European Heart Journal (2021) 42, 1654–1660 STATE OF THE ART REVIEW doi:10.1093/eurheartj/ehab084 Arrhythmias Tilt testing remains a valuable asset Richard Sutton 1*, Artur Fedorowski 2, Brian Olshansky 3, J. Gert van Dijk4, Haruhiko Abe5, Michele Brignole 6, Frederik de Lange 7, Rose Anne Kenny8, Phang Boon Lim9, Angel Moya10, Stuart D. Rosen11, Vincenzo Russo12, Julian M. Stewart 13, Roland D. Thijs 4, and David G. Benditt14 1 Department of Cardiology, Imperial College, London, UK; 2Department of Cardiology, Skåne University Hospital and Lund University, Malmö, Sweden; 3Department of Cardiology, University of Iowa, Iowa City, IA, USA; 4Department of Neurology, Leiden University Medical Centre, The Netherlands; 5Department of Heart Rhythm Management, University of Occupational and Environmental Health, Kitakyushu, Japan; 6Istituto Auxologico Italiano, Faint & Fall Programme, Ospedale San Luca, Milano, Italy; 7Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, University of Amsterdam, Heart Centre, Amsterdam, The Netherlands; 8School of Medicine, Trinity College, Dublin, Ireland; 9Department of Cardiology, Hammersmith Hospital, Imperial College, London, UK; 10Department of Cardiology, Dexeus University Hospital, Barcelona, Spain; 11National Heart & Lung Institute, Royal Brompton Hospital, Imperial College, London, UK; 12Department of Translational Sciences, University of Campania, Naples, Italy; 13Department of Pediatrics, New York Medical College, Valhalla, NY, USA; and 14Cardiac Arrhythmia Center, Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA Received 25 July 2020; revised 5 September 2020; editorial decision 29 January 2021; accepted 5 February 2021; online publish-ahead-of-print 24 February 2021 Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experi- ence supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients. ................................................................................................................................................................................................... Graphical Abstract ................................................................................................................................................................................................... Keywords Tilt-table test • Vasovagal syncope • Syncope • Orthostatic hypotension • Postural orthostatic tachycardia syndrome • Psychogenic pseudosyncope • Active stand • ECG-loop recorders * Corresponding author. Tel: þ44 20 7594 5735, Email: r.sutton@imperial.ac.uk C The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestrict- ed reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Tilt-table testing 1655 .. Introduction .. .. provocation had the highest diagnostic odds ratio (14.40; 95% CI 11.50–18.05) and greatest sensitivity (66%; 95% CI 60–72%). Head-up tilt test (TT) has been used for more than half a century by .. .. Given the preponderance of evidence, and working independently physiologists and physicians to study heart rate and blood pressure .. (a few members of each group provided reviews of the other docu- .. adaptation to positional changes, to model responses to haemor- .. ment), the European Society of Cardiology (ESC)10 and the rhage, to assess characteristics of orthostatic hypotension (OH), and .. American College of Cardiology/American Heart Association/Heart .. to evaluate haemodynamic and neuroendocrine responses in con- .. Rhythm Society collaboration11 arrived at similar and closely coher- gestive heart failure, autonomic dysfunction, and hypertension. .. ent recommendations for TT in unexplained syncope after initial clin- .. During these studies, some subjects experienced total or near-total .. ical assessment [i.e. detailed history and basic examination including transient loss of consciousness (TLOC) due to hypotension .. electrocardiogram (ECG) and orthostatic blood pressure measure- .. induced by TT (often accompanied by bradycardia/asystole).1–4 .. ment], agreeing on a class IIA indication. Furthermore, both groups .. proposed that when an autonomic disturbance was deemed likely, Consequently, beginning in late 1980s, TT was incorporated into clin- .. ical assessment of syncope of unknown origin1 as a method of trigger- .. TT (with additional cardiovascular autonomic assessment, if appro- .. ing the vasovagal reflex in susceptible individuals by exposing them to .. priate) should be a preferred component of the diagnostic strategy. controlled orthostatic challenge in a safe, monitored, clinical labora- .. Recent criticisms by Kulkarni et al.9 suggest that, like any diagnostic .. tory environment.1,5–8 However, the clinical utility of TT has been .. test, TT can be inappropriately applied. Nevertheless, extensive ex- criticised most recently by Kulkarni et al.,9 who promoted the less .. perience, as well as evidence-based practice guideline recommenda- .. well-studied active stand test largely based on the presumption of .. tions, provides clear direction for its appropriate application and .. indicates when so TT is an important, effective diagnostic tool. Use of lesser expense and, perhaps, greater convenience. In this review, .. while acknowledging TT limitations, we aim to offer counterpoint to .. other orthostatic stressors might be contemplated (e.g. active stand- .. ing, squat-stand test), but these have not undergone the scrutiny as the views of Kulkarni et al.9 by emphasizing both TT’s well- .. documented clinical value and recommendations by multiple practice .. potential clinical tools to the degree that has TT, excepting evaluation .. of initial and classical OH and postural orthostatic tachycardia syn- guidelines (Table 1). .. .. drome where active standing is well recognized, supported by evi- .. dence and, thus, by guidelines.10,11 .. Current status of tilt testing .. .. .. A positive TT has diagnostic value in syncope/collapse when the his- .. .. Syncope and tilt testing tory does not provide a conclusive explanation for symptoms.10,11 If .. .. Tilt-table testing was introduced into clinical evaluation of TLOC of the history yields a clear diagnosis, TT is not required; nonetheless, .. unknown aetiology to assess susceptibility to vasovagal reflex. Such TT may provide important patient education and reassurance, to- .. testing is unnecessary for diagnosis if medical history is classical and gether with pathophysiological evidence of the underlying mecha- .. .. diagnostic of reflex syncope. However, that is often not the case, es- nisms, critical for the selection of appropriate therapy.12 .. The methodology and interpretation of TT results have evolved .. pecially in older patients in whom the history may be inadequate due .. in part to retrograde amnesia in these older fainters.23 since it was introduced into clinical practice.1 Initially, prolonged TTs, .. up to 2 h at angles 40–60 , were used to trigger vasovagal events in .. TLOC has four features that can be derived from history taking: (i) .. tendency to fall as expression of loss of motor control; (ii) amnesia susceptible individuals. Subsequently, test duration was shortened, .. .. for duration of TLOC; (iii) abnormal responses to speech/touch; and head-up angle was defined as 60–80 , and other interventions were .. .. (iv) short duration (<5 min). added to improve test sensitivity.13–21 These interventions included .. TLOC differential diagnosis includes: (i) concussion, (ii) syncope; administration of drugs (e.g. isoproterenol, nitroglycerine, serotonin .. (iii) epileptic seizures; (iv) psychogenic spells resembling syncope agonists) alone or in conjunction with physical manoeuvres, such as .. .. [psychogenic pseudosyncope (PPS)] or seizures [psychogenic non- carotid sinus massage. Several of these provocative measures .. epileptic seizures (PNES)]; and (v) intoxication/metabolic disturbance improved TT sensitivity and remain in use; however, their addition .. .. (strictly not TLOC as duration is >5 min). may reduce specificity. .. Distinction between these diagnostic entities by careful medical .. Regarding TT for evaluating the syncope of unknown origin, .. history including eyewitness reports is often but not always possible. Forleo et al.22 reported a meta-analysis of 55 studies incorporating .. In some patients with recurrent apparent syncope, in whom previ- .. patients with unexplained syncope and asymptomatic controls with- .. ous attempts have failed to establish a diagnosis, TT is the best next out history of syncope. The authors excluded studies with <10 .. .. step and guidelines support this strategy.10,11 For example, if PPS, patients and procedures with tilt angulation <60 or >80 ; the evalu- .. PNES, or mechanical falls due to orthostatic intolerance are possible ation thereby comprised 4361 patients with syncope (aged .. .. explanations, observations during TT are likely to be diagnostic. 41 ± 17 years) and 1791 controls (aged 39 ± 17 years). The summary .. Concomitant use of electroencephalography (EEG) is readily added .. receiver-operating curve demonstrated good overall ability to differ- .. to TT and is considered essential in PPS/PNES.24 In OH, TT allows entiate symptomatic patients from asymptomatic controls with an .. safe prolonged blood pressure assessment without risk of falls and in- .. area under the curve of 0.84 [95% confidence interval (CI) 0.81– .. jury such as might occur during active stand or squat-stand tests. 0.87]. As expected, pharmacological protocols enhanced sensitivity .. However, TT is less effective than active standing for documenting .. but reduced specificity. Tilt protocols that included nitroglycerine . immediate OH, where the latter is recommended.10,11 1656 R. Sutton et al. .. Multiple observations suggest that reported syncope/collapse .. For instance, a transient sensation of ‘greying out/dizziness/light-head- associated with positive TT is comparable with spontaneous vaso- .. edness/unsteadiness’ is common immediately after upright postural .. vagal syncope (VVS), although it should be accepted that tilt-induced .. change (so-called ‘initial’ or ‘immediate’ OH). While usually harmless, syncope is not identical to the spontaneous attack. For example, the .. this sensation may cause alarm/instability in some patients.10 Active .. bradyarrhythmias seen on implantable loop recorders (ILR) are .. standing is sufficient to document this problem and initiate treatment. more prominent than during TT.6 However, VVS diagnosis from TT .. Thus, active standing should be seen as a necessary, complementary .. is based on the patient-recognizing symptom reproduction (Figure 1). .. aspect of cardiovascular autonomic workup in unexplained syncope, Thus, TT can play an important role in VVS diagnosis but much less in .. .. optimally with beat-to-beat haemodynamic monitoring for diagnostic therapy selection.5,10,11,25 .. accuracy. The Fainting Assessment Study (FAST),25 the clinical study of .. .. Delayed OH is a far more important clinical problem, especially in Wieling et al.,26 and the review of Sutton et al.27 reported a diagnostic .. older patients, debilitated patients, those with neurogenic OH, or in yield of 60% achieved by hospital physicians. The review later .. .. diseases that affect neurological responses, such as diabetes or alco- showed the diagnostic yield rises from 60% to 70% by hospital physi- .. .. hol abuse. In these cases, OH may be considerably delayed after cians following ESC guidelines to 85% in syncope units where TT, al- .. change of posture that can result in fall injury. Active standing may beit not applied in all cases, and expert history taking and .. .. not be tolerated for sufficient time to be diagnostic with additional interpretation are available.25–27 .. .. fall injury risk during testing. TT avoids injury risk while providing the Finally, clinicians caring for syncope/collapse victims realize that in .. possibility of defining the diagnosis. patients of all ages, recurrent unexplained syncope/collapse may pro- .. voke considerable anxiety in those affected and their families. In the .. .. case of faints due to VVS/OH/PPS, the patient’s understanding that .. Pathophysiology of syncope the physician or highly trained assistant28 has witnessed their attack .. .. and, thereby, has a firm diagnosis is greatly reassuring. TT offers this .. Tilt testing has added greatly to our understanding of syncope mech- .. opportunity. .. anisms and different collapse patterns,10 but these are not further dis- .. cussed in this review, which is focused on the clinical place of TT. .. .. Tilt-test methodology .. .. Detailed discussion of TT protocols is provided in several practice .. Pros and cons of tilt testing .. guidelines and consensus reports.8,10,11 Failure to follow protocols, .. Since its clinical introduction, the utility of TT has not been without especially for induction of syncope, will lead to misinterpretation. In .. .. criticism, as discussed above in light of Kulkarni et al.’s9 opinion. It addition, the European Heart Rhythm Association has recommended .. must be re-emphasized that TT is supported by evidence-based pro- staffing requirements for performing tilt-table testing including use of .. .. fessional society practice guidelines.10,11 Furthermore, guidelines highly trained personnel other than physicians.28 .. .. strongly emphasize that such testing is not necessary when the clinic- The 2018 ESC syncope guidelines10 give tilt-table testing a IIb indi- .. al history is clear-cut.10,11 cation (level of evidence C) to discriminate convulsive syncope from .. .. Mortality is not an issue in most patients who undergo TT. The epilepsy. Misdiagnosis of epilepsy as syncope is a more frequently rec- .. typical TT candidate is in a low-to-intermediate risk category, in ognized problem and tilt-table testing has been shown to be helpful .. .. whom a diagnosis is needed but has not been revealed at initial as- in this regard.29 The addition of EEG monitoring to assist in making .. .. sessment by clinical history, physical examination including orthostat- this distinction has proved particularly valuable and may readily be .. ic blood pressure measurement and 12-lead ECG.10,11,25–27 TT is one added to TT.30,31 .. Increasingly, laboratories that undertake TT are encouraged to in- .. means of reaching a diagnosis when not yet made; TT has almost no .. risks except rare, transient, atrial fibrillation, and very rare, prolonged, clude active stand testing in assessing patients.9,10 However, active .. .. self-terminating asystole.10 TT demands detailed and thoughtful ana- standing should not be confused with TT. While both introduce .. .. lysis of available data including that previously collected at initial clinic- orthostatic stress, there are important physiological differences. Active standing, unlike passive head-up tilt, invokes the skeletal .. al assessment where history from the patient and eyewitnesses of .. spontaneous syncope/collapse play the most important part. muscle pump. The European guidelines10 recommend active standing .. .. Tilt-test reproducibility and estimated specificity and sensitivity are as the initial test for patients suspected of OH. However, the addition .. of high-quality heart rate and blood pressure recordings and other .. summarised in the recent European guidelines.10 It should be reiter- .. ated that there is no gold standard with which TT can be compared, monitoring devices such as assessment of cerebral perfusion32 is .. cumbersome and thereby more difficult to achieve during active .. although the follow-up expert review committee in FAST is a step to- .. wards.25 Reproducibility of positive tests is reduced in second tests standing than during TT. Furthermore, with a diagnostic goal of induc- .. ing previously experienced symptoms, the duration of the upright .. and further in third tests to 80% positives in each.15 The decreasing .. period must be >20 min and, typically, 35 min.10 A long duration of .. positivity may be explained by the patient being aware of the unpleas- active standing cannot be expected to be tolerated by many patients, .. antness of outcome, attempting in any way to avoid it. Leg movement .. especially the frail/aged. .. is one obvious way. However, in severely affected VVS patients, re- Moving from supine to upright posture rarely induces syncope in .. producibility is high. This disadvantage of TT is rarely a clinical prob- .. normal healthy patients but may cause minor worrisome symptoms. . lem as repeat testing is seldom necessary. Tilt-table testing 1657 Figure 1 Courtesy of Artur Fedorowski MD and Fabrizio Ricci MD (Malmo, Sweden) depicting blood pressure (upper traces) and heart rate (lower trace) during a head-up tilt test-induced mixed collapse pattern of vasovagal faint. In this case, nitroglycerin was administered sublingually after 20 min of passive upright posture proved non-diagnostic. The expanded images illustrate the collapse using the same format beginning with adminis- tration of nitroglycerin; events, prodrome, syncope, tilt-down and awakening are labelled. Time base is shown between the left two panels in minutes. The scales are blood pressure 0–150 mmHg and heart rate 0–150 bpm. False-positive outcomes occur with TT just as with any medical .. ILR/insertable cardiac monitors (ICMs), which are yet unable to re- .. test, with a rate, expressed in terms of specificity and sensitivity,5 that .. cord blood pressure. TT may also have utility in reprogramming is comparable with many widely used medical tests, such as exercise .. pacemakers after syncope recurrence, although this has not been .. testing in daily cardiology practice. A positive TT in those who have .. widely adopted.40 .. never experienced syncope may be revealing a ‘hypotensive suscepti- .. Although TT may not be necessary to secure a diagnosis, it can bility’,5 which could manifest as syncope later in life. False negatives .. serve to teach patients about prodromes so they can learn to invoke .. also occur but are over-ridden by the history. Analysis of the litera- .. preventive measures, notably physical counter-measures, to abort ture shows that TT has acceptable sensitivity and specificity,10 which .. subsequent episodes.10,41 Tilt provocation of symptoms can, thus, be .. should be distinguished from the positivity rate.5,21 It is, however, less .. an educational tool and is recommended by ESC guidelines as a class good in the most difficult cases, which also applies widely in medi- .. IIB indication.10 .. cine.5 However, TT allows patients to confirm similarity, or its ab- .. In the case of treatment selection, pacing using the closed-loop sence, of induced to spontaneous symptoms. The difficulty in some .. system offers stimulation earlier in the vasovagal reflex than awaiting .. cases may be attributed to the overlap of a common reflex with an- .. bradycardia and, thus, a potentially effective therapy requiring consid- other important condition, such as hypertrophic cardiomyopathy. .. eration.12,42,43 However, if evidence from TT shows syncope due to Tilt testing to monitor the effects of therapy is not recommended ... hypotension preceding marked bradycardia by minutes, this may alter .. by European10 or North American11 practice guidelines. .. treatment strategy avoiding unnecessary pacemaker implantation.39 .. Nevertheless, TT can be useful, particularly in post-pacing syncope .. These issues have been reviewed in detail.43 Recent studies of TT recurrence in severe VVS33–38 when combined with other cardiovas- .. methodology have provided greater insight into the sequence of .. cular autonomic tests such as carotid sinus massage.10,36 TT can help .. haemodynamic events during VVS and may permit more appropriate in pacemaker therapy selection12 and predict syncope recurrence .. application of pacing systems.39,44,45 The impact of reducing venous .. after pacing; positive tilts pre-pacing are associated with a much .. return and stroke volume during evolving VVS seems to be key to higher recurrence rate than negative tilts with similarly positive ILR .. understanding the utility and limitations of pacing intervention.44 .. observations of VVS.5,34–37 An explanation may be that ‘hypotensive .. To summarize, TT has many pros in terms of its diagnostic, educa- susceptibility’ is present even when dominated by cardioinhibition. .. tional, patient reassurance and choice of pacing therapy with few .. Another may be that timing of development of hypotension ahead of .. cons other than being a lengthy procedure; importantly, it has virtual- bradycardia is very important39 but impossible to determine from .. ly no risks. In contrast, active standing is really valuable only in 1658 R. Sutton et al. Table 1 Pros and cons of tilt testing, active standing, and implantable loop recorders/insertable cardiac monitors Diagnostic 1. TT helps assess susceptibility to VVS and/or OH in a controlled, safe environment AS is useful only in immediate and classical OH ILR/ICM offers delayed diagnosis, without BP 2. TT identifies patients with asystole who may require cardiac pacing based on temporal relationship of bradycar- dia/hypotension12,39 AS has no value ILR/ICM may identify asystole during spontaneous attacks 3. TT helps determine similarity of induced to spontaneous clinical symptoms AS is unlikely to be tolerable long enough to obtain this information ILR/ICM is very useful in recording arrhythmia/muscle artefacts during spontaneous attacks 4. TT identifies syncope mimics (PPS/PNES/ictal asystole) AS has no value ILR/ICM may show normal rhythm during syncope but no BP 5. TT offers safe, accessible means to study pathophysiology of syncope using, if necessary, EEG, cerebral perfusion assessment AS has no value ILR/ICM shows only arrhythmias Educational 1. TT helps in educating patients regarding identifying prodrome prompting preventive measures Reassurance by diagnosis of observed attack promoting confidence in recommended therapy AS may have value in teaching patients counterpressure manoeuvres, especially with displayed beat-to-beat BP ILR/ICM has no value 2. TT provides insight into syncope pathophysiology and its relation to treatment options - Better understanding of the timing relationship between vasodepression, TLOC, and cardioinhibition39 - TLOC occurring before cardioinhibition implies strong reluctance towards pacing therapy39 AS has no role ILR/ICM may confirm arrhythmic component but without BP Therapy selection-pacing TT shows asystole occurring after TLOC permitting avoidance of unnecessary pacing39 TT shows asystole before or coincides with hypotension points to symptomatic improvement with pacing12,43 AS has no role ILR/ICM shows asystole in spontaneous attack but incurs diagnostic delay awaiting further syncope and yields no BP Conditions other than VVS TT is optimal in OH (especially delayed OH), PPS/PNES/ictal asystole. TT is preferred for POTS10,11 AS cannot replace TT as standing unsupported for sufficient time is intolerable plus need for beat-to-beat BP, ECG in all and EEG in some to achieve clear result AS may be adequate for POTS ILR/ICM cannot offer definitive diagnosis except arrhythmia Major limitations of TT, Tilt-induced reflex may not be identical to spontaneous attacks with bradyarrhythmias being more frequent in spon- AS, and ILR taneous attacks TT is time-consuming, requires training for adequate interpretation, examination protocols differ with results not ne- cessarily comparable TT lab requires beat-to-beat monitor for optimal diagnostic accuracy TT has false positives that should be identified as not reproducing their attack, prompting other tests; also false nega- tives over which history takes precedence AS must be interrupted as soon as patients report prodromes or cannot stand without support leading to incom- plete recording of events AS cannot be used to study pathophysiology of cardiovascular dysautonomia/syncope when prolonged orthostatic challenge is required AS invokes leg-muscle pump ILR/ICM involves diagnostic delay, recurrence of syncope required with trauma risk ILR/ICM cannot record BP during syncope ILR/ICM is minimally invasive/costly in hardware and monitoring AS, active standing; BP, blood pressure; EEG, electroencephalography; ECG, electrocardiogram; ICM, insertable cardiac monitor; ILR, implantable loop recorder; OH, orthostat- ic hypotension; PNES, psychogenic non-epileptic seizures; POTS, postural orthostatic tachycardia syndrome; PPS, psychogenic pseudosyncope; TLOC, transient loss of con- sciousness; TT, tilt test; VVS, vasovagal syncope. Tilt-table testing 1659 .. immediate/classical OH. In delayed OH, it cannot replace tilt on .. Inc. and Abbott Laboratories (SJM). A.F. reports personal fees from grounds of haemodynamics and tolerability (Table 1). .. Biotronik Inc. and Medtronic Inc. H.A. is supported in part by re- .. .. search grants from Boston Scientific Inc., Medtronic Inc., and Abbott .. Laboratories. J.M.S. has funding from NHLBI Grant RO1HL134674. Cost containment and use of .. .. R.D.T. receives research support from Medtronic, consultancy fees .. from Theravance Biopharma, and lectures fees from Medtronic, other testing .. .. Union Chimique Belge, and Novartis. B.O. reports personal fees Management of syncope has become an unnecessarily expensive .. from Amarin, Boehringer Ingelheim, Sanofi Aventis, Respicardia, and .. undertaking.46 Nevertheless, recent data indicate that up to 42% of .. Lundbeck. J.G.v.D., M.B., F.d.L., P.B.L., R.A.K., A.M., S.D.R., and V.R. de- patients admitted with syncope are discharged without a diagnosis .. clare no conflicts of interest. .. and 23% are re-admitted for recurrences, often followed by non- .. diagnostic evaluation.10,11 The risk of adverse outcomes (e.g. mortal- .. References .. ity) is small but further expensive testing is not avoided. Many of .. 1. Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigat- .. ing unexplained syncope. Lancet 1986;327:1352–1355. these patients have undiagnosed VVS, which TT can provide prevent- .. 2. McMichael J, Sharpey-Schafer EP. Cardiac output in man by a direct Fick method; ing unnecessary and potentially harmful testing. .. effect of posture, venous pressure change, atropine and adrenaline. Br Heart J .. When the diagnosis is unclear from initial evaluation and there is .. 3. 1944;6:33–640. Davies R, Slater JDH, Forsling ML, Payne N. 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College of Cardiology/American Heart Association Task Force on Clinical Conflict of interest: R.S. is a consultant to Medtronic Inc., a mem- .. Practice Guidelines and the Heart Rhythm Society. Circulation 2017;136: ber of speakers’ bureau Abbott Laboratories Inc., and a stockholder .. .. 12. e60–e122. in Edwards Lifesciences Corp. and Boston Scientific Inc. D.G.B. is sup- .. Brignole M, Russo V, Arabia F, Oliveira M, Pedrote A, Aerts A, Rapacciuolo A, ported in part by grant from the Dr Earl E Bakken Family in support .. Boveda S, Deharo JC, Maglia G, Nigro G, Giacopelli D, Gargaro A, Tomaino M; .. BioSync CLS Trial Investigators. Cardiac pacing in severe recurrent reflex syn- of Heart-Brain research and reports consultant fees from Medtronic . cope and tilt-induced asystole. Eur Heart J 2020;doi:10.1093/eurheartj/ehaa936. 1660 R. Sutton et al. 13. Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. 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