboptimal compliance [5-7].
The finding that atrial overdrive pacing reduces the number of central and obstructive
sleep apnea episodes by about 50% [8] is tantalizing, as it might give rise to a new
therapeutic concept [9]. Two key underlying mechanisms of the effect of atrial
overdrive pacing in sleep apnea have been suggested: 1.) Overdrive pacing can
improve cardiac output [10] as well as pulmonary congestion and thereby reduce
hyperventilation and central apneas [11]. 2). Overdrive pacing counteracts nocturnal
hypervagotonia by influencing cardiac vagal or sympathetic afferent neurons, thus
affecting ventilation and stabilizing respiration [11]. However, these concepts have
not been proven [9].
Biomarkers of neurohumoral activation, such as plasma and urinary norepinephrine
as well as brain-type natriuretic peptide plasma concentration, are elevated in OSA
[12-14] and are inversely correlated with left ventricular function and prognosis in
patients with heart failure [15, 16]. It is possible that the increase in heart rate due to
overdrive pacing impacts on systolic or diastolic left ventricular function and thus on
these biomarkers.
Garrigue and colleagues performed atrial overdrive pacing with a rate that was
arbitrarily set at 15 beats per minute faster than the mean nocturnal heart rate. It

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remains to be investigated whether overdrive pacing at a lower rate has the same
beneficial effect on sleep disordered breathing.
Using a single-blinded, randomized, crossover design, we investigated the effects of
nocturnal atrial overdrive pacing on sleep disordered breathing, minute ventilation
and biomarkers in patients with an implanted pacemaker (PM) or implanted
cardioverter defibrillator (ICD). Overdrive pacing was performed with a rate of 7 as
well as 15 beats per minute faster than the mean nocturnal heart rate. Some of the
results of these studies have been previously reported in the form of abstracts [17,
18].
Methods (Word count: 500)
Patient selection
Patients in our out-patients’ clinic for PMs and ICDs with stable sinus rhythm and a
dual chamber device implanted were screened for sleep apnea with an ambulatory
device (Somnocheck effort, Weinmann, Hamburg, Germany), regardless of any
symptoms suggestive of sleep apnea. To evaluate the mean nocturnal heart rate by
Holter ECG, the PM/ICD was programmed to 40 beats/min (DDD). Inclusion criterion
was an apnea/hypopnea index (AHI) >15/h with associated oxygen desaturations
>4%. Exclusion criteria were chronic atrial arrhythmias, myocardial infarction within
one month of the study, decompensated heart failure, and age groups <18 or >75
years. Written informed consent was obtained from each patient, and the study was
approved by the University of Göttingen Institutional Review Board.

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Protocol
Patients underwent full-night polysomnography for three consecutive nights in a
randomised single-blind crossover design. In the three nights, the PM/ICD was
programmed either to a backup rate of 40 beats/min (non-pacing), or to an atrial
overdrive pacing rate of 7 or 15 (pacing 7 or 15) beats higher than the mean
nocturnal heart rate of the screening night. Before the first night an
electrocardiogram, lung function tests, and echocardiography were performed. For
further information see online data supplement.
Polysomnography
An electroencephalogram, electrooculogram, electromyogram and electrocardiogram
were recorded as previously described [19]. Airflow was recorded by nasal pressure,
while thorax and abdominal wall motion was monitored by Respitrace as detailed
below. Arterial oxygen saturation (SaO2) was measured transcutaneously by pulse
oximetry (Healthdyne Technologies Inc., Marietta, USA). The polysomnogram was
visually analysed with a computer system (ALICE IV, Heinen und Löwenstein, Bad
Ems, Germany) as already described. An apnea was considered obstructive when
nasal flow was absent in the presence of abdominal or thoracic movements, and
central when movements were absent as well. Central hypopneas were defined as a
50% or greater reduction in tidal volume from the baseline value for at least 10
seconds with proportional in-phase reductions in rib cage and abdominal movements.
Obstructive hypopneas were similarly defined except that out of phase
thoracoabdominal motion had to be present [20]. Sleep stages and arousals were
evaluated according to standard criteria [21, 22].

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Ventilation, Holter monitoring, blood pressure, biomarker
Respiratory rate and tidal volume were registered by calibrated respiratory inductive
plethysmography (Respitrace Systems, Ambulatory Monitoring Inc., New York, USA)
as previously described [23]. Blood pressure was measured noninvasively by
sphygmomanometry (Dinamap XL Monitor, model 9302, Johnson & Johnson Medical
Inc., Tampa, USA) once every hour. Blood samples were taken each morning directly
after waking. Urine was collected overnight. For details see online data supplement.
Statistical Analysis
Variables are given as mean ± SEM. Primary endpoint was the apnea/hypopnea
index (AHI). Repeated measure analysis of variance (ANOVA) was used for
comparison of the three nights. For the secondary endpoints (apnea index as well as
hypopnea index) ANOVA with Bonferroni´s correction was applied. If ANOVA
revealed significant differences, a paired t-test with Bonferroni´s correction as post
hoc test was performed. Two-tailed tests were used and significance was recognized
at a value of p<0.05.
Results
Subject characteristics
From May to December 2003 a total of 655 patients visited our PM and ICD out-
patients clinic. Of these, 189 patients were excluded by the age criterion, and 215
patients because they had a single chamber device implanted. Of the remaining 251
patients, 130 gave written informed consent and fulfilled the remaining inclusion
criteria. Suspected sleep apnea in the ambulatory measurement (AHI>15/h with

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associated oxygen desaturations >4%) appeared in 28 cases. Of these, 8 patients
failed an inclusion criterion or withdrew consent after screening.
Finally twenty predominately male and overweight patients were included in the study
(Table 1). In ten patients PM and in ten ICD were implanted. Indications for
implantation were ventricular tachycardia/fibrillation in 9, atrioventricular block in 7,
sick sinus syndrome in 3 patients and prophylactic indication in 1 patient. An
underlying heart disease was apparent in 13 patients, namely coronary artery
disease in 10, dilated cardiomyopathy in two, and a Brugada syndrome in one
patient. Diuretics were prescribed to 10, beta-blockers to 9, and ACE inhibitors/AT1-
antagonists to 12 patients. Amiodarone was taken by 6, and digitalis by 2 patients.
Heart rate
In the pacing nights an effective stimulation with a significant increase in mean heart
rate was revealed by the 24-h Holter monitoring (Table 2). Minimum heart rate in the
non-pacing night was 50.0 ± 3.1 beats/min, with pacing 7 it was 54.5 ± 2.5 beats/min,
and with pacing 15 it was 60.6 ± 2.7 beats/min (p < 0.001). Maximum heart rate with
non-pacing was 66.2 ± 2.6 beats/min, increased to 72.7 ± 2.4 beats/min by pacing 7,
and to 75.8 ± 2.5 beats/min during pacing 15 (p <0.01). The percentage of atrial
pacing was 10.8 ± 6.1% during non-pacing, it increased during pacing 7 to 87.7 ±
3.2% and during pacing 15 to 94.6 ± 1.5% (p < 0.0001).
Respiratory events
The patients suffered from moderate sleep apnea. The predominant type was
obstructive (Table 1). The hypopneas were both central (central hypopnea index 8.2
± 1.6/h) and obstructive (obstructive hypopnea index 5.6 ± 1.1/h). Central apneas

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rarely occurred (central apnea index 1.8 ± 0.9/h), obstructive apneas were detected
more frequently (obstructive apnea index 5.2 ± 0.8/h). Pacing did not result in a
significant change of either the AHI (p ANOVA =0.07) or of the AI. There was a small
but significant decrease of the hypopnoea index (p<0.05 following Bonferroni´s
correction for multiple comparisons; figure 1 and table 2). The paired t-test (again
with Bonferroni´s correction) revealed a significant difference only between baseline
and pacing 15. When obstructive and central apneas as well as obstructive and
central hypopneas were analyzed separately, no significant effects of pacing were
seen.
Ventilation, sleep, biomarkers and blood pressure
As shown in table 2 pacing did not affect sleep, nocturnal ventilation or biomarkers.
Similarly the mean nocturnal blood pressure showed no significant difference.
Discussion
In this randomized, single-blinded crossover study, nocturnal atrial overdrive pacing
did not affect the primary endpoint apnea-hypopnea index nor did it improve oxygen
desaturation. Nevertheless, there was a significant but minor and thus therapeutically
not relevant reduction in the hypopnea index. Other novel findings were that higher
pacing rates had a stronger effect on hypopneas as compared to lower rates; and
ventilation as well as biomarkers were not affected by pacing.
Our results appear to differ from those in a previously published paper by Garrigue
and colleagues, who described a reduction of over 50 percent in apneas, hypopneas
and oxygen desaturations [11]. These discrepancies might be explained by the
differences in patient characteristics. As compared to the study by Garrigue and

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colleagues, our patients were slightly younger (63 versus 69 years), had a lower
ejection fraction (47 versus 54%), and more of them had predominant obstructive
sleep apnea (18 of 20 versus 7 of 15 patients) [11]. Body mass index as well as
underlying heart disease cannot be compared, as these data were not given in the
former study. It thus seems possible that the higher proportion of predominant
obstructive apneas in our population might account for the differences. Moreover, in
contrast to the Garrigue population, only ten of the twenty patients investigated in our
study had an indication for device implantation for bradycardia. Accordingly, our
patients had a higher mean nocturnal heart rate in the non-pacing night. As
mentioned below, a low nocturnal heart rate might contribute to central apnea.
Effects of pacing on heart rate and hemodynamics
Our knowledge of the effects of pacing dates back to 1871, when Bowditch described
the positive force-frequency relation in isolated hearts. Further work with animals and
humans clearly revealed improvements in left ventricular contractility, and diastolic
filling particularly following atrial pacing [24]. However, more recent work by
ourselves and others suggests a low or even negative force-frequency relation with
impaired left ventricular systolic and diastolic function and calcium-handling in older
subjects as well as in patients with heart failure [24-26]. These findings were
independent of the pacing site and can thus not be explained by pacing-induced
ventricular desynchronisation. Of note is that there are no human studies evaluating
the long-term effects of pacing-induced, slightly accelerated heart rates. It is known
however, that increasing periods of ventricular pacing cause increased risk of heart
failure, probably due to ventricular desynchronisation by right ventricular pacing [27].
In the study by Garrigue and colleagues the mean nocturnal heart rate was 51 beats/
minute as compared to 55 beats/ minute in our patient population. The acute

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hemodynamic effect of pacing depends largely on the basal heart rate. The same
absolute increase in heart rate with pacing will induce a higher increase in cardiac
output if the basal heart rate is low as compared to a higher basal heart rate [10].
Thus the difference in nocturnal basal heart rate might contribute to the more
pronounced effect of pacing in the study by Garrigue et al.. Indeed, pacemaker
implantation in six patients with pronounced bradycardia but normal ejection fraction
was effective in reducing mainly Cheyne-Stokes respiration in an uncontrolled case
series [28].
Effects on central and obstructive events, and ventilation
When explaining the effects of nocturnal overdrive pacing on sleep disordered
breathing, two key mechanisms linking overdrive pacing with ventilation were put
forward [11]. 1.) Pacing might counteract nocturnal hypervagotonia by influencing
cardiac vagal or sympathetic afferent neurons [11]. Indeed pulmonary vagal afferents
to the medullary respiratory control center stimulate ventilation. However, whether
cardiac afferents impact on ventilation is unknown [11]. 2.) Overdrive pacing might
improve cardiac function, and thus pulmonary congestion might be ameliorated in
patients with heart failure or bradycardia. In patients with heart failure, pulmonary
congestion causes activation of pulmonary J receptors, thereby inducing
hyperventilation with hypocapnia, thus destabilizing ventilatory control and favoring
central sleep apnea [29]. However, in our patients we were unable to prove the
hypothesis that overdrive pacing evokes a significant ventilatory response.
It was speculated that pacing - by impacting on cardiac function and thereby on the
ventilatory control loop as discussed above [30] - might affect predominantly central
hypopnea and apnea [9]. Recently published data supports this hypothesis [31]. In
our patients central apneas only rarely occurred. Thus the effects of pacing on these

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events could not be clarified. Central hypopneas were more common but their
reduction following pacing did not reach statistical significance. Further studies using
more elaborated tools to distinguish between obstructive and central events might
verify the concept that pacing reduces mainly central respiratory events. This is of
interest, since pacing is frequently applied in the aging population where central
respiratory events are common [27].
Sleep
Garrigue and colleagues reported no change in total sleep time, with a clear
reduction in the apnea-hypopnea index and accordingly in arousals due to disordered
breathing [11]. Sleep stages and overall arousals were not reported. In our study,
sleep stages as well as arousals were not affected by overdrive pacing, thus
confirming that pacing per se has no negative effects on sleep.
Neurohumoral activation
In the present study, overdrive pacing did not influence urinary norepinephrine
excretion or NT-proBNP concentration, suggesting that no major negative or positive
effects on sympathetic activation or ventricular filling occurred. This is reassuring
given the possibility of impaired ventricular function following tachycardia in heart
failure or aged myocardium as discussed above [25, 26]. In accord with previous
studies, NT-proBNP was increased in our patients as compared to 48 elderly healthy
subjects investigated previously in our department (median 42 (range 10-118) pg/ml).
Limitations
Limitations include, first, the single-blinded study design. In mitigation, this approach
was adopted so as to maximize patient safety. Also, even though the data were

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obtained in a single-blinded fashion, quantification of ventilatory, sleep and
biomarkers were made by two observers blinded to subject and intervention (LGCL,
DD). Second we used calibrated respiratory inductance plethysmography. This
method extrapolates semi-quantitative measures of chest wall movement to derive
quantitative approximate measures of minute ventilation. In previous studies by
others and by our group using the same method, changes in minute ventilation of
about 15% were detected [23, 32]. Thus we cannot rule out minor effects of pacing
on ventilation. More obtrusive methods, such as a tightly fitting face mask would have
been necessary. Furthermore besides blood pressure and heart rate no
hemodynamic data were obtained, thus the impact of pacing on hemodynamics has
not thoroughly been investigated.
Clinically, the lack of effect on the apnea-hypopnea index and oxygen desaturations
render atrial overdrive pacing inappropriate for treating sleep disordered breathing.
Nevertheless, with regard to pathophysiology, the heart rate-dependent reduction in
hypopneas sheds light on the complexity of the respiratory control mechanisms and
mandates further investigation.

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