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Background: The traditional nitroglycerin (NTG) head-up tilt test (HUTT) is time-consuming and the test duration is a barrier to widespread utilization in clinical practice. It was hypothesized that a short-duration protocol is not inferior to the traditional protocol regarding the positivity rate and has a similar distribution of hemodynamic response., Methods and Results: Patients undergoing HUTT were randomized 1:1 to a 10 min passive phase plus a 10 min 0.3 mg NTG if the passive phase was negative (Fast) or to a 20 min passive phase plus a 15 min 0.3 mg NTG if the passive phase was negative (Traditional). A sample size of 277 patients for each group achieved 80% power to detect an expected difference of 0% with a non-inferiority margin of -10% using a one-sided t-test and assuming a significant level alpha of 0.025. A total of 554 consecutive patients (mean age 46.6 ± 19.3 years, 47.6% males) undergoing HUTT for suspected vasovagal syncope were randomly assigned to the Fast (n = 277) or Traditional (n = 277) protocol. A positive response was defined as the induction of syncope in presence of hypotension/bradycardia, and was observed in 167 (60.3%) patients with Fast and in 162 (58.5%) patients with the Traditional protocol. There was a trend of lesser vasodepressor response (14.8% Fast vs. 20.6% Traditional) which was significant during the passive phase (P = 0.01)., Conclusion: The diagnostic value of the Fast HUTT protocol is similar to that of the Traditional protocol and therefore the Fast protocol can be used instead of the Traditional protocol., Competing Interests: Conflict of interest All authors declare no conflict of interest for this contribution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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: Unexplained syncope is an important clinical challenge. The influence of age at first syncope on the final syncope diagnosis is not well studied., Methods and Results: Consecutive head-up tilt patients (n = 1928) evaluated for unexplained syncope were stratified into age groups <30, 30-59, and ≥60 years based on age at first syncope. Clinical characteristics and final syncope diagnosis were analysed in relation to age at first syncope and age at investigation. The age at first syncope had a bimodal distribution with peaks at 15 and 70 years. Prodromes (64 vs. 26%, P < 0.001) and vasovagal syncope (VVS, 59 vs. 19%, P < 0.001) were more common in early-onset (<30 years) compared with late-onset (≥60 years) syncope. Orthostatic hypotension (OH, 3 vs. 23%, P < 0.001), carotid sinus syndrome (CSS, 0.6 vs. 9%, P < 0.001), and complex syncope (>1 concurrent diagnosis; 14 vs. 26%, P < 0.001) were more common in late-onset syncope. In patients aged ≥60 years, 12% had early-onset and 70% had late-onset syncope; older age at first syncope was associated with higher odds of OH (+31% per 10-year increase, P < 0.001) and CSS (+26%, P = 0.004). Younger age at first syncope was associated with the presence of prodromes (+23%, P < 0.001) and the diagnoses of VVS (+22%, P < 0.001) and complex syncope (+9%, P = 0.018)., Conclusion: In patients with unexplained syncope, first-ever syncope incidence has a bimodal lifetime pattern with peaks at 15 and 70 years. The majority of older patients present only recent syncope; OH and CSS are more common in this group. In patients with early-onset syncope, prodromes, VVS, and complex syncope are more common., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: In patients with atrial fibrillation (AF) and heart failure (HF), strict and regular rate control with atrioventricular junction ablation and biventricular pacemaker (Ablation + CRT) has been shown to be superior to pharmacological rate control in reducing HF hospitalizations. However, whether it also improves survival is unknown., Methods and Results: In this international, open-label, blinded outcome trial, we randomly assigned patients with severely symptomatic permanent AF >6 months, narrow QRS (≤110 ms) and at least one HF hospitalization in the previous year to Ablation + CRT or to pharmacological rate control. We hypothesized that Ablation + CRT is superior in reducing the primary endpoint of all-cause mortality. A total of 133 patients were randomized. The mean age was 73 ± 10 years, and 62 (47%) were females. The trial was stopped for efficacy at interim analysis after a median of 29 months of follow-up per patient. The primary endpoint occurred in 7 patients (11%) in the Ablation + CRT arm and in 20 patients (29%) in the Drug arm [hazard ratio (HR) 0.26, 95% confidence interval (CI) 0.10-0.65; P = 0.004]. The estimated death rates at 2 years were 5% and 21%, respectively; at 4 years, 14% and 41%. The benefit of Ablation + CRT of all-cause mortality was similar in patients with ejection fraction (EF) ≤35% and in those with >35%. The secondary endpoint combining all-cause mortality or HF hospitalization was significantly lower in the Ablation + CRT arm [18 (29%) vs. 36 (51%); HR 0.40, 95% CI 0.22-0.73; P = 0.002]., Conclusions: Ablation + CRT was superior to pharmacological therapy in reducing mortality in patients with permanent AF and narrow QRS who were hospitalized for HF, irrespective of their baseline EF., Study Registration: ClinicalTrials.gov Identifier: NCT02137187., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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 experience 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aim: The benefit of cardiac pacing in patients with severe recurrent reflex syncope and asystole induced by tilt testing has not been established. The usefulness of tilt-table test to select candidates for cardiac pacing is controversial., Methods and Results: We randomly assigned patients aged 40 years or older who had at least two episodes of unpredictable severe reflex syncope during the last year and a tilt-induced syncope with an asystolic pause longer than 3 s, to receive either an active (pacing ON; 63 patients) or an inactive (pacing OFF; 64 patients) dual-chamber pacemaker with closed loop stimulation (CLS). The primary endpoint was the time to first recurrence of syncope. Patients and independent outcome assessors were blinded to the assigned treatment. After a median follow-up of 11.2 months, syncope occurred in significantly fewer patients in the pacing group than in the control group [10 (16%) vs. 34 (53%); hazard ratio, 0.23; P = 0.00005]. The estimated syncope recurrence rate at 1 year was 19% (pacing) and 53% (control) and at 2 years, 22% (pacing) and 68% (control). A combined endpoint of syncope or presyncope occurred in significantly fewer patients in the pacing group [23 (37%) vs. 40 (63%); hazard ratio, 0.44; P = 0.002]. Minor device-related adverse events were reported in five patients (4%)., Conclusion: In patients aged 40 years or older, affected by severe recurrent reflex syncope and tilt-induced asystole, dual-chamber pacemaker with CLS is highly effective in reducing the recurrences of syncope. Our findings support the inclusion of tilt testing as a useful method to select candidates for cardiac pacing., Study Registration: ClinicalTrials.gov identifier NCT02324920, Eudamed number CIV-05-013546., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We tested the hypothesis that atrioventricular (AV) junction ablation in conjunction biventricular pacing [cardiac resynchronization (CRT)] pacing is superior to pharmacological rate-control therapy in reducing heart failure (HF) and hospitalization in patients with permanent atrial fibrillation (AF) and narrow QRS., Methods and Results: We randomly assigned 102 patients (mean age 72 ± 10 years) with severely symptomatic permanent AF (>6 months), narrow QRS (≤110 ms), and at least one hospitalization for HF in the previous year to AV junction ablation and CRT (plus defibrillator according to guidelines) or to pharmacological rate-control therapy (plus defibrillator according to guidelines). After a median follow-up of 16 months, the primary composite outcome of death due to HF, or hospitalization due to HF, or worsening HF had occurred in 10 patients (20%) in the Ablation+CRT arm and in 20 patients (38%) in the Drug arm [hazard ratio (HR) 0.38; 95% confidence interval (CI) 0.18-0.81; P = 0.013]. Significantly fewer patients in the Ablation+CRT arm died from any cause or underwent hospitalization for HF [6 (12%) vs. 17 (33%); HR 0.28; 95% CI 0.11-0.72; P = 0.008], or were hospitalized for HF [5 (10%) vs. 13 (25%); HR 0.30; 95% CI 0.11-0.78; P = 0.024]. In comparison with the Drug arm, Ablation+CRT patients showed a 36% decrease in the specific symptoms and physical limitations of AF at 1 year follow-up (P = 0.004)., Conclusion: Ablation+CRT was superior to pharmacological therapy in reducing HF and hospitalization and improving quality of life in elderly patients with permanent AF and narrow QRS., Clinicaltrials.gov Identifier: NCT02137187 (May 2018, date last accessed).

Aims: This prospective multicentre observational study assessed the efficacy of specific therapy based on implantable loop recorder (ILR) diagnostic observations in patients with recurrent suspected neurally mediated syncope (NMS)., Methods and Results: Patients with three or more clinically severe syncopal episodes in the last 2 years without significant electrocardiographic and cardiac abnormalities were included. Orthostatic hypotension and carotid sinus syncope were excluded. After ILR implantation, patients were followed until the first documented syncope (Phase I). The ILR documentation of this episode determined the subsequent therapy and commenced Phase II follow-up. Among 392 patients, the 1-year recurrence rate of syncope during Phase I was 33%. One hundred and three patients had a documented episode and entered Phase II: 53 patients received specific therapy [47 a pacemaker because of asystole of a median 11.5 s duration and six anti-tachyarrhythmia therapy (catheter ablation: four, implantable defibrillator: one, anti-arrhythmic drug: one)] and the remaining 50 patients did not receive specific therapy. The 1-year recurrence rate in 53 patients assigned to a specific therapy was 10% (burden 0.07 +/- 0.2 episodes per patient/year) compared with 41% (burden 0.83 +/- 1.57 episodes per patient/year) in the patients without specific therapy (80% relative risk reduction for patients, P = 0.002, and 92% for burden, P = 0.002). The 1-year recurrence rate in patients with pacemakers was 5% (burden 0.05 +/- 0.15 episodes per patient/year). Severe trauma secondary to syncope relapse occurred in 2% and mild trauma in 4% of the patients., Conclusion: A strategy based on early diagnostic ILR application, with therapy delayed until documentation of syncope allows a safe, specific, and effective therapy in patients with NMS.

Aims: The guidelines of the European Society of Cardiology (ESC) define the current standard for the management of syncope, but are still incompletely applied in the clinical setting., Methods and Results: Prospective systematic evaluation, on strict adherence to the guidelines, of consecutive patients referred for syncope to the emergency departments of 11 general hospitals. In order to maximize the application, a decision-making guideline-based software was used and trained core medical personnel were designated-both locally in each hospital and centrally-to verify adherence to the diagnostic pathway and give advice on its correction. A diagnostic work-up consistent with the guidelines was completed in 465/541 patients (86%). A definite diagnosis was established in 98% (unexplained in 2%): neurally mediated syncope accounted for 66% of diagnosis, orthostatic hypotension 10%, primary arrhythmias 11%, structural cardiac or cardiopulmonary disease 5%, and non-syncopal attacks 6%, respectively. The initial evaluation (consisting of history, physical examination, and standard electrocardiogram) established a diagnosis in 50% of cases. Hospitalization for the management of syncope was appropriate in 25% and was required for other reasons in a further 13% of cases. The median in-hospital stay was 5.5 days (interquartile range, 3-9). Apart from the initial evaluation, a mean of 1.9+/-1.1 appropriate tests per patient was performed in 193 patients and led to a final diagnosis in 182 of these (94%)., Conclusion: The results of this study assess the current standard for the management of syncope on the basis of a rigorous adherence to guidelines of the ESC and provide a frame of reference for daily activity when dealing with syncope.

Aim: To evaluate the incidence, diagnostic yield and safety of implantable loop recorders (ILRs) in patients with or without structural heart disease (SHD)., Methods and Results: Two-hospitals, observational, prospective study in consecutive patients with unexplained syncope who underwent an ILR implantation. Between November 1997 and December 2002, a total of 2052 patients with syncope were evaluated (referral population of 590000 inhabitants). The diagnosis remained unexplained in 371 (18%). Of these, 103 patients (5% of total, 28% of unexplained syncope) received an ILR. SHD was present in 38 (37%), and absent in 65 (63%). During a median follow-up of 13 months, syncope was recorded in 52 patients. While patients with and without SHD had similar incidence of syncope recurrence, its mechanism was different. Patients with SHD more frequently had paroxysmal AV block and tachyarrhythmias and patients without SHD more frequently had sinus bradycardia/sinus arrest or no arrhythmia. More patients with SHD finally received an ILR-guided therapy. Sudden death occurred in one patient with SHD. Five syncope-related injuries were noted in 3 patients., Conclusion: The mechanism of syncope is different in patients with and without SHD; diagnostic yield and safety are similar in both groups. About 28% of patients with unexplained syncope have an indication to ILR implantation. The need for ILR implantation in the general population is 34 implants/million inhabitants/year.