Novel spatiotemporal processing tools for body-surface potential map signals for the prediction of catheter ablation outcome in persistent atrial fibrillation.

Background: Signal processing tools are required to efficiently analyze data collected in body-surface-potential map (BSPM) recordings. A limited number of such tools exist for studying persistent atrial fibrillation (persAF). We propose two novel, spatiotemporal indices for processing BSPM data and test their clinical applicability through a comparison with the recently proposed non-dipolar component index (NDI) for prediction of single-procedure catheter ablation (CA) success rate in persAF patients. Methods: BSPM recordings were obtained with a 252-lead vest in 13 persAF patients (8 men, 63 ± 8 years, 11 ± 13 months sustained AF duration) before undergoing CA. Each recording was divided into seven 1-min segments of high signal quality. Spatiotemporal ventricular activity (VA) cancellation was applied to each segment to isolate atrial activity (AA). The two novel indices, called error-ratio, normalized root-mean-square error (ERNRMSE) and error-ratio, mean-absolute error (ERABSE), were calculated. These indices quantify the capacity of a subset of BSPM vest electrodes to accurately represent the AA, and AA dominant frequency (DF), respectively, on all BSPM electrodes over time, compared to the optimal principal component analysis (PCA) representation. The NDI, quantifying the fraction of energy retained after removal of the three largest PCs, was also calculated. The two novel indices and the NDI were statistically compared between patient groups based on single-procedure clinical CA outcome. Finally, their predictive power for univariate CA outcome classification was assessed using receiver operating characteristic (ROC) analysis with cross-validation for a logistic regression classifier. Results: Patient clinical outcomes were recorded 6 months following procedures, and those who had an arrhythmia recurrence at least 2 months post-CA were defined as having a negative outcome. Clinical outcome information was available for 11 patients, 6 with arrhythmia recurrence. Therefore, a total of 77 1-min AA-BSPM segments were available for analysis. Significant differences were found in the values of the novel indices and NDI between patients with arrhythmia recurrence post-ablation and those without. ROC analysis showed the best CA outcome predictive performance for ERNRMSE (AUC = 0.77 ± 0.08, sensitivity = 76.2%, specificity = 84.8%). Conclusion: Significant association was found between the novel indices and CA success or failure. The novel index ERNRMSE additionally shows good predictive power for single-procedure CA outcome.

ECG-Based Indices to Characterize Persistent Atrial Fibrillation Before and During Stepwise Catheter Ablation.

Background: Consistently successful patient outcomes following catheter ablation (CA) for treatment of persistent atrial fibrillation (pers-AF) remain elusive. We propose an electrocardiogram (ECG) analysis designed to (1) refine selection of patients most likely to benefit from ablation, and (2) examine the temporal evolution of AF organization indices that could act as clinical indicators of ongoing ablation effectiveness and completeness. Method: Twelve-lead ECG was continuously recorded in 40 patients (61 ± 8 years) during stepwise CA (step-CA) procedures for treatment of pers-AF (sustained duration 19 ± 11 months). Following standard pre-processing, ECG signals were divided into 10-s epochs and labeled according to their temporal placement: pre-PVI (baseline), dur-PVI (during pulmonary vein isolation), and post-PVI (during complex-fractionated atrial electrograms and linear ablation). Instantaneous frequency (IF), adaptive organization index (AOI), sample entropy (SampEn) and f-wave amplitude (FWA) measures were calculated and analyzed during each of the three temporal steps. Temporal evolution of these measures was assessed using a statistical test for mean value transitions, as an indicator of changes in AF organization. Results were then compared between: (i) patients grouped according to step-CA outcome; (ii) patients grouped according to type of arrhythmia recurrence following the procedure, if applicable; (iii) within the same patient group during the three different temporal steps. Results: Stepwise CA patient outcomes were as follows: (1) left-atrium (LA) terminated, not recurring (LTN, n = 8), (2) LA terminated, recurring (LTR, n = 20), and (3) not LA terminated, all recurring at follow-up (NLT, n = 12). Among the LTR and NLT patients, recurrence occurred as AF in seven patients and atrial tachycardia or atrial flutter (AT/AFL) in the remaining 25 patients. The ECG measures indicated the lowest level of organization in the NLT group for all ablation steps. The highest organization was observed in the LTN group, while the LTR group displayed an intermediate level of organization. Regarding time evolution of ECG measures in dur-PVI and post-PVI recordings, stepwise ablation led to increases in AF organization in most patients, with no significant differences between the LTN, LTR, and NLT groups. The median decrease in IF and increase in AOI were significantly greater in AT/AFL recurring patients than in AF recurring patients; however, changes in the SampEn and FWA parameters were not significantly different between types of recurrence. Conclusion: Noninvasive ECG measures, though unable to predict arrhythmia recurrence following ablation, show the lowest levels of AF organization in patients that do not respond well to step-CA. Increasing AF organization in post-PVI may be associated with organized arrhythmia recurrence after a single ablation procedure.

Dynamics of Intraprocedural Dominant Frequency Identifies Ablation Outcome in Persistent Atrial Fibrillation.

Background: The role of dominant frequency (DF) in tracking the efficiency of a stepwise catheter ablation (step-CA) in persistent atrial fibrillation (peAF) remains poorly studied. We hypothesized that the DF time-course during step-CA displays divergent patterns between patients in whom a step-CA successfully restores long-term sinus rhythm (SR) and those with recurrence. Methods: This study involved 40 consecutive patients who underwent a step-CA for peAF (sustained duration 19 ± 11 months). Dominant frequency was computed on electrograms recorded from the right and left atrial appendages (RAA; LAA) and the coronary sinus before and during the step-CA synchronously to the 12-lead ECG. Dominant frequency was defined as the highest peak within the power spectrum. Results: Persistent atrial fibrillation was terminated by a step-CA in 28 patients [left-terminated (LT)], whereas 12 patients remaining in AF after ablation [not left-terminated (NLT)] were cardioverted. Over a mean follow-up of 34 ± 14 months, all NLT patients had a recurrence. Among the 28 LT patients, 20 had a recurrence, while 8 remained in SR throughout follow-up. The RAA and V1 DF had the best predictive values of the procedural failure to terminate AF (area under the curve; AUC 0.84, p < 0.05). A decision tree model including a decrease in LAA DF ≥ 6.61% during the first 20 min following pulmonary vein isolation (PVI) and a baseline RAA DF <5.6 Hz predicted long-term SR restoration with a sensitivity of 83% and a specificity of 93% (p < 0.05). Conclusion: This study found that high baseline DF values are predictive of unfavorable ablation outcomes. The reduction of the LAA DF at early ablation steps following PVI is associated with procedural AF termination and long-term SR maintenance.

Author Correction: Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Severe and uniform bi-atrial remodeling measured by dominant frequency analysis in persistent atrial fibrillation unresponsive to ablation.

BACKGROUND: High values of ECG and intracardiac dominant frequency (DF) are indicative of significant atrial remodeling in persistent atrial fibrillation (peAF). We hypothesized that patients with peAF unresponsive to ablation display higher ECG and intracardiac DFs than those remaining in sinus rhythm (SR) on the long term. METHODS: Forty consecutive patients underwent stepwise ablation for peAF (sustained duration 19 ± 11 months). Electrograms were recorded before ablation at 13 left atrium (LA) sites and at the right atrial appendage (RAA) and coronary sinus (CS) synchronously to the ECG. DF was defined as the highest peak within the power spectrum. RESULTS: peAF was terminated within the LA in 28 patients (left-terminated [LT]), whereas 12 patients remaining in AF after ablation (not left-terminated [NLT]) were cardioverted. Over a mean follow-up of 34 ± 14 months, all 12 NLT patients had a recurrence. Of the LT patients, 71% had a recurrence (20/28, LT_Rec), while 29% remained in SR throughout the follow-up (8/28, LT_SR). DF values and correlations between pairs of LA appendage (LAA), RAA, and CS DFs showed distinctive patterns among the subgroups. The NLT subgroup displayed the highest ECG and intracardiac DFs, with strong intragroup homogeneity between pairs of CS and LAA DFs, and to a lesser extent between pairs of CS and RAA DFs. Conversely, the LT_SR subgroup showed the lowest DFs, with significant intragroup heterogeneity between pairs of CS and both LAA and RAA DFs. CONCLUSIONS: Patients with peAF unresponsive to ablation show high surface and intracardiac DFs indicative of severe and uniform bi-atrial remodeling.

Thyroid hormone-dependent adult pigment cell lineage and pattern in zebrafish.

Pigment patterns are useful for elucidating fundamental mechanisms of pattern formation and how these mechanisms evolve. In zebrafish, several pigment cell classes interact to generate stripes, yet the developmental requirements and origins of these cells remain poorly understood. Using zebrafish and a related species, we identified roles for thyroid hormone (TH) in pigment cell development and patterning, and in postembryonic development more generally. We show that adult pigment cells arise from distinct lineages having distinct requirements for TH and that differential TH dependence can evolve within lineages. Our findings demonstrate critical functions for TH in determining pigment pattern phenotype and highlight the potential for evolutionary diversification at the intersection of developmental and endocrine mechanisms.

Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.

Down's syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.