Clinically oriented device programming in bradycardia patients: part 2 (atrioventricular blocks and neurally mediated syncope). Proposals from AIAC (Italian Association of Arrhythmology and Cardiac Pacing)

Clinical guidelines and position paper Clinically oriented device programming in bradycardia patients: part 2 (atrioventricular blocks and neurally mediated syncope). Proposals from AIAC (Italian Association of Arrhythmology and Cardiac Pacing) Pietro Palmisanoa,, Matteo Ziacchib,, Mauro Biffib, Renato P. Riccic, Maurizio Landolinad, Massimo Zoni-Berissoe, Eraldo Occhettaf, Giampiero Magliag, Gianluca Bottoh, Luigi Padelettii, Giuseppe Borianij, on behalf of the Italian Association of Arrhythmology and Cardiac Pacing (AIAC) The purpose of this two-part consensus document is to provide specific suggestions (based on an extensive literature review) on appropriate pacemaker setting in relation to patients’ clinical features. In part 2, criteria for pacemaker choice and programming in atrioventricular blocks and neurally mediate syncope are proposed. The atrioventricular blocks can be paroxysmal or persistent, isolated or associated with sinus node disease. Neurally mediated syncope can be related to carotid sinus syndrome or cardioinhibitory vasovagal syncope. In sinus rhythm, with persistent atrioventricular block, we considered appropriate the activation of mode-switch algorithms, and algorithms for auto-adaptive management of the ventricular pacing output. If the atrioventricular block is paroxysmal, in addition to algorithms mentioned above, algorithms to maximize intrinsic atrioventricular conduction should be activated. When sinus node disease is associated with atrioventricular block, the activation of rate-responsive function in patients with chronotropic incompetence is appropriate. In permanent atrial fibrillation with atrioventricular block, algorithms for auto-adaptive management of the ventricular pacing output should be activated. If the atrioventricular block is persistent, the activation of rate-responsive Introduction Symptomatic atrioventricular block is the most common indication for permanent pacemaker implantation. In Italy, 58.3% of pacemakers implanted in 2015 were implanted for atrioventricular blocks.1,2 Trials have shown that in patients receiving a pacemaker for atrioventricular block, the correct choice of pacing modality and the appropriate device setting can maximize the benefit of pacing therapy. Although neurally mediated syncope is a very common disorder, and the most common cause of syncope, it is a rare indication for pacemaker implantation.3 Specifically, permanent pacing may have a role in preventing syncopal  Pietro Palmisano and Matteo Ziacchi contributed equally to the writing of this article. 1558-2027 ß 2018 Italian Federation of Cardiology. All rights reserved. function is appropriate. In carotid sinus syndrome, adequate rate hysteresis should be programmed. In vasovagal syncope, specialized sensing and pacing algorithms designed for reflex syncope prevention should be activated. J Cardiovasc Med 2018, 19:000–000 Keywords: atrial fibrillation, atrioventricular block, bifascicular block, bradyarrhythmias, carotid sinus syndrome, device setting, pacemaker, pacing mode, permanent pacing, vasovagal syncope a Cardiology Unit, ‘Card. G. Panico’ Hospital, Tricase, bInstitute of Cardiology, University of Bologna, S. Orsola-Malpighi University Hospital, Bologna, cSan Filippo Neri Hospital, Rome, dOspedale Maggiore, Crema, CR, eDepartment of Cardiology, ASL 3, Padre A Micone Hospital, Genoa, fDivision of Cardiology, University of Eastern Piedmont, Maggiore della Carità Hospital, Novara, g Cardiology–Coronary Care Unit, Pugliese-Ciaccio Hospital, Catanzaro, hS. Anna Hospital, Como, iOspedale Careggi, Florence and jCardiology Division, Department of Diagnostics, Clinical and Public Health Medicine University of Modena and Reggio Emilia Policlinico di Modena, Modena, Italy Correspondence to Professor Giuseppe Boriani, MD, PhD, FESC, Cardiology Division, Department of Diagnostics, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, 41124 Modena, Italy Tel: +39 059 4225836; fax: +39 059 4224498; e-mail: giuseppe.boriani@unimore.it Received 26 October 2017 Revised 5 January 2018 Accepted 11 January 2018 recurrences in selected patients with cardioinhibitory form.4,5 In this setting, the correct use of specific algorithms can increase the effectiveness of pacing. The purpose of this two-part consensus document is to provide a state-of-the-art review of the appropriate use of pacemaker algorithms in relation to patients’ clinical features, and to report suggestions of a consensus writing group, convened by the Italian Association of Arrhythmology and Cardiac Pacing (AIAC), for appropriate pacemaker setting in different clinical scenarios. In this second part, we propose criteria for a correct pacemaker choice and programming in atrioventricular blocks and neurally mediated syncope. In order to identify the device characteristics and settings required, we divided these rhythm disorders needing pacing into six clinical categories, as follows: sinus rhythm with persistent DOI:10.2459/JCM.0000000000000629 © 2018 Italian Federation of Cardiology. All rights reserved. 2 Journal of Cardiovascular Medicine 2018, Vol 00 No 00 Table 1 Appropriate type of device according to clinical scenarios Clinical scenarios Type of device Comments References SND with or without documentend atrial tachyarrhythmias/AFa DDDR 11,40,42,43 SR with persistent AV block DDD SR with paroxysmal AV block DDD SND with paroxysmal AV block Permanent AF with AV block DDDR VVIR Carotid sinus syndrome DDD Cardioinhibitory vasovagal syncope DDD Compared with VVIR, DDDR reduces the risk of AF, HF, and stroke; no significant reduction in mortality has been reported. Compared with AAIR, DDDR reduces the risk of AF and of PM re-operation; no difference in allcause mortality has been reported Compared with VVI, DDD prevents PM syndrome with positive impact on exercise capacity and quality of life; no significant reduction in mortality, HF, AF, and stroke has been reported. Compared with VDD, DDD ensures a better atrial sensing performance in the long term, and the possibility of an atrial pacing in the event of SND development. CRT should be considered if clinical symptoms of HF and a severely reduced LVEF are present DDD pacing ensures the maintenance of a physiological AV synchronism in case of progression of the block to a persistent form Compared with VVIR, DDDR reduces the risk of AF, HF, stroke, and prevents PM syndrome; no significant reduction in mortality has been reported In patients requiring a high percentage of ventricular pacing (including patients underwent AV node ablation), CRT should be considered if clinical symptoms of HF and a severely reduced LVEF are present2 Compared with VVI, DDD ensures less hemodynamic deterioration induced by CSM, and seems to be more effective in the prevention of syncopal relapses VVI and VDD pacing are not able to abort the syncope induced by tilt test 10 –14,17,20–23 23 1,44– 46 23 63 –65 78,79 AF, atrial fibrillation; AV, atrioventricular; CRT, cardiac resynchronization therapy; CSM, carotid sinus massage; HF, heart failure; LVEF, left ventricular ejection fraction; PM, pacemaker; SND, sinus node disease; SR, sinus rhythm. a See part 16 for details. atrioventricular block; sinus rhythm with paroxysmal atrioventricular block; sinus node disease (SND) with paroxysmal atrioventricular block; permanent atrial fibrillation with atrioventricular block; carotid sinus syndrome (CSS); cardioinhibitory vasovagal syncope (VVS). In the specific sections, we have summarized and discussed all the available evidence in support of the proposed pacing modality and device settings. The appropriate type of device and the minimal appropriate device settings required, according to clinical features, are summarized in Tables 1 and 2, respectively. In Table 3 are summarized the appropriate device settings in the different clinical scenarios according to goals of programming detailed in part 1.6 Sinus rhythm with persistent atrioventricular block Although no randomized controlled trials evaluating the effectiveness of pacing in patients with persistent atrioventricular block have been performed, several observational studies performed at the beginning of the pacemaker era suggest that pacing prevents the recurrence of syncope and improves survival.7,8 Type of device Compared with single-chamber ventricular pacing, dualchamber pacing maintains physiological atrioventricular synchronism in patients with persistent atrioventricular block in sinus rhythm.9 Large randomized parallel trials, however, have been unable to show the superiority of dual-chamber pacing over ventricular pacing with regard to the hard clinical endpoints of mortality and morbidity. In the Pacemaker Selection in the Elderly study, a single-blind, randomized, 10 controlled comparison of ventricular pacing and dualchamber pacing, 407 patients (50% of whom with atrioventricular block) aged 65 years or older were enrolled. During a 30-month follow-up, no differences in either quality of life or prespecified clinical outcomes (including death, stroke, heart failure, and atrial fibrillation) emerged between the two pacing modes. In the Canadian Trial of Physiologic Pacing (CTOPP) trial, patients who had undergone pacemaker implantation for symptomatic bradycardia (52% of which atrioventricular blocks) were randomly assigned to VVI or DDD pacing. After a mean follow-up of 3 years, physiologic pacing provided little benefit over ventricular pacing in the prevention of stroke or death due to cardiovascular causes.11 The United Kingdom Pacing and Cardiovascular Events (UK-PACE) study12 enrolled 2021 elderly patients (70 years or older) with a pacing indication due to atrioventricular block. During a median follow-up 4.6 years, dual-chamber cardiac pacing did not reduce allcause mortality, atrial fibrillation, heart failure, or a composite of stroke, transient ischemic attack, or other thromboembolism. A meta-analysis of five randomized, controlled, parallel-design trials comparing dual-chamber pacing with ventricular-based pacing in patients with bradycardia showed no significant reduction in mortality, heart failure, atrial fibrillation, or stroke in the subgroup of patients with atrioventricular block.13 Several crossover trials have consistently demonstrated that dual-chamber pacing prevents pacemaker syndrome, which occurs in more than a quarter of patients with atrioventricular block treated with single-chamber ventricular pacing. This effect impacts positively on exercise capacity and quality of life.10,14 This evidence justifies the preference for dual-chamber pacing. © 2018 Italian Federation of Cardiology. All rights reserved. Table 2 Minimal appropriate device settings required according to clinical scenarios SND with atrial tachyarrhythmias/ AFa SR with persistent AV block SR with paroxysmal AV block SND with paroxysmal AV block Permanent AF with paroxysmal AV block Pacing mode Lower rate limit (b.p.m.) Rate-responsive function (yes/no) Maximum sensor rate (if rate-responsive function is activated) (b.p.m.) Maximum atrial tracking rate (b.p.m.) DDD (R) 50–70 Yes in patients CI DDD (R) 50–70 Yes in patients CI DDD <50 No DDD <50 No DDD (R) 50–70 Yes in patients CI VVI 50 No VVIR 70–80 Yes DDD 50 No DDD 50 No According to patient’s clinical characteristics – – 110–120 – – 130 – – Yes No According to patient’s clinical characteristics Yes – – According to patient’s clinical characteristics Yes According to patient’s clinical characteristics Yes Rate hysteresis (yes/no) Mode-switch algorithms (yes/no) Algorithms for preventing and termitating atrial tachyarrhythmias (yes/no) Specialized sensing and pacing algorithms for VVS prevention (yes/no) Algorithms for auto-adaptive ventricular output (yes/no) Algorithms for auto-adaptive atrial output (yes/no) No Yes No Yes No Yes No Yes According to patient’s clinical characteristics According to patient’s clinical characteristics Yes (with the exception of patients with a prolonged PQ interval at baseline) No Yes – Algorithms to promote intrinsic AV conduction (yes/no) According to patient’s clinical characteristics According to patient’s clinical characteristics Yes Yes – No – Yes Yes No Yes No Yes No No No – – No No No No No No No – – No Yes No No Yes No No No Yes No No Yes Yes No No Yes – – No No Settings According to patient’s clinical characteristics AF, atrial fibrillation; AV, atrioventricular; CI, chronotropic incompetence; SND, sinus node disease; SR, sinus rhythm; VVS, vasovagal syncope. a See part 16 for details. Carotid sinus syndrome Cardioinhibitory vasovagal syncope Device programming in bradycardia patients Palmisano et al. 3 © 2018 Italian Federation of Cardiology. All rights reserved. SND without atrial tachyarrhythmias/ AFa Permanent AF with slow mean ventricular response (including AV junction ablation) 4 Journal of Cardiovascular Medicine 2018, Vol 00 No 00 Table 3 Appropriate device settings in different clinical scenarios according to goals of programming detailed in part 1 Appropriate device settings in different clinical scenarios SNDa SR with persistent AV block SR with paroxysmal AV block SND with paroxysmal AV block To preserve or restore the heart rate response Activation of RR function in patients with CI Setting a high maximum atrial tracking rate Setting a high maximum atrial tracking rate To maintain physiological conduction Activation of algorithms to promote intrinsic AV conduction – Activation of algorithms to promote intrinsic AV conduction Activation of RR function in patients with CI, and setting a high maximum atrial tracking rate Activation of algorithms to promote intrinsic AV conduction To maximize device longevity Activation of algorithms for auto-adaptive atrial output Activation of algorithms for auto-adaptive ventricular output Activation of algorithms for auto-adaptive ventricular output To detect atrial arrhythmia Activation of modeswitch algorithms Activation of mode-switch algorithms Activation of mode-switch algorithms Goals of programminga Activation of algorithms for auto-adaptive atrial and ventricular output Activation of mode-switch algorithms Permanent AF with AV block Neurally mediate syncope (including CSS and VVS) Activation of RR function in patients with CI Setting a high maximum atrial tracking rate Activation of rate hysteresis Activation of algorithms to promote intrinsic AV conduction, and of rate hysteresis Activation of algorithms for auto-adaptive atrial and ventricular output Activation of modeswitch algorithms Activation of algorithms for auto-adaptive ventricular output – AF, atrial fibrillation; AV, atrioventricular; CI, chronotropic incompetence; RR, rate-responsive; SND, sinus node disease; SR, sinus rhythm; VVS, vasovagal syncope. a See part 16 for details. Single-lead VDD pacing is a possible alternative to dualchamber pacing in patients with atrioventricular block and normal sinus node function. VDD pacing combines the physiological benefits of synchronous atrioventricular pacing with the convenience of a single-lead system (lower cost, shorter operation and fluoroscopic times, lower complication rate).15–19 However, the main limitation of single-lead VDD pacing is its poor atrial sensing performance in the long term. Indeed, atrial under-sensing requiring a switch to the VVIR pacing mode has been reported in 6.9–27.6% of patients.17,20–22 Another limitation is the potential development of SND, which is observed in 1–2% of patients with atrioventricular block and normal sinus node function at the time of pacemaker implantation.17 On the basis of this evidence, we consider the dualchamber (DDD) pacemaker to be the optimal choice for patients with complete atrioventricular block. In the subgroup of patients with clinical symptoms of heart failure and a severely reduced left ventricular ejection fraction (LVEF), the implantation of a biventricular pacemaker should be considered, in order to avoid the deleterious effect of chronic right ventricular pacing.23–26 Goals of programming In patients with isolated atrioventricular block, setting a low lower rate level (LRL) (<50 b.p.m.) is appropriate, in order to avoid forced atrial stimulation with a nonphysiological atrioventricular interval due to interatrial delay for several hours daily. This has been reported to be associated with atrial fibrillation development during follow- up.27 In order to preserve a physiological heart rate fluctuation, it is appropriate to set a high maximum atrial tracking rate (130 b.p.m.), especially in the youngest patients and in those with an active lifestyle. Activation of the mode-switch algorithm is also appropriate in this clinical category of patients.23 The report of time in mode switch is a very sensitive measure of atrial fibrillation, and should be used to assess the evolution of atrial fibrillation during follow-up, with a view to administering anticoagulant therapy when necessary. Patients with complete atrioventricular block require a high percentage of ventricular pacing and often have a slow and unstable intrinsic rhythm, or are completely pacemaker-dependent. In this setting, the algorithms for automatic management of the ventricular pacing output improve patient safety by automatically tailoring the pacing output to threshold fluctuations, while maximizing device longevity, with consequent reduction in replacement-related complications.28–30 There is much evidence showing that, beyond preventing loss of capture in the event of an unexpected pacing threshold increase,29 these algorithms enable the service life of the pacemaker to be matched with patients’ life expectancy, thereby reducing the replacement rate.30 On the basis of this evidence, activation of algorithms for the automatic management of ventricular pacing is appropriate. Sinus rhythm with paroxysmal atrioventricular block The intermittent/paroxysmal atrioventricular block that occurs in patients with underlying heart disease and/or © 2018 Italian Federation of Cardiology. All rights reserved. Device programming in bradycardia patients Palmisano et al. 5 bundle branch block is usually regarded as a manifestation of intrinsic disease of the atrioventricular conduction system (Stokes-Adams). When paroxysmal atrioventricular block occurs, the cardiac rhythm may become dependent on subsidiary (often unreliable) pacemaker sites. The delay in the emergence of these subsidiary pacemakers and their relatively slow rates (typically 25–40 b.p.m.) can cause inadequate cerebral perfusion, resulting in syncope and presyncope.23,31 In patients with a history of syncope and presyncope and documented intermittent/paroxysmal third or second-degree atrioventricular block due to intrinsic disease of the atrioventricular conduction, permanent pacing is effective in preventing syncope recurrence and may improve survival.23 Type of device In some patients with paroxysmal atrioventricular block, the episodes of block are sporadic; consequently, pacing may be required only for short periods of time. In these cases, single-chamber ventricular pacing would be enough to prevent asystoles and related symptoms. However, when the paroxysmal atrioventricular block is secondary to intrinsic disease of the atrioventricular conduction system, there is a risk of progression of the conduction disturbance over time to a persistent form. For this reason, even paroxysmal forms of atrioventricular back the optimal pacing mode is dual-chamber, because this pacing mode ensures the maintenance of physiological atrioventricular synchronism in the case of progression of the block to a persistent form.23 Goals of programming In patients with paroxysmal atrioventricular block without SND, setting a low LRL (<50 b.p.m.) is appropriate in order to avoid forced atrial stimulation with a prolonged atrioventricular interval for several hours daily, and hence reduce unnecessary right ventricular pacing. In patients with transient atrioventricular block, preserving spontaneous atrioventricular conduction by activating algorithms to minimize unnecessary right ventricular pacing is appropriate, in order to prevent the deleterious effects of excessive ventricular pacing (increased risk of atrial fibrillation or heart failure).32,33 In this setting, the promotion of spontaneous atrioventricular conduction may also slow or prevent the progression of the paroxysmal/intermittent atrioventricular block to complete atrioventricular block, and consequently to pacemaker dependency.33–35 Patients with transient atrioventricular blocks often require a very low percentage of ventricular pacing. Therefore, during routine follow-up, the percentage of ventricular pacing should be systematically assessed in order to minimize it as much as possible.23 Moreover, the conduction disturbance should be reassessed at each follow-up examination because, if progression of the atrioventricular block to a persistent form is found, it may be advisable to deactivate algorithms that search for spontaneous atrioventricular conduction. Indeed, in patients with persistent atrioventricular block, these algorithms can, in rare cases, cause inadvertent bradycardia36 and lead to potentially lethal bradycardia-related tachyarrhythmias.37–39 On the contrary, the use of these algorithms allows a continuous atrioventricular conduction assessment and management in patients with intermittent and permanent atrioventricular block.40 The evaluAtioN of the SafeR mode in patients With a dualchambER pacemaker indication (ANSWER) study41 enrolled 650 consecutive patients with a pacemaker indication and randomized them to programming either with an algorithm to minimize unnecessary right ventricular pacing (the SafeR algorithm, LivaNova, Clamart, France) or conventional DDD pacing. About 40% of patients with either intermittent or permanent atrioventricular block randomized to SafeR mode had a ventricular pacing less than 50% over a 3-year time, indicating that, in a sizeable proportion of patients with atrioventricular conduction disturbance, the atrioventricular conduction shows significant circadian and monthly variation. Atrioventricular block is therefore more dynamic than previously thought and the use of these algorithms allows adjustment of the atrioventricular conduction in response to continuous changes in patients’ conduction disturbance.41 Sinus node disease with paroxysmal atrioventricular block In SND patients, a 0.6–1.9% per year risk of developing an atrioventricular block has been reported.42 No trial has specifically addressed the role of cardiac pacing in patients with binodal dysfunction (SND þ atrioventricular block). However, a subgroup of patients with concurrent atrioventricular block has been included in many trials of patients with SND. For example, a first-degree atrioventricular block was present in 8.1% of the patients enrolled in the THEOPACE (Effects of Permanent Pacemaker and Oral Theophylline in Sick Sinus Syndrome) trial,43 and a concurrent atrioventricular block of any degree was present in 8.3% of the patients enrolled in the CTOPP trial,11 and in 21% of patients enrolled in the Mode Selection Trial (MOST).44 Type of device Considering the benefits of atrial-based pacing in patients with SND (see part 1),6,11,13,44 –46 and the need for backup ventricular pacing in the event of an atrioventricular block, dual-chamber pacing mode (DDDR) is appropriate in patients with SND and concurrent paroxysmal atrioventricular block. Goals of programming Setting a LRL between 50 and 70 b.p.m. (according to the patients’ clinical features) is appropriate, in order to avoid inappropriate sinus bradycardia and to restore a physiological atrial rate. © 2018 Italian Federation of Cardiology. All rights reserved. 6 Journal of Cardiovascular Medicine 2018, Vol 00 No 00 As discussed in part 1,6 activation of the rate-responsive function is advisable in patients with documented chronotropic incompetence, in whom this feature can lead to an increase in exercise capacity and an improvement in quality of life.47–49 In patients with transient atrioventricular blocks, unnecessary right ventricular pacing should be systematically avoided by activating an algorithm to maximize intrinsic atrioventricular conduction.32,50 Considering the deleterious effects (both hemodynamic and clinical) of prolonged atrioventricular conduction,51,52 programming an excessively long atrioventricular interval (>220 ms),42 and/or the activation of features to minimize ventricular pacing is debatable in patients with a prolonged baseline PQ interval.42,50 As reported in the setting of patients with isolated SND or atrioventricular block (see subparts ‘Type of device’ and ‘Sinus node disease with paroxysmal atrioventricular block’ under the section heading ‘Sinus rhythm with paroxysmal atrioventricular block’), activation of the mode-switch algorithm is also appropriate in patients with both sinus node and atrioventricular node dysfunction. In patients with SND and paroxysmal atrioventricular block, the need for atrial pacing prevail over the need for ventricular pacing. In addition, in patients with a low intrinsic sinus rate, a high percentage of atrial pacing is required. In this setting, the activation of auto-adaptive management of the atrial pacing output is appropriate, in order to ensure constant atrial capture and to maximize battery longevity.53,54 After pacemaker implantation, it is recommended that the patient’s conduction disturbances be reassessed at each follow-up examination, in order to detect possible progression of transient atrioventricular block to a persistent form, and to update the device settings to the new clinical needs of the patient. Permanent atrial fibrillation with atrioventricular block Patients with permanent atrial fibrillation needing pacing fall into two different clinical categories: those with a normal mean ventricular rate and sporadic prolonged asystoles due to paroxysmal atrioventricular blocks; those with a slow mean ventricular rate due to a persistent atrioventricular block. In the former, the most common clinical manifestations are syncope and presyncope; in the latter, heart failure and reduced exercise capacity due to chronotropic incompetence. Type of device In permanent atrial fibrillation, or when atrial fibrillation is the predominant rhythm or the ‘chosen’ rhythm for the patient, atrioventricular synchrony cannot be restored and single-chamber ventricular pacing (VVIR) is the appropriate choice. Goals of programming Atrial fibrillation with paroxysmal atrioventricular block Setting a low LRL (from 40 to 50 b.p.m. according to the patients’ clinical features) is appropriate, in order to prevent the detrimental effects of a high percentage of right ventricular pacing and to maximize battery longevity. Adequate rate hysteresis should be programmed in order to allow the spontaneous rhythm to emerge and to restrict pacing to the short periods of time in which the asystoles occur. Atrial fibrillation with slow mean ventricular response In comparison with fixed-rate pacing, rate-responsive pacing is associated with better exercise performance, decrease of symptoms, and improved quality of life.55,56 The LRL rate should be programmed high (70 b.p.m.) than for sinus rhythm patients, in an attempt to compensate for the loss of active atrial filling, and the maximum sensor rate should be programmed restrictively (110 –120 b.p.m.), in order to avoid ‘overpacing’, that is, pacing with a heart rate faster than necessary, which can elicit symptoms, especially in patients with coronary artery disease.23 An ‘ablate and pace’ strategy (ablation of the atrioventricular junction followed by permanent pacemaker implantation) is effective in controlling symptoms, improving quality of life and functional capacity, and reducing morbidity in patients with symptomatic permanent atrial fibruillation and uncontrolled, drugrefractory high ventricular rate.57–59 Patients treated with this strategy come within the setting of atrial fibrillation with slow mean ventricular response. Indeed, after atrioventricular junction ablation, these patients become totally pacemaker-dependent and lose the ability to increase their heart rate appropriately during physical activity (a condition of ‘iatrogenic’ chronotropic incompetence). This condition can be corrected by the use of rate-responsive pacing. In RESPONSIBLE – a randomized, single-blind study60 enrolling 60 patients with permanent uncontrolled atrial fibrillation and left ventricular dysfunction, treated with atrioventricular junction ablation and biventricular pacing – rate-responsive pacing induced an acute significant increase in functional capacity in comparison with fixed-rate pacing. Patients with a spontaneous slow ventricular response, and those treated with atrioventricular junction ablation, require a high percentage of ventricular pacing. In order to ensure constant ventricular capture, and to maximize battery longevity, the activation of algorithms for the automatic management of ventricular pacing output is recommended. In patients with clinical symptoms of heart failure and a severely reduced LVEF, cardiac resynchronization therapy should be considered.23,25 © 2018 Italian Federation of Cardiology. All rights reserved. Device programming in bradycardia patients Palmisano et al. 7 Carotid sinus syndrome Carotid sinus syndrome is part of reflex syncope (neurally mediated syncope). In its rare spontaneous form, it is a syncope triggered by mechanical manipulation of the carotid sinuses. In the more common form, no mechanical trigger is found and it is diagnosed when carotid sinus massage induces an asystole of above 3 s (cardioinhibitory form), or a fall in systolic blood pressure of greater than 50 mmHg (vasodepressor form), or both (mixed form), with reproduction of the spontaneous syncope.3,23 A few small controlled trials and retrospective observational studies have shown the benefits of pacing in reducing the burden of syncope and of related morbidities in patients affected by CSS.61 On the basis of this evidence, permanent pacing is indicated in patients with dominant cardioinhibitory CSS and recurrent unpredictable syncope.3,23 CSS is a rare indication for pacemaker implantation. Indeed, in pacemaker studies, the rate of patients undergoing implantation for CSS is 2.5–3%.1,27,62 Type of device In a small acute intrapatient study63 enrolling 11 patients with carotid hypersensitivity VVI pacing caused a marked deterioration in comparison with the DVI pacing mode; VVI pacing induced a greater fall in systolic blood pressure (59 vs. 37 mmHg; P < 0.001) and a higher rate of symptom persistence (91 vs. 27%; P ¼ 0.008). In a 2month randomized crossover study on DVI vs. VVI pacing, performed in 23 patients affected by mixed CSS,64 syncope occurred in 0 vs. 13% (P ¼ 0.25) and presyncope in 48 vs. 74% (P ¼ 0.04), respectively; DVI was the mode preferred by 64% of the patients, whereas the remaining 36% did not express any preference (P < 0.001). In the Westminster study of 202 patients,65 syncope recurred in 9% of DDD-paced patients, whereas in VVI-paced patients, the rate of recurrence was twice as high (18%). More recently, in a 6-month randomized, double-blind crossover study enrolling 21 patients with CSS,66 three pacing modalities were compared: VVI vs. DDDR vs. DDDR, with a specialized sensing and pacing algorithm for the prevention of neurally mediated syncope (see below for details). The results of the study were unable to confirm the initial study hypothesis of a superiority of one pacing modality over another, both in preventing syncopal and presyncopal recurrences, and in improving quality of life. Despite the lack of large randomized clinical trials, review of the literature supports the hypothesis that the VVI pacing mode hampers the efficacy of pacing therapy in patients with CSS. Therefore, the optimal pacing mode is dual-chamber. Goals of programming Carotid sinus syndrome is a condition characterized by intermittent bradycardia, in which pacing may be required only for rare and short periods of time. In this situation, device programming should be aimed at preventing reflex bradycardia and pauses, while at the same time avoiding the detrimental effects of a high percentage of pacing.23 To avoid forced atrial stimulation for several hours daily, setting a low LRL (50 b.p.m., according to the patients’ clinical features) is appropriate. Adequate rate hysteresis should be programmed in order to allow spontaneous sinus rate to emerge and to restrict pacing to the short period of time in which reflex bradycardia occurs.23 Manual adaptation of the atrioventricular interval (>250 ms) or programming atrioventricular hysteresis to prevent unnecessary right ventricular pacing is recommended, in order to minimize the percentage of ventricular pacing.23 Some specialized sensing and pacing algorithms for the faster detection of an insidious drop in heart rate and short-lasting intervention pacing at a high rate (see subsection ‘Goals of programming’ under the section ‘Cardioinhibitory vasovagal syncope’ for details) have been developed by manufacturers, in order to improve the effect of pacing in reflex syncope. Initial clinical experiences67 and the results of a small noncontrolled study68 suggest that these algorithms are effective in reducing the incidence of syncopal recurrences and symptoms in the setting of CSS. To date, however, no comparison with conventional dual-chamber pacing has ever been made. Therefore, the evidence is not sufficient to recommend routine activation of these algorithms in patients with CSS. Cardioinhibitory vasovagal syncope Vasovagal syncope is an abnormal cardiovascular reflex characterized by an inappropriate reduction in heart rate and systemic hypotension caused by arteriolar vasodilatation. In patients with severe recurrent VVS that is refractory to conventional and/or pharmacological treatment, and a prevalent cardioinhibitory response to the head-up tilt test (HUTT), permanent pacing prevents important bradycardia and/or systole leading to clinical benefits and reducing episodes of syncope.3,4,69,70 However, several studies have shown that VVS may not be completely prevented by conventional cardiac pacing.69– 72 These suboptimal results are probably justified by the inability of conventional electrical cardiac stimulation to counteract the vasodepressor component of the vasovagal reflex that is present in almost all subjects during syncopal episodes and that usually precedes cardioinhibition and bradycardia.72 Another possible cause of the poor efficacy of pacing in VVS patients selected on the basis of their HUTT response might be the weak correlation existing between the mechanism of spontaneous neuro-mediated syncope and HUTT response.73,74 In this regard, the Third International Study on Syncope of Uncertain Etiology (ISSUE-3) trial75 suggested that © 2018 Italian Federation of Cardiology. All rights reserved. 8 Journal of Cardiovascular Medicine 2018, Vol 00 No 00 patients with VVS should be selected for permanent pacing on the basis of the documentation of spontaneous asystole through prolonged ECG monitoring by implantable loop recorder (ILR). Initially, 511 patients received an ILR for recurrent SVV; 89 of these had documentation of syncope with moiré than 3 s asystole or more than 6 s asystole without syncope and met criteria for pacemaker implantation; 77 of the 89 patients were randomly assigned to dual-chamber pacing with rate-drop response or to sensing only. After 2 years of follow-up, patients with pacemaker on showed a significantly reduced risk of syncope recurrence. In accordance with these results, the ‘ISSUE-3 approach’ to selecting patients with suspected SVV to receive a pacemaker was implemented by current European guidelines for cardiac pacing.23 Type of device During the cardioinhibitory vasovagal reflex, the efferent vagal activity leads more frequently to a transient depression of the sinus node function, resulting in sinus bradycardia and sinus pauses; transient atrioventricular blocks are less frequently observed and are almost always associated to sinus node depression.76,77 These are the pathophysiological bases for preferring dual-chamber pacing to ventricular pacing. In a small acute study, VVI pacing was not able to abort the syncope or to prevent the symptoms of vagal reaction induced by HUTT. During the vagal reflex, the onset of ventricular pacing with retrograde atrioventricular conduction led to hemodynamic deterioration and the rapid reproduction of syncope.78 In a crossover study, the effectiveness of VDD pacing with a short atrioventricular interval in preventing tilt-induced syncope was evaluated in a series of 11 patients affected by cardioinhibitory VVS.79 VDD pacing did not prevent the initiation or progression of tilt-induced VVS. In comparison with unpaced tilt tests, VDD pacing appeared to accelerate the onset of syncope. Although weak, this evidence is sufficient to suggest that dualchamber pacing should be considered the optimal pacing mode in the setting of VVS. Goals of programming As already discussed with regard to CSS (see subsection ‘Goals of programming’ under the section heading ‘Carotid sinus syndrome’) in patients with cardioinhibitory VVS, pacing should be restricted to the short period of time in which reflex bradycardia and/or pause occur. In this view, setting a low LRL (50 b.p.m., according to the patients’ clinical features), and the activation of algorithms to maximize intrinsic atrioventricular conduction are appropriate, in order to minimize unnecessary atrial and ventricular pacing.23 Some specialized sensing and pacing algorithms designed to provide better prevention of VVS have been developed by various manufacturers. Two examples of these algorithms are the Rate Drop Response (RDR) (Medtronic Inc., Minneapolis, Minnesota, USA) and the Sudden Brady Response (SBR) (Boston Scientific Corp., Place Natick, Massachusetts, USA). The operation of these algorithms is similar. The device monitors the heart rate in order to detect any significant rate drop. When a rapid rate drop is detected, the device institutes rapid DDD pacing for a programmable time interval. While several studies have shown that, in patients with severe VVS, these algorithms are more effective than conservative treatments in reducing syncopal episodes,68–69,75 no comparison with conventional dual-chamber pacing has ever been made. In a small randomized study, DDD pacing with the RDR function was more effective than DDI pacing with rate hysteresis in cardioinhibitory VVS.80 Closed Loop Stimulation (CLS) (Biotronik GmbH & Co., Germany) is an algorithm for pacing rate modulation which responds to myocardial contraction dynamics by measuring variations in right ventricular intracardiac impedance. In the first stage of VVS, CLS detects the increased myocardial contractility and activates high-rate DDD pacing; this may anticipate the loss of sympathetic tone and counterbalance the increase in vagal tone, thus preventing arterial hypotension, bradycardia, and possibly syncope.81,82 According to this rationale, some studies have used CLS pacing in patients with VVS. In the Inotropy controlled pacing in vasovagal syncope (INVASY) – a randomized, single-blind study – CLS pacing proved more effective than DDI pacing in preventing the recurrence of VVS in patients with a cardioinhibitory response to HUTT during a mean follow-up of 19 months.83 In this study, no patient treated with CLS pacing experienced syncopal recurrence. The effectiveness of CLS pacing in preventing syncopal recurrence is maintained even in the long term, as shown by the results of a single-center long-term follow-up study,84 in which the burden of syncope episodes was compared before and after CLS implantation in 35 patients followed up for a mean of 61 months. The results of a more recent, randomized, single-blind, crossover study85 have conclusively demonstrated the superiority of CLS to DDD pacing (without hysteresis or dedicated algorithms for VVS prevention) in the prevention of syncopal relapses in 50 patients with cardioinhibitory VVS. Over a period of 36 months, fewer syncopal and presyncopal episodes were registered during CLS pacing than during DDD pacing (syncopal episodes: 2 vs. 15; P ¼ 0.007; presyncopal episodes: 5 vs. 30; P ¼ 0.004). CLS also seems to be more effective than the conventional algorithms for VVS prevention. A single-center, retrospective study86 evaluated 41 patients with recurrent, refractory VVS: 25 were treated with a dual-chamber CLS pacemaker and 16 with a dual-chamber pacemaker with conventional algorithms for VVS prevention (RDR or SBR). Over a median of 4.4 years, patients with a dual-chamber CLS pacemaker showed a significantly lower risk of syncopal relapses than the others. © 2018 Italian Federation of Cardiology. All rights reserved. Device programming in bradycardia patients Palmisano et al. 9 In summary, although no large randomized trials have compared these algorithms with conventional pacing, some evidence suggests that they can increase the effectiveness of pacing in the prevention of syncopal recurrences. For these reasons, we consider their activation appropriate in patients with cardioinhibitory VVS. 3 4 5 6 Conclusions Manufacturers have developed several algorithms designed for optimization of pacing therapy in different clinical scenarios. The appropriate use of these algorithms based on suggestions proposed in this document (derived from an extensive literature review) allows the maximum benefit from pacing therapy to be achieved.27 In patients with persistent atrioventricular blocks setting a low LRL and a high maximum atrial tracking rate is appropriate in order to preserve a physiological heart rate fluctuation. Activation of the mode-switch algorithm is also appropriate to detect atrial tachyarrhythmias and to adjust automatically the pacing mode. The activation of algorithms for the automatic management of ventricular pacing output is recommended to improve patient safety, and maximize device longevity. If the atrioventricular block is intermittent, the activation of algorithms to minimize unnecessary right ventricular pacing is appropriate, in order to prevent the deleterious effects of excessive ventricular pacing. 7 8 9 10 11 12 13 In the setting of neurally mediate syndromes, the activation of specialized sensing and pacing algorithms for prevention of VVS can increase the effectiveness of pacing in the prevention of syncopal recurrences. 14 Acknowledgements 15 Conflicts of interest P.P. reports personal fees from Speaker Honoraria from Metronic, and personal fees from Proctorship agreement with Boston Scientific for training healthcare professionals on Subcutaneous Implantable Defibrillator (SICD), outside the submitted work. R.P.R. received minor consultancy fees by Medtronic and Biotronik, outside the submitted work. M.L. has a speakers’ bureau appointment with St Jude Medical, Medtronic and Boston Scientific, and an advisory board relationship with St Jude Medical and Medtronic, outside the submitted work. L.P. has received grants and personal fees from Livanova; personal fees from Biotronik, Medtronic, St Jude Medical, Livanova, Boston Scientific, outside the submitted work. G.B. reported speaker’s fees of small amount from Biotronik, Boston, and Medtronic, outside the submitted work. There are no conflicts of interest. References 1 2 16 17 18 19 20 21 22 23 Proclemer A, Zecchin M, D’Onofrio A, et al. The Pacemaker and Implantable Cardioverter-Defibrillator Registry of the Italian Association of Arrhythmology and Cardiac Pacing: annual report 2015. G Ital Cardiol (Rome) 2017; 18:67–79. Giammaria M, Cerrato E, Imazio M, Curnis A. Active implanted cardiac devices and magnetic resonance: results of a survey among cardiologists of Piedmont. J Cardiovasc Med (Hagerstown) 2017; 18:185–195. 24 Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009; 30: 2631–2671. Alboni P, Dinelli M, Gianfranchi L, Pacchioni F. Current treatment of recurrent vasovagal syncope: between evidence-based therapy and common sense. J Cardiovasc Med (Hagerstown) 2007; 8:835–839. Christodoulides T, Ioannides M, Yiangou K, Nicolaides E. Syncope due to prolonged asystole: an indication for pacing? J Cardiovasc Med (Hagerstown) 2012; 13:465–467. Ziacchi M, Palmisano P, Biffi M, et al. Clinically-oriented device programming in bradycardia patients: part 1 (sinus node disease). Proposals from AIAC (Italian Association of Arrhythmias and Cardiac Pacing). J Cardiovasc Med (in press). Edhag O, Swahn A. Prognosis of patients with complete heart block or arrhythmic syncope who were not treated with artificial pacemakers. A longterm follow-up study of 101 patients. Acta Med Scand 1976; 200: 457–463. Johansson BW. Complete heart block. A clinical, hemodynamic and pharmacological study in patients with and without an artificial pacemaker. Acta Med Scand Suppl 1966; 451:1–127. Deniz HB, Caro JJ, Ward A, Moller J, Malik F. Economic and health consequences of managing bradycardia with dual-chamber compared to single-chamber ventricular pacemakers in Italy. J Cardiovasc Med (Hagerstown) 2008; 9:43–50. Lamas GA, Orav EJ, Stambler BS, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dualchamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med 1998; 338:1097–1104. Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med 2000; 342:1385–1391. Toff WD, Camm AJ, Skehan JD, United Kingdom Pacing and Cardiovascular Events Trial Investigators. Single-chamber versus dualchamber pacing for high-grade atrioventricular block. N Engl J Med 2005; 353:145–155. Healey JS. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation 2006; 114:11–17. Castelnuovo E, Stein K, Pitt M, Garside R, Payne E. The effectiveness and costeffectiveness of dual-chamber pacemakers compared with singlechamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation. Health Technol Assess 2005; 9:; iii, xi–xiii,1–246. Migliore F, Curnis A, Bertaglia E. Axillary vein technique for pacemaker and implantable defibrillator leads implantation: a safe and alternative approach? J Cardiovasc Med (Hagerstown) 2016; 17:309–313. Busacca P, Gheller G, Pupita M, et al. Long-term follow-up of patients paced in VDD mode for advanced atrioventricular block: a pilot study. J Cardiovasc Med (Hagerstown) 2008; 9:39–42. Wiegand UK, Bode F, Schneider R, et al. Atrial sensing and AV synchrony in single lead VDD pacemakers: a prospective comparison to DDD devices with bipolar atrial leads. J Cardiovasc Electrophysiol 1999; 10:513–520. Wiegand UK, Bode F, Bonnemeier H, Eberhard F, Schlei M, Peters W. Long-term complication rates in ventricular, single lead VDD, and dual chamber pacing. Pacing Clin Electrophysiol 2003; 26:1961–1969. Eberhardt F, Bode F, Bonnemeier H, et al. Long term complications in single and dual chamber pacing are influenced by surgical experience and patient morbidity. Heart 2005; 91:500–506. Wiegand UK, Potratz J, Bode F, et al. Age dependency of sensing performance and AV synchrony in single lead VDD pacing. Pacing Clin Electrophysiol 2000; 23:863–869. Huang CC, Tuan TC, Fong MC, Lee WS, Kong CW. Predictors of inappropriate atrial sensing in long-term VDD-pacing systems. Europace 2010; 12:1251–1255. Marchandise S, Scavée C, le Polain de Waroux JB, et al. Long-term followup of DDD and VDD pacing: a prospective nonrandomized single-centre comparison of patients with symptomatic atrioventricular block. Europace 2012; 14:496–501. Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 2013; 15:1070–1118. Ziacchi M, Diemberger I, Biffi M, et al. Predictors of nonsimultaneous interventricular delay at cardiac resynchronization therapy optimization. J Cardiovasc Med (Hagerstown) 2016; 17:299–305. © 2018 Italian Federation of Cardiology. All rights reserved. 10 Journal of Cardiovascular Medicine 2018, Vol 00 No 00 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Boriani G, Ziacchi M, Diemberger I, Biffi M, Martignani C, Leyva F. BLOCK HF: how far does it extend indications for cardiac resynchronization therapy? J Cardiovasc Med (Hagerstown) 2016; 17:306–308. Gierula J, Cubbon RM, Jamil HA, et al. Patients with long-term permanent pacemakers have a high prevalence of left ventricular dysfunction. J Cardiovasc Med (Hagerstown) 2015; 16:743–750. Biffi M, Melissano D, Rossi P, et al. The OPTI-MIND study: a prospective, observational study of pacemaker patients according to pacing modality and primary indications. Europace 2014; 16:689–697. Biffi M, Bertini M, Saporito D, et al. Actual pacemaker longevity: the benefit of stimulation by automatic capture verification. Pacing Clin Electrophysiol 2010; 33:873–881. Biffi M, Bertini M, Mazzotti A, et al. Long-term RV threshold behavior by automated measurements: safety is the standpoint of pacemaker longevity!. Pacing Clin Electrophysiol 2011; 34:89–95. Boriani G, Rusconi L, Biffi M, et al. Role of ventricular Autocapture function in increasing longevity of DDDR pacemakers: a prospective study. Europace 2006; 8:216–220. Lee S, Wellens HJ, Josephson ME. Paroxysmal atrioventricular block. Heart Rhythm 2009; 6:1229–1234. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. J Am Med Assoc 2002; 288:3115–3123. Rosenqvist M, Edhag O. Pacemaker dependence in transient high-grade atrioventricular block. Pacing Clin Electrophysiol 1984; 7:63–70. Nagatomo T, Abe H, Kikuchi K, Nakashima Y. New onset of pacemaker dependency after permanent pacemaker implantation. Pacing Clin Electrophysiol 2004; 27:475–479. Korantzopoulos P, Letsas KP, Grekas G, Goudevenos JA. Pacemaker dependency after implantation of electrophysiological devices. Europace 2009; 11:1151–1155. Pascale P, Pruvot E, Graf D. Pacemaker syndrome during managed ventricular pacing mode: what is the mechanism? J Cardiovasc Electrophysiol 2009; 20:574–576. Sweeney MO, Ruetz LL, Belk P, Mullen TJ, Johnson JW, Sheldon T. Bradycardia pacing-induced short-long-short sequences at the onset of ventricular tachyarrhythmias: a possible mechanism of proarrhythmia? J Am Coll Cardiol 2007; 50:614–622. van Mechelen R, Schoonderwoerd R. Risk of managed ventricular pacing in a patient with heart block. Heart Rhythm 2006; 3:1384–1385. Vavasis C, Slotwiner DJ, Goldner BG, Cheung JW. Frequent recurrent polymorphic ventricular tachycardia during sleep due to managed ventricular pacing. Pacing Clin Electrophysiol 2010; 33:641–644. Auricchio A, Ellenbogen KA. Reducing ventricular pacing frequency in patients with atrioventricular block: is it time to change the current pacing paradigm? Circ Arrhythm Electrophysiol 2016; 9:. Stockburger M, Boveda S, Moreno J, et al. Long-term clinical effects of ventricular pacing reduction with a changeover mode to minimize ventricular pacing in a general pacemaker population. Eur Heart J 2015; 36:151–157. Nielsen JC, Thomsen PE, Højberg S, et al. A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. Eur Heart J 2011; 32:686–696. Alboni P, Menozzi C, Brignole M, et al. Effects of permanent pacemaker and oral theophylline in sick sinus syndrome the THEOPACE study: a randomized controlled trial. Circulation 1997; 96:260–266. Lamas GA, Lee KL, Sweeney MO, et al. Mode selection trial in sinus-node dysfunction. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002; 346:1854–1862. Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet 1994; 344:1523–1528. Link MS, Hellkamp AS, Estes NA 3rd, et al. High incidence of pacemaker syndrome in patients with sinus node dysfunction treated with ventricularbased pacing in the Mode Selection Trial (MOST). J Am Coll Cardiol 2004; 43:2066–2071. Sulke N, Chambers J, Dritsas A, Sowton E. A randomized double-blind crossover comparison of four rate-responsive pacing modes. J Am Coll Cardiol 1991; 17:696–706. Capucci A, Boriani G, Specchia S, Marinelli M, Santarelli A, Magnani B. Evaluation by cardiopulmonary exercise test of DDDR versus DDD pacing. Pacing Clin Electrophysiol 1992; 15:1908–1913. Padeletti L, Pieragnoli P, Di Biase L, et al. Is a dual-sensor pacemaker appropriate in patients with sino-atrial disease? Results from the DUSISLOG study. Pacing Clin Electrophysiol 2006; 29:34–40. Sweeney MO, Bank AJ, Nsah E, et al. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357:1000–1008. 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Cheng S, Keyes MJ, Larson MG, et al. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. J Am Med Assoc 2009; 301:2571–2577. Nielsen JC, Thomsen PE, Hojberg S, et al. Atrial fibrillation in patients with sick sinus syndrome: the association with PQ-interval and percentage of ventricular pacing. Europace 2012; 14:682–689. Biffi M, Bertini M, Saporito D, et al. Automatic management of atrial and ventricular stimulation in a contemporary unselected population of pacemaker recipients: the ESSENTIAL Registry. Europace 2016; 18:1551–1560. Sperzel J, Milasinovic G, Smith TW, et al. Automatic measurement of atrial pacing thresholds in dual-chamber pacemakers: clinical experience with atrial capture management. Heart Rhythm 2005; 2:1203–1210. Lau CP, Rushby J, Leigh-Jones M, et al. Symptomatology and quality of life in patients with rate-responsive pacemakers: a double-blind, randomized, crossover study. Clin Cardiol 1989; 12:505–512. Oto MA, Muderrisoglu H, Ozin MB, et al. Quality of life in patients with rate responsive pacemakers: a randomized, cross-over study. Pacing Clin Electrophysiol 1991; 14:800–806. Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: a randomized, controlled study. Circulation 1998; 98:953–960. Lim KT, Davis MJ, Powell A, et al. Ablate and pace strategy for atrial fibrillation: long-term outcome of AIRCRAFT trial. Europace 2007; 9: 498–505. Orlov MV, Gardin JM, Slawsky M, et al. Biventricular pacing improves cardiac function and prevents further left atrial remodeling in patients with symptomatic atrial fibrillation after atrioventricular node ablation. Am Heart J 2010; 159:264–270. Palmisano P, Aspromonte V, Ammendola E, et al. Effect of fixed-rate vs. rate-RESPONSIve pacing on exercise capacity in patients with permanent, refractory atrial fibrillation and left ventricular dysfunction treated with atrioventricular junction aBLation and bivEntricular pacing (RESPONSIBLE): a prospective, multicentre, randomized, single-blind study. Europace 2017; 19:414–420. Brignole M, Menozzi C. The natural history of carotid sinus syncope and the effect of cardiac pacing. Europace 2011; 13:462–464. Ziacchi M, Palmisano P, Ammendola E, et al. Clinically guided pacemaker choice and setting: pacemaker expert programming study. Europace 2017; 19:1500–1507. Madigan NP, Flaker GC, Curtis JJ, Reid J, Mueller KJ, Murphy TJ. Carotid sinus hypersensitivity: beneficial effects of dual-chamber pacing. Am J Cardiol 1984; 53:1034–1040. Brignole M, Sartore B, Barra M, Menozzi C, Lolli G. Is DDD superior to VVI pacing in mixed carotid sinus syndrome? An acute and medium-term study. Pacing Clin Electrophysiol 1988; 11:1902–1910. Sutton R. Pacing in patients with carotid sinus and vasovagal syndromes. Pacing Clin Electrophysiol 1989; 12:1260–1263. McLeod CJ, Trusty JM, Jenkins SM, et al. Method of pacing does not affect the recurrence of syncope in carotid sinus syndrome. Pacing Clin Electrophysiol 2012; 35:827–833. Johansen JB, Bexton RS, Simonsen EH, Markowitz T, Erickson MK. Clinical experience of a new rate drop response algorithm in the treatment of vasovagal and carotid sinus syncope. Europace 2000; 2:245–250. Benditt DG, Sutton R, Gammage MD, et al. Clinical experience with Thera DR rate-drop response pacing algorithm in carotid sinus syndrome and vasovagal syncope. The International Rate-Drop Investigators Group. Pacing Clin Electrophysiol 1997; 20 (3 Pt 2):832–839. Connolly SJ, Sheldon R, Roberts RS, Gent M, The North American Vasovagal Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 1999; 33:16–20. Sutton R, Brignole M, Menozzi C, et al. Dual- chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope: pacemaker versus no therapy: a multicenter randomized study. The Vasovagal Syncope International Study (VASIS) Investigators. Circulation 2000; 102:294–299. Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. J Am Med Assoc 2003; 289:2224–2229. Raviele A, Giada F, Menozzi C, et al. A randomized, double-blind, placebocontrolled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope: the vasovagal syncope and pacing trial (SYNPACE). Eur Heart J 2004; 25:1741–1748. © 2018 Italian Federation of Cardiology. All rights reserved. Device programming in bradycardia patients Palmisano et al. 11 73 74 75 76 77 78 79 80 Brignole M, Sutton R, Menozzi C, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope. Eur Heart J 2006; 27:2232–2239. Brignole M, Sutton R. Pacing for neurally mediated syncope: is placebo powerless? Europace 2007; 9:31–33. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012; 125:2566–2571. Ellenbogen KA, Morillo CA, Wood MA, Gilligan DM, Eckberg DL, Smith ML. Neural monitoring of vasovagal syncope. Pacing Clin Electrophysiol 1997; 20:788–794. Fitzpatrick A, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol 1991; 17:125–130. Fitzpatrick AP, Travill CM, Vardas PE, et al. Recurrent symptoms after ventricular pacing in unexplained syncope. Pacing Clin Electrophysiol 1990; 13:619–624. Petersen ME, Price D, Williams T, et al. Short AV interval VDD pacing does not prevent tilt induced vasovagal syncope in patients with cardioinhibitory vasovagal syndrome. Pacing Clin Electrophysiol 1994; 17 (5 Pt 1):882–891. Ammirati F, Colivicchi F, Toscano S, et al. DDD pacing with rate drop response function versus DDI with rate hysteresis pacing for cardioinhibitory vasovagal syncope. Pacing Clin Electrophysiol 1998; 21:2178–2181. 81 82 83 84 85 86 Occhetta E, Bortnik M, Vassanelli C. The DDDR closed loop stimulation for the prevention of vasovagal syncope: results from the INVASY prospective feasibility registry. Europace 2003; 5:153–162. Palmisano P, Dell’Era G, Russo V, et al. Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refrac\tory cardioinhibitory vasovagal syncope: the Tilt test-Induced REsponse in Closed-loop Stimulation multicentre, prospective, single blind, randomized study. Europace 2017; doi: 10.1093/europace/eux015 [Epub ahead of print]. Occhetta E, Bortnik M, Audogliob R, Vassanellia C. Closed loop stimulation in prevention of vasovagal syncope: inotropy controlled pacing in vasovagal syncope (INVASY): a multicentre randomized, single blind, controlled study. Europace 2004; 6:538–547. Bortnik M, Occhetta E, Dell’Era G, et al. Long-term follow-up of DDDR closed-loop cardiac pacing for the prevention of recurrent vasovagal syncope. J Cardiovasc Med (Hagerstown) 2012; 13:242–245. Russo V, Rago A, Papa AA, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, singleblind, crossover study. Heart 2013; 99:1609–1613. Palmisano P, Zaccaria M, Luzzi G, Nacci F, Anaclerio M, Favale S. Closedloop cardiac pacing vs. conventional dual-chamber pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope: results of a long-term follow-up. Europace 2012; 14:1038–1043. © 2018 Italian Federation of Cardiology. All rights reserved.