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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). References [1] Schaldach M, Hutten H. Intracardiac impedance to determine sympathetic activity in rate responsive pacing. Pacing Clin Electrophysiol 1992; 15: 1778–86. [2] Pichlmaier AM, Braile D, Ebner E, et al. Autonomic nervous system controlled closed loop cardiac pacing. Pacing Clin Electrophysiol 1992; 15: 1787–91. [3] Osswald S. Correlation of intracardiac impedance and right ventricular contractility during dobutamin stress test. In: Raviele A, ed. Cardiac Arrhythmias. Venice: Fifth international workshop 1997: 89. [4] Witte J, Pichlmaier AM, Ebner E, et al. ANS controlled rate adaptive pacing. A clinical evaluation. Eur J Card Pacing Electrophysiol 1996; 6: 53–9. 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