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Background: Atrial fibrillation is a chronic, progressive disorder, and persistent forms of atrial fibrillation are associated with increased risks of thromboembolism and heart failure. Catheter ablation as initial therapy may modify the pathogenic mechanism of atrial fibrillation and alter progression to persistent atrial fibrillation., Methods: We report the 3-year follow-up of patients with paroxysmal, untreated atrial fibrillation who were enrolled in a trial in which they had been randomly assigned to undergo initial rhythm-control therapy with cryoballoon ablation or to receive antiarrhythmic drug therapy. All the patients had implantable loop recorders placed at the time of trial entry, and evaluation was conducted by means of downloaded daily recordings and in-person visits every 6 months. Data regarding the first episode of persistent atrial fibrillation (lasting ≥7 days or lasting 48 hours to 7 days but requiring cardioversion for termination), recurrent atrial tachyarrhythmia (defined as atrial fibrillation, flutter, or tachycardia lasting ≥30 seconds), the burden of atrial fibrillation (percentage of time in atrial fibrillation), quality-of-life metrics, health care utilization, and safety were collected., Results: A total of 303 patients were enrolled, with 154 patients assigned to undergo initial rhythm-control therapy with cryoballoon ablation and 149 assigned to receive antiarrhythmic drug therapy. Over 36 months of follow-up, 3 patients (1.9%) in the ablation group had an episode of persistent atrial fibrillation, as compared with 11 patients (7.4%) in the antiarrhythmic drug group (hazard ratio, 0.25; 95% confidence interval [CI], 0.09 to 0.70). Recurrent atrial tachyarrhythmia occurred in 87 patients in the ablation group (56.5%) and in 115 in the antiarrhythmic drug group (77.2%) (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). The median percentage of time in atrial fibrillation was 0.00% (interquartile range, 0.00 to 0.12) in the ablation group and 0.24% (interquartile range, 0.01 to 0.94) in the antiarrhythmic drug group. At 3 years, 8 patients (5.2%) in the ablation group and 25 (16.8%) in the antiarrhythmic drug group had been hospitalized (relative risk, 0.31; 95% CI, 0.14 to 0.66). Serious adverse events occurred in 7 patients (4.5%) in the ablation group and in 15 (10.1%) in the antiarrhythmic drug group., Conclusions: Initial treatment of paroxysmal atrial fibrillation with catheter cryoballoon ablation was associated with a lower incidence of persistent atrial fibrillation or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs. (Funded by the Cardiac Arrhythmia Network of Canada and others; EARLY-AF ClinicalTrials.gov number, NCT02825979.)., (Copyright © 2022 Massachusetts Medical Society.)

Purpose: 68  Ga-fibroblast-activation protein inhibitor (FAPI) positron emission tomography (PET) is a novel technique targeting FAP-alpha. This protein is expressed by activated fibroblasts which are the main contributors to tissue remodeling. The aim of this proof-of-concept study was to assess 68  Ga-FAPI uptake in the pulmonary vein (PV) region of the left atrium after pulmonary vein isolation (PVI) with cryoballoon ablation (CBA) and radiofrequency (RFA) as a surrogate for thermal damage., Methods: Twelve PVI patients (5 RFA, 7 CBA) underwent 68  Ga-FAPI-PET 20.5 ± 12.8 days after PVI. Five patients without atrial fibrillation or previous ablation served as controls. Standardized uptake values of localized tracer uptake were calculated., Results: Focal FAPI uptake around the PVs was observed in 10/12 (83.3%) PVI patients, no uptake was observed in 2 PVI patients and all controls. Patients after PVI had higher FAPI uptake in PVs compared to controls (SUV max : 4.3 ± 2.2 vs. 1.6 ± 0.2, p < 0.01; SUV peak : 2.9 ± 1.4 vs. 1.3 ± 0.2, p < 0.01). All CBA patients had an intense uptake, while in the RFA, group 2 (40%), 1 (20%), and 2 (40%) patients had an intense, moderate, and no uptake, respectively. We observed higher uptake values (SUV peak ) in CBA compared to RFA patients (4.4 ± 1.5 vs. 2.5 ± 0.8, p = 0.02)., Conclusion: We demonstrate in-vivo visualization of 68  Ga-FAPI uptake as a surrogate for fibroblast activation after PVI. CBA seems to cause more pronounced fibroblast activation following tissue injury than RFA. Future studies are warranted to assess if this modality can contribute to a better understanding of the mechanisms of AF recurrence after PVI by lesion creation and gap assessment., (© 2021. The Author(s).)

Introduction: Left atrial flutter predominantly occurs after surgical or ablation procedures but this entity has also been recently reported in individuals without previous interventions. The use of high-density electroanatomical mapping-systems (HDM) has improved the understanding of underlying mechanisms beyond entrainment maneuvers and substrate analyses. We aimed to evaluate the mechanism of left atrial (LA) flutters in preablated vs ablation-naïve individuals and sought to assess the efficacy of empiric ablations sets in these groups., Methods and Results: We included 55 patients admitted for ablation of LA flutter between July 2017 and August 2019. On the basis of HDM analyses the arrhythmia mechanism was determined with consecutive ablation targeting the suspected critical isthmus. Mean age was 69.8 ± 10.7 years, with 26 of 55 (47.3%) male patients. Thirty-nine (71%) patients had previously undergone LA ablation. Arrhythmia mechanisms differed between preablated and ablation-naïve patients as anatomical structure-related LA flutters (perimitral, roof-dependent, within-pulmonary veins) were more frequent in the preablated cohort compared to ablation-naïve individuals (74.4% vs 43.8%; P = .03). In ablation-naïve patients, most flutters (9 of 16, 56.3%) were related to low-voltage areas at the anterior/posterior wall. Acute termination rates were high (>90%) in both groups. Empirical mitral isthmus or roof lines showed a potential higher success rate in preablated patients., Conclusion: We identified different mechanisms of LA flutters in preablated vs ablation-naïve patients. In ablation-naïve patients, most tachycardias involved low-voltage areas rather than anatomical structures. Using HDM, acute success rates were high. Hypothetical linear ablations were less successful in ablation-naïve individuals, further highlighting the need to identify the specific individual tachycardia mechanism in these patients., (© 2020 Wiley Periodicals LLC.)

Atrial fibrillation and other atrial tachyarrhythmias are increasing with age and concomitant morbidity. First options in symptomatic patients are drug treatment and catheter ablation. Nevertheless, a considerable number of patients suffer from refractory atrial tachyarrhythmias despite treatment. Atrioventricular node ablation (AVNA) may be helpful in many of these patients. Therefore, we investigated AVNA patients with a long-term follow-up. We enrolled 82 patients with a follow-up longer than 1 year receiving AVNA for drug- and ablation-resistant atrial tachyarrhythmias (AA) in a retrospective manner. Mean follow-up duration was 48 ± 24 months. 50% of the patients initially received AVNA to optimize biventricular pacing in cardiac resynchronization therapy, the other 50% because of refractory symptomatic tachyarrhythmias. Persistent AV block was achieved in every patient. Symptom relief and patient satisfaction were high during follow-up. Due to system upgrades there were 63% of patients with a biventricular system during follow-up. In these patients, left-ventricular ejection fraction (LV-EF) increased by 7% (42-49%) after ablation. AVNA is effective in increasing biventricular pacing as well as for symptom relief in patients with refractory atrial tachyarrhythmias. AVNA should be considered as a valuable option in patients with refractory atrial tachyarrhythmias lacking other treatment options.

Introduction: The AliveCor Kardia ECG monitor (ACK) offers a smartphone-based one-lead ECG recording for the detection of atrial fibrillation. We compared ACK lead I recordings with the 12-lead ECG and introduce a novel parasternal lead (NPL)., Methods: Consecutive cardiac inpatients were recruited. In all patients a 12-lead ECG, ACK lead I and NPL were obtained. Two experienced electrophysiologists were blinded and separately evaluated all ECG. We calculated sensitivity, specificity, and predictive values of the ACK ECG compared to the 12-lead ECG., Results: 296 ECG from 99 patients (38 female, age 64 ± 15 years, BMI 27.8 ± 5.1 kg/m 2 ) were analyzed. 20% of ACK lead I recordings contained a critical amount of artifact. The electrophysiologists' interpretation of the ACK recordings yielded a sensitivity of 100% and specificity of 94% for atrial fibrillation or flutter in lead I (κ = 0.90) and a sensitivity of 96% and specificity of 97% in the NPL (κ = 0.92). The ACK diagnostic algorithm displayed a significantly lower sensitivity (55-70%), specificity (60-69%), and accuracy (κ = 0.4-0.53) but a high negative predictive value (100%). Patients with atrial flutter (n = 5) and with ventricular stimulation (n = 12) had a high likelihood of being misclassified by the algorithm., Conclusion: The AliveCor Kardia ECG monitor allows a highly accurate detection of atrial fibrillation by an interpreting electrophysiologist both in the standard lead I and a novel parasternal lead. The diagnostic algorithm offered by the system may be useful in screening recordings for further review. Diagnostic challenges present in atrial flutter and ventricular pacemaker stimulation., Competing Interests: Decleration of Competing Interest None., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Aims: Cryoballoon ablation is safe and efficient for achieving pulmonary vein isolation (PVI) in atrial fibrillation. Structural oesophago-mediastinal lesions, which seem to be associated with an increased risk of the lethal complication of an atrio-oesophageal fistula, have been described. MADE-PVI (Mediastino-oesophageal Alterations Detected by Endosonography after PVI) aimed at evaluating safety of cryoballoon PVI in relation to two different freeze protocols. As time-to-isolation-(TTI)-guided protocol has been reported to be as effective as conventional 'two freeze protocol', we hypothesized a TTI-guided protocol causes less oesophago-mediastinal lesions., Methods and Results: Seventy consecutive patients were scheduled for cryoballoon (2nd generation) PVI employing either a conventional protocol (n = 35: 2 × 180 s per vein) or a TTI-guided approach (n = 35: TTI + 120 s per vein or 1 × 180 s in case TTI could not be measured). Oesophagogastroduodenoscopy and endoscopic ultrasound, assessing oesophago-mediastinal alterations (e.g. ulceration, oedema) were performed blinded prior and post-ablation. Post-interventional mediastinal oedematous alterations were detected in 70% with a mean diameter of 14 mm (±0.9 mm), while only 15% revealed large mediastinal oedema >20 mm. Oesophageal lesions due to PVI occurred in 5%. Freeze protocols had a distinct impact on oesophago-mediastinal alterations as mean diameter and frequency of large oedema were significantly increased in patients after conventional protocol PVI (17 mm vs. 11 mm; 26% vs. 6%). Furthermore, every oesophageal lesion was detected in patients with conventional protocol (9%). No major complication occurred in either group., Conclusion: The present prospective study demonstrates a significant impact of freeze protocol on oesophago-mediastinal alterations. A TTI-guided protocol reduces mediastino-oesophageal lesions and may reduce short- and long-term complications of cryoballoon PVI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Implantable loop recorders (ILR) may be used to detect occult atrial fibrillation (AF) in patients with cryptogenic stroke. At present, there has been no description on the incidental findings of stored episodes in these patients. Furthermore, no standard practice has been established with respect to the duration of continued ECG monitoring in these patients., Materials and Methods: In the prospective monocentric study (TRACK-AF), a total of 173 patients with cryptogenic stroke received an ILR for detection of AF between November 2010 and December 2014. Before implantation all patients had undergone recommended protocols for detection of stroke causes., Results: During a mean follow-up of 24.8 ± 11.5 months, atrial tachyarrhythmias were detected in n = 33 pts (19.1%). Diagnosis of AF was made after a mean of 10.7 ± 11.4 months, time to first AF detection ranged between 0.2 and 39.8 months. In 15 patients (8.7%), other incidental findings were stored in the ILR memory. Short episodes of sinus arrest at night not requiring a permanent pacemaker were present in 8 pts (4.6%). DDD-pacemaker implantation due to sinus arrest or symptomatic bradyarrhythmias occurred in 5 patients (2.9%) after a median monitoring period of 23.1 ± 7.4 months. Further incidental findings were atrial flutter and an AV-nodal-reentry tachycardia in one patient, respectively. Both patients underwent successful catheter ablation. So far, ILR were explanted in 111 pts, and 71 ILR were explanted before end of service status of the battery. Main reason for ILR explantation was patients' preference (51%), followed by battery depletion (24%) and diagnosis of AF (15%)., Conclusion: The present study revealed a significant number of ECG findings during continued ECG monitoring for AF in patients with cryptogenic stroke. Apart from AF (17.5% during the first 1.5 years), other clinical relevant arrhythmias requiring, e.g., pacemaker implantations, were observed. With respect to these findings, we recommend to extend ILR monitoring to the end of battery life. However, acceptance of continued ECG monitoring until battery depletion was poor; in 71 patients (64%), the ILR were explanted before the end of battery life., Trial Registration: Registered at ClinicalTrials.gov: NCT02641678.

Aims: Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS)., Methods and Results: In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: -43 ms, P < 0.01; veratridine: -26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: -18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation., Conclusion: Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.

Background and Purpose: Detection of occult atrial fibrillation (AF) is crucial for optimal secondary prevention in stroke patients. The AF detection rate was determined by implantable cardiac monitor (ICM) and compared to the prediction rate of the probability of incident AF by software based analysis of a continuously monitored electrocardiogram at follow-up (stroke risk analysis, SRA); an optimized AF detection algorithm is proposed by combining both tools., Methods: In a monocentric prospective study 105 out of 389 patients with cryptogenic stroke despite extensive diagnostic workup were investigated with two additional cardiac monitoring tools: (a) 20 months' monitoring by ICM and (b) SRA during hospitalization at the stroke unit., Results: The detection rate of occult AF was 18% by ICM (n = 19) (range 6-575 days) and 62% (n = 65) had an increased risk for AF predicted by SRA. When comparing the predictive accuracy of SRA to ICM, the sensitivity was 95%, specificity 35%, positive predictive value 27% and negative predictive value 96%. In 18 patients with AF detected by ICM, SRA also showed a medium risk for AF. Only one patient with a very low risk predicted by SRA developed AF revealed by ICM after 417 days., Conclusions: A combination of SRA and ICM is a promising strategy to detect occult AF. SRA is reliable in predicting incident AF with a high negative predictive value. Thus, SRA may serve as a cost-effective pre-selection tool identifying patients at risk for AF who may benefit from further cardiac monitoring by ICM., (© 2017 EAN.)

Objectives: Levosimendan is a calcium sensitizer that is used as positive inotropic drug in acute decompensated heart failure. An increased incidence of atrial fibrillation after levosimendan-treatment was observed in clinical and experimental studies. Due to the limited range of antiarrhythmic drugs, the aim of the present study was to assess potential antiarrhythmic effects of ranolazine in levosimendan-pretreated isolated rabbit hearts., Methods: Twelve rabbit hearts were excised and retrogradely perfused employing the Langendorff setup. Left and right atrial catheters were used to record monophasic action potentials and to obtain cycle length-dependent atrial action potential durations (aAPD90) and effective refractory periods (aERP). After obtaining baseline data, 0.5 µmol/L levosimendan was infused. Subsequently, 10 µmol/L ranolazine was administered., Results: Infusion of levosimendan led to a reduction of aAPD90 (-9 ms, p < 0.05) and aERP (-13 ms, p < 0.05). Additional treatment with ranolazine prolonged aAPD90 (+23 ms, p < 0.01) and aERP (+30 ms, p < 0.05). Under baseline conditions, a predefined pacing protocol induced 77 episodes of atrial fibrillation. Infusion of levosimendan enhanced the vulnerability to atrial fibrillation (132 episodes, p = 0.14). Further treatment with ranolazine had a significant antiarrhythmic effect (61 episodes, p < 0.05)., Conclusions: In this study, ranolazine seems to prevent atrial fibrillation in levosimendan-pretreated hearts. Underlying mechanism is a prolongation of atrial repolarization and aERP., (© 2018 S. Karger AG, Basel.)

Background: Atrial fibrillation (AF) is an important cause of stroke. Continuous electrocardiography (ECG) monitoring with software-based analysis algorithms has been suggested to enhance the AF detection rate. We investigated the ability of stroke risk analysis (SRA) in the detection of AF in acute stroke patients., Methods: Consecutive stroke patients numbering 1,153 were screened. Patients with cardioembolic stroke related to AF (n = 296, paroxysmal n = 63, persistent n = 233) and patients with cryptogenic stroke (n = 309) after standard diagnostic work-up (bedside ECG monitoring, ultrasound, transesophageal echocardiography, 24 h Holter ECG) received SRA during their stay at the Stroke Unit. Determination of AF risk by SRA in the patients with AF and in the patient group with cryptogenic stroke was assessed and compared., Results: Median SRA monitoring analysis time was 16 h (range 2-206 h, interquartile range 10-36). In AF patients, SRA also detected a possible or definitive AF in 98%. The overall sensitivity of SRA to detect possible or definitive AF in patients with proven AF by standard diagnostic work up and cryptogenic stroke was 98%, specificity 27%, positive predictive value 56%, and the negative predictive value (NPV) was 92%. Area under ROC curve was 0.622., Conclusion: SRA was found to be highly sensitive to detect possible or definitive AF in clinical routine within a short monitoring time. However, low specificity and poor accuracy do not allow diagnosing AF by SRA alone, but with the high NPV compared to current diagnostic standard, it is a valid diagnostic tool to rule out AF. Thereby, SRA is a contribution to clarify stroke etiology., (© 2018 S. Karger AG, Basel.)

Objectives: This study sought to evaluate the spatial relationships of focal electrical sources (FSs) to complex fractionated atrial electrograms (CFAE) and continuous electrical activity (CEA)., Background: Fractionated atrial electrograms have been associated with atrial fibrillation (AF) drivers in computational studies and represent ablation targets in the management of persistent AF., Methods: We included a subset of 66 patients (age: 63 [56, 67] years, 69% persistent AF) with electroanatomic data from the SELECT AF (Selective complex fractionated atrial electrograms targeting for atrial fibrillation) randomized control trial that compared the efficacy of CFAE with CEA ablation in AF patients undergoing pulmonary vein antral ablation. Focal sources were identified based on bipolar electrogram periodicity and QS unipolar electrogram morphology., Results: A total of 77 FSs (median: 1 [1st quartile, 3rd quartile: 1, 2] per patient) were identified most commonly in the pulmonary vein antrum and left atrial appendage. The proportions of FSs inside CFAE and CEA regions were similar (13% vs. 1.3%, respectively; p = 0.13). Focal sources were more likely to be on the border zone of CFAEs than in CEAs (49% vs. 7.8%, respectively; p = 0.012). Following ablation, 53% of patients had ≥1 unablated extrapulmonary vein FS. The median number of unablated FS was higher in patients with AF recurrence post ablation than in patients without (median: 1 [0, 1] vs. 0 [0, 1], respectively; p = 0.026)., Conclusions: One-half of the FSs detected during AF localized to the border of CFAE areas, whereas most of the FSs were found outside CEA areas. CFAE or CEA ablation leaves a number of FS unablated, which is associated with AF recurrence. These findings suggest that many CFAEs may arise from passive wave propagation, remote from FS, which may limit their therapeutic efficacy in AF substrate modification., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Recent experimental studies suggested direct effects of the anti-influenza drug oseltamivir on cardiac electrophysiology. We therefore aimed at analyzing potential antiarrhythmic effects of oseltamivir on atrial fibrillation (AF) in an experimental whole-heart model. Twelve rabbit hearts were isolated and Langendorff perfused. Thereafter, hearts were paced at cycle lengths of 350, 250, and 200 ms in the atrium. A standardized protocol employing atrial burst pacing induced AF in 4 of 12 hearts under baseline conditions (33%, 11 episodes). Subsequently, a combination of acetylcholine (1 μM) and isoproterenol (1 μM) was administered to increase AF occurrence. Two monophasic action potential recordings on the left and two on the right atrial epicardium displayed a decrease of atrial action potential duration (aAPD, -38 ms, p < 0.01) and atrial effective refractory period (aERP; -20 ms, p < 0.05). Under the influence of acetylcholine/isoproterenol AF was inducible in 8 of 12 hearts (66%; 69 episodes). Additional infusion of oseltamivir (100 μM) resulted in a significant increase of both aAPD (+ 29 ms, p < 0.05) and aERP (+ 40 ms, p < 0.01) leading to an increase of atrial post-repolarization refractoriness (aPRR). Under the influence of oseltamivir only 3 of 12 hearts (25%, 8 episodes) remained inducible. In six additional hearts oseltamivir (50 μM and 100 μM) did not significantly alter ventricular APD, QRS duration and QT interval but induced a significant increase of ventricular ERP. In the present experimental study, acute infusion of the anti-influenza drug oseltamivir reduced atrial fibrillation. The antiarrhythmic effect can be explained by a significant increase in aERP and aPRR. These results suggest an antiarrhythmic potential of oseltamivir in atrial arrhythmias.

Background: Current guidelines recommend vernakalant for pharmacologic cardioversion of recent-onset atrial fibrillation. However, this drug is not established as chronic therapy., Methods and Results: In total, 15 rabbit hearts were Langendorff-perfused. A burst pacing protocol-induced atrial fibrillation in 7 of 15 hearts at baseline (10 episodes). Subsequently, a combination of acetylcholine and isoproterenol (ACH/ISO) has been administered to increase occurrence of atrial fibrillation resulting in a reduction of atrial action potential duration (-25 ms, P < 0.05) as well as atrial effective refractory period (aERP; -36 ms, P < 0.05). Then, atrial fibrillation occurred in all 15 hearts (124 episodes). Additional treatment with vernakalant (10 μmol/l) induced a significant reduction of atrial fibrillation (6 of 15 hearts, 63 episodes). Infusion of vernakalant did not significantly alter atrial action potential duration (+8 ms) but increased aERP (+16 ms, P < 0.05 as compared with ACH/ISO).Results were compared to 12 further rabbit hearts treated with ranolazine. Late sodium current inhibition by ranolazine also induced a significant increase of aERP. Here, atrial fibrillation was inducible after ranolazine infusion in 6 of 12 hearts (46 episodes). Of note, 10 of 12 hearts presented atrial fibrillation during sole treatment with ACH/ISO (174 episodes)., Conclusion: Vernakalant and ranolazine demonstrated a comparable antiarrhythmic efficacy. Therefore, vernakalant treatment may represent a potential therapeutic option to reduce atrial fibrillation recurrence.

Background: Ivabradine is an inhibitor of mixed Na + -K + -currents and routinely administered in chronic heart failure. Clinical studies reported divergent trends regarding proarrhythmic and antiarrhythmic effects in atrial fibrillation (AF)., Methods and Results: In 12 isolated rabbit hearts AF was induced in 7 of 12 hearts (13 episodes) under baseline conditions by a standardized protocol employing atrial burst pacing. Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Monophasic action potential recordings showed a decrease of atrial action potential duration (aAPD,-37ms, p<0.05) and atrial effective refractory period (aERP;-39ms, p<0.05) after infusion of both acetycholine (1μM) and isoproterenol (1μM) as compared with baseline. This led to induction of AF in 11 of 12 hearts (124 episodes). Simultaneous infusion of ivabradine (3μM) led to a significant reduction of AF (6 of 11 hearts, 63 episodes). Ivabradine induced an increase of aAPD (+9ms) and aERP (+30ms, p<0.05) leading to a marked increase of atrial post-repolarization refractoriness (aPRR), defined as the difference of aERP and aAPD (+21ms, p<0.05). Results were compared to 10 rabbits treated with flecainide. Flecainide treatment also induced a significant increase of aPRR and resulted in induction of AF in 6 of 10 hearts (58 episodes) while 9 of 10 hearts were inducible during sole treatment with acetylcholine and isoproterenol (129 episodes)., Conclusion: In the present experimental study, administration of ivabradine reduced inducibility of AF and therefore may represent a supplemental therapeutic option in AF. Of note, its antiarrhythmic efficacy was comparable to the established agent flecainide., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The calcium sensitizer levosimendan is clinically employed in decompensated heart failure. The aim of the present study was to assess effects of levosimendan on atrial electrophysiology in an experimental whole-heart model., Methods and Results: 13 rabbit hearts were isolated and Langendorff-perfused. Thereafter, hearts were paced at cycle lengths of 350ms, 250ms and 200ms in the atrium. A standardized protocol employing atrial burst pacing induced atrial fibrillation (AF) in 4 of 13 hearts under baseline conditions (mean: 3.3±2.1 episodes). Subsequently, levosimendan was administered in two concentrations (0.25μM, 0.5μM). Two monophasic action potential recordings on the left- and two on the right atrial epicardium displayed a decrease of atrial action potential duration (aAPD, -27ms, p<0.05) and atrial effective refractory period (aERP; -29ms, p<0.05) under the influence of 0.5μM levosimendan. The described alterations of atrial electrophysiology led to and increased inducibility of AF. Of note, treatment with 0.25μM levosimendan resulted in induction of AF in 11 of 13 hearts (mean: 8.9±3.5 episodes). Under the influence of 0.5μM levosimendan 12 of 13 hearts were inducible (mean: 9.8±3.8 episodes)., Conclusion: In the present study acute infusion of levosimendan in isolated rabbit hearts resulted in an abbreviation of atrial action potential duration and a reduction of aERP. This led to a significantly elevated inducibility of atrial fibrillation. These results suggest a proarrhythmic effect of levosimendan regarding atrial fibrillation. This aspect should be further investigated in the clinical setting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Controversy exists about the impact of acute atrial fibrillation (AF) termination and prolongation of atrial fibrillation cycle length (AFCL) during ablation on long-term procedural outcome., Objective: The purpose of this study was to analyze the influence of AF termination and AFCL prolongation on freedom from AF in patients from the STAR AF II (Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial-Part II) trial., Methods: Acute changes in AFCL and AF termination were collected during the index procedure of the STAR AF II trial and compared to recurrence of AF at 18 months. Recurrence was assessed by ECG, Holter (3, 6, 9, 12, 18 months), and weekly transtelephonic ECG monitoring for 18 months., Results: AF terminated in 8% of the pulmonary vein isolation (PVI) arm, 45% in the PVI+complex electrogram arm, and 22% of the PVI+linear ablation arm (P <.001), but freedom from AF did not differ among the 3 groups (P = .15). Freedom from AF was significantly higher in patients who presented to the laboratory in sinus rhythm (SR) compared to those without AF termination (63% vs 44%, P = .007). Patients with AF termination had an intermediate outcome (53%) that was not significantly different from those in SR (P = .84) or those who did not terminate (P = .08). AF termination was a univariable predictor of success (P = .007), but by multivariable analysis, presence of early SR was the strongest predictor of success (hazard ratio 0.67, P = .004). Prolongation of AFCL was not predictive of 18-month freedom from AF., Conclusion: Acute AF termination and prolongation in AFCL did not consistently predict 18-month freedom from AF. Presence of SR before or early during the ablation was the strongest predictor of better outcome., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Because of the unclear prognostic effects of ablation of atrial fibrillation (AF), oral anticoagulation (OAC) is often continued after ablation even in asymptomatic patients. We sought to determine the frequency of stroke and AF recurrence in patients on and off therapeutic OAC 1 year after a successful AF ablation., Methods and Results: Patients that underwent AF ablation and were free of AF 12 months after ablation were selected from our AF database. During follow-up (FU), patients were screened for recurrence of AF, changes in OAC or antiarrhythmic medication, and the occurrence of stroke or transient ischemic attack (TIA). A total of 398 patients (median age 60.7 years [50.8, 66.8], 25% female) were investigated. The median duration of FU was 529 (373, 111,3.5) days. OAC was discontinued in 276 patients (69.3%). During FU, 4 patients (1%) suffered from stroke and 55 patients (13.8%) experienced a recurrence of AF. Persistent AF was significantly associated with a greater chance of AF recurrence (49.1% vs. 26.8%; P = 0.001). Neither CHADS 2 nor CHA2DS2-VASc-Score nor recurrence of AF were significantly different in patients with or without stroke. There was a trend toward a higher percentage of coronary artery disease among patients that experienced stroke (50% vs. 10%; P = 0.057)., Conclusion: The overall risk of stroke and AF recurrence is low in patients with a recurrence free interval of at least 12 months after AF ablation. Of note, recurrence of AF was not associated with a higher risk of stroke in our study population., (© 2016 Wiley Periodicals, Inc.)

Background: Success rates of atrial fibrillation (AF) ablation have been shown to be significantly lower for patients with persistent AF. However, little is known about the risk factors predicting progression to persistent AF in patients awaiting AF ablation., Methods: We performed a retrospective, single-centre investigation of patients with paroxysmal AF at the time of placement on the ablation waiting list. Patients were defined as having progressed if they had developed self-reported or electrocardiogram-recorded AF durations more than 7 days while awaiting ablation. After ablation, clinical visits at 3, 6, 9, 12, and 18 months were performed with a minimum of a 48-hour-Holter and electrocardiogram. Baseline characteristics including left atrial diameter (LA) and the HATCH score were analyzed by univariable and multivariable analysis for predicting progression to persistent AF., Results: During a median waiting time of 9.7 (6.1, 14.2) months, 60 of 564 patients (11%) progressed to persistent AF. In patients who progressed, ablation took longer (180 [150, 249] minutes vs 157 [125, 210] minutes; P = 0.009) and was associated with a higher rate of recurrence after a median of 12 months (53.3% vs 39.1%; P < 0.001). The HATCH score was a poor predictor of AF progression (area under the curve 0.54), whereas an LA diameter of more than 45 mm (odds ratio 3.46, P < 0.001) and heart failure (odds ratio 3.11, P = 0.036) were strong and independent predictors of AF progression in multivariable analysis., Conclusions: Patients with an increased LA diameter or heart failure have a significantly increased risk of progression to persistent AF. These characteristics may define patients who should undergo earlier catheter ablation to optimize outcome., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Assumption of different substrates is the basis for different ablation strategies in patients with paroxysmal and persistent atrial fibrillation (AF). We aimed to investigate pulmonary vein reconnection and influence on progression of initial paroxysmal (pAF) versus persistent atrial fibrillation (perAF)., Methods: Between January 2010 and November 2012, 149 patients (117 men, mean age 59 ± 11 years, range 27-80 years) underwent at least one redo antral pulmonary vein isolation (PVI) using NavX-guided irrigated-tip radiofrequency catheter ablation. We analyzed whether and where reconnection of pulmonary veins was detected, and whether there were differences between patients with pAF and perAF., Results: Of the 149 patients who underwent a redo antral PVI, 80 patients had pAF and 69 had perAF. One, two and three redo PVIs were performed in 149, 26 and 6 patients, respectively. Reconnection of at least one PV was detected in all patients at the second PVI, in 19 of 26 patients (73 %) at the third PVI and 5 of 6 patients (83 %) at the fourth PVI. 20 (29 %) patients with perAF prior to the first PVI had pAF at the second PVI, whereas 15 (19 %) patients with initial pAF had persistent AF at the time of the first redo procedure. From the second to the third PVI, four patients had developed perAF after previous pAF and two with per AF now had pAF. PV reconnection was observed independent of underlying AF type. At the second redo procedure, of those with reconnected veins 12 had pAF and 13 perAF. At the third redo procedure, four patients had pAF and four perAF., Conclusion: Most patients with recurrent AF after PVI showed at least one reconnected vein during redo procedures. Reconnection was identified irrespective of the underlying AF type. Progression from pAF to perAF and vice versa was observed irrespective of the initial AF type.

Aims: The second-generation multi-electrode-phased radiofrequency pulmonary vein ablation catheter (PVAC GOLD(®)) was redesigned with the intent to improve its safety and efficacy., Methods and Results: Using a prospectively designed single-centre database, we retrospectively analysed 128 consecutive patients (102 paroxysmal and 43 female) who underwent their first pulmonary vein isolation with the PVAC GOLD(®). The analysis focused on procedural data as well as in-hospital complications. Baseline characteristics of the patient collective were as follows: mean age 57.9 years, mean CHA2DS2-VASC was 1.73 ± 1.30; structural heart disease was present in seven patients. The PVAC GOLD(®) exhibited procedure durations of 123.1 min ± 27.9, duration of energy delivery was 18.3 min ± 11.4, and fluoroscopy duration was 16.0 min ± 7.7. The redesigned catheter shows major complication [major bleeding, transitory ischaemic attack (TIA), and pericardial tamponade] rates of 2.3% (n = 3). The overall rate of adverse events was 5.4% (n = 7). Bleeding complications were observed in three patients (2.3%), in particular there were two cases (1.6%) of minor bleeding and one case (0.8%) of major bleeding. Two patients suffered pericardial effusion, but there was no need for pericardiocentesis. Besides one TIA, there was no other thrombo-embolic event. Furthermore, one case of post-procedural fever was observed. No deaths, stroke, or haemorrhagic shock occurred. Of the 510 pulmonary veins, 508 could be reached with the PVAC GOLD(®) device using a non-steerable long sheath., Conclusion: The PVAC GOLD(®) seems to have an acceptable safety profile. The handling is comparable with the previous generation PVAC(®)., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Little is known about the relationship between daily atrial fibrillation (AF) burden and quality of life (QOL). We sought to determine the influence of atrial tachycardia (AT) or AF burden on measures of QOL and symptoms., Methods and Results: We retrospectively analyzed patients with dual-chamber pacemakers from the Atrial Septal Pacing Efficacy Clinical Trial (ASPECT), Atrial Therapy Efficacy and Safety Trial (ATTEST), and aTRial arrhythmias dEtected by implaNted Device diagnostics Study (TRENDS) trials. All patients underwent at least one QOL evaluation. We predefined four AF burden groups: no AT/AF (group 1), ≤30 minutes (group 2), 30 minutes-2 hours (group 3), and >2 hours (group 4) per day. We compared QOL measures using the 12-item Short-Form Health Survey (SF-12; standard 4 week recall) and the AF Symptom Checklist (SC) severity and frequency between groups 2-4 to those in group 1. A total of 798 patients were analyzed (age 72 ± 11 years, 447 male [56%]). SC frequency and severity and SF-12 physical and mental scores worsened significantly when patients in group 4 were compared to patients with no AF. There were no statistically significant differences for any of the measures when comparing group 2 or 3 patients to group 1. By linear regression, only the 2-hour-cutoff had a significant impact on QOL as measured by SC frequency (+3.15, P < 0.001), severity (+3.23, P < 0.001), SF-12 physical score (-2.42, P = 0.013), and SF-12 mental score (-2.11, P = 0.021)., Conclusion: A daily AT/AF burden of more than 2 hours had significant impact on QOL. This might influence the choice of appropriate cut-off points to determine the success of an AF treatment., (©2015 Wiley Periodicals, Inc.)

Background: Clinically silent lesions on cerebral magnet resonance imaging have been found in larger numbers after pulmonary vein isolation (PVI) especially with phased radio frequency (pRF) using all ten electrodes. However, the neuropsychological effects of cerebral microembolism during the procedure remain unclear and data regarding this issue so far are inconsistent., Methods: Between August 2011 and June 2012, 76 patients undergoing their first PVI were randomized to ablation with either phased (40) or irrigated (36) radio frequency (iRF). A comprehensive neuropsychological test battery was performed the day before and after PVI as well as 6 months after ablation. The occurrence of cerebral microemboli during the procedure was performed via a transcranial Doppler ultrasound device., Results: PVI using pRF was associated with increased number of microembolic signals (MES) compared to iRF (1530.0 ± 979.8 vs. 645.7 ± 448.7; p < 0.001). Neuropsychological assessment did not reveal any changes in correlation with the used ablation technique. Besides an age-related effect there was a diffuse, sub-clinical impairment of neurologic function depending on age and the number of MES., Conclusions: There was no clinical overt cognitive deficit and no significant difference in cognitive function correlating with the used ablation technique. The number of MES correlated with a subtle, diffuse post-procedural impairment of neuropsychological function highlighting the need to reduce microemboli during ablation.

Ablation therapy for atrial fibrillation (AF) has been shown to be more efficient than medical treatment alone. Long-term success of AF ablation is still around 50% after one ablation and higher after two, with a substantial amount of asymptomatic recurrences in formerly symptomatic patients. Given the lack of evidence for superiority of rhythm control over rate control in terms of stroke reduction and mortality, AF ablation remains a treatment for symptom reduction only, although ablation has never been a part of these studies. There is early evidence that ablation could decrease the long-term risk of stroke; however, prospective studies are needed to assess whether this is the case and how patients with a successful ablation can be identified. If AF ablation can be shown to improve long-term morbidity, it could also become a reasonable treatment for patients with asymptomatic AF.

Background: There is a paucity of data that compare traditional vitamin K antagonist (VKA) with novel oral anticoagulant regimens in periprocedural management of cardioversion or ablation of atrial fibrillation (AF). We sought to compare outcomes of use of VKA, dabigatran (DABI), and rivaroxaban (RIVA) anticoagulation around the time of intervention., Methods: We studied consecutive patients undergoing cardioversion or ablation of AF at our centre from October 2010 to October 2013. There were 3 different anticoagulation groups: warfarin (VKA), DABI, and RIVA. Safety was assessed according to number of strokes, transient ischemic attacks (TIAs), and clinically important and not important bleeding events., Results: Baseline characteristics were well balanced between the groups. Average follow-up was 6 months (± 4 months). A total of 901 patients who underwent cardioversion were studied (VKA [n = 471], DABI [n = 288] and RIVA [n = 141]). In these patients there were no strokes seen during follow-up and 2 TIAs in the DABI group. Bleeding rates were low, with no significant difference between the 3 groups. A total of 680 patients who underwent ablation were studied (VKA [n = 319], DABI [n = 220] and RIVA [n = 171]). There were no strokes reported during follow-up and 3 TIAs: 2 in the VKA group and 1 in the DABI group not resulting in a significant difference between the groups. Bleeding rates were low, with no significant difference between the groups., Conclusions: Overall, there was a low incidence of adverse events for all anticoagulation regimens. Warfarin, DABI, and RIVA use around the time of the procedure are safe and reasonable options for patients who undergo cardioversion or AF ablation., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF)., Methods and Results: In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias., Conclusion: In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: Phased radiofrequency (RF) ablation for atrial fibrillation is associated with an increased number of silent cerebral lesions on magnetic resonance imaging and cerebral microembolic signals (MESs) on transcranial Doppler ultrasound imaging compared with irrigated RF. The increased rate of embolic events may be due to a specific electrical interference of ablation electrodes attributed to the catheter design. The purpose of this study was to elucidate the effect of deactivating the culprit electrodes on cerebral MESs., Methods and Results: Twenty-nine consecutive patients (60 ± 11 years, 10 female) underwent their first pulmonary vein isolation using phased RF energy. Electrode pairs 1 or 5 were deactivated to avoid electrical interference between electrodes 1 and 10 ('modified'). Detection of MESs by transcranial Doppler ultrasound was performed throughout the procedure to assess cerebral microembolism. Results were compared with the numbers of MESs in 31 patients ablated using all available electrodes ('conventional') and to 30 patients undergoing irrigated RF ablation of a previous randomized study. Ablation with 'modified' phased RF was associated with a marked decrease in MESs when compared with 'conventional' phased RF (566 ± 332 vs. 1530 ± 980; P < 0.001). This difference was mainly triggered by the reduction of MES during delivery of phased RF energy, resulting in MES numbers comparable to irrigated RF ablation (646 ± 449; P = 0.7). Total procedure duration as well as time of RF delivery was comparable between phased RF groups. Both times, however, were significantly shorter compared with the irrigated RF group (123 ± 28 vs. 195 ± 38; 15 ± 4 vs. 30 ± 9; P < 0.001, respectively)., Conclusion: Pulmonary vein isolation with 'modified' phased RF is associated with a decreased number of cerebral microembolism especially during the delivery of ablation impulses, supporting the significance of electrical interference between ablation electrodes 1 and 10. Deactivation of electrode pairs 1 or 5 might increase the safety of this approach without an increase in procedure duration or RF delivery time.

Background and Purpose: Supraventricular premature beats (SPBs) may help to assess the risk of atrial fibrillation (AF) in patients with cryptogenic stroke and therefore guide therapy., Methods: An internal loop recorder was implanted in consecutive patients with acute cryptogenic stroke. The occurrence and quantity of SPBs and short supraventricular runs (SVRs) in 24-hour ECG in patients with and without future AF were analyzed. We evaluated the relative risk of the upper quartile of SPB and SVR patients against the remainder and used binary logistic regression to evaluate a possible independent influence of SPBs and SVRs on AF occurrence., Results: Twelve of 70 included patients (mean age, 59±13 years) experienced development of AF during a mean monitoring duration of 536±212 days. Patients with AF had a median of 22.8 SPBs/h versus 1.2 SPBs/h (P<0.0001) in patients without AF and a median of 0.7 SVRs/h (AF) versus 0 SVR/h (non-AF). Patients in the upper quartile of SPBs (>14.1/h) and SVRs (>0.2/h) demonstrated a relative risk of 4.0 (95% confidence interval, 1.1-14.6; P=0.04) and 6.9 (95% confidence interval, 1.8-26.7; P=0.005) for future AF, respectively. In binary logistic regression, SPBs (P=0.02) and SVRs (P=0.05) remained significant independent predictors for occurrence of AF., Conclusions: Numerous SPBs and SVRs demonstrated a high risk for future AF in patients with cryptogenic stroke.

Background and Purpose: A significant number of patients with cryptogenic stroke suffer from intermittent atrial fibrillation (iAF) which was not detected during the standard diagnostic procedures. We investigated whether implantation of an insertable cardiac monitor (ICM) is feasible in patients with cryptogenic stroke, and compared the iAF detection rate of the ICM with 7-day Holter monitoring., Methods: Sixty patients (median age 63; interquartile range, 48.5-72 years) with acute cryptogenic stroke were included. ICM was implanted 13 days (interquartile range; 10-65 days) after the qualifying event. Seven-day Holter was performed after the ICM was implanted., Results: The iAF was detected by the ICM in 10 patients (17%; 95% CI, 7% to 26%). Only 1 patient (1.7%; 95% CI, 0% to 5%) had iAF during 7-day Holter monitoring as well (P=0.0077). Episodes of iAF lasting 2 minutes or more were detected 64 (range, 1-556) days after implantation. There were no recurrent strokes during the observation period. The implantation procedure was well tolerated with no adverse events; the daily data transmission protocol was easy to handle by the patients., Conclusions: ICM implantation for the detection of iAF during outpatient follow-up is feasible in patients with cryptogenic stroke. ICMs offer a much higher diagnostic yield than 7-day Holter monitoring.