Download The DDDR closed loop stimulation for the prevention of the

Europace (2003) 5, 153–162
doi:10.1053/eupc.2002.0292
The DDDR closed loop stimulation for the prevention
of vasovagal syncope: results from the INVASY
prospective feasibility registry
E. Occhetta, M. Bortnik and C. Vassanelli, on behalf of the ‘INVASY Italian
feasibility Study Group’
Divisione Clinicizzata di Cardiologia, Facolta’ di Medicina e Chirurgia di Novara, Universita’ degli Studi del
Piemonte Orientale, Novara, Italy
Background The contraction dynamics of the ventricular
myocardium are affected before and during vasovagal fainting suggesting that the Closed Loop Stimulation (CLS)
pacemaker could be useful for the treatment of these
patients. CLS is a new concept of heart rate modulation in
cardiac pacing. The pacemaker INOS2 CLS (Biotronik,
Germany) derives its information for heart rate optimization from myocardial contraction dynamics, by measuring
right ventricular intracardiac impedance. The pacemaker
becomes an integral part of the circulatory regulation and,
therefore, reacts appropriately to different cardiovascular
demands.
Methods In a prospective registry, 34 patients with a
history of recurrent vasovagal syncopal events were
implanted with INOS2 DDDR CLS pacemakers. The aim
of the study was to evaluate both long term clinical
outcome, including the first recurrence of syncope, with
DDDR-CLS pacing and acute precipitation of vasovagal
fainting with DDDR-CLS mode compared with DDD
during head up tilt testing.
Introduction
Closed loop control is a well-established physiological
principle that allows any system to react to external
influences in order to restore the equilibrium. The
human cardiovascular system is a highly specialized
Manuscript submitted 23 May 2002, and accepted after revision
8 December 2002.
Correspondence: Dr Occhetta Eraldo, Divisione Clinicizzata di
Cardiologia, Azienda Ospedaliera ‘Maggiore della Carita’ ’, Corso
Mazzini 18, 28100 Novara, Italy. Tel.: +39 0321 3733413; Fax:
+39 0321 3733407; E-mail: [email protected],
[email protected]
Results During a follow up period of 12–50 months, 30
patients experienced no further syncopal events in daily life;
1 patient had no syncope but night palpitations, which were
eliminated by pacemaker reprogramming; 2 patients had
presyncopal episodes but not syncopes; 3 syncopal recurrences occurred in one patient in chronic atrial fibrillation,
possibly not an ideal candidate for implantation.
Conclusions Further studies for detailed understanding
of the preventive mechanism of DDDR-CLS pacing in
vasovagal syncope are warranted. A randomized multicentre prospective new study (INotropy controlled pacing in
VAsovagal SYncope: INVASY) is now in progress to
confirm the beneficial effect of DDDR-CLS pacing in a
larger group of patients with recurrent vasovagal syncope.
(Europace 2003; 5: 153–162)
2003 The European Society of Cardiology. Published by
Elsevier Science Ltd. All rights reserved.
Key Words: Closed loop stimulation,
vasovagal syncope, head up tilt test.
pacemaker,
closed loop control system, which reacts to preserve an
adequate perfusion pressure to essential organs, according to their needs.
The ideal method to obtain a physiological pacemaker
system would be the integration of the pacing device into
the natural cardio-circulatory system. This concept has
been realized in the Closed Loop Stimulation (CLS)
system, which converts information from the circulation
applied to the right ventricle into a concordant heart
rate[1]. Even under pathophysiological conditions, the
dynamics of myocardial contraction still reflect the
information coming from the circulation[2]. Inotropic
regulation affects myocardial contractility, which consequently reflects information about the haemodynamic
1099–5129/03/000153+10 $35.00/0 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.
154
E. Occhetta et al.
Figure 1 The INOS2 CLS pacemaker, as an integral part of the circulatory
regulation, can react appropriately on various kinds of cardiovascular
demands. HR: Heart rate. SV: Stroke volume. MABP: Mean arterial blood
pressure. CO: Cardiac output, centers=centres.
state and requirements[3]. Based on that relationship, the
INOS2 CLS pacemaker (BIOTRONIK, Germany)
detects changes in myocardial contraction dynamics
through intracardiac impedance measurement and
transfers them into individual pacing rates[4] (Fig. 1).
After initialization of the CLS pacing mode,
the pacemaker system not only initiates the rate modulating function automatically, but also compensates
permanently for long-term drifts of the input signal.
Several studies have shown that vasovagal syncope
may be incompletely prevented by standard pacemaker
therapy[5,6]. More sophisticated pacemaker algorithms
aim to detect an initial fall in the heart rate, which marks
the onset of cardioinhibition, to prevent vasovagal syncope[7]. Previous investigations in patients suffering from
severe syncope have shown that changes in contraction
dynamics of the ventricular myocardium usually precede
any fall in heart rate[8]; even if this observation has not
been confirmed by other authors[9,10]. The INOS2 CLS
pacemakers can use this information for prevention of
syncope[11].
The aim of this study was to investigate whether
DDDR-CLS stimulation by means of the INOS2 CLS
pacemaker provides pacing rates adequate for the
patient’s circulatory demand and reacts with a dominant
pacing rate increase, especially in incipient vasovagal
fainting, and to investigate if this heart rate increase
could prevent vasovagal syncope. Such an effect should
be therapeutic and result in a markedly lower incidence
of syncope during head-up tilt test and daily life.
Europace, Vol. 5, April 2003
Methods
Material
In the INOS2 CLS pacemaker (Biotronik, Germany)
load-dependent changes in myocardial contractility
reflect variations in the unipolar intracardiac impedance,
measured between the ventricular electrode tip
and the pacemaker case. This principle of measurement
of intracardiac impedance has been previously
described[1].
During myocardial contraction, the proportions of
blood and myocardium vary in the close vicinity
(]1 cm3) of the electrode tip. Since the specific resistance of blood differs significantly from that of the
myocardium, the dynamics of the myocardial contraction can be well detected in a time-course impedance
curve. Therefore, by monitoring the unipolar intracardiac impedance, changes in myocardial contractility can
reliably be measured. Previous studies have shown that
the unipolar intracardiac impedance values obtained by
INOS2 CLS pacemaker were closely correlated with
myocardial contractility estimated by dP/dt in right and
left ventricles[12,13].
Due to the automatic initialization feature of INOS2
CLS, programming is reduced to a single step. The
setting of the lower and the upper rates allows restriction
of the pacing rate range according to the underlying
cardiac disease and the constitution of the patient.
DDDR-CLS pacing in vasovagal syncope
In the very first days following programme implementation, CLS adjusts itself to each individual patient: a
reference curve is created and continuously updated with
beat to beat impedance measurements. Starting from the
programmed lower pacing rate, the system is designed to
change rate dynamics within the full range between the
lower and the upper rate.
Patient’s selection
In 14 Italian centres participating in the INotropy
controlled pacing in VAsovagal SYncope (INVASY)
Italian feasibility study group (see Appendix), 34
patients (26 men; 8 women) of a mean age of 6510
years (range 33–80 years) were studied: all of them had a
severe syncopal history (range 3–20, median of 6 episodes). In all patients an INOS2 CLS pacemaker was
implanted and programmed in automatic closed loop,
contractility dependent, stimulation.
Patients were included if they met the following
criteria: (1) history of at least two vasovagal syncopal
episodes per year in the last 1–5 years; (2) documentation of one or more positive baseline Head Up Tilt
Tests (HUTTs), with cardioinhibitory or mixed (cardioinhibitory and vasodepressive) response; (3) absence of
current administration of drugs known to cause orthostatic hypotension; (4) absence of abnormal response to
right and left carotid sinus massage; (5) exclusion of any
other causes of cardiac, metabolic and or other cause of
syncope.
After implantation, all patients were discharged with a
permanent DDDR-CLS mode programmed on.
Clinical follow up was arranged every six months to
assess the incidence of syncopal recurrences during daily
life and the consequent psychological well-being.
In 12 patients HUTT was performed at one month
follow-up; 6 patients repeated HUTT at 6 months of
follow-up; moreover, 5 patients (in one hospital) performed 2 HUTTs in a blindly randomized pacing
modes: DDD versus DDDR-CLS pacing with 60 bpm
programmed lower rate.
Protocol for head-up tilt test (HUTT) and
measurements
For the HUTT, each patient was positioned in clinostatic position for 10 min; then upright at 70 for a
maximum of 45 min on a tilt table provided with a
footboard for weight bearing.
The electrocardiogram was continuously monitored: a
strip was recorded every minute to check heart rate and
atrial and/or ventricular stimulation. Blood pressure was
monitored every 1–2 min, using a cuff tube automatic
blood pressure instrument (78354A, Hewlett–Packard).
In case of a syncopal event the test was stopped by
immediate lowering of the patient.
In 5 patients myocardial contraction changes were
recorded via telemetry of intracardiac impedance
155
from the pacemaker connected to an external device
(Unilyzer, Biotronik) during HUTT in DDD mode.
Results
The pre-implant clinical data, the results of HUTTs
performed before, 3–5 weeks and 6 months after pacemaker implant, the patients subjective health conditions
at 1–6 months and at 1, 2, 3 and 4 years are shown in
Table 1.
Twenty-seven patients had one positive HUTT before
the pacemaker implant; 7 patients had two or three
positive HUTTs before enrolment.
In five patients (nos 1, 2, 3, 6, 11) HUTT was
repeated, after pacemaker implant, both during DDD
and DDDR-CLS mode. In one of these patients (no. 1)
all HUTTs after pacemaker implant were negative; in
additional 2 patients HUTT was positive during DDD
pacing (once in 1 patient: no. 3, twice in the other: no. 2)
and negative during DDDR-CLS; two patients (nos 6,
11) developed syncopes during all HUTTs tests in both
pacing modes, DDD and DDDR-CLS. Same results
were observed at 6 months of follow-up (in patients nos
1, 2, 3, 6).
Figure 2 shows a sample of the measurements
detected by the external device (Unilyzer) in a syncopal
patient with the pacemaker programmed in DDD
60 bpm. At the beginning of the HUTT, when the
patient is raised, the contractility increases and persists
on an elevated level for several minutes. Immediately
before the syncope, the contractility increases and,
simultaneously to the lowering of the patient to supine
position, it returns to initial level again. Consequently,
the arterial blood pressure dropped markedly during the
syncopal event, since the spontaneous sinus rate also
decreased slightly (Fig. 3). The same patient showed
increased pacing rates up to 90–120 bpm during the tilt
test in DDDR-CLS pacing mode. The immediate reaction of the closed loop system to contractility changes
may have blocked the hypotensive reflex and the
syncope (Fig. 4).
In 7 patients (nos 13, 14, 19, 21, 25, 30, 31) HUTT was
performed only during DDDR-CLS pacing at one
month of follow-up; 6 of them (nos 13, 14, 19, 21, 25, 31)
developed syncope during the test. In two other patients
(nos 9, 24) HUTT was repeated after 6 months of follow
up, both positive (one in DDDR-CLS: no. 9; the other
one in DDD: no. 24).
During follow-up (range from 12 to 50 months),
30 patients of the study reported no more vasovagal
spontaneous syncope (Table 1).
Two patients reported presyncopal episodes (patient
no. 9 at 6 and 24 months; patient no. 13 at 12 months)
but no true syncopal events.
One patient (no. 14) reported night palpitations but
not syncopal episodes until 12 months of follow up;
palpitations were caused by an exaggerated rate responsive pacing (confirmed by Holter monitoring) and were
eliminated by pacemaker reprogramming.
Europace, Vol. 5, April 2003
156
Clinical features of the patient population
Pt
[Age, sex]
(Imp. date)
1
B. P. [78, m] (11/97)
Pre-imp.
VVS
episodes
Pre-Imp.
HUTT
2
C.M. [77, f] (03/98)
3
G. O. [80, f] (04/98)
1995: 3
1996: 3; 1997: 1
1997: 2
1998: 2
2/yr in last 5 yr
2 pos.
4
S.MA. [63, f] (07/98)
3/yr
1 pos.
5
C.M. [77, m] (10/98)
3/yr
1 pos.
6
D.G. [63, m] (11/98)
3 in last yr
3 pos.
7
A.M. [68, m] (01/99)
2/yr
1 pos.
8
P.G. [70, m] (01/99)
1998: 3
1 pos.
9
C.D. [33, m] (03/99)
6/yr
1 pos.
10
N.L. [45, m] (03/99)
1 pos.
11
P.F. [73, m] (05/99)
1998: 2
1999: 1
2/yr 3 in last yr
2 pos.
2 pos.
2 pos.
1 month
follow-up
HUTT
DDD: 2 neg.
CLS: 1 neg.
DDD: 2 pos.
CLS: 1 neg.
DDD: 1 n; 1 p
CLS: 1 neg.
DDD: 1 pos.
CLS: 1 pos.
DDD: 1 pos.
CLS: 1 pos.
12
13
R.E. [78, f] (05/99)*
A.G. [75, m] (06/99)
3/yr, atrial fibrillation
3/yr
1 pos.
1 pos.
CLS+drug: 1 pos.
14
F.S. [68, m] (06/99)
10 in the last 6 yr
1 pos.
CLS+drug: 1 pos.
15
R.C. [72, m] (06/99)
4/yr
1 pos.
16
V.M. [72, f] (06/99)*
2/yr
1 pos.
6 months
follow-up
Clinical
outcome
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
VVS
VVS
VVS
HUTT
Clinical
outcome
DDD: 1 neg.
CLS: 1 neg.
DDD: 1 pos.
CLS: 1 neg.
DDD: 1 neg.
CLS: 1 neg.
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Episode of
pre-syncope
Good,
No more VVS
Good,
No more VVS
1 Episode
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
VVS
VVS
VVS
DDD: 1 pos.
CLS: 1 pos.
VVS
VVS
CLS: 1 pos
VVS
VVS
VVS
Night Palpitation
Good,
No more VVS
Good,
No more VVS
12 months
follow-up
24 months
follow-up
36 months
follow-up
48 months
follow-up
Clinical outcome
Clinical outcome
Clinical outcome
Clinical outcome
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
1 Episode
Episode of
pre-syncope
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Episode of
pre-syncope
Good,
No more VVS
Good,
No more VVS
1 Episode
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more VVS
Good,
No more VVS
Good,
No more VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
E. Occhetta et al.
Europace, Vol. 5, April 2003
Table 1
Table 1
Continued
Pt
[Age, sex]
(Imp. date)
18
M.A. [77, m] (07/99)
Pre-imp.
VVS
episodes
4/yr
Pre-Imp.
HUTT
1 month
follow-up
HUTT
1 pos.
C.E. [53, m] (08/99)
2/yr
1 pos.
CLS 1 pos.
20
L.B. [78, m] (09/99)
2/yr
1 pos.
21
D.G. [73, m] (10/99)
20 in the last 3 yr
1 pos.
22
B.F. [50, m] (10/99)*
1 pos.
23
L.M. [57, m] (11/99)
1999: 3
5 in last 2 yr
2/yr
24
F.G. [51, m] (11/99)
1 pos.
25
S.G. [53, m] (12/99)
1/yr
2 in last 4 yr
1999: 8
26
L.R. [70, m] (12/99)*
1/yr
1 pos.
27
C.N. [70, m] (12/99)*
2 last yr
1 pos.
28
B.D. [67, f] (02/00)
>3 last yr
2 pos
29
B.G. [69, m] (03/00)
>3 last yr
1 pos.
30
C.Z. [58, f] (05/00)
1/yr last 3 year
1 pos.
CLS: 1 neg.
31
G.P. [73, m] (06/00)
>3 last yr
1 pos.
CLS: 1 pos.
32
PR [62, m] (06/00)
>2 last yr
1 pos.
CLS+drug: 1 Pos.
1 pos.
2 pos.
M.R. [60, f] (07/00)*
>10 last yr
1 pos.
34
A.C. [61, m] (10/00)*
>10 1993, VVI PM;
6 last yr
1 pos.
HUTT
Good,
No more VVS
Good,
No more VVS
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
VVS
VVS
VVS
DDD: 1 pos.
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
Clinical
outcome
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
24 months
follow-up
36 months
follow-up
48 months
follow-up
Clinical outcome
Clinical outcome
Clinical outcome
Clinical outcome
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Good,
No more
Notes: Implant date: month/year; VVS: Vasovagal Syncope; HUTT: Head Up Tilt Test; *previous PM implanted; pos: positive.
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
VVS
157
Europace, Vol. 5, April 2003
33
CLS: 1 pos
Clinical
outcome
12 months
follow-up
DDDR-CLS pacing in vasovagal syncope
19
6 months
follow-up
158
E. Occhetta et al.
Figure 2 During the HUTT in DDD mode, intracardiac impedance waveforms were
collected by an external device (Unilyzer, BIOTRONIK) through pacemaker telemetry
transmission. Figure shows the measurements in a syncopal patient: at the beginning of the tilt
when the patient is raised, the contractility increases and persists on an elevated level for
several minutes. Shortly before the syncope occurs, the contractility increases and, simultaneously with the lowering of the patient to supine position, it returns to the initial level.
Figure 3 As shown in the figure, the arterial blood pressure fell markedly during the
syncopal event and the spontaneous sinus rate also decreased slightly. BP=blood
pressure, syst=systolic, diast=diastolic.
As shown in Table 1, 7 patients had already been
implanted with a conventional pacemaker (DDD in six
and VVI in one). Frequent recurrences of vasovagal
fainting, persuaded the physician to upgrade the imEuropace, Vol. 5, April 2003
planted system in DDDR-CLS. In six of the patients of
the registry, this measure allowed the total prevention of
vasovagal syncope recurrences, confirming the superiority of the DDDR-CLS pacing mode compared with
DDDR-CLS pacing in vasovagal syncope
159
Figure 4 Trend of arterial blood pressure and heart rate during negative HUTT in
DDD-CLS pacing. In the same patient an increased pacing rate up to 90–120 bpm
inhibited the hypotensive reflex and the syncope.
traditional DDD pacing. Only one patient (no. 12)
complained of syncopal recurrences (at 6, 12 and 24
months of follow up); the patient was a 78-year-old
woman in chronic atrial fibrillation; the role of cardiac
pacing in patients with vasovagal syncope and chronic
atrial fibrillation is still unclear and perhaps the
pacemaker implant was not appropriate.
Discussion
The results of our study show that DDDR-CLS pacing
is safe and seem to confirm that it is also effective in
preventing vasovagal syncope in patients with recurrent
episodes.
The inappropriate reduction of heart rate and systemic hypotension caused by arteriolar vasodilatation is
called ‘vasovagal’ (or ‘neurocardiogenic’ or ‘neurally
mediated’) syncope[14].
This phenomenon is associated with an abnormal
cardiovascular reflex, but the underlying pathophysiological mechanisms are largely unknown[15].
Bradycardia is thought to result from sudden increase
of efferent vagal activity and hypotension from sudden
decrease or cessation of the previously increased
sympathetic outflow.
Two different types of vasovagal syncope, central and
peripheral types, have been described[16].
In the central type the medullary cerebral centres
are directly affected by efferent hypothalamic
signals triggered by emotional stress, pain, fear, etc.,
which, increasing vagal activity, cause hypotension,
bradycardia and lypotimia.
On the other hand, the peripheral type of vasovagal
reaction is consequent upon a sudden reduction of
central blood volume: the central hypovolaemia may be
due to impaired venoconstriction and by ineffective tone
of splenic and other resistance vessels[17,18]. That induces
a compensatory increase in the sympathetic discharge,
an increase in the heart rate and in the inotropic state of
the myocardium[19,20]. The more vigorous contraction of
an insufficiently filled ventricle stimulates ventricular
mechanoreceptors[21]. The afferent signals of these receptors, transmitted through the vagus nerve, reach the
circulatory centres and trigger an increase in efferent
vagal activity and a withdrawal of efferent sympathetic
discharge[22].
Thus, in the peripheral vasovagal syncope, the triggering signals originate from myocardium and result in
severe hypotension and bradycardia[23]. This neurocardiac reflex, with its afferent and efferent limbs, is
called the Bezold–Jarisch reflex[24]: this is reproduced by
HUTT[25,26].
If the baseline HUTT is negative, the sensitivity of the
test can be improved with drugs (isoprenaline infusion
or sublingual nitroglycerin) to enhance the contractility
response and provoke the Bezold–Jarisch reflex[27,28].
A vasodepressive response is characterized by a systolic blood pressure fall, while at the time of syncope the
heart rate does not fall more than 10% from its peak. In
the mixed response, blood pressure falls before the heart
rate; the ventricular rate does not fall to less than
40 bpm, or falls to less than 40 bpm for less than 10 s,
with or without asystole (<3 s). If the bradycardia
and/or asystole are more important the HUTT response
is classified as ‘cardioinhibitory’[29].
Europace, Vol. 5, April 2003
160
E. Occhetta et al.
The present therapeutic options in vasodepressive
vasovagal syncope include general counselling, tilt
training, drugs that improve volaemia by peripheral
vasoconstriction, drugs that decrease the contractile
myocardial response resulting in blunting the Bezold–
Jarisch reflex.
On the contrary, in case of vasovagal ‘mixed’
responses, characterized by hypotension and severe
bradycardia, drugs and/or DDI pacing are indicated[30].
Dedicated algorithms, associated with pacing for a
better prevention of the vasovagal mixed peripheral
syncope, have been developed as:
DDI with rate hysteresis[31];
DDD with automatic mode commutation;
DDI with rate drop response algorithm[32,33].
Our clinical investigation suggests an additional sophisticated method in dual chamber pacing, namely DDD
Closed Loop Stimulation (CLS), for the prevention of
vasovagal syncope.
This concept of cardiac pacing integrates the pacemaker into the physiological cardiovascular control
loop. The effectiveness of CLS in preventing vasovagal
syncope may result from this integration. Our measurements, in accordance with previous investigations[34,35],
have demonstrated, that increased myocardial contractility precedes the vasovagal syncope. A pacing system
able to convert this input information into pacing rates
high enough to counteract the pathological Bezold–
Jarisch reflex, is likely to alleviate central hypotension
and prevent vigorous contractions against underfilled
ventricles[11].
The rationale for closed loop stimulation correlated
with the myocardial contractility to prevent vasovagal
syncope, may be that high rate ventricular stimulation,
correlated with the increased contractility in the first
stage of head up tilt test, could prevent the failure of
sympathetic tone and counterbalance the increase in
vagal tone avoiding arterial hypotension, bradycardia
and consequently the syncope.
The INOS2 CLS pacemaker was used to prevent vasovagal malignant syncope also in previous studies[36–38]
with good results. Other pacing systems modulated by
the sympathetic system have also been already used to
prevent vasovagal malignant syncope[39,40].
In our study, we confirmed that DDDR Closed Loop
Stimulation guided by the contractility status seems
to be a promising therapeutic approach to prevent
vasovagal mixed syncope.
In nearly all patients in our study no syncope recurrence occurred during daily life after pacemaker
DDDR-CLS implant, and patients subjective health
condition was good.
Our study confirms also the important role of the
HUTT to individualize patients suffering from vasovagal syncope; moreover our data, as those of a recent
study[31], suggest that the use of HUTT for assessing
the effectiveness of pacing therapy has some limitations.
The discrepancy observed in our study between the
negative HUTT results (six patients among the seven
Europace, Vol. 5, April 2003
that repeated the tilt test during DDDR-CLS pacing
fainted) and the very encouraging clinical outcome could
be explained if we consider that tilt test prolongs and
carries to extremes a clinical situation which, in daily
life, the patient tries to avoid.
Although the current results of Closed Loop Stimulation in vasovagal syncope seem very promising, several
issues still remain to be clarified.
The most obvious aspect in this context is that the
effectiveness of cardiac pacing concepts in preventing
vasovagal fainting is directly related to the degree of
bradycardia, which develops during the syncope. Secondly, the response of the CLS-pacemaker depends on
the grade of sympathetic changes affecting the heart
during the syncopal event. If central hypovolaemia
occurs without or only with little change in ventricular
contractility[9,10], the pacemaker will not respond properly. A reduction in contractility response can also arise
from the use of beta-blockers, which are used as an
elective drug therapy in such patients. It could be useful
to intensify investigations using contractility monitoring
during head up tilt test to screen these unresponsive
patients.
The last aspect to be discussed in this context focusses
on the possible placebo effect. This is a non-randomized
study with no control-group; so we cannot exclude that
the positive clinical results observed are partly due to
the pacemaker implantation. In the population of the
registry the placebo effect seems unlikely, as six patients
had already been treated with a DDD conventional
pacemaker and still complained of syncopal recurrences.
Beside our preliminary encouraging results, further
larger studies are mandatory to understand the preventive mechanism in detail and to confirm the beneficial
effect of Closed Loop Stimulation in vasovagal syncope
in a larger group of patients.
For this purpose, the INVASY (INotropy controlled
pacing in VAsovagal SYncope) clinical trial has been
designed[40] and is at present running[41]. Main aim of
the study is to investigate whether DDD-CLS pacing is
able to prevent syncopal recurrences. In this prospective
controlled, multicentre study, patients with recurrent
vasovagal syncope and significant bradycardia during
HUTT are centrally randomized either to DDD-CLS
pacing or to back-up DDI. The results of this study
could clarify the role of cardiac pacing, and in particular
of DDDR-CLS, in preventing vasovagal syncope.
Appendix
INVASY Italian prospective feasibility Registry:
E. Occhetta, M. Bortnik. Ospedale Maggiore della
Carità, Novara.
R. Polimeni. Ospedale S. Maria degli Ungheresi,
Polistena (Reggio Calabria).
D. Igidbashian. Ospedale Civile, Legnago (Verona).
M. Sassara, F. De Luca. Ospedale degli Infermi,
Viterbo.
DDDR-CLS pacing in vasovagal syncope
M. Jorfida, A. Mazza. Ospedale Civile, Chivasso
(Torino).
A. Galati. Ospedale Cardinale G. Panico, Tricase
(Lecce).
G. Del Giudice. Ospedale S. Giovanni-Addolorata,
Roma.
G. B. Tola, L. Dore. Ospedale S. S. Annunziata,
Sassari.
P. Marconi. Ospedale Careggi — S. Luca, Firenze.
L. Chiodi. Ospedale Civile, Bagno a Ripoli (Firenze).
I. Caico. Ospedale di Circolo Fondazione Macchi,
Varese.
G. Boriani. Ospedale S. Orsola, Bologna.
F. Zolezzi, P. Nigro. Ospedale Civile, Vigevano
(Pavia).
D. Barbieri, S. Lombroso. Ospedale di Circolo
Galmarini, Tradate (Varese).
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