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Background and Aims: Identifying the haemodynamic mechanism of autonomic syncope is the essential pre-requisite for effective and personalized therapy aimed at preventing recurrences. The present study assessed the diagnostic efficacy of a two-step assessment., Methods: Multicentre prospective, cross-sectional, observational study. Patients affected by severe autonomic syncope underwent a two-step assessment including 24-h ambulatory blood pressure monitoring and short cardiovascular autonomic function assessment (SCAFA). SCAFA consisted of carotid sinus massage (CSM), performed in patients ≥40 years old, a passive standing test, and a 'fast' head-up tilt test scheduled sequentially during one session on a tilt table., Results: The study population consisted of 333 patients, 102 ≤ 40 years old and 231 > 40 years old. Any positive response was observed in 298 (89%) patients (92 [92%] in younger and 134 [89%] in older), with hypotensive phenotype accounting for 226 (68%), bradycardic phenotype for 21 (6%) and mixed phenotype for 51 (15%) of cases. The mean duration of the SCAFA procedure was 25 (IQR 20-32) min. Ambulatory blood pressure monitoring, CSM, passive standing, and head-up tilt test were positive in 60%, 15%, 3%, and 71% of patients, respectively. More than one test was positive in 51% and 49% of patients ≤40 and >40 years, respectively. Large inter-centre variability of CSM positivity rate, which remained significant after adjustment for demographic and clinical variables, was observed (P = .003)., Conclusions: The standardized 2STEPS protocol offers an easy-to-perform and time-saving diagnostic work-up allowing identification of the haemodynamic mechanism of loss of consciousness in most patients with autonomic syncope. This protocol provides the necessary background for a personalized mechanism-specific therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. The study hypothesis was that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM., Methods and Results: ABPM data from reflex syncope patients and controls, matched by average 24 h SBP, age, sex, and hypertension were compared. Patients with constitutional hypotension, orthostatic hypotension, and predominant cardioinhibition during carotid sinus massage or prolonged electrocardiogram monitoring or competing causes of syncope were excluded. Daytime and nighttime SBP drops (<110, 100, 90, 80 mmHg) were assessed. Findings were validated in an independent sample. In the derivation sample, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drops <90 mmHg achieved 91% specificity and 32% sensitivity [odds ratio (OR) 4.6, P < 0.001]. Two or more daytime drops <100 mmHg achieved 84% specificity and 40% sensitivity (OR 3.5, P = 0.001). Results were confirmed in the validation sample of 164 syncope patients and 164 controls: one or more daytime SBP drops <90 mmHg achieved 94% specificity and 29% sensitivity (OR 6.2, P < 0.001), while two or more daytime SBP drops <100 mmHg achieved 83% specificity and 35% sensitivity (OR 2.6, P < 0.001)., Conclusion: SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope., Competing Interests: Conflicts of interests: R.S. declares the following potential conflicts of interest: consulting fees from Medtronic Inc (unrelated to present work); payment for expert testimony in medico-legal cases in UK (related to syncope but unrelated to this work); member of clinical events committee for the BioSync study (published in 2021 in European Heart Journal); Secretary to the Executive Board of World Society of Arrhythmias; private shareholder receiving only dividends from Boston Scientific Corp and Edwards Lifesciences Corp. A.F. has received speaker fees from Medtronic Inc., Biotronik, and Bristol-Myers Squibb, and is consultant to Medtronic Inc, and Argenx BV. The other authors declare no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: Indications, methodology, and diagnostic criteria for carotid sinus massage (CSM) and tilt testing (TT) have been standardized by the 2018 Guidelines on Syncope of the European Society of Cardiology. Aim of this study was to assess their effectiveness in a large cohort which reflects the performance under 'real-world' conditions., Methods and Results: We analysed all patients who had undergone CSM and TT in the years 2003-2019 for suspected reflex syncope. Carotid sinus massage was performed according to the 'Method of Symptoms'. Tilt testing was performed according to the 'Italian protocol' which consists of a passive phase followed by a sublingual nitroglycerine phase. For both tests, positive test was defined as reproduction of spontaneous symptoms in the presence of bradycardia and/or hypotension. Among 3293 patients (mean age 73 ± 12 years, 48% males), 2019 (61%) had at least one test positive. A bradycardic phenotype was found in 420 patients (13%); of these, 60% were identified by CSM, 37% by TT, and 3% had both test positive. A hypotensive phenotype was found in 1733 patients (53%); of these, 98% were identified by TT and 2% had both TT and CSM positive., Conclusion: The overall diagnostic yield of the tests in patients >40-year-old with suspected reflex syncope was 61%. Both CSM and TT are useful for identifying those patients with a bradycardic phenotype, whereas CSM has a limited value for identifying the hypotensive phenotype. Since the overlap of responses between tests is minimal, both CSM and TT should be performed in every patient over 40 years receiving investigation for unexplained but possible reflex syncope., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Either central or peripheral baroreceptor reflex abnormalities and/or alterations in neurohumoral mechanisms play a pivotal role in the genesis of neurally mediated syncope. Thus, improving our knowledge of the biochemical mechanisms underlying specific forms of neurally mediated syncope (more properly termed 'neurohumoral syncope') might allow the development of new therapies that are effective in this specific subgroup. A low-adenosine phenotype of neurohumoral syncope has recently been identified. Patients who suffer syncope without prodromes and have a normal heart display a purinergic profile which is the opposite of that observed in vasovagal syncope patients and is characterized by very low-adenosine plasma level values, low expression of A2A receptors and the predominance of the TC variant in the single nucleotide c.1364 C>T polymorphism of the A2A receptor gene. The typical mechanism of syncope is an idiopathic paroxysmal atrioventricular block or sinus bradycardia, most often followed by sinus arrest. Since patients with low plasma adenosine levels are highly susceptible to endogenous adenosine, chronic treatment of these patients with theophylline, a non-selective adenosine receptor antagonist, is expected to prevent syncopal recurrences. This hypothesis is supported by results from series of cases and from observational controlled studies., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: The aim of this study was to determine the long-term effects and determinants of success of cardiac pacing in patients affected by reflex syncope enrolled in the Syncope Unit Project 2 (SUP 2) study. Initial results have validated the effectiveness of a standardized guideline-based algorithm which can be used in clinical practice in order to select suitable candidates for cardiac pacing., Methods and Results: In this prospective, multicentre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncope, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. Of 281 patients who met the inclusion criteria, 137 (49%) received a pacemaker and were followed up for a mean of 26 ± 11 months: syncope recurred in 25 (18%) of them. At 3 years, the actuarial syncope recurrence rate was 20% [95% confidence interval (CI) 12-30] and was significantly lower than in 142 patients who did not receive a pacemaker and were observed by means of an ILR [43% (95% CI 29-57), P = 0.01]. The 3-year recurrence rate was not different among 78 CSM+, 38 TT+, and 21 ILR+ patients, whereas it was lower in 20 patients with negative TT [5% (95% CI 0-15)] than in 61 patients with positive TT [24% (95% CI 10-38)]., Conclusion: The benefit of cardiac pacing is maintained at 3 years, irrespective of the index diagnostic test, and is maximum in patients with negative TT., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01509534., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: to evaluate the safety and tolerability of Tilt Testing (TT) and Carotid Sinus Massage (CSM) in octogenarians with unexplained syncope., Methods: patients consecutively referred for transient loss of consciousness to the 'Syncope Units' of three hospitals were enrolled. TT and CSM were performed according to the European Society of Cardiology guidelines on syncope. Complications were evaluated in each group. An early interruption of TT was defined as 'intolerance' and considered as a non-diagnostic response., Results: one thousand four hundred and one patients were enrolled (mean age 72 ± 16 years, male 40.8%). Six hundred and ninety-four patients (49.5%) were 80 years old or older (mean age 83 ± 3 years) and 707 (50.5%) were younger (mean age 60 ± 17 years). Complications after TT occurred in 4.5% of older patients and in 2.1% of the younger ones (P = 0.01). All complications were 'minor/moderate', as prolonged hypotension, observed in ∼3% of patients ≥80 years. Major complications such as sustained ventricular tachycardia, ventricular fibrillation, asystole requiring cardiac massage, transient ischaemic attack, stroke and death were not observed in any patient. The presence of orthostatic hypotension and the mean number of syncopal episodes were predictors of TT complications. Intolerance was reported in 2.4% of older patients and 1% of the younger ones (P = 0.08), mainly due to orthostatic intolerance. No complications occurred after CSM., Conclusions: TT and CSM appear to be safe and well tolerated in octogenarians, who should not be excluded by age from the diagnostic work-up of syncope., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: High hospitalization rates (39-58% in the literature) of patients admitted to Emergency Department (ED) for transient loss of consciousness (T-LOC) suspected for syncope are still an unresolved issue. The presence of an Observation Unit has reduced hospital admissions and the duration of hospitalization in controlled studies, and a Syncope Unit (SU) in the hospital may reduce hospitalization and increase the number of diagnoses in patients with T-LOC. We assessed the effect of a structured organization on hospitalization rate and outcome., Methods and Results: Consecutive patients referred to the ED for a T-LOC of a suspected syncopal nature as the main diagnosis were included. The ED physician was trained to choose between: hospital admission (directly or after short observation); discharge after short (<48-h) observation; discharge on a fast track to the SU; and direct discharge without any further diagnostics. From January to June 2010, 362 patients were evaluated in the ED: 29% were admitted, 20% underwent short observation in the ED, 20% were referred to the SU, and 31% were directly discharged. Follow-up data were available on 295 patients who were discharged alive: of these, 1 (0.3%) previously hospitalized patient died within 30 days and 16 (5.4%) died within 1 year. Death rates were 12.9, 3.3, 0, and 2.5% among admitted, observation, SU, and ED-discharged patients, respectively. No death could be directly attributed to T-LOC. Re-admission within 1 year for any cause occurred in 72 (24%) patients; re-admission rates were 45.9, 19.3, 11.5, and 18.0% among admitted, observation, SU, and ED-discharged patients, respectively., Conclusions: The availability of short observation and a SU seems to reduce the hospitalization rate compared with previous reported historical reports from our and other centres. Most deaths during follow-up occurred in patients who had been hospitalized. High rates of re-admission to the ED within 1 year are still an issue., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Non-syncopal transient loss of consciousness (T-LOC) encompasses disorders that sometimes resemble syncope, and the differential diagnosis with true syncope may be challenging. The implantable loop recorder (ILR) is potentially useful, but has never been systematically assessed. The aim of the study is to evaluate the diagnostic value of ILR in distinguishing syncope from non-syncopal forms of T-LOC., Methods and Results: We implanted an ILR in 58 patients (mean age 71 ± 17 years, 25 males) who had had 4.6 ± 2.3 episodes of real or apparent T-LOC, in order to distinguishing epilepsy from syncope (#28), unexplained fall from syncope (#29), or functional pseudo-syncope from syncope (#1). During 20 ± 13 months of follow-up, 33 patients (57%) had a spontaneous event documented by ILR. A diagnosis of syncope was established by ILR documentation of an arrhythmia in 15 (26%) patients: an asystole of 6 s (IQR 4-10 s) duration was documented at the time of the spontaneous event in seven patients with initial suspicion of epilepsy and in five patients with unexplained fall; atrial tachyarrhythmia was documented at the time of the spontaneous event in 1 and 1 patient, respectively, and ventricular tachycardia in 1 patient with unexplained fall. Conversely, in another 18 patients, ILR monitoring documented no significant rhythm abnormalities at the time of T-LOC recurrence, thus excluding an arrhythmic syncope. Finally, ILR was unable to document any syncopal episode in 25 (43%) patients. Among the 15 patients with an established diagnosis of arrhythmic syncope, syncope recurred during follow-up in 2 of 11 patients who were on pacemaker therapy and in 3 of 4 patients who were on other therapies., Conclusion: Implantable loop recorder monitoring provides additional diagnostic value in 'difficult' patients with an initial diagnosis of non-syncopal real or apparent T-LOC., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)