Publications by authors named "Ulrich Schotten"

165 Publications

Incidence, prevalence, and trajectories of repetitive conduction patterns in human atrial fibrillation.

Europace 2021 Mar;23(Supplement_1):i123-i132

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

Aims: Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients.

Methods And Results: A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41-72) vs. persAF: 39% (0-51), P < 0.01], larger [pAF: = 1.54 (1.15-1.96) vs. persAF: 1.16 (0.74-1.56) cm2, P < 0.001), and more stable [normalized preferentiality (0-1) pAF: 0.38 (0.25-0.50) vs. persAF: 0.23 (0-0.33), P < 0.01]. Most repetitive patterns were peripheral waves (87%), often with conduction block (69%), while breakthroughs (9%) and re-entries (2%) occurred less frequently.

Conclusion: High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.
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http://dx.doi.org/10.1093/europace/euaa403DOI Listing
March 2021

Synergistic antiarrhythmic effect of inward rectifier current inhibition and pulmonary vein isolation in a 3D computer model for atrial fibrillation.

Europace 2021 Mar;23(Supplement_1):i161-i168

Department of Physiology, Maastricht University, Maastricht, The Netherlands.

Aims: Recent clinical studies showed that antiarrhythmic drug (AAD) treatment and pulmonary vein isolation (PVI) synergistically reduce atrial fibrillation (AF) recurrences after initially successful ablation. Among newly developed atrial-selective AADs, inhibitors of the G-protein-gated acetylcholine-activated inward rectifier current (IKACh) were shown to effectively suppress AF in an experimental model but have not yet been evaluated clinically. We tested in silico whether inhibition of inward rectifier current or its combination with PVI reduces AF inducibility.

Methods And Results: We simulated the effect of inward rectifier current blockade (IK blockade), PVI, and their combination on AF inducibility in a detailed three-dimensional model of the human atria with different degrees of fibrosis. IK blockade was simulated with a 30% reduction of its conductivity. Atrial fibrillation was initiated using incremental pacing applied at 20 different locations, in both atria. IK blockade effectively prevented AF induction in simulations without fibrosis as did PVI in simulations without fibrosis and with moderate fibrosis. Both interventions lost their efficacy in severe fibrosis. The combination of IK blockade and PVI prevented AF in simulations without fibrosis, with moderate fibrosis, and even with severe fibrosis. The combined therapy strongly decreased the number of fibrillation waves, due to a synergistic reduction of wavefront generation rate while the wavefront lifespan remained unchanged.

Conclusion: Newly developed blockers of atrial-specific inward rectifier currents, such as IKAch, might prevent AF occurrences and when combined with PVI effectively supress AF recurrences in human.
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http://dx.doi.org/10.1093/europace/euaa413DOI Listing
March 2021

Automatic reconstruction of the left atrium activation from sparse intracardiac contact recordings by inverse estimate of fibre structure and anisotropic conduction in a patient-specific model.

Europace 2021 Mar;23(Supplement_1):i63-i70

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland.

Aims: Electric conduction in the atria is direction-dependent, being faster in fibre direction, and possibly heterogeneous due to structural remodelling. Intracardiac recordings of atrial activation may convey such information, but only with high-quality data. The aim of this study was to apply a patient-specific approach to enable such assessment even when data are scarce, noisy, and incomplete.

Methods And Results: Contact intracardiac recordings in the left atrium from nine patients who underwent ablation therapy were collected before pulmonary veins isolation and retrospectively included in the study. The Personalized Inverse Eikonal Model from cardiac Electro-Anatomical Maps (PIEMAP), previously developed, has been used to reconstruct the conductivity tensor from sparse recordings of the activation. Regional fibre direction and conduction velocity were estimated from the fitted conductivity tensor and extensively cross-validated by clustered and sparse data removal. Electrical conductivity was successfully reconstructed in all patients. Cross-validation with respect to the measurements was excellent in seven patients (Pearson correlation r > 0.93) and modest in two patients (r = 0.62 and r = 0.74). Bland-Altman analysis showed a neglectable bias with respect to the measurements and the limit-of-agreement at -22.2 and 23.0 ms. Conduction velocity in the fibre direction was 82 ± 25 cm/s, whereas cross-fibre velocity was 46 ± 7 cm/s. Anisotropic ratio was 1.91±0.16. No significant inter-patient variability was observed. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps correctly predicted activation times in late regions in all patients (r = 0.88) and was robust to a sparser dataset (r = 0.95).

Conclusion: Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps offers a novel approach to extrapolate the activation in unmapped regions and to assess conduction properties of the atria. It could be seamlessly integrated into existing electro-anatomic mapping systems. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps also enables personalization of cardiac electrophysiology models.
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http://dx.doi.org/10.1093/europace/euaa392DOI Listing
March 2021

Pulmonary vein isolation in a real-world population does not influence QTc interval.

Europace 2021 Mar;23(Supplement_1):i48-i54

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.

Aims: We aimed to examine whether routine pulmonary vein isolation (PVI) induces significant ventricular repolarization changes as suggested earlier.

Methods And Results: Five-minute electrocardiograms were recorded at hospital's admission (T-1d), 1 day after the PVI-procedure (T+1d) and at 3 months post-procedure (T+3m) from a registry of consecutive atrial fibrillation (AF) patients scheduled for routine PVI with different PVI modalities (radiofrequency, cryo-ablation, and hybrid). Only patients who were in sinus rhythm at all three recordings (n = 117) were included. QT-intervals and QT-dispersion were evaluated with custom-made software and QTc was calculated using Bazett's, Fridericia's, Framingham's, and Hodges' formulas. Both QT- and RR-intervals were significantly shorter at T+1d (399 ± 37 and 870 ± 141 ms) and T+3m (407 ± 36 and 950 ± 140 ms) compared with baseline (417 ± 36 and 1025 ± 164 ms). There was no statistically significant within-subject difference in QTc Fridericia (T-1d 416 ± 28 ms, T+1d 419 ± 33 ms, and T+3m 414 ± 25 ms) and QT-dispersion (T-1d 18 ± 12 ms, T+1d 21 ± 19 ms, and T+3m 17 ± 12 ms) between the recordings. A multiple linear regression model with age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence to predict the change in QTc at T+3m with respect to QTc at T-1d did not reach significance which indicates that the change in QTc does not differ between all subgroups (age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence).

Conclusion: Based on our data a routine PVI does not result in a prolongation of QTc in a real-world population. These findings, therefore, suggest that there is no need to intensify post-PVI QT-interval monitoring.
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http://dx.doi.org/10.1093/europace/euaa390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943360PMC
March 2021

Both beat-to-beat changes in RR-interval and left ventricular filling time determine ventricular function during atrial fibrillation.

Europace 2021 Mar;23(Supplement_1):i21-i28

Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands.

Aims: The irregular atrial electrical activity during atrial fibrillation (AF) is associated with a variable left ventricular (LV) systolic function. The mechanisms determining LV function during AF remain incompletely understood. We aimed at elucidating how changes in RR-interval and LV preload affect LV function during AF.

Methods And Results: Beat-to-beat speckle-tracking echocardiography was performed in 10 persistent AF patients. We evaluated the relation between longitudinal LV peak strain and preceding RR-interval during AF. We used the CircAdapt computational model to evaluate beat-to-beat preload and peak strain during AF for each patient by imposing the patient-specific RR-interval sequences and a non-contractile atrial myocardium. Generic simulations with artificial RR-interval sequences quantified the haemodynamic changes induced by sudden irregular beats. Clinical data and simulations both showed a larger sensitivity of peak strain to changes in preceding RR-interval at slow heart rate (HR) (cycle length, CL <750 ms) than at faster HR. Simulations explained this by a difference in preload of the current beat. Generic simulations confirmed a larger sensitivity of peak strain to preceding RR-interval at fast HR (CL = 600 ms: Δ peak strain = 3.7% vs. 900 ms: Δ peak strain = 0.3%) as in the patients. They suggested that longer LV activation with respect to preceding RR-interval is determinant for this sensitivity.

Conclusions: During AF, longitudinal LV peak strain is highly variable, particularly at fast HR. Beat-to-beat changes in preload explain the differences in LV systolic function. Simulations revealed that a reduced diastolic LV filling time can explain the increased variability at fast HR.
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http://dx.doi.org/10.1093/europace/euaa387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943365PMC
March 2021

Inhibition of Small-Conductance Calcium-Activated Potassium Current () Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

Front Physiol 2021 9;12:614483. Epub 2021 Feb 9.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Background: Small-conductance Ca-activated K (K2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the K2 current-and thereby the efficacy of small-conductance Ca-activated K current () inhibition-might be negatively related to AF duration and the extent of AF-induced remodeling.

Experimental Approach And Methods: To address the hypothesis of the efficacy of inhibition being dependent on AF duration, the anti-arrhythmic properties of the inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.

Results: inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.

Conclusions: Intra-atrial heterogeneity in response to inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.
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http://dx.doi.org/10.3389/fphys.2021.614483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900437PMC
February 2021

Bi-atrial high-density mapping reveals inhibition of wavefront turning and reduction of complex propagation patterns as main antiarrhythmic mechanisms of vernakalant.

Europace 2021 Feb 20. Epub 2021 Feb 20.

Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, the Netherlands.

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF.

Methods And Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed.

Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.
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http://dx.doi.org/10.1093/europace/euab026DOI Listing
February 2021

The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats.

Front Pharmacol 2020 27;11:608410. Epub 2021 Jan 27.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.

The acetylcholine-activated inward rectifier potassium current (I) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective I inhibitor XAF-1407, the study investigates the effect of I inhibition in goats with pacing-induced, short-term AF. Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that I represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
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http://dx.doi.org/10.3389/fphar.2020.608410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873360PMC
January 2021

Dynamic risk assessment to improve quality of care in patients with atrial fibrillation: the 7th AFNET/EHRA Consensus Conference.

Europace 2021 Mar;23(3):329-344

Institute of Cardiovascular Sciences, University of Birmingham, UK.

Aims: The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes.

Methods And Results: This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence.

Conclusion: The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
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http://dx.doi.org/10.1093/europace/euaa279DOI Listing
March 2021

No antiarrhythmic effect of direct oral anticoagulants versus vitamin K antagonists in paroxysmal atrial fibrillation patients undergoing catheter ablation.

Int J Cardiol 2021 May 26;331:106-108. Epub 2021 Jan 26.

Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Austria; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Limburg, the Netherlands.

Introduction: Direct oral anticoagulants (DOACs) are superior to vitamin K antagonists (VKAs) for the prevention of stroke in atrial fibrillation (AF) patients with elevated stroke risk. Possible antiarrhythmic effects of DOACs have been discussed. We analyzed impact of DOAC treatment on recurrence-free survival after AF catheter ablation.

Methods: Two-hundred and thirty-nine consecutive patients (median age 57 [IQR 48-64] years, 26.4% female) undergoing ablation for paroxysmal AF were included into this study. 68.6% of them received DOACs (DOAC group), 31.4% VKA (VKA group). The primary outcome was arrhythmia-free one-year survival.

Results: DOAC patients had lower BMI, shorter history of AF, less arterial hypertension, less vascular disease, less use of antiarrhythmics and consequently lower CHADS-VASc and HAS-BLED Scores. There was no difference in arrhythmia-free survival between DOAC and VKA groups (DOAC: 86.6%, VKA: 76.7%, p = 0.286).

Conclusions: Despite baseline characteristics favouring a better outcome of DOAC patients, arrhythmia-free survival was similar in both groups. Consequently, DOAC treatment did not have clinically relevant antiarrhythmic properties in these patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.01.003DOI Listing
May 2021

Short P-Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations.

J Am Heart Assoc 2021 Jan 7;10(2):e018572. Epub 2021 Jan 7.

Division of Cardiology Cardiocentro Ticino Lugano Switzerland.

Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; =0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; =0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.
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http://dx.doi.org/10.1161/JAHA.120.018572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955300PMC
January 2021

Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences: A Simulation Study.

Circ Arrhythm Electrophysiol 2021 Jan 24;14(1):e009230. Epub 2020 Dec 24.

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.).

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http://dx.doi.org/10.1161/CIRCEP.120.009230DOI Listing
January 2021

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation.

Heart Rhythm 2021 Apr 21;18(4):615-622. Epub 2020 Nov 21.

Department of Cardiothoracic Surgery, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany. Electronic address:

Background: There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity.

Objective: The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats.

Methods: Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 μM, respectively).

Results: The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study.

Conclusion: The lowest investigated dose of ranolazine, which is expected to block both late I and atrial peak I, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF.
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http://dx.doi.org/10.1016/j.hrthm.2020.11.021DOI Listing
April 2021

Chronic obstructive pulmonary disease and atrial fibrillation: an interdisciplinary perspective.

Eur Heart J 2021 Feb;42(5):532-540

Centre for Heart Rhythm Disorders, University of Adelaide and Royal Adelaide Hospital, 1 Port Road, SA 5000 Adelaide, Australia.

Chronic obstructive pulmonary disease (COPD) is highly prevalent among patients with atrial fibrillation (AF), shares common risk factors, and adds to the overall morbidity and mortality in this population. Additionally, it may promote AF and impair treatment efficacy. The prevalence of COPD in AF patients is high and is estimated to be ∼25%. Diagnosis and treatment of COPD in AF patients requires a close interdisciplinary collaboration between the electrophysiologist/cardiologist and pulmonologist. Differential diagnosis may be challenging, especially in elderly and smoking patients complaining of unspecific symptoms such as dyspnoea and fatigue. Routine evaluation of lung function and determination of natriuretic peptides and echocardiography may be reasonable to detect COPD and heart failure as contributing causes of dyspnoea. Acute exacerbation of COPD transiently increases AF risk due to hypoxia-mediated mechanisms, inflammation, increased use of beta-2 agonists, and autonomic changes. Observational data suggest that COPD promotes AF progression, increases AF recurrence after cardioversion, and reduces the efficacy of catheter-based antiarrhythmic therapy. However, it remains unclear whether treatment of COPD improves AF outcomes and which metric should be used to determine COPD severity and guide treatment in AF patients. Data from non-randomized studies suggest that COPD is associated with increased AF recurrence after electrical cardioversion and catheter ablation. Future prospective cohort studies in AF patients are needed to confirm the relationship between COPD and AF, the benefits of treatment of either COPD or AF in this population, and to clarify the need and cost-effectiveness of routine COPD screening.
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http://dx.doi.org/10.1093/eurheartj/ehaa822DOI Listing
February 2021

A Novel Tool for the Identification and Characterization of Repetitive Patterns in High-Density Contact Mapping of Atrial Fibrillation.

Front Physiol 2020 15;11:570118. Epub 2020 Oct 15.

Department of Physiology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.

Introduction: Electrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF.

Materials And Methods: Recurrence plots were constructed by first transforming atrial electrograms recorded by a multi-electrode array to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent distance threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were detected in a recurrence plot as regions with a high recurrence rate. Intervals that contained similar repetitive patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF [3 weeks AF (3 wkAF, = 8) and 22 weeks AF (22 wkAF, = 8)], using a 249-electrode mapping array (2.4 mm inter-electrode distance).

Results: Recurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration [mean maximum duration 3 wkAF: 74 cycles, 95% confidence interval (54-94) vs. 22 wkAF: 41 cycles (21-62), = 0.03], and smaller recurrent regions within repetitive patterns [3 wkAF 1.7 cm (1.0-2.3) vs. 22 wkAF 0.5 cm (0.0-1.2), = 0.02]. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns.

Conclusion: Recurrence plots provide a novel way to delineate high-density contact mapping of AF. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.
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http://dx.doi.org/10.3389/fphys.2020.570118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593698PMC
October 2020

A Novel Computational Model of the Rabbit Atrial Cardiomyocyte With Spatial Calcium Dynamics.

Front Physiol 2020 9;11:556156. Epub 2020 Oct 9.

Simula Research Laboratory, Computational Physiology Department, Lysaker, Norway.

Models of cardiac electrophysiology are widely used to supplement experimental results and to provide insight into mechanisms of cardiac function and pathology. The rabbit has been a particularly important animal model for studying mechanisms of atrial pathophysiology and atrial fibrillation, which has motivated the development of models for the rabbit atrial cardiomyocyte electrophysiology. Previously developed models include detailed representations of membrane currents and intracellular ionic concentrations, but these so-called "common-pool" models lack a spatially distributed description of the calcium handling system, which reflects the detailed ultrastructure likely found in cells . Because of the less well-developed T-tubular system in atrial compared to ventricular cardiomyocytes, spatial gradients in intracellular calcium concentrations may play a more significant role in atrial cardiomyocyte pathophysiology, rendering common-pool models less suitable for investigating underlying electrophysiological mechanisms. In this study, we developed a novel computational model of the rabbit atrial cardiomyocyte incorporating detailed compartmentalization of intracellular calcium dynamics, in addition to a description of membrane currents and intracellular processes. The spatial representation of calcium was based on dividing the intracellular space into eighteen different compartments in the transversal direction, each with separate systems for internal calcium storage and release, and tracking ionic fluxes between compartments in addition to the dynamics driven by membrane currents and calcium release. The model was parameterized employing a population-of-models approach using experimental data from different sources. The parameterization of this novel model resulted in a reduced population of models with inherent variability in calcium dynamics and electrophysiological properties, all of which fall within the range of observed experimental values. As such, the population of models may represent natural variability in cardiomyocyte electrophysiology or inherent uncertainty in the underlying experimental data. The ionic model population was also able to reproduce the U-shaped waveform observed in line-scans of triggered calcium waves in atrial cardiomyocytes, characteristic of the absence of T-tubules, resulting in a centripetal calcium wave due to subcellular calcium diffusion. This novel spatial model of the rabbit atrial cardiomyocyte can be used to integrate experimental findings, offering the potential to enhance our understanding of the pathophysiological role of calcium-handling abnormalities under diseased conditions, such as atrial fibrillation.
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http://dx.doi.org/10.3389/fphys.2020.556156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583320PMC
October 2020

Repeated exposure to transient obstructive sleep apnea-related conditions causes an atrial fibrillation substrate in a chronic rat model.

Heart Rhythm 2021 Mar 17;18(3):455-464. Epub 2020 Oct 17.

Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Klinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany; University Maastricht, Cardiovascular Research Institute Maastricht (CARIM), Masstricht, The Netherlands; Centre for Heart Rhythm Disorders, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia; Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address:

Background: High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways.

Objective: We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate.

Methods: INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS).

Results: INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033).

Conclusion: Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development.
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http://dx.doi.org/10.1016/j.hrthm.2020.10.011DOI Listing
March 2021

Dynamics of Atrial Fibrillation Mechanisms and Comorbidities.

Annu Rev Physiol 2021 02 16;83:83-106. Epub 2020 Oct 16.

Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands; email:

Atrial fibrillation (AF) contributes to morbidity and mortality of millions of individuals. Its molecular, cellular, neurohumoral, and hemodynamic pathophysiological mechanisms are complex, and there is increasing awareness that a wide range of comorbidities can contribute to AF-promoting atrial remodeling. Moreover, recent research has highlighted that AF risk is not constant and that the temporal variation in concomitant conditions contributes to the complexity of AF dynamics. In this review, we provide an overview of fundamental AF mechanisms related to established and emerging comorbidities or risk factors and their role in the AF-promoting effects. We focus on the accumulating evidence for the relevance of temporally dynamic changes in these risk factors and the consequence for AF initiation and maintenance. Finally, we highlight the important implications for future research and clinical practice resulting from the dynamic interaction between AF risk factors and mechanisms.
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http://dx.doi.org/10.1146/annurev-physiol-031720-085307DOI Listing
February 2021

Changes in quality of life, cognition and functional status following catheter ablation of atrial fibrillation.

Heart 2020 Dec 12;106(24):1919-1926. Epub 2020 Oct 12.

Atrial Fibrillation NETwork association (AFNET), Munster, Germany.

Objective: To investigate changes in quality of life (QoL), cognition and functional status according to arrhythmia recurrence after atrial fibrillation (AF) ablation.

Methods: We compared QoL, cognition and functional status in patients with recurrent atrial tachycardia (AT)/AF versus those without recurrent AT/AF in the AXAFA-AFNET 5 clinical trial. We also sought to identify factors associated with improvement in QoL and functional status following AF ablation by overall change scores with and without analysis of covariance (ANCOVA).

Results: Among 518 patients who underwent AF ablation, 154 (29.7%) experienced recurrent AT/AF at 3 months. Patients with recurrent AT/AF had higher mean CHADS-VASc scores (2.8 vs 2.3, p<0.001) and more persistent forms of AF (51 vs 39%, p=0.012). Median changes in the SF-12 physical (3 (25th, 75th: -1, 8) vs 1 (-5, 8), p=0.026) and mental scores (2 (-3, 9) vs 0 (-4, 5), p=0.004), EQ-5D (0 (0,2) vs 0 (-0.1, 0.1), p=0.027) and Karnofsky functional status scores (10 (0, 10) vs 0 (0, 10), p=0.001) were more favourable in patients without recurrent AT/AF. In the overall cohort, the proportion with at least mild cognitive impairment (Montreal Cognitive Assessment <26) declined from 30.3% (n=157) at baseline to 21.8% (n=113) at follow-up. ANCOVA identified greater improvement in Karnofsky functional status (p<0.001) but not SF-12 physical (p=0.238) or mental scores (p=0.065) in those without recurrent AT/AF compared with patients with recurrent AT/AF.

Conclusions: Patients without recurrent AT/AF appear to experience greater improvement in functional status but similar QoL as those with recurrent AT/AF after AF ablation.
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http://dx.doi.org/10.1136/heartjnl-2020-316612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719908PMC
December 2020

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.

N Engl J Med 2020 10 29;383(14):1305-1316. Epub 2020 Aug 29.

From the Department of Cardiology, University Heart and Vascular Center (P.K.), and Institute of Medical Biometry and Epidemiology (A.S., E.V., K.W.), University Medical Center Hamburg-Eppendorf, LANS Cardio (K.-H.K.), and the Department of Cardiology, Asklepios Klinik St. Georg (S.W.), Hamburg, Atrial Fibrillation Network (AFNET) (P.K., A.G., L.E., T.F., D.H., K.-H.K., N.S., U.S., J.T., K.W., S.W., G.B.) and the Department of Cardiology II (Electrophysiology), University Hospital Münster (L.E., G.B.), Münster, the German Center of Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel (P.K., K.W., S.W.), St. Vincenz Hospital, Paderborn (A.G.), the Working Group of Molecular Electrophysiology, University Hospital Magdeburg, Magdeburg (A.G.), the Clinical Research Institute, Munich (T.F.), Hospital Konstanz, Konstanz (F.H.), the Department of Cardiology and Electrophysiology, University Heart Center-Helios, and Leipzig Heart Institute, Leipzig (G.H.), University Heart Center Schleswig-Holstein, Campus Lübeck, Lübeck (K.-H.K.), Cardiology Practice Schön, Mühldorf (N.S.), and Cardiology Practice Taggeselle, Markkleeberg (J.T.) - all in Germany; the Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (P.K.), the Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's University of London, London (A.J.C.), and the Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester (G.A.N.) - all in the United Kingdom; the Department of Cardiology, Odense University Hospital, and Department of Clinical Research, University of Southern Denmark, Odense (A.B.); Isala Hospital and Diagram B.V., Zwolle (A.E.), the University of Groningen, University Medical Center Groningen, Groningen (I.C.G.), and the Department of Physiology, Cardiovascular Research Institute Maastricht (U.S.), and the Department of Cardiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht (H.J.G.M.C.), Maastricht - all in the Netherlands; University Hospital Zurich, Zurich (L.M.H.), and the Division of Cardiology, Medical University Department, Kantonsspital Aarau, Aarau (L.M.H.) - both in Switzerland; University Hospital Antwerp and Antwerp University, Antwerp, Belgium (H.H.); the Institute for Clinical and Experimental Medicine, Prague, Czech Republic (J.K.); the Hospital Clinic, University of Barcelona and Institut de Recerca Biomèdica, August Pi-Sunyer, Barcelona (L.M.), and Centro Investigación Biomedica en Red Cardiovascular, Madrid (L.M.); Department of Cardiology, Hospital Wojewódzka Stacja Pogotowia Ratunkowego i Transportu Sanitarnego (WSRiTS) Meditrans, Warsaw, Poland (J.R.); the Department of Cardiology, Ospedale dell'Angelo, Venice, Italy (S.T.); and Heart Sector, Hygeia Hospitals Group, Athens (P.V.).

Background: Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk.

Methods: In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation-related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated.

Results: In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P = 0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P = 0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups.

Conclusions: Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions. (Funded by the German Ministry of Education and Research and others; EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010-021258-20.).
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http://dx.doi.org/10.1056/NEJMoa2019422DOI Listing
October 2020

Predictors of recurrence of atrial fibrillation within the first 3 months after ablation.

Europace 2020 09;22(9):1337-1344

Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Universiteitsingel 50, 6229 ER Maastricht, Netherlands.

Aims: Freedom from atrial fibrillation (AF) at 1 year can be achieved in 50-70% of patients undergoing catheter ablation. Recurrent AF early after ablation most commonly terminates spontaneously without further interventional treatment but is associated with later recurrent AF. The aim of this investigation is to identify clinical and procedural factors associated with recurrence of AF early after ablation.

Methods And Results: We retrospectively analysed data for recurrence of AF within the first 3 months after catheter ablation from the randomized controlled AXAFA-AFNET 5 trial, which demonstrated that continuous anticoagulation with apixaban is as safe and as effective compared to vitamin K antagonists in 678 patients undergoing first AF ablation. The primary outcome of first recurrent AF within 90 days was observed in 163 (28%) patients, in which 78 (48%) patients experienced an event within the first 14 days post-ablation. After multivariable adjustment, a history of stroke/transient ischaemic attack [hazard ratio (HR) 1.54, 95% confidence interval (CI) 0.93-2.6; P = 0.11], coronary artery disease (HR 1.85, 95% CI 1.20-2.86; P = 0.005), cardioversion during ablation (HR 1.78, 95% CI 1.26-2.49; P = 0.001), and an age:sex interaction for older women (HR 1.01, 95% CI 1.00-1.01; P = 0.04) were associated with recurrent AF. The P-wave duration at follow-up was significantly longer for patients with AF recurrence (129 ± 31 ms vs. 122 ± 22 ms in patients without AF, P = 0.03).

Conclusion: Half of all early AF recurrences within the first 3 months post-ablation occurred within the first 14 days post-ablation. Vascular disease and cardioversion during the procedure are strong predictors of recurrent AF. P-wave duration at follow-up was longer in patients with recurrent AF.

Trial Registration: Clinicaltrials.gov identifier NCT02227550.
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http://dx.doi.org/10.1093/europace/euaa132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478316PMC
September 2020

Acute hyperglycaemia is not associated with the development of atrial fibrillation in healthy pigs.

Sci Rep 2020 07 17;10(1):11881. Epub 2020 Jul 17.

Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.

Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200-500 mg/dL in steps of 100 mg/dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.
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http://dx.doi.org/10.1038/s41598-020-68897-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367844PMC
July 2020

Temporal patterns and short-term progression of paroxysmal atrial fibrillation: data from RACE V.

Europace 2020 08;22(8):1162-1172

Department of Cardiology, University Medical Centre Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

Aims: Atrial fibrillation (AF) often starts as a paroxysmal self-terminating arrhythmia. Limited information is available on AF patterns and episode duration of paroxysmal AF. In paroxysmal AF patients, we longitudinally studied the temporal AF patterns, the association with clinical characteristics, and prevalence of AF progression.

Methods And Results: In this interim analysis of the Reappraisal of AF: Interaction Between HyperCoagulability, Electrical Remodelling, and Vascular Destabilisation in the Progression of AF (RACE V) registry, 202 patients with paroxysmal AF were followed with continuous rhythm monitoring (implantable loop recorder or pacemaker) for 6 months. Mean age was 64 ± 9 years, 42% were women. Atrial fibrillation history was 2.1 (0.5-4.4) years, CHA2DS2-VASc 1.9 ± 1.3, 101 (50%) had hypertension, 69 (34%) heart failure. One-third had no AF during follow-up. Patients with long episodes (>12 hours) were often men with more comorbidities (heart failure, coronary artery disease, higher left ventricular mass). Patients with higher AF burden (>2.5%) were older with more comorbidities (worse renal function, higher calcium score, thicker intima media thickness). In 179 (89%) patients, 1-year rhythm follow-up was available. On a quarterly basis, average daily AF burden increased from 3.2% to 3.8%, 5.2%, and 6.1%. Compared to the first 6 months, 111 (62%) patients remained stable during the second 6 months, 39 (22%) showed progression to longer AF episodes, 8 (3%) developed persistent AF, and 29 (16%) patients showed AF regression.

Conclusions: In paroxysmal AF, temporal patterns differ suggesting that paroxysmal AF is not one entity. Atrial fibrillation burden is low and determined by number of comorbidities. Atrial fibrillation progression occurred in a substantial number.

Trial Registration Number: Clinicaltrials.gov identifier NCT02726698.
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http://dx.doi.org/10.1093/europace/euaa123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400474PMC
August 2020

A novel framework for noninvasive analysis of short-term atrial activity dynamics during persistent atrial fibrillation.

Med Biol Eng Comput 2020 Sep 13;58(9):1933-1945. Epub 2020 Jun 13.

Department of Data Science and Knowledge Engineering, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

ECG-based representation of atrial fibrillation (AF) progression is currently limited. We propose a novel framework for a more sensitive noninvasive characterization of the AF substrate during persistent AF. An atrial activity (AA) recurrence signal is computed from body surface potential map (BSPM) recordings, and a set of characteristic indices is derived from it which captures the short- and long-term recurrent behaviour in the AA patterns. A novel measure of short- and long-term spatial variability of AA propagation is introduced, to provide an interpretation of the above indices, and to test the hypothesis that the variability in the oscillatory content of AA is due mainly to a spatially uncoordinated propagation of the AF waveforms. A simple model of atrial signal dynamics is proposed to confirm this hypothesis, and to investigate a possible influence of the AF substrate on the short-term recurrent behaviour of AA propagation. Results confirm the hypothesis, with the model also revealing the above influence. Once the characteristic indices are normalized to remove this influence, they show to be significantly associated with AF recurrence 4 to 6 weeks after electrical cardioversion. Therefore, the proposed framework improves noninvasive AF substrate characterization in patients with a very similar substrate. Graphical Abstract Schematic representation of the proposed framework for the noninvasive characterization of short-term atrial signal dynamics during persistent AF. The proposed framework shows that the faster the AA is propagating, the more stable its propagation paths are in the short-term (larger values of Speed in the bottom right plot should be interpreted as lower speed of propagation of the corresponding AA propagation patters).
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http://dx.doi.org/10.1007/s11517-020-02190-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417421PMC
September 2020

Pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut reduces atrial fibrillation susceptibility in obese spontaneously hypertensive rats.

Int J Cardiol Heart Vasc 2020 Jun 20;28:100534. Epub 2020 May 20.

Klinik für Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany.

Background: Increased sodium uptake has been shown to contribute to hypertension and cardiac end-organ damage. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. Whether a reduction in intestinal sodium absorption can prevent the development of an atrial arrhythmogenic substrate in hypertension is unknown.

Methods: Eight-week-old obese spontaneously hypertensive rats (SHR-ob) were treated for six weeks with the gut-specific NHE3-inhibitor SAR (1-(β-D-glucopyranosyl)-3-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-chinolin-4-yl]phenyl}urea, 1 mg/kg/d in chow, SHR-ob SAR, n = 7) and compared to aged-matched placebo-treated SHR-ob (SHR-ob PLAC, n = 8). Cardiac magnetic resonance imaging was performed at the end of the treatment period to assess atrial emptying function. Afterwards, local conduction disturbances and inducible atrial fibrillation (AF) duration were determined and histological analysis to quantify atrial fibrosis amount were performed.

Results: Inhibition of intestinal NHE3 by SAR increased fecal sodium excretion, resulted in marked changes in feces electrolyte concentrations and water content, reduced blood pressure and preserved atrial emptying function (active total percent emptying: SHR-ob SAR: 0.47 ± 0.05% vs. SHR-ob PLAC: 0.38 ± 0.007, p < 0.0001). Atrial fibrosis content was lower (21.4 ± 2.5% vs. 36.7 ± 1.2%, p < 0.0001) and areas of slow conduction were smaller (2.5 ± 0.09% vs. 5.3 ± 0.2%, p < 0.0001) in SHR-ob SAR compared to SHR-ob PLAC. Left atrial burst stimulation resulted in shorter inducible AF-durations in SHR-ob SAR compared to SHR-ob PLAC.

Conclusions: Reduction of intestinal sodium absorption and subsequent changes in feces milieu by pharmacological NHE3 inhibition in the gut preserved atrial emptying function and reduced AF susceptibility. Whether pharmacological NHE3 inhibition in the gut prevents AF in humans warrants further study.
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http://dx.doi.org/10.1016/j.ijcha.2020.100534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243186PMC
June 2020

Effect of selective I inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation.

Br J Pharmacol 2020 08 24;177(16):3778-3794. Epub 2020 Jun 24.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Background And Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, I may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific I inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF.

Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction.

Key Results: XAF-1407 potently and selectively inhibited K 3.1/3.4 and K 3.4/3.4, underlying the I current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia.

Conclusion And Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supports I inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
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http://dx.doi.org/10.1111/bph.15100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393200PMC
August 2020

Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies.

Prog Biophys Mol Biol 2020 11 15;157:54-75. Epub 2020 Mar 15.

Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands. Electronic address:

Calcium (Ca) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca levels are regulated by a variety of Ca-handling proteins. In turn, Ca modulates numerous electrophysiological processes. Accordingly, Ca-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca handling under physiological and pathological conditions. However, numerous questions involving the Ca-dependent regulation of different macromolecular complexes, cross-talk between Ca-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.
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http://dx.doi.org/10.1016/j.pbiomolbio.2020.02.008DOI Listing
November 2020

Epicardial Fibrosis Explains Increased Endo-Epicardial Dissociation and Epicardial Breakthroughs in Human Atrial Fibrillation.

Front Physiol 2020 21;11:68. Epub 2020 Feb 21.

Department of Physiology, Maastricht University, Maastricht, Netherlands.

Background: Atrial fibrillation (AF) is accompanied by progressive epicardial fibrosis, dissociation of electrical activity between the epicardial layer and the endocardial bundle network, and transmural conduction (breakthroughs). However, causal relationships between these phenomena have not been demonstrated yet. Our goal was to test the hypothesis that epicardial fibrosis suffices to increase endo-epicardial dissociation (EED) and breakthroughs (BT) during AF.

Methods: We simulated the effect of fibrosis in the epicardial layer on EED and BT in a detailed, high-resolution, three-dimensional model of the human atria with realistic electrophysiology. The model results were compared with simultaneous endo-epicardial mapping in human atria. The model geometry, specifically built for this study, was based on MR images and histo-anatomical studies. Clinical data were obtained in four patients with longstanding persistent AF (persAF) and three patients without a history of AF.

Results: The AF cycle length (AFCL), conduction velocity (CV), and EED were comparable in the mapping studies and the simulations. EED increased from 24.1 ± 3.4 to 56.58 ± 6.2% ( < 0.05), and number of BTs per cycle from 0.89 ± 0.55 to 6.74 ± 2.11% ( < 0.05), in different degrees of fibrosis in the epicardial layer. In both mapping data and simulations, EED correlated with prevalence of BTs. Fibrosis also increased the number of fibrillation waves per cycle in the model.

Conclusion: A realistic 3D computer model of AF in which epicardial fibrosis was increased, in the absence of other pathological changes, showed increases in EED and epicardial BT comparable to those in longstanding persAF. Thus, epicardial fibrosis can explain both phenomena.
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http://dx.doi.org/10.3389/fphys.2020.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047215PMC
February 2020

Sex differences in catheter ablation of atrial fibrillation: results from AXAFA-AFNET 5.

Europace 2020 07;22(7):1026-1035

Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.

Aims: Study sex-differences in efficacy and safety of atrial fibrillation (AF) ablation.

Methods And Results: We assessed first AF ablation outcomes on continuous anticoagulation in 633 patients [209 (33%) women and 424 (67%) men] in a pre-specified subgroup analysis of the AXAFA-AFNET 5 trial. We compared the primary outcome (death, stroke or transient ischaemic attack, or major bleeding) and secondary outcomes [change in quality of life (QoL) and cognitive function] 3 months after ablation. Women were older (66 vs. 63 years, P < 0.001), more often symptomatic, had lower QoL and a longer history of AF. No sex differences in ablation procedure were found. Women stayed in hospital longer than men (2.1 ± 2.3 vs. 1.6 ± 1.3 days, P = 0.004). The primary outcome occurred in 19 (9.1%) women and 26 (6.1%) men, P = 0.19. Women experienced more bleeding events requiring medical attention (5.7% vs. 2.1%, P = 0.03), while rates of tamponade (1.0% vs. 1.2%) or intracranial haemorrhage (0.5% vs. 0%) did not differ. Improvement in QoL after ablation was similar between the sexes [12-item Short Form Health Survey (SF-12) physical 5.1% and 5.9%, P = 0.26; and SF-12 mental 3.7% and 1.6%, P = 0.17]. At baseline, mild cognitive impairment according to the Montreal Cognitive Assessment (MoCA) was present in 65 (32%) women and 123 (30%) men and declined to 23% for both sexes at end of follow-up.

Conclusion: Women and men experience similar improvement in QoL and MoCA score after AF ablation on continuous anticoagulation. Longer hospital stay, a trend towards more nuisance bleeds, and a lower overall QoL in women were the main differences observed.
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http://dx.doi.org/10.1093/europace/euaa015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336181PMC
July 2020

Nightly sleep apnea severity in patients with atrial fibrillation: Potential applications of long-term sleep apnea monitoring.

Int J Cardiol Heart Vasc 2019 Sep 18;24:100424. Epub 2019 Oct 18.

Centre for Heart Rhythm Disorders (CHRD), South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia.

In patients with atrial fibrillation (AF), the prevalence of moderate-to-severe sleep-disordered breathing (SDB) ranges between 21% and 72% and observational studies have demonstrated that SDB reduces the efficacy of rhythm control strategies, while treatment with continuous positive airway pressure lowers the rate of AF recurrence. Currently, the number of apneas and hypopneas per hour (apnea-hypopnea-index, AHI) determined during a single overnight sleep study is clinically used to assess the severity of SDB. However, recent studies suggest that SDB-severity in an individual patient is not stable over time but exhibits a considerable night-to-night variability which cannot be detected by only one overnight sleep assessment. Nightly SDB-severity assessment rather than the single-night diagnosis by one overnight sleep study may better reflect the exposure to SDB-related factors and yield a superior metric to determine SDB-severity in the management of AF. In this review we discuss mechanisms of night-to-night SDB variability, arrhythmogenic consequences of night-to-night SDB variability, strategies for longitudinal assessment of nightly SDB-severity and clinical implications for screening and management of SDB in AF patients.
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http://dx.doi.org/10.1016/j.ijcha.2019.100424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859526PMC
September 2019