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Short-coupled idiopathic ventricular fibrillation (SC-IVF) is a rare, life-threatening arrhythmia, accountable for 5–10% of out-of-hospital cardiac arrests (OHCA). Catheter ablation of the short-coupled premature ventricular contraction (PVC) that triggers VF has been shown to prevent VF recurrences in outdated case series. Aim To evaluate the clinical outcome and summarize the recent experience of 3D electrophysiological mapping and radiofrequency catheter ablation (RFCA) of SC-IVFs in a tertiary high-volume referral centre. Methods from January 2016, we enrolled all consecutive patients diagnosed with SC-IVF and treated by RFCA. Structural heart disease was excluded in all patients by means of echocardiography, cardiac magnetic resonance, coronary angiography, and exercise test. Brugada syndrome and long QT syndrome were excluded by Ajmaline and Epinephrine tests, respectively. The CARTO system was used to construct detailed 3D electroanatomic maps of the right and left ventricle. Mapping and ablation were performed with a standard 3.5- irrigated tip catheter. The PVCs were localized by mapping the earliest bipolar electrogram relative to the onset of the ectopic surface QRS (confirmed by QS complex in the unipolar configuration). Pace mapping was used in patients with infrequent PVCs. The origin of PVCs from fascicles/Purkinje network was indicated by initial sharp potentials preceding the ectopic QRS complex. The procedural end point was the abolition of all clinical PVCs. Outcome (freedom from SC-PVCs and VF episodes) was assessed by Holter monitoring and defibrillator memory interrogation. Results eleven consecutive patients [8 men, 3 women; median age 41 (± 5 years)] were enrolled. 10/11 patients (91%) were asymptomatic prior the index VF event, while 1 patient (9%) experienced recurrent syncope. An aborted OHCA was the index event in all patients. Arrhythmic storm was observed at the index presentation in 2 patients (18%). No patient had family history of sudden cardiac death. All patients were implanted with an ICD after the index event. The delay in SC-IVF diagnosis was 3 (± 2 years) from the index event. 2 patients (18%) had ≥ 2 SC-PVC morphologies. The mean coupling interval (CI) of the SC-PVCs ranged from 230 to 330 msec (mean 303 ± 26 msec). The CI/QT ratio ranged from 0.6 to 1 (mean 0.81 ± 0.15). 10 patients underwent RFCA for recurrent VF/ICD shocks and 1 patient for refractory electrical storm. RFCA was based on activation mapping, pace-mapping, and both in 1 (9%), 1 (9%), and 9 (82%) patients, respectively. The sites of ablation were LV Purkinje, RV Purkinje, RV non-Purkinje (RV outflow tract and tricuspid annulus), and LV non-Purkinje (LV Summit) in 3 (27%), 4 (36%), 3 (27%), and 1 (9%) patient, respectively. The first ablation was acutely successful in all patients. 1 patient experienced recurrence of SC-PVCs and VF episodes after 5 days from the first ablation and underwent a second RFCA. There were no peri-procedural complications. After a median follow-up of 22 months (ranging from 6 to 39 months) all patients were free from sustained ventricular arrhythmia recurrences: 10 patients (91%) were free from VF and PVCs; 1 patient (9%) had recurrent SC-PVCs without VF episodes. Conclusions this retrospective study explored the effectiveness of RFCA combined with the advanced electroanatomic mapping in a current cohort of patients with history of OHCA diagnosed with SC-IVF. RFCA of SC-PVCs was safe and highly effective in abolishing VF episodes in all patients.

Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients and they mainly disrupt the cardiac sodium channel NaV1.5, which is considered the main cause of the disease. However, voltage-gated channel’s activity could be impacted by post-translational modifications such as sialylation, but their role in BrS remains unknown. Thus, we analyzed high risk BrS patients (n = 42) and healthy controls (n = 42) to assess an involvement of sialylation in BrS. Significant alterations in gene expression and protein sialylation were detected in Peripheral Blood Mononuclear Cells (PBMCs) from BrS patients. These changes were significantly associated with the phenotypic expression of the disease, as the size of the arrhythmogenic substrate and the duration of epicardial electrical abnormalities. Moreover, protein desialylation caused a reduction in the sodium current in an in vitro NaV1.5-overexpressing model. Dysregulation of the sialylation machinery provides definitive evidence that BrS affects extracardiac tissues, suggesting an underlying cause of the disease. Moreover, detection of these changes at the systemic level and their correlation with the clinical phenotype hint at the existence of a biomarker signature for BrS.

Brugada syndrome (BrS) is a cardiac arrhythmia associated with a higher risk of SCD. BrS is considered a genetic disorder, and the most commonly mutated gene is SCN5A, encoding the alpha subunit of the voltage-gated cardiac sodium channel (NaV1.5). Mutations of SCN5A usually lead to impairment of NaV1.5 functionality, which is considered the main mechanism of the disease. However, SCN5A mutations are responsible for only 30% of BrS cases. Therefore, it is conceivable that other mechanisms such as post-translational modifications (PTMs) affect NaV1.5 activity. Among others, sialylation may alter ion channel activity by carrying a sugar with a negative charge. Alterations in sialylation have been described in several cardiovascular diseases, as myocardial infarction, Chagas disease, and congenital disorders of glycosylation. For these reasons, the aim was to investigate changes in sialylation in BrS patients to obtain new information on the pathogenesis of BrS. Peripheral blood mononuclear cells (PBMCs) were collected from BrS patients and healthy controls. SNA lectin, a sialic acid-binding protein, was used to characterize the protein sialylation status of PBMCs by Western blot and flow cytometry. Gene expression of enzymes involved in the sialic acid pathway was also examined. The results showed a significant decrease in intracellular and extracellular protein sialylation levels in BrS PBMCs compared with controls. In addition, changes in gene expression of enzymes involved in the sialic acid pathway were detected. Moreover, these changes correlated with clinical parameters associated with phenotypic expression of the disease, such as arrhythmogenic BrS substrate area and potential duration. These findings support that BrS should be considered a systemic disease and are consistent with the presence of overlapping non-cardiac pathologies, as epilepsy, cancer, diabetes, skeletal muscle channelopathies, and laminopathies in BrS patients. Moreover, the discovery that molecular alterations can be found in the peripheral blood of BrS patients supports the existence of a biomarker of the disease. It is a challenge to develop an effective diagnostic test to screen broadly for BrS. In this direction, a multiomic study is ongoing in our center.

Aims The long-QT syndrome (LQTS) represents a leading cause of sudden cardiac death (SCD). The aim of this study was to assess the presence of an underlying electroanatomical arrhythmogenic substrate in high-risk LQTS patients. Methods and results The present study enrolled 11 consecutive LQTS patients who had experienced frequent implantable cardioverter-defibrillator (ICD discharges triggered by ventricular fibrillation (VF). We acquired electroanatomical biventricular maps of both endo and epicardial regions for all patients and analyzed electrograms sampled from several myocardial regions. Abnormal electrical activities were targeted and eliminated by the means of radiofrequency catheter ablation. VF episodes caused a median of four ICD discharges in eleven patients (6 male, 54.5%; mean age 44.0 ± 7.8 years, range 22–53) prior to our mapping and ablation procedures. The average QTc interval was 500.0 ± 30.2 ms. Endo-epicardial biventricular maps displayed abnormally fragmented, low-voltage (0.9 ± 0.2 mV) and prolonged electrograms (89.9 ± 24.1 ms) exclusively localized in the right ventricular epicardium. We found electrical abnormalities extending over a mean epicardial area of 15.7 ± 3.1 cm2. Catheter ablation of the abnormal epicardial area completely suppressed malignant arrhythmias over a mean 12 months of follow-up (median VF episodes before vs. after ablation, 4 vs. 0; P = 0.003). After the procedure, the QTc interval measured in a 12-lead ECG analysis shortened to a mean of 461.8 ± 23.6 ms (P = 0.004). Conclusion This study reveals that, among high-risk LQTS patients, regions localized in the epicardium of the right ventricle harbour structural electrophysiological abnormalities. Elimination of these abnormal electrical activities successfully prevented malignant ventricular arrhythmia recurrences.

Aims Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype–phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype–phenotype correlation in BrS. Methods and results Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area. Conclusion In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

Despite significant advances in the prevention of cardiovascular diseases, sudden cardiac death (SCD) persists as a major public health problem. Among young and apparently healthy individuals, Long-QT syndrome (LQTS) represents a leading progenitor of SCD owing to fatal ventricular arrhythmia. Scientific understanding of this association has grown in recent years, and the mortality rate after LQTS diagnosis has significantly decreased. However, despite medical treatment advances, life-threatening ventricular arrhythmias still occur. Until now, no research has established the degree to which this inherited condition arises from an underlying arrhythmogenic electroanatomical substrate. Here, we present direct evidence showing that LQTS patients who survive spontaneous malignant arrhythmias harbor structural electrophysiological abnormalities localized in the epicardium of the right ventricle. We further show that the elimination of these abnormalities by means of catheter ablation successfully suppresses malignant arrhythmias, offering a new approach for the effective treatment of LQTS patients.

Background: Brugada syndrome (BrS) is considered a purely electrical disease with variable electrical substrates. Variable rates of mechanical abnormalities have been also reported. Whether exists a link between electrical and mechanical abnormalities has never been previously explored. This investigational physiopathological study aimed to determine the relationship between the substrate size/location, as exposed by ajmaline provocation, and the severity of mechanical abnormalities, as assessed by cardiac magnetic resonance in patients with BrS. Methods: Twenty-four consecutive high-risk patients with BrS (mean age, 38±11 years, 17 males), presenting with malignant syncope and documented polymorphic ventricular tachycardia/ventricular fibrillation, and candidate to implantable cardioverter defibrillator implantation, underwent cardiac magnetic resonance and electroanatomic maps. During each examination, ajmaline test (1 mg/kg over 5 minutes) was performed. Cardiac magnetic resonance findings were compared with 24 age, sex, and body surface area-matched controls. In patients with BrS, the correlation between the electrical substrate extent and right ventricular regional mechanical abnormalities before/after ajmaline challenge was analyzed. Results: After ajmaline, patients with BrS showed a reduction of right ventricular (RV) ejection fraction ( P P P P P 2 to 14.2±7.3 cm 2 ( P r =−0.830, P Conclusions: BrS is a dynamic RV electromechanical disease, where functional abnormalities correlate with the maximal extent of the substrate size. These findings open new lights on the physiopathology of the disease. Registration: URL: https://clinicaltrial.gov ; Unique identifier: NCT03524079.

Patients with COVID-19 frequently have non-typical ECG changes in the QRS and T-wave morphology. The novel CineECG uses using the mean temporal spatial isochrones (mTSI) to relate the activation and recovery pathway to the cardiac anatomy. The aim of this feasib ility study is to use the novel CineECG to separate normal from abnormal ECGs. The ECGs of 100 normal controls were used to obtain the normal mTSI paths values for the QRS, ST segment and T-wave. These normal CineECG values were used to classify the COVID-19 ECGs as either as normal or abnormal of 107 patients being treatedfor COVID-19 in the University Medical Center Utrecht. The CineECG was able to classify 98% of the normal ECG correctly and 94% of the abnormal ECG in comparison to expert ECG classifications. The ability of the CineECG to relate the ECG to the cardiac anatomy supports the detection of abnormal ECGs. The CineECG might be a novel ECG screening tool to detect potential cardiac involvement of the COVID-19 disease for non-ECG experts.

Aims Balloon-based technologies have been developed to simplify catheter ablation of atrial fibrillation (AF), to improve the clinical outcome of the procedure and to achieve durable pulmonary vein isolation (PVI). The objective of this study is to evaluate the safety and efficacy of second-generation laser balloon (LB2) ablation in the treatment of AF using a continuous cardiac rhythm monitoring strategy. Atrial tachyarrhythmias (ATas) recurrences were assessed with implantable cardiac monitors (ICMs) or devices. Methods and results All patients underwent LB2 ablation procedure. The primary endpoint was the first recurrence of any, >5.5 and >24 h duration ATas after the blanking period (90 days). In-hospital visits were performed at 3, 6, and 12 months. Seventy-three patients (68% male, mean age 59.8 ± 11.3) were included in the study. The average procedure, fluoroscopy, and laser ablation times were 81.5 ± 30.1, 21.5 ± 12.4, and 33.8 ± 9.7, respectively. All PVs were isolated using the LB2 with no need of touch-up using focal catheters. No major complications occurred during or after the procedures. The one-year freedom from recurrences was 66.9% (95% CI: 57.0–76.7%), 81.0% (69.5–88.5%), and 86.8% (76.1–92.9%) considering any, 5.5-h and 24-h cut-off duration, respectively. At 3, 6, and 12 months, any ATas was recorded in 22%, 32%, and 25% of patients, with a ≥5% arrhythmic burden documented in 4%, 5%, and 3%, respectively. Few patients reported AF-related symptoms (7%, 8%, and 5%). Conclusion LB2 ablation is a safe and effective procedure, showing a high freedom from recurrences and low arrhythmic burden as documented by a continuous rhythm monitoring strategy.

Background: In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS. Methods: The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined. Results: In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results. Conclusions: In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.

Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the SCN5A gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS.

Background Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population. Methods A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT). Results A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3452 ± 26.4 vs Group 2436.3 ± 28.4 vs Group 1424.4 ± 24.3 ms, respectively; p, Highlights • Only the use of HCQ in combination with AZT causes a significant increase of QT interval. • Older patients are at higher risk of prolonged QT when treated with HCQ with/without AZT. • The use of HCQ alone or in combination with AZT might be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients.

Background: The relationship between the typical electrocardiographic pattern and electromechanical abnormalities has never been systematically explored in Brugada syndrome (BrS). Objectives: The aims of this study were to characterize the electromechanical substrate in patients with BrS and to evaluate the relationship between electrical and mechanical abnormalities. Methods: We enrolled 50 consecutive high-risk patients with BrS (mean age 42 ± 7.2 years), with implantable cardioverter-defibrillator implantation for primary or secondary prevention of ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]), undergoing substrate mapping and ablation. Patients underwent 3-dimensional (3D) echocardiography with 3D wall motion/deformation quantification and electroanatomic mapping before and after ajmaline administration (1 mg/kg in 5 minutes); 3D mechanical changes were compared with 50 age- and sex-matched controls. The effect of substrate ablation on electromechanical abnormalities was also assessed. Results: In all patients, ajmaline administration induced Brugada type 1 pattern, with a significant increase in the electrical substrate (P

Objectives This study investigates the electrocardiographic-electrophysiological effects of administration of anesthetic drugs for general anesthesia (GA) in patients with BrS at high risk of sudden cardiac death (SCD). Background The safety of anesthetic agents in Brugada syndrome (BrS) is under debate. Methods All consecutive patients with spontaneous type 1 BrS electrocardiographic (ECG) patterns undergoing epicardial ablation of the arrhythmogenic substrate (AS) under GA were enrolled. Anesthesia was induced with single bolus of propofol and maintained with sevofluorane. ECG measurements were collected before, immediately after, and 20 min after induction of GA. Three-dimensional maps during GA and after ajmaline indicated the epicardial AS before ablation. Results Thirty-six patients with BrS (32 male, 88.9%; mean age 38.8 ± 12.0 years) with a spontaneous type 1 ECG pattern underwent GA. Induction was performed using propofol at mean dose of 1.6 to 2.6 mg/kg (2.1 ± 0.3 mg/kg). Twenty-eight (28 of 36, 77.8%) patients showed a reversion to a nondiagnostic pattern. ST-segment elevation (0.32 ± 0.01 mV vs. 0.19 ± 0.02 mV, p 2 vs. 20.3 ± 0.8 cm 2 ). No patient developed malignant arrhythmias during GA induction and maintenance. Conclusions This study shows that GA using single-bolus propofol and volatile anesthetics is safe in high-risk patients with BrS, and it may exert a modulating effect by reducing the manifestation of type 1 BrS pattern and AS in the form of epicardial abnormal ECGs. (Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701).

Background: Multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], Abbott, Sylmar, CA, USA) improves the response rate to cardiac resynchronization therapy (CRT). We evaluated the feasibility of noninvasive radial artery tonometry (RAT) to characterize arterial pressure morphology changes (pre-ejection period [PEP] and ejection duration [ED]) between conventional CRT and MPP pacing interventions. Methods: Patients with a MPP-enabled CRT device (Quadra Assura MP™, Abbott) underwent noninvasive RAT assessment (SphygmoCor CVMS, AtCor Medical Inc., Itasca, IL, USA) at 3–6 months after implantation. A pacing protocol was performed in a randomized order including one optimized conventional biventricular CRT (CONV) configuration using the distal electrode and five MPP configurations. The PEP, ED, and PEP/ED ratio were determined for each intervention from the RAT pressure waveform and electrocardiogram. Results: Pressure waveforms were successfully recorded in 19 patients (89% male, QRS 147 ± 16ms, 63% ischemic). In 17/19 (89%) patients, at least one MPP intervention resulted in improved PEP, ED, and PEP/ED compared to CONV. The MPP intervention with greatest separation of LV cathodes and minimum intra-LV delay significantly improved PEP (mean PEP –15 ± 33%vs –8 ± 32% [CONV], P=0.04) and ED (mean ED +8 ± 8% [MPP] vs +4 ± 7% [CONV], P=0.02), and PEP/ED (–0.07 ± 0.14 [MPP] vs –0.04 ± 0.13 [CONV], P=0.02) compared with CONV. Conclusions: Noninvasive RAT efficiently characterizes changes in PEP and ED between CONV and MPP interventions. MPP configurations using the widest separation among LV cathodes and minimum intra-LV delay may significantly improve RAT-derived parameters as compared to conventional CRT.

Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the SCN5A gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery in about half of the cases, with the remaining cases being attributed to variants in any of a number of genes. Before research models can be developed, it is imperative to understand the genetics in patients. Even data from humans is complicated, since variants in the most common gene in BrS, SCN5A, are associated with a number of pathologies, or could even be considered benign, depending on the variant. Here, we provide crucial human data on a novel NM_198056.2:c.2091G>A (p.Trp697X) point-nonsense heterozygous variant in the SCN5A gene, as well as its segregation with BrS. The results herein suggest a pathogenic effect of this variant. These results could be used as a stepping stone for functional studies to better understand the molecular effects of this variant in BrS.

Aims Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs. Methods and Results Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P Conclusion The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity. ClinicalTrials.gov number (NCT02641431; NCT03106701).

Aims The Brugada syndrome (BrS) is an inherited disease associated with an increased risk of sudden cardiac death. Often, the genetic cause remains undetected. Perhaps due at least in part because the NaV1.8 protein is expressed more in both the central and peripheral nervous systems than in the heart, the SCN10A gene is not included in diagnostic arrhythmia/sudden death panels in the vast majority of cardiogenetics centres. Methods and results Clinical characteristics were assessed in patients harboring either SCN5A or novel SCN10A variants. Genetic testing was performed using Next Generation Sequencing on genomic DNA. Clinical characteristics, including the arrhythmogenic substrate, in BrS patients harboring novel SCN10A variants and SCN5A variants are comparable. Clinical characteristics, including gender, age, personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate are not significantly different between probands harboring SCN10A or SCN5A variants. Conclusion Future studies are warranted to further characterize the role of these specific SCN10A variants.

Aims Clinical outcomes after radiofrequency catheter ablation (RFCA) remain suboptimal in the treatment of non-paroxysmal atrial fibrillation (AF). Electrophysiological mapping may improve understanding of the underlying mechanisms. To describe the arrhythmia substrate in patients with persistent (Pers) and long-standing persistent (LSPers) AF, undergoing RFCA, using an integrated mechanism mapping technique. Methods and results Patients underwent high-density electroanatomical mapping before and after catheter ablation. Integrated maps characterized electrogram (EGM) cycle length (CL) in regions with repetitive–regular (RR) activations, stable wavefront propagation, fragmentation, and peak-to-peak bipolar voltage. Among 83 patients (72% male, 60 ± 11 years old), RR activations were identified in 376 regions (mean CL 180 ± 31 ms). PersAF patients (n = 43) showed more RR sites per patient (5.3 ± 2.4 vs. 3.7 ± 2.1, P = 0.002) with faster CL (166 ± 29 vs. 190 ± 29 ms; P 75% of RR sites (Q4 82.6%, Q3 63.1%, Q2 35.1%, and Q1 0%; P Conclusion The integrated mapping technique allowed characterization of multiple arrhythmic substrates in non-paroxysmal AF patients. This technique might serve as tool for a substrate-targeted ablation approach.

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the SCN5A gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant.

Purpose: Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP]) improves long-term LV reverse remodeling, though questions persist about how to program LV pacing vectors and delays. We evaluated if an empirical method of programming MPP vectors and delays between pacing pulses improved CRT response similar to pressure-volume loop (PVL) optimized MPP programming. Methods: Patients undergoing CRT implant (Quadra Assura MP™ CRT-D and Quartet™ LV lead) received MPP with programmed settings optimized either by PVL measurements at implant (PVL-OPT group) or empirically determined by maximizing the spatial separation between the two cathodes and minimal delays between the three ventricular pacing pulses (MAX-SEP group). CRT response was prospectively defined as a reduction in end-systolic volume (ESV) of ≥ 15% relative to baseline at 6months as determined by a blinded observer. Results: Patient characteristics at baseline (NYHA II–III, ejection fraction [EF] 27 ± 6%, QRS 151 ± 17ms) were not significantly different between the PVL-OPT (n = 27) and MAX-SEP (n = 26) groups. During the follow-up period, there were no differences in the number of patients requiring reprogramming due to phrenic nerve stimulation or a high threshold for PVL-OPT vs. MAX-SEP (5/27 [19%] vs. 7/26 [27%], p= 0.53). After 6months, ESV reduction, EF increase, and CRT response rate (RR) were similar for PVL-OPT vs. MAX-SEP (ESV − 20 ± 11 vs. − 22 ± 11%, p = 0.59; EF + 10 ± 4 vs. + 9 ± 7%, p = 0.53; RR 20/27 [74%] vs. 21/26 [81%], p = 0.74), while fewer patients in the PVL-OPT group experienced NYHA class reduction ≥ 2 (4/27 [15%] vs.15/26 [58%], p = 0.002). Conclusions: Both evaluated methods of MPP programming resulted in similar CRT outcomes. Empirical MPP programming by maximum spatial separation of LV cathodes may be an effective, simple, and non-invasive alternative to pressure-volume optimization.

Aims Continuous rhythm monitoring is valuable for adequate atrial fibrillation (AF) management in the clinical setting. Subcutaneous leadless implantable cardiac monitors (ICMs) yield an improved AF detection, overcoming the intrinsic limitations of the currently available external recording systems, thus resulting in a more accurate patient treatment. The study purpose was to assess the detection performance of a novel three-vector ICM device equipped with a dedicated AF algorithm. Methods and results Sixty-six patients (86.4% males; mean age 60.4 ± 9.4 years) at risk to present AF episodes, having undergone the novel ICM implant (BioMonitor, Biotronik SE&Co. KG, Berlin, Germany), were enrolled. External 48-h ECG Holter was performed 4 weeks after the device implantation. The automatic ICM AF classification was compared with the manual Holter arrhythmia recordings. Of the overall study population, 63/66 (95.5%) had analysable Holter data, 39/63 (62%) showed at least one true AF episode. All these patients had at least one AF episode stored in the ICM. On Holter monitoring, 24/63 (38%) patients did not show AF episodes, in 16 of them (16/24, 67%), the ICM confirmed the absence of AF. The AF detection sensitivity and positive predictive value for episodes' analysis were 95.4 and 76.3%, respectively. Conclusion Continuous monitoring using this novel device, equipped with a dedicated detection algorithm, yields an accurate and reliable detection of AF episodes. The ICM is a promising tool for tailoring individual AF patient management. Further long-term prospective studies are necessary to confirm these encouraging results.

In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs*221) in a single copy of the SCN5A gene and its association with Brugada syndrome (BrS). The proband experienced a life-threatening ventricular arrhythmia successfully treated with DC-shock and he also suffered from supraventricular tachycardia. Ajmaline test confirmed the BrS diagnosis. No other mutation nor low frequency variants in the other 23 analyzed genes were detected. The same mutation was found in the father and sister, who were both diagnosed with BrS. We hypothesize that this mutation could be responsible for BrS and potentially linked to supraventricular tachycardias. Further studies are needed to confirm this observation and to assess the clinical relevance of this mutation, in terms of risk-stratification.

Background: Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it. Objectives: This prospective registry study was designed to explore clinical and electrophysiological predictors of malignant ventricular tachyarrhythmia inducibility in Brugada syndrome. Methods: A total of 191 consecutive selected patients with (group 1; n = 88) and without (group 2; n = 103) Brugada syndrome–related symptoms were prospectively enrolled in the registry. Patients underwent electrophysiological study and substrate mapping or ablation before and after ajmaline testing (1 mg/kg/5 min). Results: Overall, before ajmaline testing, 53.4% of patients had ventricular tachyarrhythmia inducibility, which was more frequent in group 1 (65.9%) than in group 2 (42.7%; p < 0.001). Regardless of clinical presentation, larger substrates with more fragmented long-duration ventricular potentials were found in patients with inducible arrhythmias than in patients without inducible arrhythmias (p < 0.001). One extrastimulus was used in more extensive substrates (median 13 cm2; p < 0.001), and ventricular fibrillation was the more frequently induced rhythm (p < 0.001). After ajmaline, patients without arrhythmia inducibility had arrhythmia inducibility without a difference in substrate characteristics between the 2 groups. The substrate size was the only independent predictor of inducibility (odds ratio: 4.51; 95% confidence interval: 2.51 to 8.09; p < 0.001). A substrate size of 4 cm2 best identified patients with inducible arrhythmias (area under the curve: 0.98; p < 0.001). Substrate ablation prevented ventricular tachyarrhythmia reinducibility. Conclusions: In Brugada syndrome dynamic substrate variability represents the pathophysiological basis of lethal ventricular tachyarrhythmias. Substrate size is independently associated with arrhythmia inducibility, and its determination after ajmaline identifies high-risk patients missed by clinical criteria. Substrate ablation is associated with electrocardiogram normalization and not arrhythmia reinducibility. (Epicardial Ablation in Brugada Syndrome [BRUGADA_I]; NCT02641431; Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701)

Background: Clinical outcomes after ablation of persistent atrial fibrillation remain suboptimal. Identification of AF drivers using a novel integrated mapping technique may be crucial to ameliorate the clinical outcome. Methods and Results: Persistent AF patients were prospectively enrolled to undergo high-density electrophysiological mapping to identify repetitive-regular activities (RRas) before modified circumferential pulmonary vein (PV) ablation. They have been randomly assigned (1:1 ratio) to ablation of RRa followed by modified circumferential PV ablation (mapping group; n=41) or modified circumferential PV ablation alone (control group; n=40). The primary end point was freedom from arrhythmic recurrences at 1 year. In total, 81 persistent AF patients (74% male; mean age, 61.7±10.6 years) underwent mapping/ablation procedure. The regions exhibiting RRa were 479 in 81 patients (5.9±2.4 RRa per patient): 232 regions in the mapping group (n=41) and 247 in the control group (n=40). Overall, 185 of 479 (39%) RRas were identified within the PVs, whereas 294 of 479 (61%) in non-PV regions. Mapping-guided ablation resulted in higher arrhythmia termination rate when compared with conventional strategy (25/41, 61% versus 12/40, 30%; P P =0.38), mapping ( P =0.46), and fluoroscopy times ( P =0.69) were not significantly different between the groups. No major procedure-related adverse events occurred. After 1 year, 73.2% of mapping group patients were free from recurrences versus 50% of control group ( P =0.03). Conclusions: Targeted ablation of regions showing RRa provided an adjunctive benefit in terms of arrhythmia freedom at 1-year follow-up in the treatment of persistent AF. These findings might support a patient-tailored strategy in subjects with nonparoxysmal AF and should be confirmed by additional larger, randomized, multicenter studies. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier NCT02571218.

Background Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing (MultiPoint™ Pacing [MPP], St. Jude Medical) improves acute LV function and LV reverse remodeling at 3 months. Objective The purpose of this study was to test the hypothesis that MPP can also improve LV function at 12 months. Methods Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical) were randomized to receive pressure–volume (PV) loop optimized biventricular pacing with either conventional cardiac resynchronization therapy (CONV) or MPP. CRT response was defined by a reduction in end-systolic volume (ESV) ≥15% relative to BASELINE as determined by a blinded observer and alive status. Results Forty-four patients (New York Heart Association class III, ejection fraction [EF] 29% ± 6%, QRS 152 ± 17 ms) were enrolled and randomized to either CONV (N = 22) or MPP (N = 22). During the observation period, 2 patients died of noncardiac causes and 2 patients were lost to follow-up. After 12 months, 12 of 21 patients (57%) in the CONV group and 16 of 21 patients (76%) in the MPP group were classified as CRT responders ( P = .33). ESV reduction and EF increase relative to BASELINE were significantly greater with MPP than with CONV (ESV: median –25%, interquartile range [IQR] [–39% to –20%] vs median –18%, IQR [–25% to –2%], P = .03; EF: median +15%, IQR [8% to 20%] vs median +5%, IQR [–1% to 8%], P Conclusion Sustaining the trend observed 3 months postimplant, PV loop-guided multipoint LV pacing resulted in greater LV reverse remodeling and increased LV function at 12 months compared to PV loop-guided conventional CRT.

The aim of this article is to understand the natural history of WPW syndrome to prevent sudden death is important to clinicians in establishing accurate prognosis and appropriate treatment. We report our experience on untreated WPW patients purely looking at the natural history of the disease. In a 15-year period (1995-2010), among 11 237 WPW patients referred to our Arrhythmology Department, a total of 1847 selected patients (820 symptomatic) underwent electrophysiological testing without ablation and were followed for a median (25th-75th) follow-up of 8 (5-8) years. During follow-up, malignant arrhythmias (MA) occurred in 16 patients (0.9%) of whom 14 (1.4%) were initially asymptomatic and two (0.2%) symptomatic (P = 0.01). Potentially MA developed in 143 patients (7.7%) without difference between asymptomatic and symptomatic population (P = 0.663). Benign recurrences developed in 295 patients (16%) while ventricular pre-excitation disappeared in 356 patients (19.3%) of whom 155 were initially asymptomatic. All patients were successfully ablated after arrhythmia occurrence. Patients with MA had similar accessory pathways antegrade refractory periods (AP-AERP) (P = 0.064) and more frequently inducible atrioventricular reciprocating tachycardia triggering atrial fibrillation (AVRT-AF) than those with potentially MA (P < 0.001). Symptoms did not predict MA, which were predicted by AP-AERP (HR 0.912, 95% CI 0.887-0.939, P < 0.001) and AVRT-AF (HR 8.306, 95% CI 2.269-30.405, P = 0.001). The natural history of WPW syndrome and the risk of sudden death essentially depend on intrinsic electrophysiological accessory pathway properties rather than on symptoms and electrophysiologic testing is the gold standard to identify patients at risk. The Authors encourage more intensive screening programs to identify asymptomatic patients at risk for prophylactic ablation.

The Remote Monitoring (RM) technology has recently become available in insertable cardiac monitors (ICM) [(1)][1]. The purpose of this analysis was to assess feasibility, clinical reactions, and arrhythmic alerts burden of remote management for patients implanted with the novel long-dipole ICM (

This study investigates the electrocardiographic-electrophysiological effects of administration of anesthetic drugs for general anesthesia (GA) in patients with BrS at high risk of sudden cardiac death (SCD).The safety of anesthetic agents in Brugada syndrome (BrS) is under debate.All consecutive patients with spontaneous type 1 BrS electrocardiographic (ECG) patterns undergoing epicardial ablation of the arrhythmogenic substrate (AS) under GA were enrolled. Anesthesia was induced with single bolus of propofol and maintained with sevofluorane. ECG measurements were collected before, immediately after, and 20 min after induction of GA. Three-dimensional maps during GA and after ajmaline indicated the epicardial AS before ablation.Thirty-six patients with BrS (32 male, 88.9%; mean age 38.8 ± 12.0 years) with a spontaneous type 1 ECG pattern underwent GA. Induction was performed using propofol at mean dose of 1.6 to 2.6 mg/kg (2.1 ± 0.3 mg/kg). Twenty-eight (28 of 36, 77.8%) patients showed a reversion to a nondiagnostic pattern. ST-segment elevation (0.32 ± 0.01 mV vs. 0.19 ± 0.02 mV; p 0.001) and J-wave amplitude (0.47 ± 0.02 mV vs. 0.31 ± 0.03 mV; p 0.001) decreased after propofol. The AS area during GA, in the absence of BrS pattern, significantly enlarged after administration of ajmaline (3.6 ± 0.5 cmThis study shows that GA using single-bolus propofol and volatile anesthetics is safe in high-risk patients with BrS, and it may exert a modulating effect by reducing the manifestation of type 1 BrS pattern and AS in the form of epicardial abnormal ECGs. (Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701).

A huge thrombus, developing after percutaneous left atrial appendage occlusion, has been successfully treated with dabigatran and aspirin as combination therapy.Although novel oral anticoagulants alone may be effective in thrombus dissolution, the association of an antiplatelet drug may safely enhance this process.

Multipoint LV Pacing Improves Mid-Term CRT Response Introduction Cardiac resynchronization therapy (CRT) with multipoint left ventricular (LV) pacing in a single coronary sinus branch improves acute LV function. We hypothesized that multipoint pacing (MPP) can improve midterm echocardiographic and clinical response compared with conventional CRT. Methods and Results Consecutive patients receiving a CRT implant (Unify Quadra MP™ or Quadra Assura MP™ CRT-D and Quartet™ LV lead, St. Jude Medical, Sylmar, CA, USA) were randomized to receive biventricular (BiV) pacing with either conventional LV pacing (CONV group) or MPP (MPP group). For each patient, an optimal pacing configuration for the assigned pacing mode was programmed based on intraoperative pressure-volume (PV) loop measurements. A clinical evaluation and transthoracic echocardiogram were performed before implant (BASELINE) and at 3 months postimplant and analyzed by a blinded observer. A reduction in end-systolic volume (ESV) of ≥15% relative to BASELINE was prospectively defined as response to CRT. Forty-four patients (NYHA Class III, EF 29 ± 6%, QRS duration 152 ± 17 milliseconds) were enrolled and randomized. One patient in the MPP group was lost to follow-up and excluded from further analysis. After 3 months, 11 of 22 (50%) CONV patients and 16 of 21 (76%) MPP patients were classified as responders. ESV reduction, EF increase, and NYHA class reduction relative to BASELINE were significantly greater in the MPP group than in the CONV group (ESV: −21.0 ± 13.9 vs. −12.6 ± 11.1%, P = 0.03; EF: +9.8 ± 5.1 vs. +2.0 ± 7.8 percentage points, P < 0.001; ΔNYHA: −1.05 ± 0.22 vs. −0.72 ± 0.46 functional classes, P = 0.006). Conclusion PV loop optimized BiV pacing with MPP resulted in an improved rate of response to CRT.

There is evidence for a higher prevalence of atrial fibrillation (AF) in athletes engaged in long-term endurance sports training compared with the general population. Although atrial anatomic adaptations, alterations in autonomic nervous system, chronic systemic inflammation and fibrosis have been proposed as potential mechanisms, they remain speculative. Medical therapy with long-term antiarrhythmic agents or ‘pill in the pocket’ medications is hampered by limitations, such as sports eligibility and interference with exercise tolerance. AF ablation represents a valid therapeutic option with results similar to these achieved in other patients. Nevertheless, further clinical trials are needed to confirm whether endurance sport practice affects the maintenance of sinus rhythm following catheter ablation of AF.

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. The trigger for initiation of AF is generally an enhanced vulnerability of pulmonary vein cardiomyocyte sleeves to either focal or re-entrant activity. The maintenance of AF is based on a "driver" mechanism in a vulnerable substrate. Cardiac mapping technology is providing further insight into these extremely dynamic processes. AF can lead to electrophysiological and structural remodelling, thereby promoting the condition. The management includes prevention of stroke by oral anticoagulation or left atrial appendage (LAA) occlusion, upstream therapy of concomitant conditions, and symptomatic improvement using rate control and/or rhythm control. Nonpharmacological strategies include electrical cardioversion and catheter ablation. There are substantial geographical variations in the management of AF, though European data indicate that 80% of patients receive adequate anticoagulation and 79% adequate rate control. High rates of morbidity and mortality weigh against perceived difficulties in management. Clinical research and growing experience are helping refine clinical indications and provide better technical approaches. Active research in cardiac electrophysiology is producing new antiarrhythmic agents that are reaching the experimental clinical arena, inhibiting novel ion channels. Future research should give better understanding of the underlying aetiology of AF and identification of drug targets, to help the move toward patient-specific therapy.

Nonirrigated magnetic ablation may result in potential char, ineffective lesions, and longer procedure times.This study sought to report the safety and long-term efficacy of irrigated-tip magnetic ablation of atrial fibrillation (AF).Catheter ablation was remotely performed using a new irrigated-tip magnetic catheter (ThermoCool NaviStar-RMT, Biosense Webster, Diamond Bar, CA) in 130 consecutive patients (mean age 59.7 ± 10.5 years) with symptomatic paroxysmal (81 patients) or persistent (49 patients) AF. The radiofrequency (RF) generator was set to fixed power of 30 W. The primary end point of the study was freedom from atrial tachycardia (AT)/AF off antiarrhythmic drugs.The procedure was safely performed in all conventional ablation targets, but crossover to manual catheters was required in 12 patients to complete the mitral isthmus line. The total procedure time was 94.6 ± 15.3 minutes. Impedance values significantly decreased during RF applications (P.001) and the maximum temperature on the catheter tip was 36.4°C ± 0.8°C. The follow-up duration was 15.3 ± 4.9 months. The primary end point was achieved in 66 of 81(81.4%) patients with paroxysmal AF and in 33 of 49 (67.3%) with persistent AF (P = .035, by log-rank test). Patients with paroxysmal AF had higher late AF recurrence (P =.044). Overall, postablation incessant left AT developed in 7 of 130 (5.4%) patients. Major complications were not observed. Left atrial diameter (P.001) and heart failure (P = .032) predicted arrhythmia recurrence after remote irrigated-tip ablation.Remote ablation with irrigated-tip magnetic catheters can be safely and effectively performed in patients with AF, but longer follow-up periods are required to evaluate late AF recurrences.

Background Pulmonary vein isolation (PVI) is one of the common endpoints of all atrial fibrillation (AF) ablation procedures and is most often validated using a preshaped circular catheter. However, three-dimensional (3D) electroanatomical systems used for anatomy reconstruction and to guide coalescent delivery of ablation lesions avoid the use of multiple transeptal punctures and multiple catheters in the left atrium. Objective To assess correspondence in PVI validation between a 3D electroanatomical system and a Lasso catheter. Methods Twenty-five patients affected by nonpermanent AF were enrolled after giving informed consent. After ablation of all four pulmonary vein (PV) ostia, encircled areas were extensively mapped (15 ± 5 points acquired for each PV ostium) to assess the absence of any electrical activity conducted from the left atrium to the PV. At the end of the procedure, the physician performing the ablation procedure judged the complete versus incomplete PVI according to Carto/ablation catheter mapping during coronary sinus pacing. Thereafter, a second operator blinded to the result of the ablation procedure positioned a preshaped Lasso catheter in each PV ostium and annotated complete/incomplete PVI during pacing from the coronary sinus. Results PVI as assessed with CARTO was 100% concordant with Lasso evaluation of PVI. Fluoroscopic times were 2.5 ± 0.9 minutes to complete circumferential PV ablation and 5.5 ± 1.9 minutes to properly position the Lasso catheter. No acute complications were reported in this series of patients. Conclusions PVI assessment using a 3D electroanatomical system is as accurate as Lasso evaluation, with excellent concordance.

Objectives The aim of this study was to describe the natural history of asymptomatic ventricular pre-excitation in children and to determine predictors of potentially life-threatening arrhythmic events. Background Sudden death can be the first clinical manifestation in asymptomatic children with ventricular pre-excitation, but reduction of its incidence by prophylactic ablation requires the identification of subjects at high risk. Methods Between 1995 and 2005 we prospectively collected clinical and electrophysiologic data from 184 children (66% male; median age 10 years; range 8 to 12 years) with asymptomatic ventricular pre-excitation on the electrocardiogram. After electrophysiologic testing, subjects were followed as outpatients taking no medications. The primary end point of the study was the occurrence of arrhythmic events. Predictors of potentially life-threatening arrhythmias were analyzed. Results Over a median follow-up of 57 months (min/max 32/90 months) after electrophysiologic testing, 133 children (mean age 10 years; range 8 to 12 years) did not experience arrhythmic events, remaining totally asymptomatic, while 51 children had within 20 months (min/max 8/60 months) a first arrhythmic event, which was potentially life-threatening in 19 of them (mean age 10 years; range 10 to 14 years). Life-threatening tachyarrhythmias resulted in cardiac arrest (3 patients), syncope (3 patients), atypical symptoms (8 patients), or minimal symptoms (5 patients). Univariate analysis identified tachyarrhythmia inducibility (p Conclusions These findings are potentially relevant in terms of early identification of high-risk asymptomatic children with ventricular pre-excitation. Subjects with short APERPs and multiple pathways are at higher risk of developing life-threatening arrhythmic events and are the best candidates for prophylactic ablation.

Few data on atrial fibrillation (AF) progression from the first paroxysmal episode are available.The purpose of this study was to assess the progression of AF not due to potentially reversible causes in patients treated according to current guidelines recommendations that also include catheter ablation.Among 402 screened patients with first AF, 106 patients (mean age 57.5 years) were selected and followed for 5 years. Of these patients, 54 had lone AF and 52 had comorbidities.Fifty patients (61.1% with lone AF) had no further recurrence after 5 years. The remaining 56 patients within 19 months after the first episode developed recurrent paroxysmal AF requiring long-term antiarrhythmic drug therapy, which was continued in 45 patients and was stopped because of intolerance/failure in 11 patients who underwent catheter ablation. AF became persistent in 24 of the 45 patients on antiarrhythmic drug therapy and then permanent in 16, of whom 6 had refused catheter ablation at the time of persistence. No AF recurrences or AF progression occurred after ablation. Kaplan-Meier curves demonstrated that patients with comorbidities were more likely to progress than were those with lone AF (P.001) and that patients who underwent catheter ablation were at lower risk for progression to permanent AF than were those on antiarrhythmic drug therapy (P = .029). Age, diabetes, and heart failure (P.001) predict final progression to permanent AF.Patients with first AF and comorbidities are at higher risk for rapid progression to permanent AF, and age, diabetes, and heart failure are independent predictors. Catheter ablation rather than antiarrhythmic drug therapy is beneficial in eliminating recurrences delaying arrhythmia progression.