Twenty-five years of research on syncope.

Over the last 25 years, the Europace journal has greatly contributed to dissemination of research and knowledge in the field of syncope. More than 400 manuscripts have been published in the journal. They undoubtedly improved our understanding of syncope. This symptom is now clearly differentiated from other forms of transient loss of consciousness. The critical role of vasodepression and/or cardioinhibition as final mechanisms of reflex syncope is emphasized. Current diagnostic approach sharply separates between cardiac and autonomic pathways. Physiologic insights have been translated, through rigorously designed clinical trials, into non-pharmacological or pharmacological interventions and interventional therapies. The following manuscript is intended to give the reader the current state of the art of knowledge of syncope by highlighting landmark contributions of the Europace journal.

Adenosinergic System and Neuroendocrine Syncope: What Is the Link?

Although very common, the precise mechanisms that explain the symptomatology of neuroendocrine syncope (NES) remain poorly understood. This disease, which can be very incapacitating, manifests itself as a drop in blood pressure secondary to vasodilation and/or extreme slowing of heart rate. As studies continue, the involvement of the adenosinergic system is becoming increasingly evident. Adenosine, which is an ATP derivative, may be involved in a large number of cases. Adenosine acts on G protein-coupled receptors with seven transmembrane domains. A1 and A2A adenosine receptor dysfunction seem to be particularly implicated since the activation leads to severe bradycardia or vasodilation, respectively, two cardinal symptoms of NES. This mini-review aims to shed light on the links between dysfunction of the adenosinergic system and NHS. In particular, signal transduction pathways through the modulation of cAMP production and ion channels in relation to effects on the cardiovascular system are addressed. A better understanding of these mechanisms could guide the pharmacological development of new therapeutic approaches.

Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system's signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential's duration and induce the resting membrane's potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors' activation and whether this would be a cause or consequence of AF.

Adenosine Concentration in Patients With Neurally Mediated Syncope.

Background: Either high or low values of adenosine blood level (ABL) can differentiate some forms of neurally mediated syncope (NMS). A rapid method of measurement has recently been developed. The aim of the present study was: (1) to compare ABLs in an unselected population of consecutive patients referred for evaluation of suspected NMS syncope and in healthy controls; and (2) to assess the relative prevalence of low and high adenosine forms among an unselected syncope population. Method: Whole blood was collected after finger puncture, blood being deposit on a blot paper and adenosine concentration was measured by liquid chromatography/mass spectrometry (LC-MS/MS). Results: Among 89 control subjects, the median ABL value was 0.54 µM (IQR, 0.46-0.65). The lowest 5% and the upper 95% percentile were 0.40 and 0.80 µM, respectively. Compared with healthy subjects, the 146 patients with syncope showed, on average, a higher median ABL value [0.63 (IQR 0.45-0.73, p = 0.04)] and a larger distribution of values. Low ABL values below the 5th percentile were observed in 28 (19%) patients, and, in five controls, p = 0.003 and high ABL values were observed in 26 (18%) patients and five controls, p = 0.009. Conclusions: ABL is different in patients with suspected NMS than in healthy subjects. Patients with low and high adenosine values account for 19% and 18% of the general population. Thus, low and high ABL limits, as defined in this study, may help to define the purinergic profile of unselected subjects with a clinical diagnosis of suspected NMS.

Adenosine, Adenosine Receptors and Neurohumoral Syncope: From Molecular Basis to Personalized Treatment.

Adenosine is a ubiquitous nucleoside that is implicated in the occurrence of clinical manifestations of neuro-humoral syncope (NHS). NHS is characterized by a drop in blood pressure due to vasodepression together with cardio inhibition. These manifestations are often preceded by prodromes such as headaches, abdominal pain, feeling of discomfort or sweating. There is evidence that adenosine is implicated in NHS. Adenosine acts via four subtypes of receptors, named A1 (A1R), A2A (A2AR), A2B (A2BR) and A3 (A3R) receptors, with all subtypes belonging to G protein membrane receptors. The main effects of adenosine on the cardiovascular system occurs via the modulation of potassium ion channels (IK Ado, K ATP), voltage-gate calcium channels and via cAMP production inhibition (A1R and A3R) or, conversely, through the increased production of cAMP (A2A/BR) in target cells. However, it turns out that adenosine, via the activation of A1R, leads to bradycardia, sinus arrest or atrioventricular block, while the activation of A2AR leads to vasodilation; these same manifestations are found during episodes of syncope. The use of adenosine receptor antagonists, such as theophylline or caffeine, should be useful in the treatment of some forms of NHS. The aim of this review was to summarize the main data regarding the link between the adenosinergic system and NHS and the possible consequences on NHS treatment by means of adenosine receptor antagonists.

Safety, Pharmacokinetic, and Pharmacodynamic Study of a Sublingual Formula for the Treatment of Vasovagal Syncope.

BACKGROUND: Vasovagal syncope is a common cause of syncope which, if recurrent, can have multiple negative consequences such as injury and occupational disability. Various medications can be used to decrease the recurrence of vasovagal syncope but there are no drugs that can be used by patients to interrupt a perceived vasovagal episode. METHODS: A phase I study was performed to evaluate the tolerability and safety of a gel formulation containing capsaicin (1 mg), phenylephrine HCL (PE) and caffeine citrate (200 mg) (CPC) in normal adult volunteers. Secondary objectives were to characterize the pharmacokinetics (PK) of the CPC formulation and the highest dose of PE needed to achieve a target increase in systolic BP of at least 40 mmHg. After receiving the first dose, a second dose of the CPC mixture was administered at 2 h. Suboptimal changes in systolic blood pressure (SBP) were noted at PE doses of 0.6, 1.2, and 1.8 mg, therefore a second cohort was studied at PE doses of 10, 20, and 30 mg. Blood samples were collected in rapid sequence and were assayed for all three drugs. RESULTS: A total of 17 subjects received the drug with no serious adverse effects reported. All doses were well tolerated, although the capsaicin content usually caused expected temporary oral and gastric discomfort. One subject did not complete the study because of a vasovagal reaction that was associated with the frequent blood sampling. There was a 5-25 min lag in the appearance of measurable blood concentrations of capsaicin and phenylephrine. Most subjects had baseline caffeine concentrations from dietary use, with a gradual increase noted after 15 min consistent with GI absorption. Although the intended criterion of a 40 mmHg increase in SBP was not reached, a clinically significant increase in BP for at least 15 min was noted in the six subjects who received the highest dose of PE (30 mg), with a gradual decline over the next 2 h. CONCLUSION: The ternary mixture of capsaicin, phenylephrine, and caffeine was well tolerated when administered as two sublingual/oral doses over a 2-h period.

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.

A2 Adenosine Receptor Subtypes Overproduction in Atria of Perioperative Atrial Fibrillation Patients Undergoing Cardiac Surgery: A Pilot Study.

Objective: Although atrial fibrillation is a common cardiac arrhythmia in humans, the mechanism that leads to the onset of this condition is poorly elucidated. Adenosine is suspected to be implicated in the trigger of atrial fibrillation (AF) through the activation of its membrane receptors, mainly adenosine receptor (AR) subtypes A1R and A2R. In this study, we compared blood adenosine concentration (BAC), and A1R, A2AR, and A2BR production in right (RA) and left atrium (LA), and on peripheral blood mononuclear cells (PBMCs) in patients with underlying structural heart disease undergoing cardiac surgery with or without peri-operative AF (PeOpAF). Methods: The study group consisted of 39 patients (30 men and 9 women, mean age, range 65 [40-82] years) undergoing cardiac surgery and 20 healthy patients (8 women and 12 men; mean age, range 60 [39-72] years) as controls were included. Among patients, 15 exhibited PeOpAF. Results: Blood adenosine concentration was higher in patients with PeOpAF than others. A2AR and A2BR production was higher in PBMCs of patients compared with controls and was higher in PeOpAF patients than other patients. In LA and RA, the production of A2AR and A2BR was higher in patients with PeOpAF than in other patients. Both A2AR and A2BR production were higher in LA vs. RA. A1R production was unchanged in all situations. Finally, we observed a correlation between A1R, A2AR, and A2BR production evaluated on PBMCs and those evaluated in LA and RA. Conclusions: Perioperative AF was associated with high BAC and high A2AR and A2BR expression, especially in the LA, after cardiac surgery in patients with underlying structural heart disease. Whether these increases the favor in triggering the AF in this patient population needs further investigation.

Leadless left ventricular endocardial pacing for CRT upgrades in previously failed and high-risk patients in comparison with coronary sinus CRT upgrades.

AIMS: Cardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades. METHOD AND RESULTS: Prospective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). CONCLUSION: Despite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.

Adenosine Receptor Reserve and Long-Term Potentiation: Unconventional Adaptive Mechanisms in Cardiovascular Diseases?

While the concept of a receptor reserve (spare receptors) is old, their presence on human cells as an adaptive mechanism in cardiovascular disease is a new suggestion. The presence of spare receptors is suspected when the activation of a weak fraction of receptors leads to maximal biological effects, in other words, when the half-maximal effective concentration (EC50) for a biological effect (cAMP production, for example) is lower than the affinity (KD) of the ligand for a receptor. Adenosine is an ATP derivative that strongly impacts the cardiovascular system via its four membrane receptors, named A1R, A2AR, A2BR, and A3R, with the A1R being more particularly involved in heart rhythm, while the A2AR controls vasodilation. After a general description of the tools necessary to explore the presence of spare receptors, this review focuses on the consequences of the presence of spare adenosine receptors in cardiovascular physiopathology. Finally, the role of the adenosinergic system in the long-term potentiation and its possible consequences on the physiopathology are also mentioned.

Management of sleep apnoea syndrome (SAS) in patients with vasovagal syncope (VVS): a protocol for the VVS-SAS cohort study.

INTRODUCTION: Recurrent vasovagal syncope (VVS) is associated with decreased quality-of-life and frequent use of emergency services. The evidence base for causality, diagnostic procedures and potential VVS treatments is poor. Scattered observations in the literature suggest a link between respiratory disturbances during sleep and VVS. Empirical observations lead us to further hypothesise that the appropriate management of sleep apnoea syndrome (SAS) may help resolve comorbid recurrent VVS in certain patients. We therefore designed this pilot study to provide a framework for the observation of changes in outcomes accompanying the deployment of SAS treatments in patients with VVS. METHODS AND ANALYSIS: This is a multicentre, registry-based study whose primary objective is to evaluate the effect of SAS management on the number of syncope/presyncope episodes in a population suffering from both VVS and SAS. To this effect, syncope rates prior to the treatment of SAS will be compared with those occurring after the initiation of the latter. In addition, yearly assessments will collect data for echocardiography, polysomnography, Holter monitoring, table tilt tests, multiple sleep latency tests, SAS management parameters and questionnaires describing fatigue, depression and quality-of-life. Sixty patients will be included with a minimum follow-up period of 12 months. The primary analysis will use comparisons of centrality for paired data to describe the changes in syncope rates before versus after the initiation of SAS management. Longitudinal data will be analysed using mixed models with patients set as a random effect. Subgroup analyses will be performed for SAS-treatment adherence and efficacy. ETHICS AND DISSEMINATION: The VVS-SAS registry was approved by an ethics committee (Comité pour la Protection des Personnes Ile-de-France VI, Reference number CPP/2-18) in accordance with French law. The princeps publication will present before-after SAS management results and longitudinal analyses. TRIAL REGISTRATION NUMBER: NCT04294524. Pre-results.

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.

Adenosine and the Cardiovascular System: The Good and the Bad.

Adenosine is a nucleoside that impacts the cardiovascular system via the activation of its membrane receptors, named A1R, A2AR, A2BR and A3R. Adenosine is released during hypoxia, ischemia, beta-adrenergic stimulation or inflammation and impacts heart rhythm and produces strong vasodilation in the systemic, coronary or pulmonary vascular system. This review summarizes the main role of adenosine on the cardiovascular system in several diseases and conditions. Adenosine release participates directly in the pathophysiology of atrial fibrillation and neurohumoral syncope. Adenosine has a key role in the adaptive response in pulmonary hypertension and heart failure, with the most relevant effects being slowing of heart rhythm, coronary vasodilation and decreasing blood pressure. In other conditions, such as altitude or apnea-induced hypoxia, obstructive sleep apnea, or systemic hypertension, the adenosinergic system activation appears in a context of an adaptive response. Due to its short half-life, adenosine allows very rapid adaptation of the cardiovascular system. Finally, the effects of adenosine on the cardiovascular system are sometimes beneficial and other times harmful. Future research should aim to develop modulating agents of adenosine receptors to slow down or conversely amplify the adenosinergic response according to the occurrence of different pathologic conditions.

European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

Pacemakers, implantable cardiac defibrillators, and cardiac resynchronization therapy devices are potentially lifesaving treatments for a number of cardiac conditions but are not without risk. Most concerning is the risk of a cardiac implantable electronic device (CIED) infection, which is associated with significant morbidity, increased hospitalizations, reduced survival, and increased health care costs. Recommended preventive strategies such as administration of intravenous antibiotics before implantation are well-recognized. Uncertainties have remained about the role of various preventive, diagnostic, and treatment measures such as skin antiseptics, pocket antibiotic solutions, antibacterial envelopes, prolonged antibiotics post-implantation, and others. When compared with previous guidelines or consensus statements, the present consensus document gives guidance on the use of novel device alternatives, novel oral anticoagulants, antibacterial envelopes, prolonged antibiotics post-implantation, as well as definitions on minimum quality requirements for centres and operators and volumes. The recognition that an international consensus document focused on management of CIED infections is lacking, the dissemination of results from new important randomized trials focusing on prevention of CIED infections, and observed divergences in managing device-related infections as found in an European Heart Rhythm Association worldwide survey, provided a strong incentive for a Novel 2019 International State-of-the-art Consensus document on risk assessment, prevention, diagnosis, and treatment of CIED infections.

European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

Pacemakers, implantable cardiac defibrillators, and cardiac resynchronization therapy devices are potentially life-saving treatments for a number of cardiac conditions, but are not without risk. Most concerning is the risk of a cardiac implantable electronic device (CIED) infection, which is associated with significant morbidity, increased hospitalizations, reduced survival, and increased healthcare costs. Recommended preventive strategies such as administration of intravenous antibiotics before implantation are well recognized. Uncertainties have remained about the role of various preventive, diagnostic, and treatment measures such as skin antiseptics, pocket antibiotic solutions, anti-bacterial envelopes, prolonged antibiotics post-implantation, and others. Guidance on whether to use novel device alternatives expected to be less prone to infections and novel oral anticoagulants is also limited, as are definitions on minimum quality requirements for centres and operators and volumes. Moreover, an international consensus document on management of CIED infections is lacking. The recognition of these issues, the dissemination of results from important randomized trials focusing on prevention of CIED infections, and observed divergences in managing device-related infections as found in an European Heart Rhythm Association worldwide survey, provided a strong incentive for a 2019 International State-of-the-art Consensus document on risk assessment, prevention, diagnosis, and treatment of CIED infections.

European Heart Rhythm Association (EHRA) international consensus document on how to prevent, diagnose, and treat cardiac implantable electronic device infections-endorsed by the Heart Rhythm Society (HRS), the Asia Pacific Heart Rhythm Society (APHRS), the Latin American Heart Rhythm Society (LAHRS), International Society for Cardiovascular Infectious Diseases (ISCVID) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).

Pacemakers, implantable cardiac defibrillators, and cardiac resynchronization therapy devices are potentially life-saving treatments for a number of cardiac conditions, but are not without risk. Most concerning is the risk of a cardiac implantable electronic device (CIED) infection, which is associated with significant morbidity, increased hospitalizations, reduced survival, and increased healthcare costs. Recommended preventive strategies such as administration of intravenous antibiotics before implantation are well recognized. Uncertainties have remained about the role of various preventive, diagnostic, and treatment measures such as skin antiseptics, pocket antibiotic solutions, anti-bacterial envelopes, prolonged antibiotics post-implantation, and others. Guidance on whether to use novel device alternatives expected to be less prone to infections and novel oral anticoagulants is also limited, as are definitions on minimum quality requirements for centres and operators and volumes. Moreover, an international consensus document on management of CIED infections is lacking. The recognition of these issues, the dissemination of results from important randomized trials focusing on prevention of CIED infections, and observed divergences in managing device-related infections as found in an European Heart Rhythm Association worldwide survey, provided a strong incentive for a 2019 International State-of-the-art Consensus document on risk assessment, prevention, diagnosis, and treatment of CIED infections.

Understanding Outcomes with the EMBLEM S-ICD in Primary Prevention Patients with Low EF Study (UNTOUCHED): Clinical characteristics and perioperative results.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has shown favorable outcomes in large registries with broad inclusion criteria. The cohorts reported had less heart disease and fewer comorbidities than standard ICD populations. OBJECTIVE: The purpose of this study is to characterize acute performance for primary prevention patients with a left ventricular ejection fraction (LVEF) ≤35% (primary prevention ≤35%). METHODS: Primary prevention ≤35% patients with no prior documented sustained ventricular tachycardia (VT), pacing indication, end-stage heart failure, or advanced renal failure were prospectively enrolled. Analyses included descriptive statistics, Kaplan-Meier time to event, and multivariable linear and logistic regression. RESULTS: In 1112 of 1116 patients, an S-ICD was successfully implanted (99.6%). Predictors for longer procedure time included 3-incision technique, higher body mass index (BMI), performing defibrillation testing (DFT), imaging, younger age, black race, and European vs North American centers. Patients undergoing DFT (82%) were successfully converted (99.2%; 93.5% converting at ≤65 J). Higher BMI was predictive of failing DFT at ≤65 J. The rate of 30-day freedom from complications was 95.8%. Most complications involved postoperative healing (45%) or interventions after DFT or impedance check (19%). CONCLUSION: The procedural outcome data of UNTOUCHED reinforce that S-ICD therapy has low perioperative complication rates and high conversion efficacy of induced ventricular fibrillation, even in a higher-risk cohort with low LVEF and more comorbidities than previous S-ICD studies. Higher BMI warrants more careful attention to implant technique.

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.