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There is a growing interest in the study of the mechanisms of heart and brain interactions with the aim to improve the management of high-impact cardiac rhythm disorders, first of all atrial fibrillation. However, there are several topics to which the scientific interests of cardiologists and neurologists converge constituting the basis for enhancing the development of neuro-arrhythmology. This multidisciplinary field should cover a wide spectrum of diseases, even beyond the classical framework corresponding to stroke and atrial fibrillation and include the complex issues of seizures as well as loss of consciousness and syncope. The implications of a more focused interaction between neurologists and cardiologists in the field of neuro-arrhythmology should include in perspective the institution of research networks specifically devoted to investigate 'from bench to bedside' the complex pathophysiological links of the abovementioned diseases, with involvement of scientists in the field of biochemistry, genetics, molecular medicine, physiology, pathology and bioengineering. An investment in the field could have important implications in the perspectives of a more personalized approach to patients and diseases, in the context of 'precision'medicine. Large datasets and electronic medical records, with the approach typical of 'big data' could enhance the possibility of new findings with potentially important clinical implications. Finally, the interaction between neurologists and cardiologists involved in arrythmia management should have some organizational implications, with new models of healthcare delivery based on multidisciplinary assistance, similarly to that applied in the case of syncope units.

Aims Syncope without prodromes in subjects with normal heart and normal electrocardiogram (ECG) is classified as non-classical neurally mediated syncope and is characterized by low adenosine plasma levels (APLs) and frequent asystolic syncope. We assessed the efficacy of theophylline, a non-selective adenosine receptor antagonist, in preventing syncopal events. Methods and results Participants received an implantable cardiac monitor, underwent APL measurement, and received oral theophylline at maximum tolerated dose (starting dose 300 mg b.i.d.). They were compared with a historical cohort of untreated patients with implantable cardiac monitor who had the same inclusion criteria and were balanced with the propensity score (PS) method as regard age, sex, lifetime syncopal episodes, APL, and antihypertensive drugs. Primary endpoint was time to first syncopal recurrence at 24 months. There were 76 patients in the theophylline group and 58 in the control group. Syncope recurred in 25 (33%) patients in the theophylline group and in 27 (47%) patients in the control group, with an estimated 2-year recurrence rate of 33% and 60%, respectively, and a hazard ratio of 0.53 [95% confidence interval (CI), 0.30–0.95; P = 0.034]. Most of the benefit of theophylline is derived from reduction of syncope due to asystolic atrioventricular (AV) block (hazard ratio of 0.13; 95% CI, 0.03–0.58; P = 0.008). Thirty (39%) patients discontinued theophylline after a median of 6.4 (interquartile range 1.7–13.8) months due to side effects. Conclusion Theophylline was effective in preventing recurrences in patients with syncope without prodromes, normal heart, and normal ECG. The benefit was greater in patients with syncope due to asystolic AV block. ClinicalTrials.gov Identifier NCT03803215.

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.

In aged patients, the most frequent indications for anticoagulation are atrial fibrillation (AF) and venous thromboembolism for stroke and systemic embolism prevention. Despite systemic anticoagulation recommended by current guidelines for patients over 65 years, in clinical practice up to 50 % of elderly patients do not receive maintenance anticoagulation therapy. This is particularly evident in frail subjects at risk of syncopal and not-syncopal fall, fearing intracranial bleeding following a fall. As the risk of bleeding associated with falls is still debated, the boards of the Academy of Emergency Medicine and Care (AcEMC) and the Italian Multidisciplinary Working Group on Syncope (GIMSI), in order to write a consensus document, submitted to a panel of experts eight statement which could represent as many controversial topics for anticoagulant prescription in patients over 75 years. The Delphi method was used to obtain consensus between 15 physicians from different medical specialties; some of them were expert in syncope management and worked in a Syncope Unit. All had experience in prescribing oral anticoagulation. A questionnaire was sent on the appropriateness of oral anticoagulation in eight clinical situations where the risk of fall is present (frailty, cognitive impairment, previous falls, absence of caregiver, chronic renal impairment, nonvalvular AF with HAS-BLED score ≥3 or CHA2DS2-VASc score ≥3). All experts completed the questionnaire within three rounds and the consensus was reached on many but not all statements, leaving room for debate on some clinical situations. The consensus document gives useful advice for elderly patients’ management, who need oral anticoagulant therapy but are at risk of syncopal or not-syncopal fall. Nonetheless, there are some unresolved issues where an individual decision should be taken by the physician in agreement with the patient.

Objectives Most elderly patients affected by reflex vasodepressor syncope take one or more hypotensive drugs. The role of these drugs in causing syncope has not yet been established. We hypothesised that recurrence of syncope and presyncope can be reduced by discontinuing/reducing vasoactive therapy without increasing the risk of cardiovascular and neurological events. Methods This randomised, parallel, prospective, trial was conducted from January 2014 to March 2016 in four general hospitals. Of 328 initially screened participants, 58 patients (mean (SD) age 74±11 years) affected by vasodepressor reflex syncope, which was reproduced by tilt testing (n=54) or carotid sinus massage (n=4), were randomised to stop/reduce vasoactive therapy or to continue it. Primary end point was recurrence of syncope, presyncope or adverse events (defined as stroke, cerebral transient ischaemic attacks, worsening heart failure, myocardial infarction). Results Of 58 patients who were randomised, 55 completed the trial. After 1 month, systolic blood pressure was significantly higher in the ‘stop/reduce’ group than in the ‘continue’ group, in both supine (141±13 mm Hg vs 128±14 mm Hg; p=0.004) and standing (133±13 mm Hg vs 122±15 mm Hg; p=0.02) positions. During a mean follow-up of 13±7 months, the primary combined end point occurred in seven ‘stop/reduce’ patients (23%): three had syncope, three had presyncope and one had heart failure. Conversely, it occurred in 13 ‘continue’ patients (54%): 10 had syncope, 2 had presyncope and 1 had cerebral transient ischaemic attack. The log-rank p value was 0.02 and the HR was 0.37 (95% CI 0.15 to 0.91). Conclusions Recurrence of syncope and presyncope can be reduced by discontinuing/reducing vasoactive therapy in most elderly patients affected by reflex vasodepressor syncope. Trial registration number NCT01509534; EudraCT2013-004364-63; Results.

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International audience; Aim; Although the efficacy of cardiac pacing in patients with neurally mediated syncope (NMS) and documented asystole is established, a more robust point estimate of the benefit, which is not possible with any individual study, is lacking.Methods and results: We undertook a meta-analysis of individual participant data from four studies that reported follow-up data on syncope recurrence with cardiac pacing in patients with NMS who had had an electrocardiographic (ECG) documentation of an asystolic event by means of implantable loop recorder (ILR). Of a total of 1046 patients, who had ILR implanted, 383 (36.6%) patients had an ECG documentation of a diagnostic event during mean follow-up of 13 ± 10 months. Of these, 201 (52%) patients, corresponding to 19.2% of the total ILRs, had an asystolic event of 12.8 ± 11.0 s duration documented and met the criteria for pacemaker therapy. Follow-up was available in 121 (60%) of those patients with asystolic events. Syncope recurred after pacing in 18 (14.9%) patients with an actuarial rate of 13% [95% confidence interval (CI) ±6] at 1 year, 21% (95%CI ±10) at 2 years, and 24% (95%CI ±11) at 3 years. On multivariable Cox regression analysis, positive tilt test response was the only significant predictor of syncope recurrence with a hazard ratio (95% CI) of 4.3 (1.4–13). On the contrary, type of asystolic event (sinus arrest or atrioventricular block), prodrome, cardiac abnormalities, number and duration of history of syncope, age, and gender were not predictors of recurrence of syncope.Conclusion: A long asystolic pause, suitable for pacemaker therapy, was found in one of five patients with ILR. After pacemaker implantation, most of these patients remained free of syncope recurrence for up to 3 years. The benefit of pacemaker was greater in patients with negative tilt test.

Ritme cardíac; Síncope reflex neurològic; Prova de la taula d’inclinació Ritmo cardíaco; Síncope reflejo neuromediado; Prueba de la mesa inclinada Cardiac pacing; Neuro-mediated reflex syncope; Tilt-Table test Background: The efficacy of dual-chamber cardiac pacing in neuro-mediated reflex syncope with a cardio-inhibitory response to the Tilt-Table test (TT) has not been definitively assessed so far. The lack of reproducibility of results from previous studies may be partially explained by discrepancies in subject selection and some weaknesses in design and methods. The European Society of Cardiology (ESC) has set a class IIb indication to pacemaker implantation in this population recommending further research. Methods/design: The BIOSync study is a multicenter, patient- and outcome-assessor-blind, randomized, parallel-arm, placebo-controlled trial with the objective of assessing the clinical benefit of cardiac pacing in patients with frequently recurrent reflex syncope, suspected (but not proven) to be triggered by asystolic pauses as showing a VASIS 2B response to the TT (>3-s pause regardless of blood pressure drop). The primary and secondary endpoints are time to first post-implantation recurrence of syncope or the combination of pre-syncope or syncope, respectively. One hundred and twenty-eight consenting patients will be 1:1 randomized to dual-chamber cardiac pacing 'on' or 'off' after pacemaker implantation, and followed up until the first adjudicated primary endpoint event for a maximum of 2 years. The so-called Closed Loop Stimulation function on top of dual-chamber pacing is the pacing mode selected in the study active arm. Participating patients are asked to self-report syncopal symptoms at least every 3 months with self-administered questionnaires addressed to an independent Adjudication Committee. Patients and members of the Adjudicating Committee are blinded to randomization. The study is designed to detect a 40% relative reduction in the 2-year incidence of syncopal recurrences with 80% statistical power. Discussion: The BIOSync study is designed to definitively assess the benefit of pacing against placebo in reflex syncope patients with a cardio-inhibitory response to the TT. The study will also provide important information on the efficiency of the TT in appropriately selecting reflex syncope patients for cardiac pacing. All study-related costs are being directly supported by the sponsor of the study (BIOTRONIK SE & Co. KG, Berlin, Germany). No further funding is provided.

Whereas cardiac pacing has a very limited role overall in patients with vasovagal syncope (VVS), there are three reasons which support pacing efficacy in tilt-induced asystolic VVS. These are: (1) contrary to mixed and vasodepressor forms, an asystolic tilt response is specific, i.e., diagnostic, of VVS and is unlikely to occur in control patients without history of syncope and in patients with cardiac syncope; (2) contrary to mixed and vasodepressor forms, an asystolic tilt response predicts a similar asystolic event during prolonged ECG monitoring with a positive predictive value of 86%; (3) the available evidence from trials supports the efficacy of dual-chamber pacing with a low recurrence rate of syncope after pacing ranging from 6% up to 23% during 3 years of follow-up. The latter results should be confirmed by an ongoing double-blind randomized controlled trial before cardiac pacing becomes an established indication. It is commonly believed that the most frequent cause of recurrence of syncope in patients treated with a pacemaker is an associated hypotensive reflex. In these cases additional measures should be used to counteract hypotension. Recognizing prodromal symptoms, avoiding triggers, and performing counterpressure maneuvers are the well-known first steps. There are two additional useful measures when these fail: stopping/reducing hypotensive drugs and (in selected cases) adding fludrocortisone.

Background " Unexplained syncope, no prodromes, and normal heart " has been described as a distinct clinical and biological entity. Objective The purpose of this study was to assess the mechanism of syncope. Methods In this prospective multicenter study, 58 patients presenting with unexplained syncope, no prodromes, and a normal heart received an implantable loop recorder (ILR) and were followed up until a diagnosis was established. Their outcomes were compared with those of 389 patients affected by reflex syncope with prodromes who received an ILR. Results During a mean observation period of 16 ± 13 months, a diagnostic event was documented by the ILR in 29 patients (50%); an asystolic pause of 11 ± 5 seconds (range 3.5–22 seconds) was present at the time of the diagnostic event in 19 patients (66%). Compared with patients affected by reflex syncope with prodromes, patients with unexplained syncope, no prodromes, and a normal heart more frequently had an asystolic syncope (66% vs 47%; P = .001), and this was more frequently due to idiopathic paroxysmal atrioventricular block (47% vs 21%; P = .04). Ten patients with asystolic pauses underwent cardiac pacing, and 8 patients underwent oral theophylline treatment. During the subsequent 17 ± 12 months of follow-up, syncope recurred in 1 patient on theophylline and presyncope occurred in 1 patient with pacemaker. Conclusion A long asystolic pause, frequently due to idiopathic paroxysmal atrioventricular block, played a role in the mechanism of syncope in two-thirds of patients who had electrocardiographic documentation of a diagnostic event. When a specific therapy was administered in patients with asystolic syncope, the short outcome was favorable.

Aims Physical counter-pressure manoeuvres (PCM) are effective in young patients with vasovagal syncope and recognizable prodromal symptoms. The aim of this study was to investigate their effectiveness in patients ≥40 years with severe neurally mediated syncope (NMS) enroled in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3). Methods and results In the ISSUE-3 study, 63 out of 162 patients had a diagnosis of hypotensive NMS (Types 2, 3, and 4A) documented by implantable loop recorder; of these, 40 were instructed to perform isometric leg and arm PCM therapy. Their mean age was 62 ± 13 years; 47% of patients had a history of some episodes without prodrome. A group of 45 untreated patients acted as controls. The primary endpoint was the time to first syncope recurrence. During follow-up, syncope recurred in 15 PCM patients (37%) and in 24 control patients (53%) ( P = 0.14). At 21 months, the modelled syncope recurrence rates were 42% [95% confidence interval (CI): 27–61] and 64% (95% CI: 48–80), respectively ( P = 0.27). Conclusion In conclusion, many ISSUE-3 patients affected by hypotensive NMS have syncopal recurrence despite PCM. Older age and the absence of sufficiently long recognizable prodromal symptoms in the ISSUE-3 population might have hampered the effectiveness of PC therapy.

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: . Unique identifier: [NCT01509534][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01509534&atom=%2Feuropace%2F18%2F9%2F1427.atom

Background— In the Third International Study on Syncope of Uncertain Etiology (ISSUE-3), cardiac pacing was effective in reducing recurrence of syncope in patients with presumed neurally mediated syncope (NMS) and documented asystole but syncope still recurred in 25% of them at 2 years. We have investigated the role of tilt testing (TT) in predicting recurrences. Methods and Results— In 136 patients enrolled in the ISSUE-3, TT was positive in 76 and negative in 60. An asystolic response predicted a similar asystolic form during implantable loop recorder monitoring, with a positive predictive value of 86%. The corresponding values were 48% in patients with non–asystolic TT and 58% in patients with negative TT ( P =0.001 versus asystolic TT). Fifty-two patients (26 TT+ and 26 TT–) with asystolic neurally mediated syncope received a pacemaker. Syncope recurred in 8 TT+ and in 1 TT– patients. At 21 months, the estimated product-limit syncope recurrence rates were 55% and 5%, respectively ( P =0.004). The TT+ recurrence rate was similar to that seen in 45 untreated patients (control group), which was 64% ( P =0.75). The recurrence rate was similar between 14 patients with asystolic and 12 with non–asystolic responses during TT ( P =0.53). Conclusions— Cardiac pacing was effective in neurally mediated syncope patients with documented asystolic episodes in whom TT was negative; conversely, there was insufficient evidence of efficacy from this data set in patients with a positive TT even when spontaneous asystole was documented. Present observations are unexpected and need to be confirmed by other studies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01463358.

Background The onset of symptoms is crucial in the natural history of severe aortic stenosis. In contrast, the impact of the degree of valve obstruction and left ventricular dysfunction on clinical outcome in terms of progression of symptoms and mortality is undefined. Methods and Results Between April 1989 and June 1996, 108 patients (75% male, aged 68.7 ± 10.3 years) with pure and isolated aortic stenosis of at least moderate degree had a complete Doppler echocardiography. Left ventricular end-diastolic and end-systolic diameters, thickness of ventricular septum, mass and ejection fraction, and maximal instantaneous aortic gradient were measured. Patients were followed up through March 1999. Sixty-five patients who underwent aortic valve replacement were censored at the time of surgery. The end point was considered to be death or symptomatic progression (onset of new symptoms or worsening of symptoms). At the time of diagnosis 64 (59%) were in New York Heart Association (NYHA) class I-II and 44 (41%) in NYHA class III-IV. After a mean follow-up of 46 ± 21 months 6 patients died and 45 had worsening of symptoms. Univariate predictors of clinical outcome (death and worsening of symptoms) included left ventricular end-diastolic diameter (hazard ratio 1.03, P =.08), left ventricular end-systolic diameter (HR 1.04, P =.012), and left ventricular septum thickness (HR 1.14, P =.009) but not the degree of aortic obstruction. Multivariate predictors of clinical outcome were left ventricular septum thickness ( P =.016) and left ventricular end-systolic diameter ( P =.008). Conclusion In patients with various degrees of aortic stenosis the rate of clinical outcome is predicted by left ventricular function and septum thickness. Therefore both the left ventricular and aortic valve gradients should be taken into account when choosing the timing of intervention. (Am Heart J 2000;140:766-71.)

Although surgery is highly effective for symptomatic relief in patients with aortic stenosis, symptoms of congestive heart failure may be still present postoperatively. This group of patients with aortic stenosis is characterized by a wide range of left atrial size, which can predict postoperative symptomatic improvement.

Central or peripheral baroreceptor reflex abnormalities, alterations in neurohumoral mechanisms, or both, are thought to play a role in causing neurally-mediated syncope. Because adenosine and its receptors are involved in some forms of syncope [(1–3)][1], we evaluated the purinergic profile of 4