Comparing efficacy and safety in catheter ablation strategies for atrial fibrillation: a network meta-analysis.

BACKGROUND: There is no consensus on the most efficient catheter ablation (CA) strategy for patients with atrial fibrillation (AF). The objective of this study was to compare the efficacy and safety of different CA strategies for AF ablation through network meta-analysis (NMA). METHODS: A systematic search of PubMed, Web of Science, and CENTRAL was performed up to October 5th, 2020. Randomized controlled trials (RCT) comparing different CA approaches were included. Efficacy was defined as arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of 6 months. RESULTS: In total, 67 RCTs (n = 9871) comparing 19 different CA strategies were included. The risk of recurrence was significantly decreased compared to pulmonary vein isolation (PVI) alone for PVI with renal denervation (RR: 0.60, CI: 0.38-0.94), PVI with ganglia-plexi ablation (RR: 0.62, CI: 0.41-0.94), PVI with additional ablation lines (RR: 0.8, CI: 0.68-0.95) and PVI in combination with bi-atrial modification (RR: 0.32, CI: 0.11-0.88). Strategies including PVI appeared superior to non-PVI strategies such as electrogram-based approaches. No significant differences in safety were observed. CONCLUSIONS: This NMA showed that PVI in combination with additional CA strategies, such as autonomic modulation and additional lines, seem to increase the efficacy of PVI alone. These strategies can be considered in treating patients with AF, since, additionally, no differences in safety were observed. This study provides decision-makers with comprehensive and comparative evidence about the efficacy and safety of different CA strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number: CRD42020169494 .

Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

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Ultrasound-guided versus anatomic landmark-guided vascular access in cardiac electrophysiology procedures: A systematic review and meta-analysis.

INTRODUCTION: Electrophysiology (EP) procedures are nowadays the gold-standard method for tachyarrhythmia treatment with impressive success rates, but also with a considerable risk of complications, mainly vascular. A systematic review and meta-analysis was performed to evaluate the safety of ultrasound (US)-guided femoral vein access in EP procedures compared to the traditional anatomic landmark-guided method. METHODS: We searched Pubmed (MEDLINE), Embase, Web of Science, and Cochrane electronic databases for relevant entries, dated from January 1st, 2000 to June 30th, 2021. Only observational studies and randomized controlled trials were included in this analysis. Data extraction included study details, patient characteristics, procedure details, and all types of vascular complications. Complications were classified as major if any intervention, prolongation of hospitalization, or readmission was required. RESULTS: 9 studies (1 randomized controlled trial and 8 observational), with 7858 participants (3743 in the US-guided group, 4115 in the control group), were included in the meta-analysis. Overall vascular complication rates were significantly decreased in the US-guided group compared to the control group (1.2 versus 3.2%, RR = 0.38, 95% CI, 0.27-0.53), in all EP procedures. Sub-group analysis of AF ablation procedures yielded similar results (RR 0.41, 95% CI, 0.29-0.58, p < 0.00001). The event reduction effect was significant for both major and minor vascular complications. CONCLUSION: US-guided vascular access in EP procedures is associated with significantly reduced vascular complications, compared to the standard anatomic landmark-guided approach, regardless of procedure complexity.

Excessive Supraventricular Ectopic Activity and Adverse Cardiovascular Outcomes: a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Excessive supraventricular ectopic activity (ESVEA), in the form of frequent premature atrial contractions (PACs) and runs of PACs, is commonly observed in clinical practice and is frequently considered to be benign. Yet, recent studies have demonstrated a link between ESVEA and adverse cardiovascular outcomes. The aim of this meta-analysis was to examine the association between ESVEA and the risk of atrial fibrillation (AF), stroke, and mortality. RECENT FINDINGS: A systematic search was performed in PubMed, EMBASE, and the Cochrane Library up to December 2017 to identify studies assessing adverse cardiovascular outcomes in patients with ESVEA, recorded on ambulatory electrocardiography. ESVEA was defined as a burden of PACs > 30 PACs/h or any runs of ≥20 PACs. The risk estimates for EVSEA and each clinical endpoint were pooled and analyzed separately. RESULTS: Five studies comprising 7545 participants were included in this meta-analysis. The pooled analysis showed that ESVEA doubled the risk of AF (HR 2.19, 95% CI 1.70-2.82). ESVEA was also associated with a higher incidence of stroke (HR 2.23, 95% CI 1.24-4.02). Finally, ESVEA was associated with higher all-cause mortality (HR 1.61, 95% CI 1.25-2.07). Our meta-analysis found that ESVEA is closely associated with AF, stroke, and all-cause mortality. Further studies are required to examine the implication of therapeutic strategies in patients with ESVEA, in order to prevent potential subsequent adverse cardiovascular outcomes.

Evolving understanding of the heterogeneous natural history of individual coronary artery plaques and the role of local endothelial shear stress.

PURPOSE OF REVIEW: Anatomic and morphologic features of high-risk coronary plaque have been identified by novel imaging modalities, but it has been less clear which ostensibly high-risk plaques will actually destabilize and cause a new cardiac event. Different plaques with different morphologies coexist within the same artery, but the impact of this heterogeneity on the natural history of coronary artery disease has not been extensively investigated. RECENT FINDINGS: Coronary plaques exhibit remarkable heterogeneity of local morphological and blood-flow patterns, including endothelial shear stress (ESS), along their longitudinal axis, with important implications for the heterogeneous natural history of coronary disease. The natural history of individual plaques is considerably divergent, with most plaques, even ostensibly high-risk plaques, becoming quiescent and only a minority progressing to destabilize and precipitate a new clinical event. Local areas of proinflammatory low ESS appear to be an important condition for plaque destabilization. SUMMARY: Characterization of an individual atherosclerotic plaque based on a snapshot of morphological features at a specific location, such as the minimal lumen diameter, may not be sufficiently comprehensive to accurately reflect the risk associated with that plaque. A detailed assessment of both anatomical and functional pathobiologic characteristics in the longitudinal plaque dimension may enhance our understanding of atherosclerosis progression and improve the management of individual patients with coronary artery disease.

Updates in Cardiac Resynchronization Therapy for Chronic Heart Failure: Review of Multisite Pacing.

PURPOSE OF REVIEW: Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality of patients with left ventricular (LV) systolic dysfunction and intra-ventricular conduction delay. However, its clinical outcomes are heterogeneous and not all patients show a beneficial response. Multisite pacing (MSP), by stimulating the myocardium from more than one locations, is a potential therapeutic option in patients requiring CRT. This article provides a current update in the methods and outcomes of MSP, as well as in challenges in this field and opportunities for further research and development. RECENT FINDINGS: MSP can be delivered either with multiple leads or with quadripolar LV leads which can stimulate the LV from two separate sites. Initial results are promising but not always consistent across studies. Larger patient subgroups and longer follow-up duration are required for more conclusive evaluation of MSP. Routine use of MSP in clinical practice cannot be advocated at present. In selected patient subgroups, however, MSP could be considered. Newer devices and expanding knowledge are expected to facilitate the more widespread implementation of MSP and the assessment of its effects in the clinical outcomes of CRT.

Heterogeneity of Coronary Plaque Morphology and Natural History: Current Understanding and Clinical Significance.

PURPOSE OF REVIEW: Despite the important progress in identifying high-risk atherosclerotic plaques, many key elements are elusive. Advanced imaging modalities provide valuable information about the anatomic and functional plaque characteristics and underscore the presence of multiple plaque morphologies. However, how the heterogeneity of atherosclerotic plaque can alter our current understanding of coronary artery disease is not fully understood. RECENT FINDINGS: Along the length of an individual plaque, the morphology patterns display marked heterogeneity. Contrary to previous beliefs, plaque morphology is also highly dynamic over time, with the vast majority of high-risk plaques becoming quiescent and mild plaques becoming severely obstructive in a short period of time. Endothelial shear stress, a local hemodynamic factor known for its critical effects in plaque initiation and progression, also displays longitudinal heterogeneity contributing to the arterial wall response in all time points. Risk stratification of plaques based on the morphological characteristics at one region of the plaque, usually the minimal lumen diameter, and at one point in time may be misleading. The evaluation of both morphological and hemodynamic characteristics along the length of a plaque will improve the risk assessment of individual plaques.

Multisite Pacing for Cardiac Resynchronization Therapy: Promise and Pitfalls.

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality of patients with symptomatic heart failure and intraventricular conduction delay. However, its clinical outcomes are non-uniform and up to one third of treated patients are subsequently classified as non-responders. Multisite pacing (MSP), i.e. stimulating the myocardium from multiple locations, has emerged as a potential therapeutic option in patients requiring CRT. The rationale for MSP is based on the hypothesis that increasing the pacing locations in the left ventricle results in a more physiologic and coordinated myocardial systole. MSP can be achieved by additional leads in the right or left ventricle but this can lead to high battery drain and more frequent generator replacements. Multipolar left ventricular leads can deliver pacing at multiple sites, and therefore, a single lead can be used for MSP. However, the optimal programming settings and the outcomes of this approach remain yet to be determined.

Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress.

OBJECTIVE: The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. APPROACH AND RESULTS: Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. CONCLUSIONS: Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps-2 critical determinants of coronary plaque vulnerability.

Iron therapy and severe arrhythmias in HFrEF: rationale, study design, and baseline results of the RESAFE-HF trial.

AIMS: The Iron Intravenous Therapy in Reducing the burden of Severe Arrhythmias in HFrEF (RESAFE-HF) registry study aims to provide real-word evidence on the impact of intravenous ferric carboxymaltose (FCM) on the arrhythmic burden of patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency (ID), and implanted cardiac implantable electronic devices (CIEDs). METHODS AND RESULTS: The RESAFE-HF (NCT04974021) study was designed as a prospective, single-centre, and open-label registry study with baseline, 3, 6, and 12 month visits. Adult patients with HFrEF and CIEDs scheduled to receive IV FCM as treatment for ID as part of clinical practice were eligible to participate. The primary endpoint is the composite iron-related endpoint of haemoglobin ≥ 12 g/dL, ferritin ≥ 50 ng/L, and transferrin saturation > 20%. Secondary endpoints include unplanned HF-related hospitalizations, ventricular tachyarrhythmias detected by CIEDs and Holter monitors, echocardiographic markers, functional status (VO2 max and 6 min walk test), blood biomarkers, and quality of life. In total, 106 patients with a median age of 72 years (14.4) were included. The majority were male (84.9%), whereas 92.5% of patients were categorized to New York Heart Association II/III. Patients' arrhythmic burden prior to FCM administration was significant-19 patients (17.9%) received appropriate CIED therapy for termination of ventricular tachyarrhythmia in the preceding 12 months, and 75.5% of patients have frequent, repetitive multiform premature ventricular contractions. CONCLUSIONS: The RESAFE-HF trial is expected to provide evidence on the effect of treating ID with FCM in HFrEF based on real-world data. Special focus will be given on the arrhythmic burden post-FCM administration.

Sinus nodal response to adenosine relates to the severity of sinus node dysfunction.

AIMS: It is unknown as to whether the result of adenosine testing for the diagnosis of sinus node dysfunction (SND) depends on the clinical presentation. We investigated whether syncope or presyncope are associated with a more pronounced sinus nodal inhibition by adenosine in SND. METHODS AND RESULTS: We studied 46 patients with SND, 33 with syncope or presyncope and 13 without such history. Controls were 30 subjects undergoing electrophysiological studies for supraventricular tachycardia or unexplained syncope. We calculated the corrected sinus node recovery time after intravenous adenosine 0.15 mg/kg (ADSNRT) as well as after atrial pacing (CSNRT). Corrected sinus node recovery time values >525 ms were considered abnormal. Corrected sinus node recovery time after adenosine injection was more prolonged in SND patients with syncope or presyncope as compared with those without such history [median: 4900 inter-quartile range (IQR): 920-8560 ms vs. median: 280 IQR: 5-908 ms; P< 0.005]. In SND patients with syncope or presyncope ADSNRT was more prolonged than CSNRT (median: 4900 IQR: 920-8560 ms vs. median: 680 IQR: 359-1650 ms, P< 0.01). In SND patients without syncope or presyncope no statistical difference was noted between ADSNRT and CSNRT (median: 280 IQR: 5-908 ms vs. median: 396 IQR: 270-600 ms, P = 0.80). The sensitivity of CSNRT for SND diagnosis was 57% and the specificity was 100%. A cut-off of 1029 ms for ADSRNT yields the same sensitivity with a specificity of 96.6%. CONCLUSION: In patients with SND syncope or presyncope relate to an exaggerated sinus nodal suppression by adenosine. Prolonged ADSNRT can diagnose cases with severe underlying SND where a more aggressive management strategy is probably warranted.

The effect of statins on high-risk atherosclerotic plaque associated with low endothelial shear stress.

PURPOSE OF REVIEW: Low endothelial shear stress (ESS) plays an important role in the progression and severity of atherosclerotic lesions. As 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) appear to stabilize plaque, it would be valuable to understand how statins affect the nature of lesions in the proatherogenic and proinflammatory environment of low ESS and the effect of statins on that atherosclerotic process. The purpose of this review is to summarize the relationship among low ESS, high-risk plaque and statins. RECENT FINDINGS: Low ESS is a critically important determinant of plaque development and progression to high-risk plaques with large necrotic lipid core, intensive inflammation and thin fibrous cap. In addition to the proatherogenic phenotypic switching in areas of low ESS, local LDL cholesterol concentrations are also increased in areas of low ESS, which exacerbates the local atherogenic process. In experimental models, statins appear to reduce the inflammation in lesions associated with low ESS and reduce the atherosclerotic phenotype even in these high-risk prone vascular areas. SUMMARY: The relationship between low ESS and statins has not been fully investigated, but the available data underscore the vasculoprotective effect of statins. Understanding the mechanisms whereby statins reduce the atherogenic and inflammatory phenotype resulting from a low ESS environment would provide new insights to design strategies to prevent regional formation of high-risk, inflamed plaques likely to rupture and cause an adverse clinical event.

The usability and effect of an mHealth disease management platform on the quality of life of patients with paroxysmal atrial fibrillation - The emPOWERD-AF study.

Atrial fibrillation (AF) is the most common arrhythmia. myAlgos is an mHealth disease management system consisting of physician-oriented platform and patient-oriented smartphone app. Our purpose was to assess the usability of myAlgos by physicians and patients and the effect of myAlgos on the quality of life (QoL) in patients with paroxysmal AF (PAF). Physicians rated the platform with the Post-Study System Usability Questionnaire (PSSUQ). Patients rated the app with the mHealth App Usability Questionnaire (MAUQ). The e-medicine Platform for Optimizing the Workflow in hEaRt Diseases (emPOWERD-AF) study investigated the effect of myAlgos in PAF patients randomized to full/control version. QoL was measured by the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) and 5-level EQ-5D (EQ-5D-5L) questionnaires. myAlgos got a PSSUQ score of 2.52 ± 0.36 by five physicians and a MAUQ score of 79.9% by 33 patients. In emPOWERD-AF, 80 patients were randomized 1:1 (58.1 ± 8.7 years, 66% male). The median AFEQT change at 6 months was +2.63% in full version users and -1.63% in controls (p < .001). The myAlgos platform and app were easy-to-use and improved QoL in patients.

Comparing Efficacy and Safety in Catheter Ablation Strategies for Paroxysmal Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials.

Although catheter ablation (CA) is an established treatment for paroxysmal atrial fibrillation (PAF), there is no consensus regarding the most efficient CA strategy. The objective of this network meta-analysis (NMA) was to compare the efficacy and safety of different CA strategies for PAF. A systematic search was performed in PubMed, Web of Science, and CENTRAL until the final search date, 5 October 2020. Randomised controlled trials (RCT) comparing different CA strategies and methods for pulmonary vein isolation (PVI) were included. Efficacy was defined as lack of arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of six months. In total, 43 RCTs comparing 11 different CA strategies involving 6701 patients were included. The risk of recurrence was significantly decreased in comparison with PVI with radiofrequency only for the following treatments: PVI with adjuvant ablation (RR: 0.79, CI: 0.65-0.97) and PVI with sympathetic modulation (RR: 0.64, CI: 0.46-0.88). However, PVI with radiofrequency was superior to non-PVI strategies (RR: 1.65, CI: 1.2-2.26). No statistically significant difference was found in safety between different CA strategies. Concerning different PVI strategies, no difference was observed either in efficacy or in safety between tested strategies. This NMA suggests that different PVI strategies are generally similar in terms of efficacy, while PVI with additional ablation or sympathetic modulation may be more effective than PVI alone. This study provides decision-makers with insights into the efficacy and safety of different CA strategies.

Sex-related differences in plaque characteristics and endothelial shear stress related plaque-progression in human coronary arteries.

BACKGROUND AND AIMS: Clinical atherosclerosis manifestations are different in women compared to men. Since endothelial shear stress (ESS) is known to play a critical role in coronary atherosclerosis development, we investigated differences in anatomical characteristics and endothelial shear stress (ESS)-related plaque growth in human coronary arteries in men compared to women. METHODS: 1183 coronary arteries (male/female: 944/239) from the PREDICTION study were studied for differences in artery/plaque and ESS characteristics, and ESS-related plaque progression (6-10 months follow-up) among men and women and after stratification for age. All characteristics were derived from IVUS-based vascular profiling and reported per 3 mm-segments (13,030 3-mm-segments (male/female: 10,465/2,565)). RESULTS: Coronary arteries and plaques were significantly smaller in females compared to males; but no important differences were observed in plaque burden, ESS and rate of plaque progression. Change in plaque burden was inversely related to ESS (p<0.001) with no difference between women versus men (ß: -0.62 ± 0.13 vs -0.68 ± 0.05, p=0.62). However, stratification for age demonstrated that ESS-related plaque growth was more marked in young women compared to men (<55 years, ß: -2.02 ± 0.61 vs -0.33 ± 0.10, p=0.007), reducing in magnitude over the age-categories up till 75 years. CONCLUSIONS: Coronary artery and plaque size are smaller in women compared to men, but ESS and ESS- related plaque progression were similar. Sex-related differences in ESS-related plaque growth were evident after stratification for age. These observations suggest that although the fundamental processes of atherosclerosis progression are similar in men versus women, plaque progression may be influenced by age within gender.

P-Wave Beat-to-Beat Analysis to Predict Atrial Fibrillation Recurrence after Catheter Ablation.

The identification of patients prone to atrial fibrillation (AF) relapse after catheter ablation is essential for better patient selection and risk stratification. The current prospective cohort study aims to validate a novel P-wave index based on beat-to-beat (B2B) P-wave morphological and wavelet analysis designed to detect patients with low burden AF as a predictor of AF recurrence within a year after successful catheter ablation. From a total of 138 consecutive patients scheduled for AF ablation, 12-lead ECG and 10 min vectorcardiogram (VCG) recordings were obtained. Univariate analysis revealed that patients with higher B2B P-wave index had a two-fold risk for AF recurrence (HR: 2.35, 95% CI: 1.24-4.44, p: 0.010), along with prolonged P-wave, interatrial block, early AF recurrence, female gender, heart failure history, previous stroke, and CHA2DS2-VASc score. Multivariate analysis of assessable predictors before ablation revealed that B2B P-wave index, along with heart failure history and a history of previous stroke or transient ischemic attack, are independent predicting factors of atrial fibrillation recurrence. Further studies are needed to assess the predictive value of the B2B index with greater accuracy and evaluate a possible relationship with atrial substrate analysis.

Syncope without prodromes is associated with excessive plasma release of adenosine at the time of syncope during head-up tilt table test.

BACKGROUND: In syncopal patients without underlying structural disease, we sought to investigate the association of Adenosine Plasma Levels (ADP) with the clinical presentation of neurally mediated syncope (NMS) and the outcomes of Head-Up Tilt Table Test (HUTT) and Adenosine test (ADT). METHODS: We studied 124 patients with different clinical types of NMS, i.e., Vasovagal (VVS, n=58), non-prodromes (NPS, n=18), or situational syncope (SS, n=48), using a standard protocol including HUTT and ADT. During HUTT, ADP was measured in the supine position, at table tilting and in syncope. RESULTS: Baseline ADP did not differ among groups. ADP at syncope were higher in NPS (n=5) compared to VVS (n=20): 0.23 vs. 0.12 µΜ, p=0.03, and SS (n=22): 0.04 µΜ, p=0.02. In NPS, ADP increased from supine to syncope (n=5): 0.15 vs. 0.23 µΜ, p=0.04. In VVS, ADP increased only from supine to tilt position: 0.11 vs. 0.14 µΜ, p=0.02. In SS, ADP did not change during HUTT. In positive vasodepressor HUTT, ADP increased from supine to tilt position (p=0.002) and at syncope (p=0.01). In SS, 20.0% exhibited cardioinhibitory HUTT vs. 6.8% in other forms of syncope (p=0.04). In SS, 22.9% manifested positive ADT vs 6.6% in other types of syncope (p=0.012). CONCLUSION: The subset of NPS patients with positive HUTT, show excessive ADP release at the time of syncope. This may explain the lack of prodromes in this form of syncope. Such observations contribute to the understanding of distinct profiles of clinical forms of syncope and may differentiate the management approach accordingly.

The use of a novel nitinol guidewire to facilitate transseptal puncture and left atrial catheterization for catheter ablation procedures.

AIMS: An increasing number of transseptal punctures (TSPs) are performed worldwide for atrial ablations. Transseptal punctures can be complex and can be associated with potentially life threatening complications. The purpose of the study was to evaluate the safety and efficacy of a novel transseptal guidewire (TSGW) designed to facilitate TSPs. METHODS AND RESULTS: Transseptal punctures were performed using a SafeSept TSGW passed through a standard TSP apparatus. Transseptal punctures were performed by standard technique with additional use of a TSGW allowing probing of the interatrial septum without needle exposure and penetration of the fossa into the left atrium (LA). Transseptal puncture using the TSGW was performed in 210 patients. Left atrial access was achieved successfully in 205 of 210 patients (97.6%) and in 96.3% of patients undergoing repeat TSP. Left atrial access was achieved with the first pass in 81.2% (mean 1.4 ± 0.9 passes, range 1-6) using the TSGW. No serious complications were attributable to the use of the TSGW, even in cases of failed TSP. CONCLUSIONS: The TSGW is associated with a high success rate for TSP and may be a useful alternative to transoesophageal or intracardiac echocardiogram-guided TSP.

Is the Adenosine Test Obsolete in the Clinical Assessment of Syncope of Unknown Origin?

Syncope is a common clinical condition affecting 50% of the general population; however, its exact pathophysiology and underlying mechanisms remain elusive. The adenosine test (ADT) has been proposed as a complementary diagnostic test in the work-up of syncope of unknown origin aiming to further elucidate the underlying pathogenetic mechanism of spontaneous syncope. Although ADT has not been endorsed by the recent European Society of Cardiology guidelines on syncope management, the use of a quick, safe and non-invasive test which can contribute to an accurate diagnosis and rationalised therapy, may deserve further consideration. This review summarises the evidence on the role of ADT in the investigation and management of syncope of unknown origin and highlights future perspectives in this area. The authors also analyse the current challenges and research targets on adenosine plasma levels and its receptors due to the involvement of the adenosine pathway in the ADT response.