Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor.

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.

Complementary effectiveness of carotid sinus massage and tilt testing for the diagnosis of reflex syncope in patients older than 40 years: a cohort study.

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.

Plasma adenosine and neurally mediated syncope: ready for clinical use.

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.

Reproducibility of carotid sinus massage.

AIMS: The reproducibility of carotid sinus massage (CSM) is debated. The aim of this study was to assess the reproducibility according to the methodology and diagnostic criteria defined by the guidelines on syncope of the European Society of Cardiology. METHOD: Among 2800 patients with syncope who underwent CSM in the years 2005-2019, 109 patients (62 males; mean age 76 ± 10 years) had performed a second CSM after a median of 28 months. Carotid sinus hypersensitivity (CSH) was diagnosed when CSM elicited a pause of >3 s and/or a fall in systolic blood pressure >50 mm Hg without reproduction of spontaneous symptoms. Carotid sinus syndrome (CSS) was established when spontaneous symptoms were reproduced in the presence of bradycardia and/or hypotension. RESULTS: The reproducibility of CSM was 78% for 18 CSS patients, 41% for 29 CSH patients, and 77% for 62 negative patients. The corresponding interrater agreement was good for CSS (kappa = 0.66), moderate for negative CSM (kappa = 0.42), and poor for CSH (kappa = 0.30). Combining CSH and negative tests, their reproducibility rose to 90% with kappa = 0.66. CONCLUSION: CSS but not CSH has a good reproducibility. About half of patients with CSH had a negative response at the second test, thus suggesting a great overlap between them.

Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG.

BACKGROUND: Patients affected by syncope without or with very short (≤5 s) prodrome with normal heart and normal ECG have been seen to present low plasma adenosine levels. We investigated whether chronic treatment of these patients with theophylline, a non-selective adenosine receptor antagonist, results in clinical benefit. METHODS: In a consecutive case-series of 16 patients (mean age 47 ±â€¯25 years, 9 females) who had ECG documentation of asystolic syncope, we compared the incidence of syncopal recurrence during a period without and a period with tailored theophylline therapy. RESULTS: During a median of 60 months before ECG documentation of the index episode, the patients had a median of 2 syncopes per year. During the 6 months of the study phase without therapy, the patients had a median of 2.6 syncopes per year, p = 0.63. During the 23 months of the study phase with theophylline, the patients had a median of 0.4 syncopes per year, p = 0.005 vs history and p = 0.005 vs no therapy. In the 13 patients who had an implantable loop recorder during both study phases, the incidence of asystolic episodes > 3 s decreased from 9.6 per year to 1.1 per year, p = 0.0007. During theophylline treatment, syncope recurred in 1/5 (20%) patients who had an idiopathic atrioventricular block as the index event versus 9/11 (81%) patients who had a sinus arrest, p = 0.005. CONCLUSION: Theophylline is effective in reducing syncopal burden in patients with syncope without prodromes with normal heart and normal ECG. Its efficacy is greater in those with idiopathic atrioventricular block.

Optimization of coronary sinus lead placement targeted to right-to-left delay in patients undergoing cardiac resynchronization therapy.

AIMS: Anatomical placement of the coronary sinus (CS) lead in basal or mid-ventricular positions of the posterior and lateral walls is associated with a better clinical outcome of cardiac resynchronization therapy (CRT). We hypothesized that optimization of CS lead placement targeted the right-to-left electrical delay (RLD) predicts an additional clinical benefit. METHODS AND RESULTS: The CS lead was placed according to current standards in 90 patients (Conventional group) and at the site of the longest RLD in 121 patients (RLD group). Non-responders were defined as those who died or underwent hospitalization for heart failure or did not improve in their Clinical Composite Score within 6 months. There were 67 (32%) non-responders. Compared with Conventional group, the final CS pacing site was more frequently in the basal segments in the RLD group (40% vs. 23%, P = 0.007); moreover, the RLD ratio (%RLD) of the total QRS width was longer (77 ± 13 vs. 73 ± 15, P = 0.05) and biventricular QRS shortened more from the baseline (-31 ± 21 ms vs. -21 ± 26 ms, P = 0.004). Nevertheless, the rate of non-responders was similar in the RLD and Conventional groups (35% vs. 28%, P = 0.30), as was %RLD (76 ± 16 vs. 75 ± 13, P = 0.66). QRS width during right ventricular (RV) pacing was an independent predictors of adverse outcome, with a 2% increase in the risk of failure for each 1 ms increase in QRS (P = 0.006). CONCLUSION: Optimization of CS lead placement targeted to latest electrical activation does not provide additional clinical benefit to anatomical placement in basal or mid-ventricular positions of the posterior and lateral walls. QRS width during RV pacing was a strong predictor of CRT failure. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT03204864.

Incidence and predictors of syncope recurrence after cardiac pacing in patients with carotid sinus syndrome.

BACKGROUND: Cardiac pacing is the treatment of choice for cardioinhibitory carotid sinus syndrome (CSS), but syncope recurrence occurs in up to 20% of patients within 3 years. The present study aims at assessing incidence and identifying predictors of syncope recurrence in patients receiving pacing therapy for CSS. METHODS: The Syncope Clinics of two large regional hospitals in Northern Italy, both following European Syncope Guidelines, combined to perform this study. Retrospective analysis of 3127 consecutive patients undergoing carotid sinus massage (CSM) was performed 2004-2014. Ten-second supine and standing CSM was systematically assessed in patients aged >40 years with suspected reflex syncope as part of the initial evaluation. Syncope recurrence was investigated in those paced for CSS having >6 months' available follow-up. Data were collected from clinical records and patient interviews. RESULTS: CSS was diagnosed in 261 patients (8.3%). Pacemakers were implanted in 158, with follow-up data available in 112: 19 (17%) experienced 73 syncope recurrences during a mean follow-up of 89 ±â€¯42 months, yielding an incidence of 0.5 episodes per patient/year. Prodrome, predisposing situations preceding syncope and chronic nitrate therapy were more frequent in patients reporting recurrence. Prodrome and predisposing situations remained independent predictors of post-implantation recurrence on multivariable analysis. CONCLUSIONS: CSS is a frequent cause of syncope, if CSM is performed during the initial evaluation. Most patients treated by pacing remain asymptomatic during long-term follow-up. In those who have recurrence, its incidence is very low. Prodrome and predisposing situations are predictors of post-implantation recurrence, suggesting presence of hypotensive susceptibility.

Optimization of coronary sinus lead placement targeted to the longest right-to-left delay in patients undergoing cardiac resynchronization therapy: The Optimal Pacing SITE 2 (OPSITE 2) acute study and protocol.

AIMS: Left ventricular (LV) lead positioning at the site of delayed electrical activation is associated with better response to cardiac resynchronization therapy (CRT). We hypothesized that a long electrical conduction delay between right ventricular (RV) and coronary sinus (CS) leads during RV pacing (RLD index) is correlated with a better clinical outcome METHODS AND RESULTS: RLD is measured intraprocedurally, during RV pacing, as the time interval between the intracardiac electrograms of RV and CS leads. Initially, we did a prove-of-concept, feasibility, acute study in 97 patients who underwent CRT implantation. The CS lead position was assessed in the 40° right anterior oblique and 40° left anterior oblique views and assigned to one of 11 prespecified segments of a schematic eyeball depiction of the LV walls. Acute outcomes were QRS width during biventricular (BIV) pacing. The longest RLD were found in the basal and mid lateral segments; these accounted for 82% and 78%, respectively, of the total QRS width (%RLD). %RLD was inversely correlated with BIV-paced QRS (P  =  0.0001). A similar slope was present either in the 78 patients with preserved atrioventricular (AV) conduction and in the 19 without AV conduction (- 0.34 vs - 0.27, P  =  0.7). CONCLUSION: We showed that RLD can be used to guide lead placement at the time of CRT implantation and that it is correlated with BIV-QRS width, an indirect predictor of clinical outcome. Based on these findings we started the prospective, multicenter Optimal Pacing SITE 2 (OPSITE 2) trial with the objective to demonstrate a relationship between RLD and clinical outcomes assessed as death, hospitalization for heart failure, New York Heart Association class, and clinical composite score. The protocol is provided.

Methods, accuracy and clinical implications of atrial fibrillation detection by cardiac implantable electronic devices.

Atrial fibrillation (AF) is the most common arrhythmia in the developed countries and is associated with an increased risk of thromboembolic events and heart failure. Episodes of AF are often asymptomatic and intermittent, eluding diagnosis with non-continuous monitoring techniques. Cardiac implantable electronic devices (CIEDs) represent the gold standard for detecting asymptomatic AF. Improper CIED programming may however increase the risk of false-positive detection of atrial tachyarrhythmias, leading to inappropriate clinical management of patients. A faster rate and a longer duration of the tachyarrhythmic episodes, in addition to a greater AT/AF burden, have been proposed as potential criteria for differentiating between CIED-detected atrial tachyarrhythmias and true AF. Nonetheless, manual overreading of intracardiac electrograms recorded by the CIED remains crucial for a correct diagnosis. Asymptomatic atrial tachyarrhythmias may carry a higher risk of systemic thromboembolism, though clinical thromboembolic risk factors seem to play a greater if not absolute role in prognostication. In addition, there is no clear temporal relationship between CIED-detected atrial tachyarrhythmias and stroke, and the anticoagulation strategy to be pursued in these patients is still a matter of debate and the focus of current prospective randomized studies.

Stop vasodepressor drugs in reflex syncope: a randomised controlled trial.

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.

Syncope in patients paced for atrioventricular block.

AIMS: Although syncope is the main reason for cardiac pacing in ∼40% of patients affected by atrioventricular block (AVB), very few data are available on the benefit of cardiac pacing in preventing syncopal recurrences. METHODS AND RESULTS: We retrospectively evaluated 229 consecutive patients (124 males, age 80 ± 10 years) who had received a permanent pacemaker from January 2009 to December 2013 for AVB and syncope (94 patients, 41%) or AVB without syncope (135 patients, 59%). In patients with AVB and syncope, a third-degree or Mobitz II second-degree AVB had been documented in 73 and was only suspected in another 21, all of whom had bundle branch block. Follow-up was available in 223 patients. At 5 years, the actuarial syncope recurrence rate was 1% (95% CI, 0-3) in patients with documented AVB plus syncope and 3% (95% CI, 1-5) in those without syncope, whereas it was 14% (95% CI, 0-28) in patients with undocumented AVB plus syncope (P = 0.001). The actuarial combined recurrence rate of syncope and/or pre-syncope was 2% (95% CI, 0-4) in patients without syncope, 8% (95% CI, 0-17) in patients with documented AVB plus syncope, and 19% (95% CI, 1-37) in patients with undocumented AVB plus syncope, P = 0.002. All syncopes occurred in patients without overt structural heart disease (SHD), the corresponding actuarial estimate being 4% (95% CI, 0-6) at 1 year and 6% (95% CI, 4-8) at 5 years (P = 0.002 vs. patients with SHD). CONCLUSIONS: Cardiac pacing is highly effective in preventing syncopal recurrences when AVB is documented. Syncope may recur in a non-negligible minority of paced patients when AVB is suspected but not documented and in patients without SHD.

Assessment of the vasodepressor reflex in carotid sinus syndrome.

BACKGROUND: Assessment of the vasodepressor reflex in carotid sinus syndrome is influenced by the method of execution of the carotid sinus massage and the coexistence of the cardioinhibitory reflex. METHODS AND RESULTS: Carotid sinus massage reproduced spontaneous symptoms in 164 patients in the presence of hypotension or bradycardia (method of symptoms). When an asystolic pause was induced, the vasodepressor reflex was reassessed after suppression of the asystolic reflex by means of 0.02 mg/kg IV atropine. An isolated vasodepressor form was found in 32 (20%) patients, who had lowest systolic blood pressure (SBP) of 65±15 mm Hg. Of these, only 21 (66%) patients had an SBP fall ≥50 mm Hg, which is the universally accepted cut-off value for the diagnosis of the vasodepressor form. Conversely, a lowest SBP value of ≤85 mm Hg (corresponding to the fifth percentile) detected 97% of vasodepressor patients, but was also present in 84% of the 132 patients with an asystolic reflex. These latter patients had both asystole ≥3 s (mean 7.6±2.2 s) and SBP fall to 63±22 mm Hg: in 46 (28%) patients, symptoms persisted after atropine (mixed form), in the remaining 86 (52%) patients, symptoms did not (cardioinhibitory form) persist. CONCLUSIONS: The current definition of ≥50 mm Hg SBP fall failed to identify one third of patients with isolated vasodepressor form. A cut-off value of symptomatic SBP of ≤85 mm Hg seems more appropriate, but it is unable to identify cardioinhibitory forms. In asystolic forms, atropine testing is able to distinguish a cardioinhibitory form from a mixed form.

Additional diagnostic value of implantable loop recorder in patients with initial diagnosis of real or apparent transient loss of consciousness of uncertain origin.

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.

Clinical context and outcome of carotid sinus syndrome diagnosed by means of the 'method of symptoms'.

AIMS: The prevalence and outcome of carotid sinus syndrome (CSS) reported in the literature vary owing to differences in indications and methods of carotid sinus massage (CSM). METHODS AND RESULTS: We performed CSM on all patients aged 40 years and above with unexplained syncope after the initial evaluation. Carotid sinus massage was performed in the supine and standing positions on both sides for 10 s during continuous electrocardiogram and blood pressure monitoring; CSS was diagnosed in the event of an abnormal response to CSM in association with reproduction of spontaneous symptoms ('method of symptoms'). From July 2005 to July 2012, CSS was found in 164 (8.8%) of 1855 patients (mean age 77 ± 9 years, 73% males): 81% had an asystolic reflex (mean pause 7.6 ± 2.2 s) and 19% a vasodepressor reflex (mean lowest systolic blood pressure 65 ± 15 mmHg). Potential multifactorial causes of syncope (orthostatic hypotension, bundle branch block, bradycardia, tachyarrhythmias) were found in 74% of patients. One hundred forty-one patients received the proper care [advice on lifestyle measures in all, discontinuation (#40) or reduction (#17) of antihypertensive drugs, pacemaker implantation (#57)] and were followed up for 39 ± 25 months. Syncope recurred in 23 patients; the actuarial syncopal recurrence rate was 7% at 1 year and 26% at 5 years. Total syncopal episodes decreased from 91 per year during the 2 years before evaluation to 21 episodes per year during follow-up (P = 0.001). On Cox proportional-hazards regression, a mixed or vasodepressor response to tilt testing was the only independent predictor of syncopal recurrence (hazard ratio = 1.8; P = 0.01). CONCLUSION: Carotid sinus massage by means of the 'method of symptoms' indentifies a clinical syndrome with definite features and outcome. A treatment strategy involving lifestyle measures, reduction of antihypertensive drugs and cardiac pacing when appropriate is effective in reducing the syncopal recurrence rate.