Evaluating spatial disparities of rotor sites and high dominant frequency regions during catheter ablation for PersAF patients targeting high dominant frequency sites using non-contacting mapping.

Purpose: Several studies have emphasised the significance of high dominant frequency (HDF) and rotors in the perpetuation of AF. However, the co-localisation relationship between both attributes is not completely understood yet. In this study, we aim to evaluate the spatial distributions of HDF regions and rotor sites within the left atrium (LA) pre and post HDF-guided ablation in PersAF. Methods: This study involved 10 PersAF patients undergoing catheter ablation targeting HDF regions in the LA. 2048-channels of atrial electrograms (AEG) were collected pre- and post-ablation using a non-contact array (EnSite, Abbott). The dominant frequency (DF, 4-10 Hz) areas with DF within 0.25 Hz of the maximum out of the 2048 points were defined as "high" DF (HDF). Rotors were defined as PSs that last more than 100 ms and at a similar location through subsequent phase frames over time. Results: The results indicated an extremely poor spatial correlation between the HDF regions and sites of the rotors in pre-versus post-ablation cases for the non-terminated (pre: CORR; 0.05 ± 0.17. vs. post: CORR; -0.030 ± 0.19, and with terminated patients (pre: CORR; -0.016 ± 0.03. post: CORR; -0.022 ± 0.04). Rotors associated with AF terminations had a long-lasting life-span post-ablation (non-terminated vs. terminated 120.7 ± 6.5 ms vs. 139.9 ± 39.8 ms), high core velocity (1.35 ± 1.3 mm/ms vs. 1.32 ± 0.9 mm/ms), and were less meandering (3.4 ± 3.04 mm vs. 1.5 ± 1.2 mm). Although the results suggest a poor spatial overlapping between rotors' sites and sites of AFCL changes in terminated and non-terminated patients, a higher correlation was determined in terminated patients (spatial overlapping percentage pre: 25 ± 4.2% vs. 17 ± 3.8% vs. post: 8 ± 4.2% vs. 3.7 ± 1.7% p < 0.05, respectively). Conclusion: Using non-contact AEG, it was noted that the correlation is poor between the spatial distribution of HDF regions and sites of rotors. Rotors were longer-lasting, faster and more stationary in patients with AF termination post-ablation. Rotors sites demonstrated poor spatial overlapping with sites of AFCL changes that lead to AF termination.

Simultaneous Whole-Chamber Non-contact Mapping of Highest Dominant Frequency Sites During Persistent Atrial Fibrillation: A Prospective Ablation Study.

Purpose: Sites of highest dominant frequency (HDF) are implicated by many proposed mechanisms underlying persistent atrial fibrillation (persAF). We hypothesized that prospectively identifying and ablating dynamic left atrial HDF sites would favorably impact the electrophysiological substrate of persAF. We aim to assess the feasibility of prospectively identifying HDF sites by global simultaneous left atrial mapping. Methods: PersAF patients with no prior ablation history underwent global simultaneous left atrial non-contact mapping. 30 s of electrograms recorded during AF were exported into a bespoke MATLAB interface to identify HDF regions, which were then targeted for ablation, prior to pulmonary vein isolation. Following ablation of each region, change in AF cycle length (AFCL) was documented (≥ 10 ms considered significant). Baseline isopotential maps of ablated regions were retrospectively analyzed looking for rotors and focal activation or extinction events. Results: A total of 51 HDF regions were identified and ablated in 10 patients (median DF 5.8Hz, range 4.4-7.1Hz). An increase in AFCL of was seen in 20 of the 51 regions (39%), including AF termination in 4 patients. 5 out of 10 patients (including the 4 patients where AF termination occurred with HDF-guided ablation) were free from AF recurrence at 1 year. The proportion of HDF occurrences in an ablated region was not associated with change in AFCL (τ = 0.11, p = 0.24). Regions where AFCL decreased by 10 ms or more (i.e., AF disorganization) after ablation also showed lowest baseline spectral organization (p < 0.033 for any comparison). Considering all ablated regions, the average proportion of HDF events which were also HRI events was 8.0 ± 13%. Focal activations predominated (537/1253 events) in the ablated regions on isopotential maps, were modestly associated with the proportion of HDF occurrences represented by the ablated region (Kendall's τ = 0.40, p < 0.0001), and very strongly associated with focal extinction events (τ = 0.79, p < 0.0001). Rotors were rare (4/1253 events). Conclusion: Targeting dynamic HDF sites is feasible and can be efficacious, but lacks specificity in identifying relevant human persAF substrate. Spectral organization may have an adjunctive role in preventing unnecessary substrate ablation. Dynamic HDF sites are not associated with observable rotational activity on isopotential mapping, but epi-endocardial breakthroughs could be contributory.

Local impedance for the optimization of radiofrequency lesion delivery: A review of bench and clinical data.

INTRODUCTION: Radiofrequency catheter ablation is a cornerstone of treatment for many cardiac arrhythmias. Progression in three-dimensional mapping and contact-force sensing technologies have improved our capability to achieve success, but challenges still remain. METHODS: In this article, we discuss the importance of overall circuit impedance in radiofrequency lesion formation. This is followed by a review of the literature regarding recently developed "local impedance" technology and its current and future potential applications and limitations, in the context of established surrogate markers currently used to infer effective ablation. RESULTS: We discuss the role of local impedance in assessing myocardial substrate, as well as its role in clinical studies of ablation. We also discuss safety considerations, limitations and ongoing research. CONCLUSION: Local impedance is a novel tool which has the potential to tailor ablation in a manner distinct from other established metrics.

Automatic Extraction of Recurrent Patterns of High Dominant Frequency Mapping During Human Persistent Atrial Fibrillation.

Purpose: Identifying targets for catheter ablation remains challenging in persistent atrial fibrillation (persAF). The dominant frequency (DF) of atrial electrograms during atrial fibrillation (AF) is believed to primarily reflect local activation. Highest DF (HDF) might be responsible for the initiation and perpetuation of persAF. However, the spatiotemporal behavior of DF remains not fully understood. Some DFs during persAF were shown to lack spatiotemporal stability, while others exhibit recurrent behavior. We sought to develop a tool to automatically detect recurrent DF patterns in persAF patients. Methods: Non-contact mapping of the left atrium (LA) was performed in 10 patients undergoing persAF HDF ablation. 2,048 virtual electrograms (vEGMs, EnSite Array, Abbott Laboratories, USA) were collected for up to 5 min before and after ablation. Frequency spectrum was estimated using fast Fourier transform and DF was identified as the peak between 4 and 10 Hz and organization index (OI) was calculated. The HDF maps were identified per 4-s window and an automated pattern recognition algorithm was used to find recurring HDF spatial patterns. Dominant patterns (DPs) were defined as the HDF pattern with the highest recurrence. Results: DPs were found in all patients. Patients in atrial flutter after ablation had a single DP over the recorded time period. The time interval (median [IQR]) of DP recurrence for the patients in AF after ablation (7 patients) decreased from 21.1 s [11.8 49.7 s] to 15.7 s [6.5 18.2 s]. The DF inside the DPs presented lower temporal standard deviation (0.18 ± 0.06 Hz vs. 0.29 ± 0.12 Hz, p < 0.05) and higher OI (0.35 ± 0.03 vs. 0.31 ± 0.04, p < 0.05). The atrial regions with the highest proportion of HDF region were the septum and the left upper pulmonary vein. Conclusion: Multiple recurrent spatiotemporal HDF patterns exist during persAF. The proposed method can identify and quantify the spatiotemporal repetition of the HDFs, where the high recurrences of DP may suggest a more organized rhythm. DPs presented a more consistent DF and higher organization compared with non-DPs, suggesting that DF with higher OI might be more likely to recur. Recurring patterns offer a more comprehensive dynamic insight of persAF behavior, and ablation targeting such regions may be beneficial.

Procedural efficiencies, lesion metrics, and 12-month clinical outcomes for Ablation Index-guided 50 W ablation for atrial fibrillation.

AIMS: The safety of Ablation Index (AI)-guided 50 W ablation for atrial fibrillation (AF) remains uncertain, and mid-term clinical outcomes have not been described. The interplay between AI and its components at 50 W has not been reported. METHODS AND RESULTS: Eighty-eight consecutive AF patients (44% paroxysmal) underwent AI-guided 50 W ablation. Procedural and 12-month clinical outcomes were compared with 93 consecutive controls (65% paroxysmal) who underwent AI-guided ablation using 35-40 W. Posterior wall isolation (PWI) was performed in 44 (50%) and 23 (25%) patients in the 50 and 35-40 W groups, respectively, P < 0.001. The last 10 patients from each group underwent analysis of individual lesions (n = 1230) to explore relationships between different powers and the AI components. Pulmonary vein isolation was successful in all patients. Posterior wall isolation was successful in 41/44 (93.2%) and 22/23 (95.7%) in the 50 and 35-40 W groups, respectively (P = 0.685). Radiofrequency times (20 vs. 26 min, P < 0.001) and total procedure times (130 vs. 156 min, P = 0.002) were significantly lower in the 50 W group. No complication or steam pop was seen in either group. Twelve-month freedom from arrhythmia was similar (80.2% vs. 82.8%, P = 0.918). A higher proportion of lesions in the 50 W group were associated with impedance drop >7 Ω (54.6% vs. 45.5%, P < 0.001). Excessive ablation (AI >600 anteriorly, >500 posteriorly) was more frequent in the 50 W group (9.7% vs. 4.3%, P < 0.001). CONCLUSION: Ablation Index-guided 50 W AF ablation is as safe and effective as lower powers and results in reduced ablation and procedure times. Radiofrequency lesions are more likely to be therapeutic, but there is a higher risk of delivering excessive ablation.

Update on Etripamil Nasal Spray for the At-home Treatment of Acute Paroxysmal Supraventricular Tachycardia.

The current treatment of sustained paroxysmal supraventricular tachycardia (PSVT) often requires attendance at a medical facility. This burden is driven by the lack of an effective self-administered treatment for PSVT. Etripamil (Milestone Pharmaceuticals, Saint-Laurent, QC, Canada) is a novel intra-nasal preparation of a rapidly effective but short-acting calcium-channel blocker, which shows promise in offering out-of-hospital treatment for patients with PSVT. Studies, to date, have demonstrated good tolerability and potential efficacy, with a safety profile that is acceptable for unsupervised self-administration. This article reviews the current epidemiology and international guidelines for the treatment of acute PSVT, the pharmacology and clinical trial evidence behind the novel agent etripamil, and considers its potential role in the management of patients with PSVT.

Unsupervised Classification of Atrial Electrograms for Electroanatomic Mapping of Human Persistent Atrial Fibrillation.

OBJECTIVE: Ablation treatment for persistent atrial fibrillation (persAF) remains challenging due to the absence of a 'ground truth' for atrial substrate characterization and the presence of multiple mechanisms driving the arrhythmia. We implemented an unsupervised classification to identify clusters of atrial electrograms (AEGs) with similar patterns, which were then validated by AEG-derived markers. METHODS: 956 bipolar AEGs were collected from 11 persAF patients. CARTO variables (Biosense Webster; ICL, ACI and SCI) were used to create a 3D space, and subsequently used to perform an unsupervised classification with k-means. The characteristics of the identified groups were investigated using nine AEG-derived markers: sample entropy (SampEn), dominant frequency, organization index (OI), determinism, laminarity, recurrence rate (RR), peak-to-peak (PP) amplitude, cycle length (CL), and wave similarity (WS). RESULTS: Five AEG classes with distinct characteristics were identified (F = 582, P<0.0001). The presence of fractionation increased from class 1 to 5, as reflected by the nine markers. Class 1 (25%) included organized AEGs with high WS, determinism, laminarity, and RR, and low SampEn. Class 5 (20%) comprised fractionated AEGs with in low WS, OI, determinism, laminarity, and RR, and in high SampEn. Classes 2 (12%), 3 (13%) and 4 (30%) suggested different degrees of AEG organization. CONCLUSIONS: Our results expand and reinterpret the criteria used for automated AEG classification. The nine markers highlighted electrophysiological differences among the five classes found by the k-means, which could provide a more complete characterization of persAF substrate during ablation target identification in future clinical studies.

Standardizing Single-Frame Phase Singularity Identification Algorithms and Parameters in Phase Mapping During Human Atrial Fibrillation.

PURPOSE: Recent investigations failed to reproduce the positive rotor-guided ablation outcomes shown by initial studies for treating persistent atrial fibrillation (persAF). Phase singularity (PS) is an important feature for AF driver detection, but algorithms for automated PS identification differ. We aim to investigate the performance of four different techniques for automated PS detection. METHODS: 2048-channel virtual electrogram (VEGM) and electrocardiogram signals were collected for 30 s from 10 patients undergoing persAF ablation. QRST-subtraction was performed and VEGMs were processed using sinusoidal wavelet reconstruction. The phase was obtained using Hilbert transform. PSs were detected using four algorithms: (1) 2D image processing based and neighbor-indexing algorithm; (2) 3D neighbor-indexing algorithm; (3) 2D kernel convolutional algorithm estimating topological charge; (4) topological charge estimation on 3D mesh. PS annotations were compared using the structural similarity index (SSIM) and Pearson's correlation coefficient (CORR). Optimized parameters to improve detection accuracy were found for all four algorithms using F ß score and 10-fold cross-validation compared with manual annotation. Local clustering with density-based spatial clustering of applications with noise (DBSCAN) was proposed to improve algorithms 3 and 4. RESULTS: The PS density maps created by each algorithm with default parameters were poorly correlated. Phase gradient threshold and search radius (or kernels) were shown to affect PS detections. The processing times for the algorithms were significantly different (p < 0.0001). The F ß scores for algorithms 1, 2, 3, 3 + DBSCAN, 4 and 4 + DBSCAN were 0.547, 0.645, 0.742, 0.828, 0.656, and 0.831. Algorithm 4 + DBSCAN achieved the best classification performance with acceptable processing time (2.0 ± 0.3 s). CONCLUSION: AF driver identification is dependent on the PS detection algorithms and their parameters, which could explain some of the inconsistencies in rotor-guided ablation outcomes in different studies. For 3D triangulated meshes, algorithm 4 + DBSCAN with optimal parameters was the best solution for real-time, automated PS detection due to accuracy and speed. Similarly, algorithm 3 + DBSCAN with optimal parameters is preferred for uniform 2D meshes. Such algorithms - and parameters - should be preferred in future clinical studies for identifying AF drivers and minimizing methodological heterogeneities. This would facilitate comparisons in rotor-guided ablation outcomes in future works.

A case report: upgrade to cardiac resynchronization therapy with a blocked persistent left-sided superior vena cava.

BACKGROUND: Pacemaker-induced cardiomyopathy (PICM) can occur in up to 9% of patients having a pacemaker. Pacemaker-induced cardiomyopathy can be treated by upgrade to a biventricular pacemaker with a left ventricular (LV) lead implantation. The procedure can be technically challenging in patients with persistent left-sided superior vena cava (PLSVC). CASE SUMMARY: We report the case of a 72-year-old gentleman with a PLSVC, who had a dual-chamber pacemaker implanted 15 years ago for complete heart block. After 12 years of good health, the gentleman developed breathlessness due to PICM. At upgrade to biventricular pacemaker, his coronary sinus was found to be occluded and a collateral branch was used to successfully position an LV lead. Marked clinical improvement was seen before representation with syncope after 2 years due to simultaneous failure of both LV and right ventricular leads. Subsequently, a right-sided de novo biventricular pacemaker was implanted. In this instance, the PLSVC was beneficial because it isolated the existing leads from the new implant, thereby reducing the risk of SVC obstruction. DISCUSSION: Although implantation of pacemaker leads through a PLSVC constitutes a challenging procedure due to manoeuvring difficulties of the pacing leads into the cardiac chambers, in this particular case, the presence of PLSVC was beneficial because it meant that no leads were present in the true SVC, reducing the risk of occlusion and avoiding the need for lead extraction.

ElectroMap: High-throughput open-source software for analysis and mapping of cardiac electrophysiology.

The ability to record and analyse electrical behaviour across the heart using optical and electrode mapping has revolutionised cardiac research. However, wider uptake of these technologies is constrained by the lack of multi-functional and robustly characterised analysis and mapping software. We present ElectroMap, an adaptable, high-throughput, open-source software for processing, analysis and mapping of complex electrophysiology datasets from diverse experimental models and acquisition modalities. Key innovation is development of standalone module for quantification of conduction velocity, employing multiple methodologies, currently not widely available to researchers. ElectroMap has also been designed to support multiple methodologies for accurate calculation of activation, repolarisation, arrhythmia detection, calcium handling and beat-to-beat heterogeneity. ElectroMap implements automated signal segmentation, ensemble averaging and integrates optogenetic approaches. Here we employ ElectroMap for analysis, mapping and detection of pro-arrhythmic phenomena in silico, in cellulo, animal model and in vivo patient datasets. We anticipate that ElectroMap will accelerate innovative cardiac research and enhance the uptake, application and interpretation of mapping technologies leading to novel approaches for arrhythmia prevention.

Systematic differences of non-invasive dominant frequency estimation compared to invasive dominant frequency estimation in atrial fibrillation.

Non-invasive analysis of atrial fibrillation (AF) using body surface mapping (BSM) has gained significant interest, with attempts at interpreting atrial spectro-temporal parameters from body surface signals. As these body surface signals could be affected by properties of the torso volume conductor, this interpretation is not always straightforward. This paper highlights the volume conductor effects and influences of the algorithm parameters for identifying the dominant frequency (DF) from cardiac signals collected simultaneously on the torso and atrial surface. Bi-atrial virtual electrograms (VEGMs) and BSMs were recorded simultaneously for 5 min from 10 patients undergoing ablation for persistent AF. Frequency analysis was performed on 4 s segments. DF was defined as the frequency with highest power between 4 and 10 Hz with and without applying organization index (OI) thresholds. The volume conductor effect was assessed by analyzing the highest DF (HDF) difference of each VEGM HDF against its BSM counterpart. Significant differences in HDF values between intra-cardiac and torso signals could be observed, independent of OI threshold. This difference increases with increasing endocardial HDF (BSM-VEGM median difference from -0.13 Hz for VEGM HDF at 6.25 ±â€¯0.25 Hz to -4.24 Hz at 9.75 ±â€¯0.25 Hz), thereby confirming the theory of the volume conductor effect in real-life situations. Applying an OI threshold strongly affected the BSM HDF area size and location and atrial HDF area location. These results suggest that volume conductor and measurement algorithm effects must be considered for appropriate clinical interpretation.

Characterization of human persistent atrial fibrillation electrograms using recurrence quantification analysis.

Atrial fibrillation (AF) is regarded as a complex arrhythmia, with one or more co-existing mechanisms, resulting in an intricate structure of atrial activations. Fractionated atrial electrograms (AEGs) were thought to represent arrhythmogenic tissue and hence have been suggested as targets for radiofrequency ablation. However, current methods for ablation target identification have resulted in suboptimal outcomes for persistent AF (persAF) treatment, possibly due to the complex spatiotemporal dynamics of these mechanisms. In the present work, we sought to characterize the dynamics of atrial tissue activations from AEGs collected during persAF using recurrence plots (RPs) and recurrence quantification analysis (RQA). 797 bipolar AEGs were collected from 18 persAF patients undergoing pulmonary vein isolation (PVI). Automated AEG classification (normal vs. fractionated) was performed using the CARTO criteria (Biosense Webster). For each AEG, RPs were evaluated in a phase space estimated following Takens' theorem. Seven RQA variables were obtained from the RPs: recurrence rate; determinism; average diagonal line length; Shannon entropy of diagonal length distribution; laminarity; trapping time; and Shannon entropy of vertical length distribution. The results show that the RQA variables were significantly affected by PVI, and that the variables were effective in discriminating normal vs. fractionated AEGs. Additionally, diagonal structures associated with deterministic behavior were still present in the RPs from fractionated AEGs, leading to a high residual determinism, which could be related to unstable periodic orbits and suggesting a possible chaotic behavior. Therefore, these results contribute to a nonlinear perspective of the spatiotemporal dynamics of persAF.

The temporal behavior and consistency of bipolar atrial electrograms in human persistent atrial fibrillation.

The unstable temporal behavior of atrial electrical activity during persistent atrial fibrillation (persAF) might influence ablation target identification, which could explain the conflicting persAF ablation outcomes in previous studies. We sought to investigate the temporal behavior and consistency of atrial electrogram (AEG) fractionation using different segment lengths. Seven hundred ninety-seven bipolar AEGs were collected with three segment lengths (2.5, 5,and 8 s) from 18 patients undergoing persAF ablation. The AEGs with 8-s duration were divided into three 2.5-s consecutive segments. AEG fractionation classification was applied off-line to all cases following the CARTO criteria; 43% of the AEGs remained fractionated for the three consecutive AEG segments, while nearly 30% were temporally unstable. AEG classification within the consecutive segments had moderate correlation (segment 1 vs 2: Spearman's correlation ρ = 0.74, kappa score κ = 0.62; segment 1 vs 3: ρ = 0.726, κ = 0.62; segment 2 vs 3: ρ = 0.75, κ = 0.68). AEG classifications were more similar between AEGs with 5 and 8 s (ρ = 0.96, κ = 0.87) than 2.5 versus 5 s (ρ = 0.93, κ = 0.84) and 2.5 versus 8 s (ρ = 0.90, κ = 0.78). Our results show that the CARTO criteria should be revisited and consider recording duration longer than 2.5 s for consistent ablation target identification in persAF.

Atrial Electrogram Fractionation Distribution before and after Pulmonary Vein Isolation in Human Persistent Atrial Fibrillation-A Retrospective Multivariate Statistical Analysis.

Purpose: Complex fractionated atrial electrograms (CFAE)-guided ablation after pulmonary vein isolation (PVI) has been used for persistent atrial fibrillation (persAF) therapy. This strategy has shown suboptimal outcomes due to, among other factors, undetected changes in the atrial tissue following PVI. In the present work, we investigate CFAE distribution before and after PVI in patients with persAF using a multivariate statistical model. Methods: 207 pairs of atrial electrograms (AEGs) were collected before and after PVI respectively, from corresponding LA regions in 18 persAF patients. Twelve attributes were measured from the AEGs, before and after PVI. Statistical models based on multivariate analysis of variance (MANOVA) and linear discriminant analysis (LDA) have been used to characterize the atrial regions and AEGs. Results: PVI significantly reduced CFAEs in the LA (70 vs. 40%; P < 0.0001). Four types of LA regions were identified, based on the AEGs characteristics: (i) fractionated before PVI that remained fractionated after PVI (31% of the collected points); (ii) fractionated that converted to normal (39%); (iii) normal prior to PVI that became fractionated (9%) and; (iv) normal that remained normal (21%). Individually, the attributes failed to distinguish these LA regions, but multivariate statistical models were effective in their discrimination (P < 0.0001). Conclusion: Our results have unveiled that there are LA regions resistant to PVI, while others are affected by it. Although, traditional methods were unable to identify these different regions, the proposed multivariate statistical model discriminated LA regions resistant to PVI from those affected by it without prior ablation information.

An interactive platform to guide catheter ablation in human persistent atrial fibrillation using dominant frequency, organization and phase mapping.

BACKGROUND AND OBJECTIVE: Optimal targets for persistent atrial fibrillation (persAF) ablation are still debated. Atrial regions hosting high dominant frequency (HDF) are believed to participate in the initiation and maintenance of persAF and hence are potential targets for ablation, while rotor ablation has shown promising initial results. Currently, no commercially available system offers the capability to automatically identify both these phenomena. This paper describes an integrated 3D software platform combining the mapping of both frequency spectrum and phase from atrial electrograms (AEGs) to help guide persAF ablation in clinical cardiac electrophysiological studies. METHODS: 30s of 2048 non-contact AEGs (EnSite Array, St. Jude Medical) were collected and analyzed per patient. After QRST removal, the AEGs were divided into 4s windows with a 50% overlap. Fast Fourier transform was used for DF identification. HDF areas were identified as the maximum DF to 0.25Hz below that, and their centers of gravity (CGs) were used to track their spatiotemporal movement. Spectral organization measurements were estimated. Hilbert transform was used to calculate instantaneous phase. RESULTS: The system was successfully used to guide catheter ablation for 10 persAF patients. The mean processing time was 10.4 ± 1.5min, which is adequate comparing to the normal electrophysiological (EP) procedure time (120∼180min). CONCLUSIONS: A customized software platform capable of measuring different forms of spatiotemporal AEG analysis was implemented and used in clinical environment to guide persAF ablation. The modular nature of the platform will help electrophysiological studies in understanding of the underlying AF mechanisms.

Minimizing discordances in automated classification of fractionated electrograms in human persistent atrial fibrillation.

Ablation of persistent atrial fibrillation (persAF) targeting complex fractionated atrial electrograms (CFAEs) detected by automated algorithms has produced conflicting outcomes in previous electrophysiological studies. We hypothesize that the differences in these algorithms could lead to discordant CFAE classifications by the available mapping systems, giving rise to potential disparities in CFAE-guided ablation. This study reports the results of a head-to-head comparison of CFAE detection performed by NavX (St. Jude Medical) versus CARTO (Biosense Webster) on the same bipolar electrogram data (797 electrograms) from 18 persAF patients. We propose revised thresholds for both primary and complementary indices to minimize the differences in CFAE classification performed by either system. Using the default thresholds [NavX: CFE-Mean ≤ 120 ms; CARTO: ICL ≥ 7], NavX classified 70 % of the electrograms as CFAEs, while CARTO detected 36 % (Cohen's kappa κ ≈ 0.3, P < 0.0001). Using revised thresholds found using receiver operating characteristic curves [NavX: CFE-Mean ≤ 84 ms, CFE-SD ≤ 47 ms; CARTO: ICL ≥ 4, ACI ≤ 82 ms, SCI ≤ 58 ms], NavX classified 45 %, while CARTO detected 42 % (κ ≈ 0.5, P < 0.0001). Our results show that CFAE target identification is dependent on the system and thresholds used by the electrophysiological study. The thresholds found in this work counterbalance the differences in automated CFAE classification performed by each system. This could facilitate comparisons of CFAE ablation outcomes guided by either NavX or CARTO in future works.

Correction: evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.

[This corrects the article DOI: 10.1371/journal.pone.0078053.].

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines.

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.