Europace (2012) 14, 1038–1043 CLINICAL RESEARCH

doi:10.1093/europace/eur419 Syncope and Implantable Loop Recorders

Closed-loop cardiac pacing vs. conventional

dual-chamber pacing with specialized sensing
and pacing algorithms for syncope prevention
in patients with refractory vasovagal

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syncope: results of a long-term follow-up
Pietro Palmisano*, Maria Zaccaria, Giovanni Luzzi, Frida Nacci, Matteo Anaclerio,
and Stefano Favale
Department of Emergency and Organ Transplantation, Cardiology Unit, University of Bari, Pietro Palmisano, Piazza Giulio Cesare 11, 70124 Bari, Italy

Received 18 September 2011; accepted after revision 16 December 2011; online publish-ahead-of-print 13 January 2012

Aims Closed-loop stimulation (CLS) pacing has shown greater efficacy in preventing the recurrence of vasovagal syncope
(VVS) in patients with a cardioinhibitory response to head-up tilt test (HUTT) compared with conventional pacing.
Moreover, there is no conclusive evidence to support the superiority of CLS over the conventional algorithms for
syncope prevention. This study retrospectively evaluated the effectiveness of CLS pacing compared with dual-
chamber pacing with conventional specialized sensing and pacing algorithms for syncope prevention in the prevention
of syncope recurrence in patients with refractory VVS and a cardioinhibitory response to HUTT during a long-term
follow-up.
.....................................................................................................................................................................................
Methods Forty-one patients (44% male, 53 + 16 years) with recurrent, refractory VVS (26% with trauma) and a cardioinhibitory
and results response to HUTT who had undergone pacemaker implantation were included in the analysis. Twenty-five patients
received a dual-chamber CLS pacemaker (CLS group) and 16 patients received a dual-chamber pacemaker with conven-
tional algorithms for syncope prevention (conventional pacing group): 9 patients with Medtronic rate drop response
algorithm and 7 patients with Guidant-Boston Scientific sudden brady response algorithm. During the follow-up
(mean 4.4 + 3.0 years, interquartile range 2.2 –7.4 years) one patient (4%) in the CLS group and six (38%) in the con-
ventional pacing group had syncope recurrences (P ¼ 0.016). The Kaplan –Meier actuarial estimate of first recurrence of
syncope after 8 years was 4% in the CLS group and 40% in the conventional pacing group (P ¼ 0.010).
.....................................................................................................................................................................................
Conclusions The results of this retrospective analysis show that, in order to prevent a recurrence of VVS in patients with a car-
dioinhibitory response to HUTT, dual-chamber CLS pacing was more effective than dual-chamber pacing with con-
ventional algorithms for syncope prevention in preventing bradycardia-related syncope.
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Keywords Vasovagal syncope † Cardioinhibitory † Pacemaker † Closed-loop stimulation † Rate drop response † Head-up
tilt test

severe, cardioinhibitory VVS can result in serious physical injuries

Introduction and psychological impairment, including substantial limitations to
Vasovagal syncope (VVS) is a common disorder of the autonomic their social and working life.3 – 7
cardiovascular regulation.1,2 Significant bradycardia or prolonged Some initial, uncontrolled, follow-up studies8 – 11 as well as sub-
asystole and concomitant hypotension in patients with recurrent, sequent, randomized, controlled trials12 – 14 have suggested that,

* Corresponding author. Tel: +390805592765/+390805575720; fax: +390805478796, Email: dr.palmisano@libero.it

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com.
Closed-loop cardiac pacing vs. conventional dual-chamber pacing 1039

when VVS is refractory to conventional measures and/or pharma-
cological treatment, permanent pacing may induce clinical benefit
with a reduction in syncope recurrence.
Small and large controlled studies have shown that dual-
chamber pacing, incorporating algorithms that monitor the heart
for faster detection of a significant rate drop and respond by
pacing at a high rate, reduces syncope in patients with severe
forms of neurocardiogenic syncope8,12,14 – 17 and may be preferable
to the DDI pacing mode with rate hysteresis.18
Closed Loop Stimulationw (CLS) function, performed by INOS2,
PROTOS, CYLOS, and EVIA CLS dual-chamber pacemakers (by
Biotronik GmbH & Co., Germany), is a form of rate-adaptive
pacing which responds to myocardial contraction dynamics by
position had been performed on all patients. Exercise tests were per-
formed in 15% when clinically indicated. Cardiac catheterization with
coronary angiogram was performed in 2% to exclude coronary
disease and ischaemia-driven arrhythmias.
Tilt test protocol
Head-up tilt test had been performed according to current guide-
lines.22 The tests were performed between 9:00 and 11:00 a.m. in a
temperature-controlled room (238C) by an experienced nurse super-
vised by a physician. Electrocardiogram and systolic and diastolic blood
pressure were continuously monitored and recorded using a Task
Force Monitor (CNSystems, Graz, Austria). After 10 min of supine
rest, the patients were tilted to 708 using an electronically operating
tilt-table with a footboard. If VVS had not occurred after 20 min,

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measuring variations in right ventricular intracardiac impedance:19
during an incipient VVS it could increase paced heart rate and
avoid bradycardia, arterial hypotension, and syncope.20 The pro-
spective, controlled, randomized, single-blind, multicentric
INVASY study showed that the dual-chamber CLS pacing was
more effective than the DDI pacing [without the rate drop response
(RDR) function or rate hysteresis] in preventing a recurrence of VVS
in patients with a cardioinhibitory response to head up tilt test
(HUTT) during a mean follow-up period of 19 months.21
It is generally accepted that the natural history of VVS is variable
with long, recurrence free periods and that the clinical benefit of
CLS pacing in the long term is unknown. Moreover, there is no
conclusive evidence to support the superiority of CLS over con-
ventional algorithms for syncope prevention.
This study retrospectively evaluated the efficacy of DDD pacing
with conventional sensing and pacing algorithms for syncope pre-
vention in the prevention of syncope recurrence in patients with
refractory VVS and a cardioinhibitory response to HUTT during
a long-term follow-up.
Methods
300 mg of nitroglycerin was administered sublingually, and the test
was continued for a further 20 min.23 Fourteen patients were included
after a positive response to nitroglycerine. Based on the modified
Vasovagal Syncope International Study (VASIS) classification, syncope
was classified as type 1 (mixed), type 2A (cardioinhibition without
asystole), type 2B (cardioinhibition with asystole), or type 3
(vasodepressive).24
Pacemaker programming
Twenty-five patients had received a dual-chamber pacemaker with CLS
function (CLS group), 16 a dual-chamber conventional pacemaker pro-
grammed in DDD mode with the RDR function activated (convention-
al pacing group). Table 1 lists the pacemaker models implanted in the
two groups and the algorithms for syncope prevention in each model.
In the CLS group the device had been programmed in DDD– CLS
mode with a lower rate limit (LRL) of between 40 and 60 b.p.m. and
a maximum, sensor-driven pacing rate of between 100 and
120 b.p.m. The CLS algorithm initializes automatically. This pacing
system tracks the variations in intracardiac impedance measured
between the ventricular electrode tip and the pacemaker case during
the systolic phase of the cardiac cycle on a beat-to-beat basis.19
Changes in intracardiac impedance are closely correlated with both
right and left ventricular contractility.25 Inotropic regulation affects

Patient selection
The study group included 41 consecutive patients who had undergone Table 1 Pacemaker models implanted in the two
dual-chamber pacemaker implantation for recurrent, severe, cardioin- groups and the algorithms for syncope prevention in
hibitory VVS at our institute between January 2001 and October 2010.
each model
The clinical and pacemaker records and the test results for all patients
were reviewed. Pacemaker model Patients, Algorithm for
The inclusion criteria were a history of recurrent unpredictable n (%) syncope
syncope (≥2 in the year prior to pacemaker implantation) with signifi- prevention
cant limitation of social and working life, a positive type 2A or 2B ................................................................................
(according to the VASIS classification) cardioinhibitory response to CLS group 25 (61)
HUTT, refractoriness to conventional drug therapy, and/or tilt training. BIOTRONIK INOS2 6 (15) Biotronik CLS
In addition to a positive HUTT result, the diagnosis of VVS was based BIOTRONIK CYLOS 18 (44) Biotronik CLS
on a complete systematic cardiac and neurological evaluation to BIOTRONIK EVIA 1 (2) Biotronik CLS
exclude all other possible causes of syncope. Conventional pacing group 16 (39)
The exclusion criteria included second- or third-degree atrioven- MEDTRONIC KAPPA 700 7 (17) Medtronic RDR
tricular block, sinus node disease, carotid sinus hypersensitivity, GUIDANT INSIGNA I PLUS 2 (5) Guidant-Boston
tachyarrhythmia, an obstructive cardiac pathology, severe valvular Scientific SDR
heart disease, pulmonary hypertension, severe heart failure or severe GUIDANT INSIGNA I ULTRA 4 (10) Guidant-Boston
neurological or psychiatric disorders found during clinical assessment, Scientific SDR
and conventional investigation. BOSTON SCIENTIFIC ALTRUA 3 (7) Guidant-Boston
Before pacemaker implantation resting electrocardiography, con- Scientific SDR
ventional 24 h Holter electrocardiogram (ECG) monitoring, transthor-
acic echocardiography, and carotid sinus massage in the supine
1040
myocardial contractility, which consequently reflects information
about the haemodynamic state and requirements.26 Based on that re-
lationship, CLS transfers the detected changes in myocardial contrac-
tion dynamics into individual pacing rates. In the very first days
following programme implementation, CLS is adjusted to each individ-
ual patient: a reference curve is created and continuously updated with
beat-to-beat impedance measurements. Starting from the programmed
LRL, the system is designed to change rate dynamics within the full
range between the lower and the upper rates.
In the conventional pacing group the device had been programmed
in DDDR mode with an LRL of between 40 and 60 b.p.m. and a
maximum sensor-driven pacing rate of between 100 and 120 b.p.m.
In this group, nine patients had received a pacemaker implemented
with Medtronic RDR algorithm (Medtronic Inc., Minneapolis, MN,
USA) and seven patients received a pacemaker with Guidant-Boston
Scientific sudden brady response (SBR) algorithm (Boston Scientific
Corp., Place Natick, MA, USA).
The operation of these algorithms is similar. The device monitors
the heart for rate drops to detect any significant changes, it then inter-
venes when the ventricular rate drops by a specified number of beats
per minute to below a specified heart rate within a specified period of
time or when the atrium is paced at the LRL for the number of con-
secutive beats. When a rate drop is detected the device paces the
heart at a programmable rate for a programmable time interval.
When this is complete, the device gradually reduces the pacing rate
until the sinus rate or LRL or sensor-indicated rate is reached. The al-
gorithm parameters had been programmed in each patient according
to the rate behaviour during HUTT,27 the underlying cardiac disease,
and the constitution of the patient.
Follow-up
All patients were followed up until March 2011. Follow-up consisted of
twice-yearly pacemaker interrogation, outpatient clinic visits, and tele-
phone contact. At the time of implantation and follow-up, no patients
in either group received medication for syncope. Other drug treat-
ments in progress were continued in both groups without significant
dosage modification. During follow-up no significant changes in pace-
maker programming were performed.
Definitions
Syncope was defined as a transient loss of consciousness characterized
by rapid onset, short duration, and spontaneous complete recovery.22
Pre-syncope was defined as any of the various premonitory signs
and symptoms of imminent syncope (e.g. severe weakness or light
headedness).28
Data collection
The complete record of personal details, symptoms, and test results
before implantation, implantation details, and symptoms after implant-
ation were obtained for all patients from a review of the hospital and
outpatient notes and pacemaker records and supplemented, where ne-
cessary, by additional patient interview.
Statistical analysis
Continuous variables were expressed as mean values + standard devi-
ation and frequencies were expressed as the number and percentage
of patients. Categorical variables were compared between groups
using the x2 or Fisher’s exact test as appropriate. Other
between-group comparisons were made using the Student’s t-test.
The event and event-free curves were based on Kaplan –Meier
P. Palmisano et al.
analyses, stratified by study group, and compared using the log-rank
test. P values of ,0.05 were considered statistically significant.
The data were analysed using the statistical software package Statis-
tica version 6.1 (StatSoft Inc., Tulsa, Oklahoma).
Results
Patient characteristics
Forty-one patients who had been implanted at our centre between
January 2001 and October 2010 were included in the analysis.
Twenty five were in the CLS group and 16 in the conventional
pacing group. The baseline characteristics of patients are summar-
ized in Table 2.
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Fourteen patients (34%) had significant anomalies at resting elec-
trocardiography: sinus bradycardia (eight patients), nonspecific
ST-T wave abnormalities (four patients), and ECG signs of left ven-
tricular hypertrophy (two patients). Four patients (10%) showed
anomalies at transthoracic echocardiography, the most frequent
(three patients, 75%) was a mild left ventricular systolic dysfunc-
tion. Of the patients who had undergone exercise tests or coron-
ary angiogram, those with significant coronary disease and/or
ischaemia-driven arrhythmias were excluded. Twenty-two of the
25 patients in the CLS group (88%) and 12 of the 16 patients in
the conventional pacing group (75%) (P ¼ 0.281) had a severe car-
dioinhibitory response to HUTT, causing a prolonged asystolic
pause .3 s (VASIS 2B). The clinical characteristics of the two
groups did not differ significantly.
Follow-up
The mean follow-up was 4.4 + 3.0 years (interquartile range 2.2 –
7.4 years) and was similar in both groups (4.3 + 3.2 years in the
CLS group and 4.5 + 2.9 years in the conventional pacing group;
P ¼ 0.819).
During the follow-up period, 1 of the 25 patients (4%) in the
CLS group experienced syncopal recurrence only 22 days after
pacemaker implantation. The patient was a 36-year-old woman
with a history of numerous syncopal episodes occurring in the
year preceding implantation. She had already had a cardioinhibitory
response to HUTT, with an asystolic pause of 16 s, performed
before implantation. After implantation the patient continued to
have frequent syncopal episodes (three to four per month) none
with trauma. Closed-loop stimulation algorithm activation was
not found in any of the repeated device interrogations performed
with the manufacturer’s technical support. A later, neuropsychi-
atric evaluation diagnosed a conversion disorder. The patient
began psychological and antidepressant drug therapy with a conse-
quently significant reduction in syncopal episodes.
In the conventional pacing group, 6 of 16 patients (44%) experi-
enced syncopal recurrence after a mean period of 11 months
(range 5– 47 months). There were no cases of physical injury
due to the syncopal recurrences. The difference in the syncopal re-
currence rate between the two groups was significant (P ¼ 0.016).
The Kaplan–Meier actuarial estimates of first recurrence of
syncope after 1, 3, 5, and 8 years were 4, 4, 4, and 4% in the
CLS group and 25, 31, 40, and 40% in the control group, respect-
ively (Figure 1). In the conventional pacing group, no significant
Closed-loop cardiac pacing vs. conventional dual-chamber pacing 1041

Table 2 Baseline clinical characteristics of the study population

Characteristics All patients CLS group Conventional pacing P

(n 5 41) (n 5 25) group (n 5 16)
...............................................................................................................................................................................
Age in years, mean + standard deviation 53 + 16 54 + 15 52 + 18 0.649
Male, n (%) 18 (44) 9 (36) 9 (56) 0.202
Syncope episodes in lifetimes, n, median (interquartile range) 3 (2– 12) 6 (3–12) 2 (2 –7) 0.142
Syncope episodes in last 1 year, N, median (interquartile range) 2 (2– 5) 3 (2–5) 2 (2 –3) 0.373
Duration of symptoms, year, median (interquartile range) 5 (2– 20) 5 (3–20) 3 (1 –17) 0.143
Pre-syncope, n (%) 15 (37) 6 (24) 7 (44) 0.185
Pre-syncope episodes in last 1 year, n, median (interquartile range) 0 (0– 2) 0 (0–1) 1 (0 –6) 0.119
Trauma secondary to syncope, n (%) 11 (26) 7 (28) 4 (25) 0.833

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Previous drug treatment, n (%) 4 (10) 2 (8) 2 (13) 0.636
Previous tilt training, n (%) 5 (12) 3 (8) 2 (13) 0.962
Associated cardiovascular disorders, n (%) 23 (56) 11 (44) 12 (75) 0.051
Hypertension on therapy, n 18 7 11
Atherosclerotic, n 3 3 0
Valvular, n 2 1 1
ECG abnormalities, n (%) 14 (34) 9 (36) 5 (21) 0.754
Echocardiographic abnormalities, n (%) 4 (10) 3 (12) 1 (6) 0.545
Response to baseline tilt testing
Type 2A, n (%) 7 (17) 3 (12) 4 (25) 0.281
Type 2B, n (%) 34 (83) 22 (88) 12 (75) 0.281
Asystole, s, mean + standard deviation, median, range 15 + 8, 14, 5 –35 14 + 7, 15, 5– 35 12 + 4, 10, 8–18 0.338
Nitroglycerin provocation, n (%) 14 (34) 9 (36) 5 (31) 0.754

Figure 1 Kaplan– Meier estimates of probability of remaining
free of syncopal recurrences in 25 patients in closed-loop stimu-
lation group (blue line) and 16 patients in control group (red
line).
Figure 2 Kaplan –Meier estimates of probability of remaining
free of syncopal recurrences in seven patients who received a
pacemaker with Medtronic rate drop response algorithm (blue
line) and nine who received a pacemaker with Guidant-Boston
Scientific sudden brady response algorithm (red line).

difference was found in syncopal recurrence rate in patients who During follow-up, 3 of 34 patients without syncopal recurrences
had received a pacemaker with Medtronic RDR algorithm com- (7%) reported at least one episode of pre-syncopal symptoms [2 of
pared with those who had received a pacemaker with Guidant- 24 patients (8%) in the CLS group and 1 of 10 patients (10%) in the
Boston Scientific SBR algorithm (Figure 2). control group (P ¼ 0.876)] without any impairment to daily life.
1042
Discussion
The results of this retrospective analysis show that, in order to
prevent a recurrence of VVS in patients with a cardioinhibitory re-
sponse to HUTT, dual-chamber CLS pacing was more effective
than dual-chamber pacing with conventional algorithms in prevent-
ing bradycardia-related syncope. The benefit was maintained for up
to 8 years. In the group of patients treated with dual-chamber CLS
pacing, only one case of syncopal recurrences was reported.
However, according to the patient clinical history, these were
probably related to a psychiatric disorder.
Vasovagal syncope is an abnormal cardiovascular reflex charac-
terized by an inappropriate reduction in heart rate and systemic
hypotension caused by arteriolar vasodilatation.
In patients with severe, recurrent VVS and a prevalent cardioin-
hibitory response to HUTT, permanent pacing that prevents the
important bradycardia and/or asystole induces clinical benefit
with a reduction in syncope recurrence.8 – 14 However, several
studies have shown that VVS may not be completely prevented
by conventional cardiac pacing. These suboptimal results are
probably justified by the inability of conventional electrical
cardiac stimulation to counteract the vasodepressor component
of the vasovagal reflex present in almost all subjects during
syncopal episodes and usually precedes cardioinhibition and
bradycardia.29
Closed-loop stimulation is an algorithm which provides the
pacing rate modulation that integrates information for heart rate
optimization from myocardial contraction dynamics by measuring
right ventricular intracardiac impedance. After initialization of the
CLS pacing mode, the pacemaker system not only initiates the
rate modulating function automatically, but also permanently com-
pensates for long-term drifts of the input signal. In the first stage of
VVS, CLS detects increased myocardial contractility by measuring
the intracardiac impedance30 – 32 and activates a high-rate atrioven-
tricular sequential pacing that may anticipate withdrawal of sympa-
thetic tone and counterbalance the increase in vagal tone, thus
preventing arterial hypotension, bradycardia, and possibly syncope.
According to this rationale, previous studies have used CLS
pacing in patients with cardioinhibitory VVS to prevent syncope
during HUTT and daily life, with good results.32 Moreover,
INVASY, a prospective, controlled, randomized, single-blind, multi-
centre study has shown that CLS pacing was more effective than
DDI pacing in preventing VVS recurrence in patients with a cardi-
oinhibitory response to HUTT during a mean follow-up of 19
months.21 In this study no patient treated with CLS pacing experi-
enced syncopal recurrence.
More dedicated algorithms associated with pacing for a better
prevention of VVS have been developed, such as the Medtronic
RDR algorithm and the Guidant-Boston Scientific SBR algorithm
in the control group of this study. These algorithms have been
designed for the early detection of an insidious drop in heart
rate and short-lasting intervention pacing at a high rate. Several
studies have shown that, in patients with severe VVS, these algo-
rithms are more effective than conservative treatments in the re-
duction of syncopal episodes.8,12,14 – 17 Moreover, in a small
study, DDD pacing with RDR function was more effective than
DDI pacing with rate hysteresis in cardioinhibitory VVS.18 These
P. Palmisano et al.
algorithms were not compared with CLS pacing in any other pre-
vious experiences.
This study compared the efficacy of CLS pacing with dual-
chamber pacing with conventional algorithms in preventing
bradycardia-related syncope in a selected population of patients
with severe, recurrent VVS. Closed-loop stimulation pacing main-
tained over a long-term follow-up was shown to be significantly
superior.
Our results do not provide a definite explanation, we may only
suggest that the interactions between electrical cardiac pacing and
the neuroendocrine mechanisms of the vasovagal reflex may
explain the better results of the CLS pacing reported from our
experience.
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In pacemakers with conventional algorithms for syncope preven-
tion, the high-rate pacing therapy is triggered by a sudden drop in
heart rate. Therefore, the pacing may be delivered late in the affer-
ent phase vasovagal reflex, when an excessive vagal activity is trig-
gered by the signals from the ventricular mechanoreceptors. This
delay may lead to hypotension becoming prominent and pacing
may be inadequate to prevent syncope.
On the other hand, by detecting the variations in myocardial
contractility, CLS may react quickly in the early phase of vasovagal
reflex when the sudden reduction of central blood volume induces
a compensatory increase in the sympathetic discharge, with an in-
crease in the inotropic state of the myocardium. This timely inter-
vention may suppress the resultant bradycardia and
counterbalance the hypotension of decreased venous return by
maintaining cardiac output.
This analysis confirms the results of the INVASY study which
reported an extremely low, or no syncope episodes, in the
CLS-treated patients.
Study limitations
This is an observational, retrospective study. The patients included
in the analysis were implanted over a period of 10 years, and there-
fore they received different pacemaker models with different
technological features. Moreover, despite the long-term mean
follow-up of the entire study population, the follow-up duration
was very heterogeneous (range 0.4 –10.2 years). On the basis of
these considerations, the results of this study should be inter-
preted with caution as confounding factors may not be entirely
excluded.
The total population evaluated in the study was relatively low as
pacemaker implantation is rarely indicated for patients evaluated
for VVS at our centre.
Patients in the conventional pacing group received pacemakers
with two different algorithms. In this study no significant difference
was found between the two algorithms. Due to the small number
of cases evaluated in these two subgroups, this evidence is not
conclusive. Moreover, the outcome measurement used in the
study, namely the time to first recurrence of syncope, was not suf-
ficiently sensitive in detecting differences in efficacy between these
two subgroups. It is possible that a different outcome measure-
ment, i.e. the total burden of syncope, would have been better
able to detect the efficacy of the two algorithms evaluated.
Vasovagal syncope and pacemaker implantation can have im-
portant psychological consequences. Unfortunately, this study did
Closed-loop cardiac pacing vs. conventional dual-chamber pacing
not assess the impact of the two pacing systems on the perceived
quality of life.
Conclusions
The data of this retrospective experience suggest that dual-
chamber CLS pacing is more effective than DDD pacing with con-
ventional specialized sensing and pacing algorithms for syncope
prevention in preventing syncope recurrence in patients with re-
fractory VVS and a cardioinhibitory response to HUTT, and that
this benefit may be long term.
Further prospective, large population studies are needed to
confirm these results. If this evidence is confirmed, CLS pacing
may be considered as the optimal treatment for patients with re-
current, severe VVS, refractory to conventional measures, and/or
pharmacological treatment.
Conflict of interest: none declared.
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