Publications by authors named "Stef Zeemering"

33 Publications

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

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

Europace 2021 Jan 12. Epub 2021 Jan 12.

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 proplems 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
January 2021

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

Heart Rhythm 2020 Nov 21. 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
November 2020

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

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

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

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

Rotors Detected by Phase Analysis of Filtered, Epicardial Atrial Fibrillation Electrograms Colocalize With Regions of Conduction Block.

Circ Arrhythm Electrophysiol 2018 10;11(10):e005858

Department of Physiology, Maastricht University, the Netherlands (P.P., S.Z., A.v.H., S.V.).

Background: Several recent studies suggest rotors detected by phase mapping may act as main drivers of persistent atrial fibrillation. However, the electrophysiological nature of detected rotors remains unclear. We performed a direct, 1:1 comparison between phase and activation time mapping in high-density, epicardial, direct-contact mapping files of human atrial fibrillation.

Methods: Thirty-eight unipolar electrogram files of 10 s duration were recorded in patients with atrial fibrillation (n=20 patients) using a 16×16 electrode array placed on the epicardial surface of the left atrial posterior wall or the right atrial free wall. Phase maps and isochrone wave maps were constructed for all recordings. For each detected phase singularity (PS) with a lifespan of >1 cycle length, the corresponding conduction pattern was investigated in the isochrone wave maps.

Results: When using sinusoidal recomposition and Hilbert Transform, 138 PSs were detected. One hundred and four out of 138 PSs were detected within 1 electrode distance (1.5 mm) from a line of conduction block between nonrotating wavefronts detected by activation mapping. Far fewer rotating wavefronts were detected when rotating activity was identified based on wave mapping (18 out of 8219 detected waves). Fourteen out of these 18 cases were detected as PSs in phase mapping. Phase analysis of filtered electrograms produced by simulated wavefronts separated by conduction block also identified PSs on the line of conduction block.

Conclusions: PSs identified by phase analysis of filtered epicardial electrograms colocalize with conduction block lines identified by activation mapping. Detection of PSs using phase analysis has a low specificity for identifying rotating wavefronts during human atrial fibrillation using activation mapping.
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http://dx.doi.org/10.1161/CIRCEP.117.005858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553551PMC
October 2018

Stationary Atrial Fibrillation Properties in the Goat Do Not Entail Stable or Recurrent Conduction Patterns.

Front Physiol 2018 27;9:947. Epub 2018 Jul 27.

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

Electro-anatomical mapping of the atria is used to identify the substrate of atrial fibrillation (AF). Targeting this substrate by ablation in addition to pulmonary vein ablation did not consistently improve outcome in clinical trials. Generally, the assessment of the substrate is based on short recordings (≤10 s, often even shorter). Thus, targeting the AF substrate assumes spatiotemporal stationarity but little is known about the variability of electrophysiological properties of AF over time. Atrial fibrillation (AF) was maintained for 3-4 weeks after pericardial electrode implantation in 12 goats. Within a single AF episode 10 consecutive minutes were mapped on the left atrial free wall using a 249-electrode array (2.25 mm inter-electrode spacing). AF cycle length, fractionation index (FI), lateral dissociation, conduction velocity, breakthroughs, and preferentiality of conduction (Pref) were assessed per electrode and AF property maps were constructed. The Pearson correlation coefficient (PCC) between the 10 AF-property maps was calculated to quantify the degree spatiotemporal stationarity of AF properties. Furthermore, the number of waves and presence of re-entrant circuits were analyzed in the first 60-s file. Comparing conduction patterns over time identified recurrent patterns of AF with the use of recurrence plots. The averages of AF property maps were highly stable throughout the ten 60-s-recordings. Spatiotemporal stationarity was high for all 6 property maps, PCC ranged from 0.66 ± 0.11 for Pref to 0.98 ± 0.01 for FI. High stationarity was lost when AF was interrupted for about 1 h. However, the time delay between the recorded files within one episode did not affect PCC. Yet, multiple waves (7.7 ± 2.3) were present simultaneously within the recording area and during 9.2 ± 11% of the analyzed period a re-entrant circuit was observed. Recurrent patterns occurred rarely and were observed in only 3 out of 12 goats. During non-self-terminating AF in the goat, AF properties were stationary. Since this could not be attributed to stable recurrent conduction patterns during AF, it is suggested that AF properties are determined by anatomical and structural properties of the atria even when the conduction patterns are very variable.
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http://dx.doi.org/10.3389/fphys.2018.00947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072874PMC
July 2018

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation.

Heart Rhythm 2018 09 23;15(9):1328-1336. Epub 2018 May 23.

Division of Cardiology, Department of Medicine, Medical University of Graz, Graz, Austria; Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms.

Objective: We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT.

Methods: Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed.

Results: DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm in AF+HT vs 78 ± 23 cm in AF; P < .05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm in AF+HT vs 0.96 ± 0.3 cm in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the in vivo experiments associated with increased atrial size.

Conclusion: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.
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http://dx.doi.org/10.1016/j.hrthm.2018.05.016DOI Listing
September 2018

Concealed abnormal atrial phenotype in patients with Brugada syndrome and no history of atrial fibrillation.

Int J Cardiol 2018 02;253:66-70

Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland; Centre for Computational Medicine in Cardiology, Faculty of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.

Objectives: The electrocardiogram (ECG) of patients with BrS in sinus rhythm might reflect intrinsic atrial electrical abnormalities independent from any previous atrial fibrillation (AF). Aim of this study is to investigate the presence of P-wave abnormalities in patients with BrS and no history of AF, and to compare them with those displayed by patients with documented paroxysmal AF and by healthy subjects.

Methods: Continuous 5-min 16-lead ECG recordings in sinus rhythm were obtained from 72 participants: 32 patients with a type 1 Brugada ECG, 20 patients with a history of paroxysmal AF and 20 age-matched healthy subjects. Different ECG-based features were computed on the P-wave first principal component representing the predominant morphology across leads and containing the maximal information on atrial depolarization: duration, full width half maximum (FWHM), area under the curve and number of peaks in the wave.

Results: Patients with BrS and no history of AF (mean age: 53±12years; males: 28 pts., spontaneous type 1 ECG: 20 pts., SCN5A mutation: 10 pts) presented with longer P-wave duration, higher FWHM and wider area under the curve in comparison with the other two groups. Although P-wave features were abnormal in BrS patients, no significant difference was found between patients with spontaneous type 1 ECG and ajmaline-induced type 1 ECG, symptomatic and asymptomatic ones, and between patients with a pathogenic SCNA5 mutation and patients without a known gene mutation.

Conclusions: Patients with BrS without previous occurrence of AF present with a concealed abnormal atrial phenotype. In these patients atrial electrical abnormalities can be detected even in the absence of an overt ECG ventricular phenotype, symptoms and a SCN5A mutation.
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http://dx.doi.org/10.1016/j.ijcard.2017.09.214DOI Listing
February 2018

The electrocardiogram as a predictor of successful pharmacological cardioversion and progression of atrial fibrillation.

Europace 2018 07;20(7):e96-e104

Department of Physiology, Maastricht University, Universiteitssingel 50, ER Maastricht, The Netherlands.

Aims: Non-invasive characterization of atrial fibrillation (AF) substrate complexity based on the electrocardiogram (ECG) may improve outcome prediction in patients receiving rhythm control therapies for AF. Multiple parameters to assess AF complexity and predict treatment outcome have been suggested. A comparative study of the predictive performance of complexity parameters on response to therapy and progression of AF in a large patient population is needed to standardize non-invasive analysis of AF.

Methods And Results: A large variety of ECG complexity parameters were systematically compared in patients with recent onset AF undergoing pharmacological cardioversion (PCV) with flecainide. Parameters were computed on 10-s 12-lead ECGs of 221 patients before drug administration. The ability of ECG parameters to predict successful PCV and progression to persistent AF (mean follow-up 49 months) was evaluated and compared with common clinical predictors. Optimal prediction performance of successful PCV using only one ECG parameter was low, using dominant atrial frequency [lead II, receiver operating area under curve (AUC) 0.66, 95% confidence interval [0.64-0.67]], but the optimal combination of several ECG parameters strongly improved predictive performance (AUC 0.78 [0.76-0.79]). While predictive value of the optimal combination of clinical predictors was low (AUC 0.68 [0.66-0.70], using right atrial volume and weight), adding ECG parameters strongly increased performance (AUC 0.81 [0.79-0.82], P < 0.001). Interestingly, higher dominant frequency and higher f-wave amplitude were associated with increased risk of progression to persistent AF during follow-up.

Conclusion: Assessment of AF complexity from 12-lead ECGs significantly improves prediction of successful PCV and progression to persistent AF compared with common clinical and echocardiographic predictors.
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http://dx.doi.org/10.1093/europace/eux234DOI Listing
July 2018

Evaluation of the use of unipolar voltage amplitudes for detection of myocardial scar assessed by cardiac magnetic resonance imaging in heart failure patients.

PLoS One 2017 5;12(7):e0180637. Epub 2017 Jul 5.

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

Background: Validation of voltage-based scar delineation has been limited to small populations using mainly endocardial measurements. The aim of this study is to compare unipolar voltage amplitudes (UnipV) with scar on delayed enhancement cardiac magnetic resonance imaging (DE-CMR).

Methods: Heart failure patients who underwent DE-CMR and electro-anatomic mapping were included. Thirty-three endocardial mapped patients and 27 epicardial mapped patients were investigated. UnipV were computed peak-to-peak. Electrograms were matched with scar extent of the corresponding DE-CMR segment using a 16-segment/slice model. Non-scar was defined as 0% scar, while scar was defined as 1-100% scar extent.

Results: UnipVs were moderately lower in scar than in non-scar (endocardial 7.1 [4.6-10.6] vs. 10.3 [7.4-14.2] mV; epicardial 6.7 [3.6-10.5] vs. 7.8 [4.2-12.3] mV; both p<0.001). The correlation between UnipV and scar extent was moderate for endocardial (R = -0.33, p<0.001), and poor for epicardial measurements (R = -0.07, p<0.001). Endocardial UnipV predicted segments with >25%, >50% and >75% scar extent with AUCs of 0.72, 0.73 and 0.76, respectively, while epicardial UnipV were poor scar predictors, independent of scar burden (AUC = 0.47-0.56). UnipV in non-scar varied widely between patients (p<0.001) and were lower in scar compared to non-scar in only 9/22 (41%) endocardial mapped patients and 4/19 (21%) epicardial mapped patients with scar.

Conclusion: UnipV are slightly lower in scar compared to non-scar. However, significant UnipV differences between and within patients and large overlap between non-scar and scar limits the reliability of accurate scar assessment, especially in epicardial measurements and in segments with less than 75% scar extent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180637PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498065PMC
October 2017

P-wave complexity in normal subjects and computer models.

J Electrocardiol 2016 Jul-Aug;49(4):545-53. Epub 2016 May 12.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes.

Objective: We systematically investigated P-wave complexity in normal volunteers using high-fidelity electrocardiographic techniques without filtering.

Methods: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria.

Results: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria.

Conclusion: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats.
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http://dx.doi.org/10.1016/j.jelectrocard.2016.05.005DOI Listing
November 2017

Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations.

IEEE Trans Biomed Eng 2017 02 15;64(2):310-318. Epub 2016 Apr 15.

Objective: To explore technical challenges of phase singularity (PS) mapping during atrial fibrillation (AF) using direct contact electrograms.

Methods: AF mapping was performed in high-density epicardial recordings of human paroxysmal (PAF) or persistent (PersAF) (N = 20 pts) AF with an array of 16 × 16 electrodes placed on atrial epicardium. PS points were detected using subsets of electrodes forming rings of varying sizes.

Results: PS detection using a 2 × 2 electrode ring identified 0.88 ± 1.00 PS/s in PAF group and 3.91 ± 2.51 per s in PersAF group (p < 0.001) in 2.4 × 2.4 cm mapping area. All detected PS had a short lifespan with the longest being 1100 ms (6.8 rotations). Exploration of the PS detection in a numerical model demonstrated that at least eight electrodes are required to avoid frequent false positive PS detection due to chance. Application of a detection grid consisting a double ring of electrodes (2 × 2 and 4 × 4 rings) decreased the number of false positive detections. The double ring was more resilient to electrode swapping (with just three instances of false positives versus 4380 false positives using 2 × 2 ring).

Conclusions: The number of detected rotors critically depends upon the parameters of the detection algorithm, especially the number of electrodes used to detect PS. Based on our results, we recommend double ring comprised of 2 × 2 and 4 × 4 grid of electrodes for robust rotor detection.

Significance: Great methodological care has to be taken before equating detected PS with rotating waves and using PS detection algorithms to guide catheter ablation of AF.
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http://dx.doi.org/10.1109/TBME.2016.2554660DOI Listing
February 2017

Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation.

Eur Heart J 2017 01 12;38(1):38-50. Epub 2016 Apr 12.

Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

Aims: Atrial fibrillation (AF) produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors provokes pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues. We studied the effects of thrombin on atrial fibroblasts and tested the hypothesis that hypercoagulability contributes to the development of a substrate for AF.

Methods And Results: In isolated rat atrial fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signalling molecules Akt and Erk and increased the expression of transforming growth factor β1 (2.7-fold) and the pro-inflammatory factor monocyte chemoattractant protein-1 (6.1-fold). Thrombin also increased the incorporation of H-proline, suggesting enhanced collagen synthesis by fibroblasts (2.5-fold). All effects could be attenuated by the thrombin inhibitor dabigatran. In transgenic mice with a pro-coagulant phenotype (TM), the inducibility of AF episodes lasting >1 s was higher (7 out of 12 vs. 1 out of 10 in wild type) and duration of AF episodes was longer compared with wild type mice (maximum episode duration 42.8 ± 68.4 vs. 0.23 ± 0.39 s). In six goats with persistent AF treated with nadroparin, targeting Factor Xa-mediated thrombin generation, the complexity of the AF substrate was less pronounced than in control animals (LA maximal activation time differences 23.3 ± 3.1 ms in control vs. 15.7 ± 2.1 ms in nadroparin, P < 0.05). In the treated animals, AF-induced α-smooth muscle actin expression was lower and endomysial fibrosis was less pronounced.

Conclusion: The hypercoagulable state during AF causes pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts. Hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF. In AF goats, nadroparin attenuates atrial fibrosis and the complexity of the AF substrate. Inhibition of coagulation may not only prevent strokes but also inhibit the development of a substrate for AF.
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http://dx.doi.org/10.1093/eurheartj/ehw119DOI Listing
January 2017

Atrial Fibrillation Complexity Parameters Derived From Surface ECGs Predict Procedural Outcome and Long-Term Follow-Up of Stepwise Catheter Ablation for Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2016 Feb;9(2):e003354

From the Departments of Cardiology (T.L., H.J.C.) and Physiology (T.L., S.Z., P.K., U.S.), Maastricht University Medical Centre, Maastricht, the Netherlands; Division of Cardiology, Department of Medicine, Medical University of Graz, Graz, Austria (D.S., B.P.); Department Cardiology-Electrophysiology, University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany (P.K., B.A.H., S.W.); and Department of Cardiology, Hôpital Cardiologique du Haut Lévêque, Université Bordeaux, IHU LIRYC ANR-10-IAHU-04, Bordeaux, France (M.H., P.J.).

Background: The success rate of catheter ablation for persistent atrial fibrillation (AF) is still far from satisfactory. Identification of patients who will benefit from ablation is highly desirable. We investigated the predictive value of noninvasive AF complexity parameters derived from standard 12-lead ECGs for AF termination and long-term success of catheter ablation and compared them with clinical predictors.

Methods And Results: The study included a training (93 patients) and a validation set (81 patients) of patients with persistent AF undergoing stepwise radiofrequency ablation. In the training set AF terminated in 81% during catheter ablation, 77% were in sinus rhythm after 6 years and multiple ablations. ECG-derived complexity parameters were determined from a baseline 10-s 12-lead ECG. Prediction of AF termination was similar using only ECG (cross-validated mean area under the curve [AUC], 0.76±0.15) or only clinical parameters (mean AUC, 0.75±0.16). The combination improved prediction to a mean AUC of 0.79±0.13. Using a combined model of ECG and clinical parameters, sinus rhythm at long-term follow-up could be predicted with a mean AUC of 0.71±0.12. In the validation set AF terminated in 57%, 61% were in sinus rhythm after 4.6 years. The combined models predicted termination with an AUC of 0.70 and sinus rhythm at long-term follow-up with an AUC of 0.61. Overall, fibrillation-wave amplitude provided the best rhythm prediction.

Conclusions: The predictive performance of ECG-derived AF complexity parameters for AF termination and long-term success of catheter ablation in patients with persistent AF is at least as good as known clinical predictive parameters, with fibrillation-wave amplitude as the best predictor.
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http://dx.doi.org/10.1161/CIRCEP.115.003354DOI Listing
February 2016

Systematic analysis of ECG predictors of sinus rhythm maintenance after electrical cardioversion for persistent atrial fibrillation.

Heart Rhythm 2016 05 8;13(5):1020-1027. Epub 2016 Jan 8.

Department of Physiology, Maastricht University Medical Centre, Maastricht, The Netherlands. Electronic address:

Background: Electrical cardioversion (ECV) is one of the rhythm control strategies in patients with persistent atrial fibrillation (AF). Unfortunately, recurrences of AF are common after ECV, which significantly limits the practical benefit of this treatment in patients with AF.

Objectives: The objectives of this study were to identify noninvasive complexity or frequency parameters obtained from the surface electrocardiogram (ECG) to predict sinus rhythm (SR) maintenance after ECV and to compare these ECG parameters with clinical predictors.

Methods: We studied a wide variety of ECG-derived time- and frequency-domain AF complexity parameters in a prospective cohort of 502 patients with persistent AF referred for ECV.

Results: During 1-year follow-up, 161 patients (32%) maintained SR. The best clinical predictor of SR maintenance was antiarrhythmic drug (AAD) treatment. A model including clinical parameters predicted SR maintenance with a mean cross-validated area under the receiver operating characteristic curve (AUC) of 0.62 ± 0.05. The best single ECG parameter was the dominant frequency (DF) on lead V6. Combining several ECG parameters predicted SR maintenance with a mean AUC of 0.64 ± 0.06. Combining clinical and ECG parameters improved prediction to a mean AUC of 0.67 ± 0.05. Although the DF was affected by AAD treatment, excluding patients taking AADs did not significantly lower the predictive performance captured by the ECG.

Conclusion: ECG-derived parameters predict SR maintenance during 1-year follow-up after ECV at least as good as known clinical predictors of rhythm outcome. The DF proved to be the most powerful ECG-derived predictor.
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http://dx.doi.org/10.1016/j.hrthm.2016.01.004DOI Listing
May 2016

Recurrence quantification analysis applied to spatiotemporal pattern analysis in high-density mapping of human atrial fibrillation.

Annu Int Conf IEEE Eng Med Biol Soc 2015 ;2015:7704-7

Spatiotemporal complexity of atrial fibrillation (AF) patterns is often quantified by annotated intracardiac contact mapping. We introduce a new approach that applies recurrence plot (RP) construction followed by recurrence quantification analysis (RQA) to epicardial atrial electrograms, recorded with a high-density grid of electrodes. In 32 patients with no history of AF (aAF, n=11), paroxysmal AF (PAF, n=12) and persistent AF (persAF, n=9), RPs were constructed using a phase space electrogram embedding dimension equal to the estimated AF cycle length. Spatial information was incorporated by 1) averaging the recurrence over all electrodes, and 2) by applying principal component analysis (PCA) to the matrix of embedded electrograms and selecting the first principal component as a representation of spatial diversity. Standard RQA parameters were computed on the constructed RPs and correlated to the number of fibrillation waves per AF cycle (NW). Averaged RP RQA parameters showed no correlation with NW. Correlations improved when applying PCA, with maximum correlation achieved between RP threshold and NW (RR1%, r=0.68, p <; 0.001) and RP determinism (DET, r=-0.64, p <; 0.001). All studied RQA parameters based on the PCA RP were able to discriminate between persAF and aAF/PAF (DET persAF 0.40 ± 0.11 vs. 0.59 ± 0.14/0.62 ± 0.16, p <; 0.01). RP construction and RQA combined with PCA provide a quick and reliable tool to visualize dynamical behaviour and to assess the complexity of contact mapping patterns in AF.
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http://dx.doi.org/10.1109/EMBC.2015.7320177DOI Listing
September 2016

Far-field effect in unipolar electrograms revisited: High-density mapping of atrial fibrillation in humans.

Annu Int Conf IEEE Eng Med Biol Soc 2015 Aug;2015:5680-3

Unipolar electrogram can detect local as well as remote electrical activity of the heart. Information on how the amplitude and morphology of the recorded signal changes with the distance from the source tissue undergoing depolarization can help to better understand unipolar electrograms fractionation and provide insights into the passive conduction properties of the atrial tissue. Ten second unipolar atrial fibrillation (AF) electrograms were recorded using high-density electrode array from the posterior left atrium (LA) and right atrium (RA) of 19 (8 persistent - PERS & 11 paroxysmal - PAF) AF patients undergoing cardiac surgery. Conduction along lines of conduction block was detected in the recorded activation patterns by a proposed automated algorithm. Changes of the amplitude of the unipolar electrogram with increasing distance from the conduction blocks were assessed and compared to predictions of a theoretical model. For each recording, the median far-field decay space constant (FF0.5) was calculated. Overall, we found a significant difference between FF0.5 for patients with paroxysmal and persistent AF. Estimation of maximum FF0.5 from both RA and LA resulted in a mean FF0.5 of 1.5±0.2 mm for PERS patients and 2.1±0.6 mm for PAF patients (p=0.03). Moreover, detected conduction blocks demonstrated high spatial organization and appeared in distinctive areas of the mapped area in all patients, regardless of the type of AF, while the total number of detected block lines was higher in PERS patients.
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http://dx.doi.org/10.1109/EMBC.2015.7319681DOI Listing
August 2015

Antiarrhythmic effect of vernakalant in electrically remodeled goat atria is caused by slowing of conduction and prolongation of postrepolarization refractoriness.

Heart Rhythm 2016 Apr 8;13(4):964-72. Epub 2015 Dec 8.

Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. Electronic address:

Background: Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.

Objective: The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.

Methods: Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia.

Results: Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing.

Conclusion: The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria.
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http://dx.doi.org/10.1016/j.hrthm.2015.12.009DOI Listing
April 2016

Indices of bipolar complex fractionated atrial electrograms correlate poorly with each other and atrial fibrillation substrate complexity.

Heart Rhythm 2015 Jul 12;12(7):1415-23. Epub 2015 Mar 12.

Department of Physiology, Maastricht University, Maastricht,The Netherlands. Electronic address:

Background: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood.

Objective: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF.

Methods: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined.

Results: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block.

Conclusion: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE.
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http://dx.doi.org/10.1016/j.hrthm.2015.03.017DOI Listing
July 2015

Reconstruction of instantaneous phase of unipolar atrial contact electrogram using a concept of sinusoidal recomposition and Hilbert transform.

IEEE Trans Biomed Eng 2015 Jan 20;62(1):296-302. Epub 2014 Aug 20.

The Hilbert transform has been used to characterize wave propagation and detect phase singularities during cardiac fibrillation. Two mapping modalities have been used: optical mapping (used to map atria and ventricles) and contact electrode mapping (used only to map ventricles). Due to specific morphology of atrial electrograms, phase reconstruction of contact electrograms in the atria is challenging and has not been investigated in detail. Here, we explore the properties of Hilbert transform applied to unipolar epicardial electrograms and devise a method for robust phase reconstruction using the Hilbert transform. We applied the Hilbert transform to idealized unipolar signals obtained from analytical approach and to electrograms recorded in humans. We investigated effects of deflection morphology on instantaneous phase. Application of the Hilbert transform to unipolar electrograms demonstrated sensitivity of reconstructed phase to the type of deflection morphology (uni- or biphasic), the ratio of R and S waves and presence of the noise. In order to perform a robust phase reconstruction, we propose a signal transformation based on the recomposition of the electrogram from sinusoidal wavelets with amplitudes proportional to the negative slope of the electrogram. Application of the sinusoidal recomposition transformation prior to application of the Hilbert transform alleviates the effect of confounding features on reconstructed phase.
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http://dx.doi.org/10.1109/TBME.2014.2350029DOI Listing
January 2015

Systematic comparison of non-invasive measures for the assessment of atrial fibrillation complexity: a step forward towards standardization of atrial fibrillation electrogram analysis.

Europace 2015 Feb 13;17(2):318-25. Epub 2014 Aug 13.

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

Aims: To present a comparison of electrocardiogram-based non-invasive measures of atrial fibrillation (AF) substrate complexity computed on invasive animal recordings to discriminate between short-term and long-term AF. The final objective is the selection of an optimal sub-set of measures for AF complexity assessment.

Methods And Results: High-density epicardial direct contact mapping recordings (234 leads) were acquired from the right and the left atria of 17 goats in which AF was induced for 3 weeks (short-term AF group, N = 10) and 6 months (long-term AF group, N = 7). Several non-invasive measures of AF organization proposed in the literature in the last decade were investigated to assess their power in discriminating between the short-term and long-term group. The best performing measures were identified, which when combined attained a correct classification rate of 100%. Their ability to predict standard invasive AF complexity measures was also tested, showing an average R(2) of 0.73 ± 0.04.

Conclusion: An optimal set of measures of the AF substrate complexity was identified out of the set of non-invasive measures analysed in this study. These measures may contribute to improve patient-tailored diagnosis and therapy of sustained AF.
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http://dx.doi.org/10.1093/europace/euu202DOI Listing
February 2015

The ECG as a tool to determine atrial fibrillation complexity.

Heart 2014 Jul 16;100(14):1077-84. Epub 2014 May 16.

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

The use of the ECG for atrial fibrillation (AF) in clinical daily practice is still limited to its diagnosis. Recent research shows however that ECG-derived parameters can also be used to assess the spatiotemporal properties of AF. Specifically, the complexity of the f-waves in the ECG reflects the complexity of the fibrillatory conduction during AF and therefore can be used for quantification of the degree of electrophysiological alterations in the atria. This information might be useful for guiding AF therapy and might form the basis for classification of AF. This review focuses on technical and mathematical aspects of ECG-based atrial complexity assessment and its potential ability to guide treatment strategies.
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http://dx.doi.org/10.1136/heartjnl-2013-305149DOI Listing
July 2014

Catheter Ablation Targeting Complex Fractionated Atrial Electrogram in Atrial Fibrillation.

J Atr Fibrillation 2013 Oct-Nov;6(3):907. Epub 2013 Oct 31.

Department of Physiology, Maastricht University,Medical Center; Maastricht, The Netherlands.

The relatively low success rates seen with pulmonary vein ablation in non-paroxysmal atrial fibrillation (AF) patients as compared to those with the paroxysmal form of the arrhythmia have prompted electrophysiologists to search for newer ablative strategies. A decade has passed since the initial description of complex fractionated atrial electrogram (CFAE) ablation aimed at targeting the electrophysiological substrate in atrial fibrillation. Despite intensive research, superiority of CFAE-based ablation over other contemporary approaches could not be demonstrated. Nevertheless, the technique has an adjunctive role to pulmonary vein ablation in non-paroxysmal AF patients. Perhaps our incomplete understanding of the complex AF pathophysiology and inadequate characterization or determination of CFAE has limited our success so far. This review aims to highlight the current challenges and future role of CFAE ablation.  .
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http://dx.doi.org/10.4022/jafib.907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153035PMC
October 2013

Rearrangement of atrial bundle architecture and consequent changes in anisotropy of conduction constitute the 3-dimensional substrate for atrial fibrillation.

Circ Arrhythm Electrophysiol 2013 Oct 22;6(5):967-75. Epub 2013 Aug 22.

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

Background: Anisotropy of conduction facilitates re-entry and is, therefore, a key determinant of the stability of atrial fibrillation (AF). Little is known about the effect of AF on atrial bundle architecture and consequent changes in anisotropy of conduction and maintenance of AF.

Methods And Results: Direct contact mapping was performed in left atria of goats with acute AF (n=6) or persistent AF (n=5). The degree and direction of anisotropic conduction were analyzed. Mapped tissue regions were imaged by high-resolution MRI for identification of endocardial and epicardial bundle directions. Correlation between endocardial and epicardial bundle directions and between bundle directions and anisotropic conduction was quantified. In persistent AF, epicardial bundles were oriented more perpendicularly to endocardial bundles than in acute AF (% angles<20° between epicardial and endocardial bundle directions were 7.63% and 21.25%, respectively; P<0.01). In acute AF, the direction of epicardially mapped anisotropic conduction correlated with endocardial but not with epicardial bundles. In persistent AF, the direction of anisotropic conduction correlated better with epicardial than with endocardial bundles (% angles<20° between direction of anisotropic conduction and bundle direction were 28.77% and 18.45%, respectively; P<0.01).

Conclusions: During AF, atrial bundle rearrangement manifests itself in more perpendicular orientation of epicardial to endocardial bundles. Propagation of fibrillation waves is dominated by endocardial bundles in acute AF and by epicardial bundles in persistent AF. Together with the loss of endo-epicardial electrical connections, rearrangement of atrial bundles underlies endo-epicardial dissociation of electrical activity and the development of a 3-dimensional AF substrate.
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http://dx.doi.org/10.1161/CIRCEP.113.000050DOI Listing
October 2013

Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping.

Circ Arrhythm Electrophysiol 2013 Apr 19;6(2):334-41. Epub 2013 Mar 19.

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

Background: Endo-epicardial dissociation (EED) of electric activations resulting in transmural conduction of fibrillation waves (breakthroughs) has been postulated to contribute to the complexity of the substrate of atrial fibrillation (AF). The aim of this study was to elucidate the correlation between EED and incidence of breakthrough and to test the plausibility of transmural conduction versus ectopic focal discharges as sources of breakthrough.

Methods And Results: We analyzed high-resolution simultaneous endo-epicardial in vivo mapping data recorded in left atrial free walls of goats with acute AF, 3 weeks and 6 months of AF (all n=7). Waves were analyzed for number, size, and width and categorized according to their origin outside (peripheral wave) or within the mapping area (breakthrough). Breakthrough incidence was lowest (2.1±1.0%) in acute AF, higher (11.4±6.1%) after 3 weeks (P<0.01 versus acute AF) and highest (14.2±3.8%) after 6 months AF (P<0.001 versus acute AF) and similar in the epicardium and endocardium. Most of the breakthroughs (86%; n=564) could be explained by transmural conduction, whereas only 13% (n=85) could be explained by ectopic focal discharges. Transmural microreentry did not play a role as source of breakthrough.

Conclusions: This is the first study to present simultaneous endo-epicardial in vivo mapping data at sites of breakthrough events. Breakthrough incidence and degree of EED increased with increasing AF substrate complexity. In goat left atrial free walls, most of the breakthroughs can be explained by transmural conduction, whereas ectopic focal discharges play a limited role as source of breakthrough.
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http://dx.doi.org/10.1161/CIRCEP.113.000342DOI Listing
April 2013

Loss of continuity in the thin epicardial layer because of endomysial fibrosis increases the complexity of atrial fibrillatory conduction.

Circ Arrhythm Electrophysiol 2013 Feb 6;6(1):202-11. Epub 2013 Feb 6.

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

Background: The transition from persistent to permanent atrial fibrillation (AF) is associated with increased complexity of fibrillatory conduction. We have investigated the spatial distribution of fibrillation waves and structural alterations in the atrial free walls in a goat model of AF.

Methods And Results: AF was maintained for 3 weeks (short term [ST], persistent AF) or 6 months (long term [LT], permanent AF). Fibrillation patterns were assessed with epicardial mapping. The origin of fibrillation waves and sites of conduction abnormalities were more homogeneously distributed in LT than in ST goats. Histologically, the total area fraction occupied by fibrous tissue and the degree of perimysial fibrosis (separation between myocyte bundles) were not significantly different between groups. However, endomysial fibrosis (distance between myocytes within bundles) was significantly larger in LT goats, particularly in the outer millimeter of the atria. By contrast, myocyte diameters were larger in LT goats throughout the atrial walls. High-resolution optical mapping showed that epicardial wavefront expansion was slower and more anisotropic in LT than in ST goats. Finally, a mathematical model of a simplified atrial architecture confirmed the potential impact of epicardial endomysial fibrosis on AF complexity.

Conclusions: Altered propagation after 6 months of AF is consistent with homogeneous structural remodeling in the outer millimeter of the atria. Loss of continuity of the epicardial layer because of endomysial fibrosis may reduce its synchronizing effect, thereby increasing the complexity of fibrillatory conduction pathways. The exact distribution of fibrosis may be more important for the occurrence of conduction disturbances than the overall quantity.
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http://dx.doi.org/10.1161/CIRCEP.112.975144DOI Listing
February 2013

Stability of complex fractionated atrial electrograms: a systematic review.

J Cardiovasc Electrophysiol 2012 Sep 3;23(9):980-7. Epub 2012 May 3.

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

Unlabelled: Stability of CFAE.

Introduction: The efficacy of complex fractionated atrial electrograms (CFAE) ablation as additional substrate modification in atrial fibrillation (AF) patients has been shown to be highly variable. Recently, the validity of sequential CFAE mapping has been challenged by concerns regarding temporal stability of CFAE. Existing studies on CFAE stability are small with very different CFAE definitions. Here, we undertook a systematic literature review to address these controversial findings.

Methods And Results: A systematic search of the scientific literature was performed through to September 1, 2011. From a total of 162 manuscripts, 7 were identified to contain assessment of the temporal stability of CFAE in human AF. These studies included a total of 96 (80 persistent/16 paroxysmal AF) patients (79% male, mean 58 years old). Varying CFAE mapping techniques or definitions were utilized. CFAE stability averaged 81% between 2 high-density sequential fractionation maps over an average time interval of 19 minutes. However, CFAE stability only averaged at 75% from shorter term continuous recordings (mean 15 comparisons within 75 seconds). Although the variability in CFAE cycle length was small (12-15 ms), coefficients of variation in continuous electrical activity were high (up to 300%). The overall spatial distribution of CFAE was found to be stable. Nevertheless, sequential mapping may not capture all CFAE sites given their dynamic characteristics.

Conclusion: CFAE are temporally variable in keeping with the diverse mechanisms underlying their existence. The dynamic nature of CFAE will continue to pose a challenge for electrophysiologists in search of critical sites requiring ablation to combat AF. (J Cardiovasc Electrophysiol, Vol. 23, pp. 980-987, September 2012).
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http://dx.doi.org/10.1111/j.1540-8167.2012.02335.xDOI Listing
September 2012