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Populations of in silico myocytes and tissues reveal synergy of multi-atrial-predominant K+ -current block in atrial fibrillation. British journal of pharmacology Ni, H., Iseppe, A. F., Giles, W. R., Narayan, S. M., Zhang, H., Edwards, A. G., Morotti, S., Grandi, E. 2020
Abstract

BACKGROUND AND PURPOSE: Current pharmacological therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, remain unsatisfactory due to low efficacy and safety concerns. New promising strategies for AF pharmacotherapy include targeting atrial-predominant ion-channels and multi-channel block (poly)therapy. Further, as AF is characterized by rapid and irregular atrial activations, compounds displaying potent antiarrhythmic effects at fast rates and minimal effects at slow rates are desirable. We present a novel Systems Pharmacology framework to quantitatively evaluate synergistic anti-AF effects of combined block of multiple atrial-predominant K+ currents (ultra-rapid delayed rectifier K+ current, IKur , small conductance Ca2+ -activated K+ current, IKCa , K2P 3.1 2-pore-domain K+ current, IK2P ) in AF.EXPERIMENTAL APPROACH: We constructed experimentally calibrated populations of virtual atrial myocyte models in both normal sinus rhythm (nSR) and AF-remodeled conditions using two distinct, well-established atrial models. Next, we conducted sensitivity analyses on our atrial populations to investigate the rate dependence of action potential duration (APD) changes due to blocking IKur , IK2P or IKCa , and uncover interactions among block of these three currents in modulating APD. Block was simulated in both single myocytes and one-dimensional tissue strands to confirm insights from the sensitivity analyses and examine anti-arrhythmic effects of multi-atrial-predominant K+ current block in single cells and coupled tissue.KEY RESULTS: In both virtual atrial myocytes and tissues, multiple atrial-predominant K+ -current block promoted favorable positive rate-dependent APD prolongation and displayed positive rate-dependent synergy, i.e., increasing synergistic antiarrhythmic effects at fast pacing vs slow rates.CONCLUSION AND IMPLICATIONS: Simultaneous block of multiple atrial-predominant K+ currents may be a valuable antiarrhythmic pharmacotherapeutic strategy for AF.

View details for DOI 10.1111/bph.15198

View details for PubMedID 32667679
Machine Learning to Classify Intracardiac Electrical Patterns during Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Alhusseini, M. I., Abuzaid, F., Rogers, A. J., Zaman, J. A., Baykaner, T., Clopton, P., Bailis, P., Zaharia, M., Wang, P. J., Rappel, W., Narayan, S. M. 2020
Abstract

Background - Advances in ablation for atrial fibrillation (AF) continue to be hindered by ambiguities in mapping, even between experts. We hypothesized that convolutional neural networks (CNN) may enable objective analysis of intracardiac activation in AF, which could be applied clinically if CNN classifications could also be explained. Methods - We performed panoramic recording of bi-atrial electrical signals in AF. We used the Hilbert-transform to produce 175,000 image grids in 35 patients, labeled for rotational activation by experts who showed consistency but with variability (kappa=0.79). In each patient, ablation terminated AF. A CNN was developed and trained on 100,000 AF image grids, validated on 25,000 grids, then tested on a separate 50,000 grids. Results - In the separate test cohort (50,000 grids), CNN reproducibly classified AF image grids into those with/without rotational sites with 95.0% accuracy (CI 94.8-95.2%). This accuracy exceeded that of support vector machines, traditional linear discriminant and k-nearest neighbor statistical analyses. To probe the CNN, we applied Gradient-weighted Class Activation Mapping which revealed that the decision logic closely mimicked rules used by experts (C-statistic 0.96). Conclusions - Convolutional neural networks improved the classification of intracardiac AF maps compared to other analyses, and agreed with expert evaluation. Novel explainability analyses revealed that the CNN operated using a decision logic similar to rules used by experts, even though these rules were not provided in training. We thus describe a scaleable platform for robust comparisons of complex AF data from multiple systems, which may provide immediate clinical utility to guide ablation.

View details for DOI 10.1161/CIRCEP.119.008160

View details for PubMedID 32631100
Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology. Circulation. Arrhythmia and electrophysiology Feeny, A. K., Chung, M. K., Madabhushi, A., Attia, Z. I., Cikes, M., Firouznia, M., Friedman, P. A., Kalscheur, M. M., Kapa, S., Narayan, S. M., Noseworthy, P. A., Passman, R. S., Perez, M. V., Peters, N. S., Piccini, J. P., Tarakji, K. G., Thomas, S. A., Trayanova, N. A., Turakhia, M. P., Wang, P. J. 2020
Abstract

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.

View details for DOI 10.1161/CIRCEP.119.007952

View details for PubMedID 32628863
LARGER ORGANIZED AREAS IN PERSISTENT ATRIAL FIBRILLATION PREDICTS TERMINATION DURING ABLATION Ravi, N., Rogers, A. J., Bhatia, N., Tung, J. S., Krummen, D., Sauer, W., Alhusseini, M., Baykaner, T., Wang, P., Rappel, W., Narayan, S. ELSEVIER SCIENCE INC. 2020: 279
View details for Web of Science ID 000522979100273
PREDICTING SUDDEN CARDIAC DEATH BY MACHINE LEARNING OF VENTRICULAR ACTION POTENTIALS Selvalingam, A., Alhusseini, M., Rogers, A. J., Krummen, D., Abuzaid, F. M., Baykaner, T., Clopton, P., Bailis, P., Zaharia, M., Wang, P., Narayan, S. ELSEVIER SCIENCE INC. 2020: 427
View details for Web of Science ID 000522979100416
What Cannot Be Missed: Important Publications on Electrophysiology in 2019 Foreword ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Grace, A., Calkins, H., Ellenbogen, K., Lambiase, P. D., Lip, G. H., Narayan, S. M., Katritsis, D. G. 2020; 9 (1): 4
View details for DOI 10.15420/aer.2020.06

View details for Web of Science ID 000539058200001
Getting in Contact With AtrialFibrillationor Not. JACC. Clinical electrophysiology Verma, A., Narayan, S. M. 2020; 6 (2): 182?84
View details for DOI 10.1016/j.jacep.2019.10.023

View details for PubMedID 32081220
Automatic quality electrogram assessment improves phase-based reentrant activity identification in atrial fibrillation. Computers in biology and medicine Costoya-Sanchez, A., Climent, A. M., Hernandez-Romero, I., Liberos, A., Fernandez-Aviles, F., Narayan, S. M., Atienza, F., Guillem, M. S., Rodrigo, M. 2020; 117: 103593
Abstract

Identification of reentrant activity driving atrial fibrillation (AF) is increasingly important to ablative therapies. The goal of this work is to study how the automatically-classified quality of the electrograms (EGMs) affects reentrant AF driver localization. EGMs from 259 AF episodes obtained from 29 AF patients were recorded using 64-poles basket catheters and were manually classified according to their quality. An algorithm capable of identifying signal quality was developed using time and spectral domain parameters. Electrical reentries were identified in 3D phase maps using phase transform and were compared with those obtained with a 2D activation-based method. Effect of EGM quality was studied by discarding 3D phase reentries detected in regions with low-quality EGMs. Removal of reentries identified by 3D phase analysis in regions with low-quality EGMs improved its performance, increasing the area under the ROC curve (AUC) from 0.69 to 0.80. The EGMs quality classification algorithm showed an accurate performance for EGM classification (AUC 0.94) and reentry detection (AUC 0.80). Automatic classification of EGM quality based on time and spectral signal parameters is feasible and accurate, avoiding the manual labelling. Discard of reentries identified in regions with automatically-detected poor-quality EGMs improved the specificity of the 3D phase-based method for AF driver identification.

View details for DOI 10.1016/j.compbiomed.2019.103593

View details for PubMedID 32072974
Action Potential Dynamics in Human Atrial Fibrillation CARDIAC REPOLARIZATION: BASIC SCIENCE AND CLINICAL MANAGEMENT Zaman, J., Narayan, S. M., Franz, M. R., ElSherif, N. 2020: 333?45
View details for DOI 10.1007/978-3-030-22672-5_20

View details for Web of Science ID 000544795500022
Termination of persistent atrial fibrillation by ablating sites that control large atrial areas. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology Bhatia, N. K., Rogers, A. J., Krummen, D. E., Hossainy, S., Sauer, W., Miller, J. M., Alhusseini, M. I., Peszek, A., Armenia, E., Baykaner, T., Brachmann, J., Turakhia, M. P., Clopton, P., Wang, P. J., Rappel, W. J., Narayan, S. M. 2020
Abstract

Persistent atrial fibrillation (AF) has been explained by multiple mechanisms which, while they conflict, all agree that more disorganized AF is more difficult to treat than organized AF. We hypothesized that persistent AF consists of interacting organized areas which may enlarge, shrink or coalesce, and that patients whose AF areas enlarge by ablation are more likely to respond to therapy.We mapped vectorial propagation in persistent AF using wavefront fields (WFF), constructed from raw unipolar electrograms at 64-pole basket catheters, during ablation until termination (Group 1, N?=?20 patients) or cardioversion (Group 2, N?=?20 patients). Wavefront field mapping of patients (age 61.1?�?13.2 years, left atrium 47.1?�?6.9?mm) at baseline showed 4.6?�?1.0 organized areas, each separated by disorganization. Ablation of sites that led to termination controlled larger organized area than competing sites (44.1?�?11.1% vs. 22.4?�?7.0%, P?
View details for DOI 10.1093/europace/euaa018

View details for PubMedID 32243508
What Cannot Be Missed: Important Publications on Electrophysiology in 2019. Arrhythmia & electrophysiology review Grace, A., Calkins, H., Ellenbogen, K., Lambiase, P. D., Lip, G. Y., Narayan, S. M., Katritsis, D. G. 2020; 9 (1): 4
View details for DOI 10.15420/aer.2020.06

View details for PubMedID 32637112

View details for PubMedCentralID PMC7330725
The interconnected atrium: Acute impact of pulmonary vein isolation on remote atrial tissue. Journal of cardiovascular electrophysiology Rogers, A. J., Baykaner, T., Narayan, S. M. 2020
View details for DOI 10.1111/jce.14389

View details for PubMedID 32090385
Continuous Ablation Improves Lesion Maturation Compared with Intermittent Ablation Strategies. Journal of cardiovascular electrophysiology Rogers, A. J., Borne, R. T., Ho, G., Sauer, W. H., Wang, P. J., Narayan, S. M., Zheng, L., Nguyen, D. T. 2020
Abstract

Interrupted ablation is increasingly proposed as part of high-power short duration radiofrequency ablation (RFA) strategies and may also result from loss of contact from respiratory patterns or cardiac motion.To study the extent that ablation interruption affects lesions.In ex vivo and in vivo experiments, lesion characteristics and tissue temperatures were compared between continuous (Group 1) and interrupted (Groups 2,3) RFA with equal total ablation duration and contact force. Extended duration ablation lesions were also characterized from 1 to 5 minutes.In the ex vivo study, continuous RFA (Group 1) produced larger total lesion volumes compared with each interrupted ablation lesion group (273.8�36.5 mm3 vs. 205.1�34.2 and vs. 174.3�32.3, all p<0.001). Peak temperatures for Group 1 were higher at 3mm and 5mm than Groups 2 and 3. In vivo, continuous ablation resulted in larger lesions, greater lesion depths, and higher tissue temperatures. Longer ablation durations created larger lesion volumes and increased lesion depths. However, after 3 min of ablation, the rate of lesion volume and depth formation decreased.Continuous RFA delivery resulted in larger and deeper lesions with higher tissue temperatures compared to interrupted ablation. This work may have implications for high-power short duration ablation strategies, motivates strategies to reduce variations in ablation delivery, and provides an upper limit for ablation duration beyond which power delivery has diminishing returns. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/jce.14510

View details for PubMedID 32323395
Non-Invasive Assessment of Complexity of Atrial Fibrillation: Correlation with Contact Mapping and Impact of Ablation. Circulation. Arrhythmia and electrophysiology Rodrigo, M., Climent, A. M., Hern�ndez-Romero, I., Liberos, A., Baykaner, T., Rogers, A. J., Alhusseini, M., Wang, P. J., Fern�ndez-Avil�s, F., Guillem, M. S., Narayan, S. M., Atienza, F. 2020
Abstract

Background - It is difficult to non-invasively phenotype atrial fibrillation (AF) in a way that reflects clinical endpoints such as response to therapy. We set out to map electrical patterns of disorganization and regions of reentrant activity in AF from the body surface using electrocardiographic imaging (ECGI), calibrated to panoramic intracardiac recordings and referenced to AF termination by ablation. Methods - Bi-atrial intracardiac electrograms of 47 AF patients at ablation (30 persistent, 29 male, 63�9 years) were recorded with 64-pole basket catheters and simultaneous 57-lead body surface ECGs. Atrial epicardial electrical activity was reconstructed and organized sites were invasively and non-invasively tracked in 3D using phase singularity (PS). In a subset of 17 patients, sites of AF organization were targeted for ablation. Results - Body surface mapping showed greater AF organization near intracardially-detected drivers than elsewhere, both in PS density (2.3�2.1 vs 1.9�1.6, p=0.02) and number of drivers (3.2�2.3 vs 2.7�1.7, p=0.02). Complexity, defined as the number of stable AF reentrant sites, was concordant between non-invasive and invasive methods (r2 =0.5, CC=0.71). In the subset receiving targeted ablation, AF complexity showed lower values in those in whom AF terminated than those in whom AF did not terminate (p<0.01). Conclusions - AF complexity tracked non-invasively correlates well with organized and disorganized regions detected by panoramic intracardiac mapping, and correlates with the acute outcome by ablation. This approach may assist in bedside monitoring of therapy or in improving the efficacy of ongoing ablation procedures.

View details for DOI 10.1161/CIRCEP.119.007700

View details for PubMedID 32078374
Re-evaluating The Multiple Wavelet Hypothesis for Atrial Fibrillation. Heart rhythm Ganesan, P., Narayan, S. M. 2020
View details for DOI 10.1016/j.hrthm.2020.07.009

View details for PubMedID 32673795
Novel Three-Dimensional Imaging Approach for Cryoballoon Navigation and Confirmation of Pulmonary Vein Occlusion. Pacing and clinical electrophysiology : PACE Kowalewski, C. A., Rodrigo, M., Brodt, C., Haddad, F., Wang, P. J., Narayan, S. M. 2019
Abstract

BACKGROUND: Cryoballoon apposition is crucial for durable pulmonary vein isolation (PVI) in atrial fibrillation, yet the balloon is difficult to visualize by conventional mapping systems, and pulmonary venography may miss small or out-of-plane leaks. We report a novel imaging system that offers real-time 3-D navigation of the cryoballoon within atrial anatomy that may circumvent these issues.METHODS AND RESULTS: A novel overlay guidance system(OGS) (Siemens Healthcare, Forchheim, Germany) registers already-acquired segmented atrial cardiac tomography (CT) with fluoroscopy, enabling real-time visualization of the cryoballoon within tomographic left atrial imaging during PVI. Phantom experiments in a patient-specific 3D printed left atrium showed feasibility for confirming PV apposition and leaks. We applied OGS prospectively to 68 PVs during PVI in 17 patients. The cryoballoon was successfully reconstructed in all cases, and its apposition was compared to concurrent PV venography. The OGS uncovered leaks undetected by venography in 9 veins (8 cases) which enabled repositioning, confirming apposition in remaining 68 veins. Concordance of OGS to venography was 83.8% (chi2 , p<0.01) CONCLUSIONS: We report a new system for real-time imaging of cryoballoon catheters to ensure PV apposition within the tomography of the left atrium. While providing high concordance with other imaging modalities for confirming balloon apposition or leak, the system also identified leaks missed by venography. Future studies should determine if this tool can provide a new reference for cryoballoon positioning. This article is protected by copyright. All rights reserved Cryoballoon ablation is increasingly used for pulmonary vein isolation (PVI), but it may be difficult to track cryoballoon position relative to the PV for complete occlusion. We describe a novel overlay guidance system (OGS) for real-time 3D visualization of the cryoballoon within atrial anatomy, by registering atrial computed tomography in 2 fluoroscopic planes. Phantom experiments with a custom 3D printed left atrium showed feasibility for visualizing balloon apposition within PVs. In 68 PVs in 17 patients, the OGS prospectively identified cryoballoon position relative to PVs, and uncovered leaks undetected by venography. Future studies should test if the OGS can serve as a new reference for cryoballoon positioning.

View details for DOI 10.1111/pace.13858

View details for PubMedID 31868241
Mapping and Ablation of Rotational and Focal Drivers in Atrial Fibrillation. Cardiac electrophysiology clinics Zaman, J., Baykaner, T., Narayan, S. M. 2019; 11 (4): 583?95
Abstract

Drivers are increasingly studied ablation targets for atrial fibrillation (AF). However, results from ablation remain controversial. First, outcomes vary between centers and patients. Second, it is unclear how best to perform driver ablation. Third, there is a lack of practical guidance on how to identify critical from secondary sites using different AF mapping methods. This article addresses each of these issues.

View details for DOI 10.1016/j.ccep.2019.08.010

View details for PubMedID 31706467
Atrial Fibrillation Burden Signature and Near-Term Prediction of Stroke: A Machine Learning Analysis. Circulation. Cardiovascular quality and outcomes Han, L., Askari, M., Altman, R. B., Schmitt, S. K., Fan, J., Bentley, J. P., Narayan, S. M., Turakhia, M. P. 2019; 12 (10): e005595
Abstract

BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke 5-fold and there is rising interest to determine if AF severity or burden can further risk stratify these patients, particularly for near-term events. Using continuous remote monitoring data from cardiac implantable electronic devices, we sought to evaluate if machine learned signatures of AF burden could provide prognostic information on near-term risk of stroke when compared to conventional risk scores.METHODS AND RESULTS: We retrospectively identified Veterans Health Administration serviced patients with cardiac implantable electronic device remote monitoring data and at least one day of device-registered AF. The first 30 days of remote monitoring in nonstroke controls were compared against the past 30 days of remote monitoring before stroke in cases. We trained 3 types of models on our data: (1) convolutional neural networks, (2) random forest, and (3) L1 regularized logistic regression (LASSO). We calculated the CHA2DS2-VASc score for each patient and compared its performance against machine learned indices based on AF burden in separate test cohorts. Finally, we investigated the effect of combining our AF burden models with CHA2DS2-VASc. We identified 3114 nonstroke controls and 71 stroke cases, with no significant differences in baseline characteristics. Random forest performed the best in the test data set (area under the curve [AUC]=0.662) and convolutional neural network in the validation dataset (AUC=0.702), whereas CHA2DS2-VASc had an AUC of 0.5 or less in both data sets. Combining CHA2DS2-VASc with random forest and convolutional neural network yielded a validation AUC of 0.696 and test AUC of 0.634, yielding the highest average AUC on nontraining data.CONCLUSIONS: This proof-of-concept study found that machine learning and ensemble methods that incorporate daily AF burden signature provided incremental prognostic value for risk stratification beyond CHA2DS2-VASc for near-term risk of stroke.

View details for DOI 10.1161/CIRCOUTCOMES.118.005595

View details for PubMedID 31610712
Electrographic flow mapping in persistent atrial fibrillation Baykaner, T., Alhusseini, M., Rogers, A., Sauer, W., Ruppersberg, P., Narayan, S. WILEY. 2019: 1745?46
View details for Web of Science ID 000485280500073
Wavefront Field Mapping Reveals a Physiologic Network Between Drivers Where Ablation Terminates Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Leef, G., Shenasa, F., Bhatia, N. K., Rogers, A. J., Sauer, W., Miller, J. M., Swerdlow, M., Tamboli, M., Alhusseini, M. I., Armenia, E., Baykaner, T., Brachmann, J., Turakhia, M. P., Atienza, F., Rappel, W., Wang, P. J., Narayan, S. M. 2019; 12 (8): e006835
Abstract

BACKGROUND: Localized drivers are proposed mechanisms for persistent atrial fibrillation (AF) from optical mapping of human atria and clinical studies of AF, yet are controversial because drivers fluctuate and ablating them may not terminate AF. We used wavefront field mapping to test the hypothesis that AF drivers, if concurrent, may interact to produce fluctuating areas of control to explain their appearance/disappearance and acute impact of ablation.METHODS: We recruited 54 patients from an international registry in whom persistent AF terminated by targeted ablation. Unipolar AF electrograms were analyzed from 64-pole baskets to reconstruct activation times, map propagation vectors each 20 ms, and create nonproprietary phase maps.RESULTS: Each patient (63.6�8.5 years, 29.6% women) showed 4.0�2.1 spatially anchored rotational or focal sites in AF in 3 patterns. First, a single (type I; n=7) or, second, paired chiral-antichiral (type II; n=5) rotational drivers controlled most of the atrial area. Ablation of 1 to 2 large drivers terminated all cases of types I or II AF. Third, interaction of 3 to 5 drivers (type III; n=42) with changing areas of control. Targeted ablation at driver centers terminated AF and required more ablation in types III versus I (P=0.02 in left atrium).CONCLUSIONS: Wavefront field mapping of persistent AF reveals a pathophysiologic network of a small number of spatially anchored rotational and focal sites, which interact, fluctuate, and control varying areas. Future work should define whether AF drivers that control larger atrial areas are attractive targets for ablation.

View details for DOI 10.1161/CIRCEP.118.006835

View details for PubMedID 31352796
Deep learning for cardiovascular medicine: a practical primer EUROPEAN HEART JOURNAL Krittanawong, C., Johnson, K. W., Rosenson, R. S., Wang, Z., Aydar, M., Baber, U., Min, J. K., Tang, W., Halperin, J. L., Narayan, S. M. 2019; 40 (25): 2058-+
View details for DOI 10.1093/eurheartj/ehz056

View details for Web of Science ID 000490138100016
Propagation velocity at atrial fibrillation sources: Go with the flow INTERNATIONAL JOURNAL OF CARDIOLOGY Rogers, A. J., Bhatia, N. K., Brodt, C. R., Narayan, S. M. 2019; 286: 76?77
View details for DOI 10.1016/j.ijcard.2019.04.007

View details for Web of Science ID 000465271500018
Editorial: High density mapping of atrial fibrillation sources JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Rogers, A. J., Bhatia, N. K., Brodt, C., Narayan, S. M. 2019; 30 (6): 964?65
View details for DOI 10.1111/jce.13949

View details for Web of Science ID 000472680300020
Propagation velocity at atrial fibrillation sources: Go with the flow. International journal of cardiology Rogers, A. J., Bhatia, N. K., Brodt, C. R., Narayan, S. M. 2019
View details for PubMedID 30979605
MACHINE LEARNING IDENTIFIES SITES WHERE ABLATION TERMINATES PERSISTENT ATRIAL FIBRILLATION Alhusseini, M., Abuzaid, F., Clopton, P., Rogers, A., Rodrigo, M., Baykaner, T., Wang, P., Rappel, W., Narayan, S. ELSEVIER SCIENCE INC. 2019: 301
View details for Web of Science ID 000460565900301
Deep learning for cardiovascular medicine: a practical primer. European heart journal Krittanawong, C., Johnson, K. W., Rosenson, R. S., Wang, Z., Aydar, M., Baber, U., Min, J. K., Tang, W. H., Halperin, J. L., Narayan, S. M. 2019
Abstract

Deep learning (DL) is a branch of machine learning (ML) showing increasing promise in medicine, to assist in data classification, novel disease phenotyping and complex decision making. Deep learning is a form of ML typically implemented via multi-layered neural networks. Deep learning has accelerated by recent advances in computer hardware and algorithms and is increasingly applied in e-commerce, finance, and voice and image recognition to learn and classify complex datasets. The current medical literature shows both strengths and limitations of DL. Strengths of DL include its ability to automate medical image interpretation, enhance clinical decision-making, identify novel phenotypes, and select better treatment pathways in complex diseases. Deep learning may be well-suited to cardiovascular medicine in which haemodynamic and electrophysiological indices are increasingly captured on a continuous basis by wearable devices as well as image segmentation in cardiac imaging. However, DL also has significant weaknesses including difficulties in interpreting its models (the 'black-box' criticism), its need for extensive adjudicated ('labelled') data in training, lack of standardization in design, lack of data-efficiency in training, limited applicability to clinical trials, and other factors. Thus, the optimal clinical application of DL requires careful formulation of solvable problems, selection of most appropriate DL algorithms and data, and balanced interpretation of results. This review synthesizes the current state of DL for cardiovascular clinicians and investigators, and provides technical context to appreciate the promise, pitfalls, near-term challenges, and opportunities for this exciting new area.

View details for PubMedID 30815669
Efficacy of Ablation Lesion Sets in Addition to Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation: Findings From the SMASH - AF Meta-Analysis Study Cohort. Journal of the American Heart Association Cluckey, A., Perino, A. C., Yunus, F. N., Leef, G. C., Askari, M., Heidenreich, P. A., Narayan, S. M., Wang, P. J., Turakhia, M. P. 2019; 8 (1): e009976
Abstract

Background The objective was to explore the efficacy of ablation lesion sets in addition to pulmonary vein isolation ( PVI ) for paroxysmal atrial fibrillation. The optimal strategy for catheter ablation of paroxysmal atrial fibrillation is debated. Methods and Results The SMASH-AF (Systematic Review and Meta-analysis of Ablation Strategy Heterogeneity in Atrial Fibrillation) study cohort includes trials and observational studies identified in PubMed, Scopus, and Cochrane databases from January 1 1990, to August 1, 2016. We included studies reporting single procedure paroxysmal atrial fibrillation ablation success rates. Exclusion criteria included insufficient reporting of outcomes, ablation strategies that were not prespecified and uniform, and a sample size of fewer than 40 patients. We analyzed lesion sets performed in addition to PVI ( PVI plus) using multivariable random-effects meta-regression to control for patient, study, and procedure characteristics. The analysis included 145 total studies with 23263 patients ( PVI- only cohort: 115 studies, 148 treatment arms, 16500 patients; PVI plus cohort: 39 studies; 46 treatment arms, 6763 patients). PVI plus studies, as compared with PVI -only studies, included younger patients (56.7years versus 58.8years, P=0.001), fewer women (27.2% versus 32.0% women, P=0.002), and were more methodologically rigorous with longer follow-up (29.5 versus 17.1months, P 0.004) and more randomization (19.4% versus 11.8%, P<0.001). In multivariable meta-regression, PVI plus studies were associated with improved success (7.6% absolute improvement [95% CI, 2.6-12.5%]; P<0.01, I2=88%), specifically superior vena cava isolation (4 studies, 4 treatment arms, 1392 patients; 15.1% absolute improvement [95%CI, 2.3-27.9%]; P 0.02, I2=87%). However, residual heterogeneity was large. Conclusions Across the paroxysmal atrial fibrillation ablation literature, PVI plus ablation strategies were associated with incremental improvements in success rate. However, large residual heterogeneity complicates evidence synthesis.

View details for PubMedID 30587059
New Concepts in Sudden Cardiac Arrest to Addressan Intractable Epidemic: JACC State-of-the-Art Review. Journal of the American College of Cardiology Narayan, S. M., Wang, P. J., Daubert, J. P. 2019; 73 (1): 70?88
Abstract

Sudden cardiac arrest (SCA) is one of the largest causes of mortality globally, with an out-of-hospital survival below 10% despite intense research. This document outlines challenges in addressing the epidemic of SCA, along the framework of respond, understand and predict, and prevent. Response could be improved by technology-assisted orchestration of community responder systems, access to automated external defibrillators, and innovations to match resuscitation resources to victims in place and time. Efforts to understand and predict SCA may be enhanced by refining taxonomy along phenotypical and pathophysiological "axes of risk," extending beyond cardiovascular pathology to identify less heterogeneous cohorts, facilitated by open-data platforms and analytics including machine learning to integrate discoveries across disciplines. Prevention of SCA must integrate these concepts, recognizing that all members of society are stakeholders. Ultimately, solutions to the public health challenge of SCA will require greater awareness, societal debate and focused public policy.

View details for PubMedID 30621954
Integrating blockchain technology with artificial intelligence for cardiovascular medicine. Nature reviews. Cardiology Krittanawong, C., Rogers, A. J., Aydar, M., Choi, E., Johnson, K. W., Wang, Z., Narayan, S. M. 2019
View details for DOI 10.1038/s41569-019-0294-y

View details for PubMedID 31605093
Response by Bhatia et al to Letter Regarding Article, "Wavefront Field Mapping Reveals a Physiologic Network Between Drivers Where Ablation Terminates Atrial Fibrillation". Circulation. Arrhythmia and electrophysiology Bhatia, N. K., Rappel, W. J., Narayan, S. M. 2019; 12 (11): e008022
View details for DOI 10.1161/CIRCEP.119.008022

View details for PubMedID 31726861
Editorial: High density mapping of atrial fibrillation sources. Journal of cardiovascular electrophysiology Rogers, A. J., Bhatia, N. K., Brodt, C., Narayan, S. M. 2019
View details for PubMedID 31056801
Urinary tract infection after catheter ablation of atrial fibrillation. Pacing and clinical electrophysiology : PACE Cluckey, A., Perino, A. C., Fan, J., Askari, M., Nasir, J., Marcus, G. M., Baykaner, T., Narayan, S. M., Wang, P. J., Turakhia, M. P. 2019
Abstract

Urinary tract infection (UTI) is common after surgical procedures and a quality improvement target. For non-surgical procedures such as catheter ablation of atrial fibrillation (AF), UTI risk has not been characterized. We sought to determine incidence and risk factors of UTI after AF ablation and risk variation across sites.Using Marketscan commercial claims databases, we performed a retrospective cohort study of patients that underwent AF ablation from 2007 to 2011. The primary outcome was UTI diagnosis within 30 days after ablation. We performed multivariate analyses to determine risk factors for UTI and risk of sepsis within 30 days after ablation with UTI as the predictor variable. Median odds ratio was used to quantify UTI site variation.Among 21,091 patients (age 59.2�10.9; 29.1% female; CHA2 DS2 -VASc 2.0�1.6), 622 (2.9%) were diagnosed with UTI within 30 days. In multivariate analyses, UTI was independently associated with age, female sex, prior UTI, and general anesthesia (all p < 0.01). UTI diagnosis was associated with a substantial increased risk of sepsis within 30 days (5.0% vs. 0.3%; OR 17.5; 95% CI 10.8 - 28.2; p < 0.0001). Among 416 sites, 211 had at least one UTI. Among these 211 sites, the incidence of post-ablation UTI ranged from 0.7%-26.7% (median: 5.4%; IQR: 3.0%-7.1%; 95th percentile: 14.3%; median odds ratio: 1.45; 95% CI 1.41-1.50).UTI after AF ablation is not uncommon and varies substantially across sites. Consideration of UTI as a quality measure and interventions targeted at high-risk patients or sites warrant consideration. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/pace.13738

View details for PubMedID 31168821
Moving the Needle: Tissue Characterization and Lesion Formation During Infusion-Needle Ablation. Heart rhythm Nguyen, D. T., Narayan, S. M. 2019
View details for DOI 10.1016/j.hrthm.2019.10.018

View details for PubMedID 31614225
Electroporation: The End of the Thermal Ablation Era? Journal of the American College of Cardiology Narayan, S. M., Baykaner, T. 2019; 74 (3): 327?29
View details for DOI 10.1016/j.jacc.2019.06.013

View details for PubMedID 31319914
Rapid Point-by-Point Pulmonary�Vein�Isolation. JACC. Clinical electrophysiology Michaud, G. F., Narayan, S. M. 2019; 5 (7): 787?88
View details for DOI 10.1016/j.jacep.2019.05.007

View details for PubMedID 31320007
Dielectric-Based Imaging And Navigation Of The Heart. Heart rhythm Rogers, A. J., Narayan, S. M. 2019
View details for DOI 10.1016/j.hrthm.2019.07.016

View details for PubMedID 31323349
Catheter ablation or surgery to eliminate longstanding persistent atrial fibrillation. International journal of cardiology Shah, R. L., Zaman, J. A., Narayan, S. M. 2019
View details for DOI 10.1016/j.ijcard.2019.12.048

View details for PubMedID 31924396
Transparent Sharing of Digital Health Data: A Call to Action. Heart rhythm Slotwiner, D. J., Tarakji, K. G., Al-Khatib, S. M., Passman, R. S., Saxon, L. A., Peters, N. S., McCall, D., Turakhia, M. P., Schaeffer, J., Mendenhall, G. S., Hindricks, G., Narayan, S. M., Davenport, E. E., Marrouche, N. F. 2019
View details for PubMedID 31077802
Online webinar training to analyse complex atrial fibrillation maps: A randomized trial. PloS one Mesquita, J., Maniar, N., Baykaner, T., Rogers, A. J., Swerdlow, M., Alhusseini, M. I., Shenasa, F., Brizido, C., Matos, D., Freitas, P., Santos, A. R., Rodrigues, G., Silva, C., Rodrigo, M., Dong, Y., Clopton, P., Ferreira, A. M., Narayan, S. M. 2019; 14 (7): e0217988
Abstract

Specific tools have been recently developed to map atrial fibrillation (AF) and help guide ablation. However, when used in clinical practice, panoramic AF maps generated from multipolar intracardiac electrograms have yielded conflicting results between centers, likely due to their complexity and steep learning curve, thus limiting the proper assessment of its clinical impact.The main purpose of this trial was to assess the impact of online training on the identification of AF driver sites where ablation terminated persistent AF, through a standardized training program. Extending this concept to mobile health was defined as a secondary objective.An online database of panoramic AF movies was generated from a multicenter registry of patients in whom targeted ablation terminated non-paroxysmal AF, using a freely available method (Kuklik et al-method A) and a commercial one (RhythmView-method B). Cardiology Fellows naive to AF mapping were enrolled and randomized to training vs no training (control). All participants evaluated an initial set of movies to identify sites of AF termination. Participants randomized to training evaluated a second set of movies in which they received feedback on their answers. Both groups re-evaluated the initial set to assess the impact of training. This concept was then migrated to a smartphone application (App).12 individuals (median age of 30 years (IQR 28-32), 6 females) read 480 AF maps. Baseline identification of AF termination sites by ablation was poor (40%�12% vs 42%�11%, P = 0.78), but similar for both mapping methods (P = 0.68). Training improved accuracy for both methods A (P = 0.001) and B (p = 0.012); whereas controls showed no change in accuracy (P = NS). The Smartphone App accessed AF maps from multiple systems on the cloud to recreate this training environment.Digital online training improved interpretation of panoramic AF maps in previously inexperienced clinicians. Combining online clinical data, smartphone apps and other digital resources provides a powerful, scalable approach for training in novel techniques in electrophysiology.

View details for DOI 10.1371/journal.pone.0217988

View details for PubMedID 31269029
Transient Outward K+ Current Can Strongly Modulate Action Potential Duration and Initiate Alternans in Human Atrium. American journal of physiology. Heart and circulatory physiology Ni, H., Zhang, H., Grandi, E., Narayan, S. M., Giles, W. 2018
Abstract

Efforts to identify the mechanisms that are responsible for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in one or more elements of the atrial 'substrate'. These correspond to the electrophysiological properties and/or structural elements. We have used experimentally validated mathematical models of the human atrial myocyte action potential, both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current, Ito, to electrophysiological instability and arrhythmia initiation. Specifically, our initial simulations explored whether changes in the recovery or restitution of the action potential duration (APD), and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified spatial differences in the expression levels of specific K+ channel alpha-subunits that underlie Ito in the left atrium. We observed that following replacement of 50% of the native Ito current, Kv4.3; and its replacement with Kv1.4, significant changes in the stability of human atrial action potential waveform arose. This isoform switch resulted in discontinuities in the initial slope of the APD restitution curve and APD alternans sometimes emerged. Important insights into cellular mechanisms for these changes are based on known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. The emerging pattern of in silico results resemble some of the changes observed in high resolution MAP recordings during clinical electrophysiological studies. The resulting insights provide a basis for considering novel Kv1.4-based pharmacological treatment(s) in management of AF.

View details for PubMedID 30576220
Comparison of phase-mapping and electrogram-based driver mapping for catheter ablation in atrial fibrillation. Pacing and clinical electrophysiology : PACE Lin, C., Lin, Y., Narayan, S. M., Baykaner, T., Lo, M., Chung, F., Chen, Y., Chang, S., Lo, L., Hu, Y., Liao, J., Tuan, T., Chao, T., Te, A. L., Kuo, L., Vicera, J. J., Chang, T., Salim, S., Chien, K., Chen, S. 2018
Abstract

INTRODUCTION: Adjunctive driver-guided ablation in addition to pulmonary vein isolation has been proposed as a strategy to improve procedural success and outcomes for various populations with atrial fibrillation (AF). This study firstly aimed to evaluate the different mapping techniques for driver/rotor identification and secondly to evaluate the benefit of driver/rotor guided ablation in patients with paroxysmal and persistent AF.METHODS: We searched the electronic database in PubMed using the keywords "atrial fibrillation", "rotor", "rotational driver", "atrial fibrillation source", and "drivers" for both randomized controlled trials and observational controlled trials. Clinical studies reporting efficacy or safety outcomes of driver-guided ablation for paroxysmal AF (PAF) or PerAF were identified. We performed subgroup analyses comparing different driver mapping methods in patients with PerAF. The odds ratios (OR) with random-effects were analyzed.RESULTS: Out of 175 published articles, 7 met the inclusion criteria, of which 2 were randomized controlled trials, 1 quasi-experimental study, and four observational studies (three case-controlled studies and one cross-sectional study). Overall, adjunctive driver-guided ablation was associated with higher rates of acute AF termination (OR: 4.62, 95% confidence interval [CI]: 2.12-10.08; P<0.001), lower recurrence of any atrial arrhythmia (OR: 0.44, 95% CI: 0.30-0.065; P<0.001), and comparable complication incidence.CONCLUSIONS: Adjunctive driver-guided catheter ablation suggested increased freedom from AF/AT relative to conventional strategies, irrespective of the mapping technique. Furthermore, phase-mapping appears to be superior to electrogram-based driver mapping in PerAF ablation. This article is protected by copyright. All rights reserved.

View details for PubMedID 30536679
Structurally-based electrical predictors of atrial arrhythmias. International journal of cardiology Rogers, A. J., Moosvi, N. F., Brodt, C. R., Narayan, S. M. 2018
View details for PubMedID 30528625
Predictability in Complex Atrial Arrhythmias: the N/N-1 Algorithm to Guide Ablation of Atrial Tachycardias. Heart rhythm Kaiser, D. W., Rogers, A. J., Narayan, S. M. 2018
View details for PubMedID 30465903
Secular trends in success rate of catheter ablation for atrial fibrillation: The SMASH-AF cohort. American heart journal Perino, A. C., Leef, G. C., Cluckey, A., Yunus, F. N., Askari, M., Heidenreich, P. A., Narayan, S. M., Wang, P. J., Turakhia, M. P. 2018
Abstract

BACKGROUND: Approaches, tools, and technologies for atrial fibrillation (AF) ablation have evolved significantly since its inception. We sought to characterize secular trends in AF ablation success rates.METHODS: We performed a systematic review and meta-analysis of AF ablation from January 1, 1990, to August 1, 2016, searching PubMed, Scopus, and Cochrane databases. Major exclusion criteria were insufficient outcome reporting and ablation strategies that were not prespecified and uniform. We stratified treatment arms by AF type (paroxysmal AF; nonparoxysmal AF) and analyzed single-procedure outcomes. Multivariate meta-regressions analyzed effects of study, patient, and procedure characteristics on success rate trends. Registered in PROSPERO (CRD42016036549).RESULTS: A total of 180 trials and observational studies with 28,118 patients met inclusion. For paroxysmal AF ablation studies, unadjusted success rate summary estimates ranged from 73.1% in 2003 to 77.1% in 2016, increasing by 0.9%/year (95% CI 0.4%-1.4%; P = .001; I2 = 90%). After controlling for study design and patient demographics, rate of improvement in success rate summary estimate increased (1.6%/year; 95% CI 0.9%-2.2%; P = .001; I2 = 87%). For nonparoxysmal AF ablation studies, unadjusted success rate summary estimates ranged from 70.0% in 2010 to 64.3% in 2016 (1.1%/year; 95% CI -1.3% to 3.5%; P = .37; I2 = 85%), with no improvement in multivariate analyses.CONCLUSIONS: Despite substantial research investment and health care expenditure, improvements in AF ablation success rates have been incremental. Meaningful improvements may require major paradigm or technology changes, and evaluation of clinical outcomes such as mortality and quality of life may prove to be important going forward.

View details for PubMedID 30502925
Characterizing Electrogram Signal Fidelity and the Effects of Signal Contamination on Mapping Human Persistent Atrial Fibrillation FRONTIERS IN PHYSIOLOGY Vidmar, D., Alhusseini, M., Narayan, S. M., Rappel, W. 2018; 9
View details for DOI 10.3389/fphys.2018.01232

View details for Web of Science ID 000443769500001
Integrating mapping methods for atrial fibrillation. Pacing and clinical electrophysiology : PACE Rogers, A. J., Tamboli, M., Narayan, S. M. 2018
View details for DOI 10.1111/pace.13476

View details for PubMedID 30144115
Interaction of Localized Drivers and Disorganized Activation in Persistent Atrial Fibrillation: Reconciling Putative Mechanisms Using Multiple Mapping Techniques CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Kowalewski, C. B., Shenasa, F., Rodrigo, M., Clopton, P., Meckler, G., Alhusseini, M. I., Swerdlow, M. A., Joshi, V., Hossainy, S., Zaman, J. B., Baykaner, T., Rogers, A. J., Brachmann, J., Miller, J. M., Krummen, D. E., Sauer, W. H., Peters, N. S., Wang, P. J., Narayan, S. M. 2018; 11 (6): e005846
Abstract

Mechanisms for persistent atrial fibrillation (AF) are unclear. We hypothesized that putative AF drivers and disorganized zones may interact dynamically over short time scales. We studied this interaction over prolonged durations, focusing on regions where ablation terminates persistent AF using 2 mapping methods.We recruited 55 patients with persistent AF in whom ablation terminated AF prior to pulmonary vein isolation from a multicenter registry. AF was mapped globally using electrograms for 360�45 cycles using (1) a published phase method and (2) a commercial activation/phase method.Patients were 62.2�9.7 years, 76% male. Sites of AF termination showed rotational/focal patterns by methods 1 and 2 (51/55 vs 55/55; P=0.13) in spatially conserved regions, yet fluctuated over time. Time points with no AF driver showed competing drivers elsewhere or disordered waves. Organized regions were detected for 61.6�23.9% and 70.6�20.6% of 1 minute per method (P=nonsignificant), confirmed by automatic phase tracking (P<0.05). To detect AF drivers with >90% sensitivity, 8 to 32 s of AF recordings were required depending on driver definition.Sites at which persistent AF terminated by ablation show organized activation that fluctuate over time, because of collision from concurrent organized zones or fibrillatory waves, yet recur in conserved spatial regions. Results were similar by 2 mapping methods. This network of competing mechanisms should be reconciled with existing disorganized or driver mechanisms for AF, to improve clinical mapping and ablation of persistent AF.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02997254.

View details for PubMedID 29884620
Improving sudden cardiac death risk stratification by evaluating electrocardiographic measures of global electrical heterogeneity and clinical outcomes among patients with implantable cardioverter-defibrillators: rationale and design for a retrospective, multicenter, cohort study JOURNAL OF INTERVENTIONAL CARDIAC ELECTROPHYSIOLOGY Waks, J. W., Hamilton, C., Das, S., Ehdaie, A., Minnier, J., Narayan, S., Niebauer, M., Raitt, M., Tompkins, C., Varma, N., Chugh, S., Tereshchenko, L. G. 2018; 52 (1): 77?89
Abstract

Implantable cardioverter-defibrillators (ICDs) improve survival of systolic heart failure (HF) patients who are at risk of sudden cardiac death (SCD). We recently showed that electrocardiographic (ECG) global electrical heterogeneity (GEH) is independently associated with SCD in the community-dwelling cohort and developed GEH SCD risk score. The Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study is a retrospective multicenter cohort designed with two goals: (1) validate an independent association of ECG GEH with sustained ventricular tachyarrhythmias and appropriate ICD therapies and (2) validate GEH ECG risk score for prediction of sustained ventricular tachyarrhythmias and appropriate ICD therapies in systolic HF patients with primary prevention ICD.All records of primary prevention ICD recipients with available data for analysis are eligible for inclusion. Records of ICD implantation in patients with inherited channelopathies and cardiomyopathies are excluded. Raw digital 12-lead pre-implant ECGs will be used to measure GEH (spatial QRST angle, spatial ventricular gradient magnitude, azimuth, and elevation, and sum absolute QRST integral). The primary endpoint is defined as a sustained ventricular tachyarrhythmia event with appropriate ICD therapy. All-cause death without preceding sustained ventricular tachyarrhythmia with appropriate ICD therapy will serve as a primary competing outcome. The study will draw data from the academic medical centers.We describe the study protocol of the first multicenter retrospective cohort of primary prevention ICD patients with recorded at baseline digital 12-lead ECG.Findings from this study will inform future trials to identify patients who are most likely to benefit from primary prevention ICD.URL: http://www.clinicaltrials.gov . Unique identifier: NCT03210883.

View details for PubMedID 29541969
Statistical guidance of VT ablation. Journal of cardiovascular electrophysiology Rodrigo, M., Narayan, S. M. 2018
View details for PubMedID 29771455
Interpreting Activation Mapping of Atrial Fibrillation: A Hybrid Computational/Physiological Study ANNALS OF BIOMEDICAL ENGINEERING Costabal, F., Zaman, J. B., Kuhl, E., Narayan, S. M. 2018; 46 (2): 257?69
Abstract

Atrial fibrillation is the most common rhythm disorder of the heart associated with a rapid and irregular beating of the upper chambers. Activation mapping remains the gold standard to diagnose and interpret atrial fibrillation. However, fibrillatory activation maps are highly sensitive to far-field effects, and often disagree with other optical mapping modalities. Here we show that computational modeling can identify spurious non-local components of atrial fibrillation electrograms and improve activation mapping. We motivate our approach with a cohort of patients with potential drivers of persistent atrial fibrillation. In a computational study using a monodomain Maleckar model, we demonstrate that in organized rhythms, electrograms successfully track local activation, whereas in atrial fibrillation, electrograms are sensitive to spiral wave distance and number, spiral tip trajectories, and effects of fibrosis. In a clinical study, we analyzed n�=�15 patients with persistent atrial fibrillation that was terminated by limited ablation. In five cases, traditional activation maps revealed a spiral wave at sites of termination; in ten cases, electrogram timings were ambiguous and activation maps showed incomplete reentry. By adjusting electrogram timing through computational modeling, we found rotational activation, which was undetectable with conventional methods. Our results demonstrate that computational modeling can identify non-local deflections to improve activation mapping and explain how and where ablation can terminate persistent atrial fibrillation. Our hybrid computational/physiological approach has the potential to optimize map-guided ablation and improve ablation therapy in atrial fibrillation.

View details for PubMedID 29214421

View details for PubMedCentralID PMC5880222
Independent mapping methods reveal rotational activation near pulmonary veins where atrial fibrillation terminates before pulmonary vein isolation. Journal of cardiovascular electrophysiology Navara, R., Leef, G., Shenasa, F., Kowalewski, C., Rogers, A. J., Meckler, G., Zaman, J. A., Baykaner, T., Park, S., Turakhia, M. P., Zei, P., Viswanathan, M., Wang, P. J., Narayan, S. M. 2018
Abstract

OBJECTIVE: To investigate mechanisms by which atrial fibrillation (AF) may terminate during ablation near the pulmonary veins before the veins are isolated (PVI).INTRODUCTION: It remains unstudied how AF may terminate during ablation before PVs are isolated, or how patients with PV reconnection can be arrhythmia-free. We studied patients in whom PV antral ablation terminated AF before PVI, using two independent mapping methods.METHODS: We studied patients with AF referred for ablation, in whom biatrial contact basket electrograms were studied by both an activation/phase mapping method and by a second validated mapping method reported not to create false rotational activity.RESULTS: In 22 patients (age 60.1 � 10.4, 36% persistent AF), ablation at sites near the PVs terminated AF (77% to sinus rhythm) prior to PVI. AF propagation revealed rotational (n=20) and focal (n=2) patterns at sites of termination by mapping method 1 and method 2. Both methods showed organized sites that were spatially concordant (P<0.001) with similar stability (P<0.001). Vagal slowing was not observed at sites of AF termination.DISCUSSION: PV antral regions where ablation terminated AF before PVI exhibited rotational and focal activation by two independent mapping methods. These data provide an alternative mechanism for the success of PVI, and may explain AF termination before PVI or lack of arrhythmias despite PV reconnection. Mapping such sites may enable targeted PV lesion sets and improved freedom from AF.

View details for PubMedID 29377478
Geographic and racial representation and reported success rates of studies of catheter ablation for atrial fibrillation: Findings from the SMASH-AF meta-analysis study cohort. Journal of cardiovascular electrophysiology Leef, G. C., Perino, A. C., Cluckey, A., Yunus, F. N., Askari, M., Heidenreich, P. A., Narayan, S. M., Wang, P. J., Turakhia, M. P. 2018
Abstract

INTRODUCTION: We performed a systematic review and meta-analysis of geographic and racial representation and reported success rates of studies of catheter ablation for atrial fibrillation (AF).METHODS AND RESULTS: We searched PubMed, Scopus, and Cochrane databases from 1/1/1990 to 8/1/2016 for trials and observational studies reporting AF ablation outcomes. Major exclusion criteria were insufficient reporting of outcomes, non-English language articles, and ablation strategies that were not prespecified and uniform. We described geographic and racial representation and single-procedure ablation success rates by country, controlling for patient demographics and study design characteristics. The analysis cohort included 306 studies (49,227 patients) from 28 countries. Over half of the paroxysmal (PAF) and nonparoxysmal AF (NPAF) treatment arms were conducted in 5 and 3 countries, respectively. Reporting of race or ethnicity demographics and outcomes were rare (1 study, 0.3%) and nonexistent, respectively. Unadjusted success rates by country ranged from 63.5% to 83.0% for PAF studies and 52.7% to 71.6% for NPAF studies, with substantial variation in patient demographics and study design. After controlling for covariates, South Korea and the United States had higher PAF ablation success rates, with large residual heterogeneity. NPAF ablation success rates were statistically similar by country.CONCLUSIONS: Studies of AF ablation have substantial variation in patient demographics, study design, and reported outcomes by country. There is limited geographic representation of trials and observational studies of AF ablation and a paucity of race- or ethnicity-stratified results. Future AF ablation studies and registries should aim to have broad representation by race, geography, and ethnicity to ensure generalizability.

View details for PubMedID 29364570
Clinical Implications of Ablation of Drivers for Atrial Fibrillation: A Systematic Review and Meta-Analysis. Circulation. Arrhythmia and electrophysiology Baykaner, T., Rogers, A. J., Meckler, G. L., Zaman, J., Navara, R., Rodrigo, M., Alhusseini, M., Kowalewski, C. A., Viswanathan, M. N., Narayan, S. M., Clopton, P., Wang, P. J., Heidenreich, P. A. 2018; 11 (5): e006119
Abstract

The outcomes from pulmonary vein isolation (PVI) for atrial fibrillation (AF) are suboptimal, but the benefits of additional lesion sets remain unproven. Recent studies propose ablation of AF drivers improves outcomes over PVI, yet with conflicting reports in the literature. We undertook a systematic literature review and meta-analysis to determine outcomes from ablation of AF drivers in addition to PVI or as a stand-alone procedure.Database search was done using the terms atrial fibrillation and ablation or catheter ablation and driver or rotor or focal impulse or FIRM (Focal Impulse and Rotor Modulation). We pooled data using random effects model and assessed heterogeneity with I2 statistic.Seventeen studies met inclusion criteria, in a cohort size of 3294 patients. Adding AF driver ablation to PVI reported freedom from AF of 72.5% (confidence interval [CI], 62.1%-81.8%; P<0.01) and from all arrhythmias of 57.8% (CI, 47.5%-67.7%; P<0.01). AF driver ablation when added to PVI or as stand-alone procedure compared with controls produced an odds ratio of 3.1 (CI, 1.3-7.7; P=0.02) for freedom from AF and an odds ratio of 1.8 (CI, 1.2-2.7; P<0.01) for freedom from all arrhythmias in 4 controlled studies. AF termination rate was 40.5% (CI, 30.6%-50.9%) and predicted favorable outcome from ablation(P<0.05).In controlled studies, the addition of AF driver ablation to PVI supports the possible benefit of a combined approach of AF driver ablation and PVI in improving single-procedure freedom from all arrhythmias. However, most studies are uncontrolled and are limited by substantial heterogeneity in outcomes. Large multicenter randomized trials are needed to precisely define the benefits of adding driver ablation to PVI.

View details for PubMedID 29743170
Characterizing Electrogram Signal Fidelity and the Effects of Signal Contamination on Mapping Human Persistent Atrial Fibrillation. Frontiers in physiology Vidmar, D., Alhusseini, M. I., Narayan, S. M., Rappel, W. J. 2018; 9: 1232
Abstract

Objective: Determining accurate intracardiac maps of atrial fibrillation (AF) in humans can be difficult, owing primarily to various sources of contamination in electrogram signals. The goal of this study is to develop a measure for signal fidelity and to develop methods to quantify robustness of observed rotational activity in phase maps subject to signal contamination. Methods: We identified rotational activity in phase maps of human persistent AF using the Hilbert transform of sinusoidally recomposed signals, where localized ablation at rotational sites terminated fibrillation. A novel measure of signal fidelity was developed to quantify signal quality. Contamination is then introduced to the underlying electrograms by removing signals at random, adding noise to computations of cycle length, and adding realistic far-field signals. Mean tip number N and tip density ?, defined as the proportion of time a region contains a tip, at the termination site are computed to compare the effects of contamination. Results: Domains of low signal fidelity correspond to the location of rotational cores. Removing signals and altering cycle length accounted for minor changes in tip density, while targeted removal of low fidelity electrograms can result in a significant increase in tip density and stability. Far-field contamination was found to obscure rotation at the termination site. Conclusion: Rotational activity in clinical AF can produce domains of low fidelity electrogram recordings at rotational cores. Observed rotational patterns in phase maps appear most sensitive to far-field activation. These results may inform novel methods to map AF in humans which can be tested directly in patients at electrophysiological study and ablation.

View details for PubMedID 30237766

View details for PubMedCentralID PMC6135945
Patient and facility variation in costs of catheter ablation for atrial fibrillation. Journal of cardiovascular electrophysiology Perino, A. C., Fan, J., Schmitt, S., Kaiser, D. W., Heidenreich, P. A., Narayan, S. M., Wang, P. J., Chang, A. Y., Turakhia, M. P. 2018
Abstract

Cost-effectiveness or value of cardiovascular therapies may be undermined by unwarranted cost variation, particularly for heterogeneous procedures such as catheter ablation for atrial fibrillation (AF). We sought to characterize cost variation of AF ablation in the U.S. health care system and the relationship between cost and outcomes.We performed a retrospective cohort study using data from the MarketScan� commercial claims and Medicare supplemental databases including patients who received an AF ablation from 2007 through 2011. We aggregated encounter cost, reflecting total payments received for the encounter, to the facility level to calculate median facility cost. We classified procedures as outpatient or inpatient and assessed for association between cost and 30-day and one-year outcomes. The analysis cohort included 9,415 AF ablations (59�11 years; 28% female; 52% outpatient) occurring at 327 facilities, with large cost variation across facilities (median: $25,100; 25th percentile: $18,900, 75th percentile: $35,600, 95th percentile: $57,800). Among outpatient procedures, there was reduced health care utilization in higher cost quintiles with reductions in rehospitalization at 30-days (Quintile 1: 16.1%, Quintile 5: 8.8%, p�<�0.001) and one-year (Quintile 1: 34.8%, Quintile 5: 25.6%, p�<�0.001), which remained significant in multivariate analysis.Although median costs of AF ablation are below amounts used in prior cost-effectiveness studies that demonstrated good value, large facility variation in cost suggests opportunities for cost reduction. However, for outpatient encounters, association of cost to modestly improved outcomes suggests cost containment strategies could have variable effects. This article is protected by copyright. All rights reserved.

View details for PubMedID 29864193
Identification and Characterization of Sites Where Persistent Atrial Fibrillation Is Terminated by Localized Ablation CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Zaman, J. B., Sauer, W. H., Alhusseini, M. I., Baykaner, T., Borne, R. T., Kowalewski, C. B., Busch, S., Zei, P. C., Park, S., Viswanathan, M. N., Wang, P. J., Brachmann, J., Krummen, D. E., Miller, J. M., Rappel, W., Narayan, S. M., Peters, N. S. 2018; 11 (1): e005258
Abstract

The mechanisms by which persistent atrial fibrillation (AF) terminates via localized ablation are not well understood. To address the hypothesis that sites where localized ablation terminates persistent AF have characteristics identifiable with activation mapping during AF, we systematically examined activation patterns acquired only in cases of unequivocal termination by ablation.We recruited 57 patients with persistent AF undergoing ablation, in whom localized ablation terminated AF to sinus rhythm or organized tachycardia. For each site, we performed an offline analysis of unprocessed unipolar electrograms collected during AF from multipolar basket catheters using the maximum -dV/dt assignment to construct isochronal activation maps for multiple cycles. Additional computational modeling and phase analysis were used to study mechanisms of map variability. At all sites of AF termination, localized repetitive activation patterns were observed. Partial rotational circuits were observed in 26 of 57 (46%) cases, focal patterns in 19 of 57 (33%), and complete rotational activity in 12 of 57 (21%) cases. In computer simulations, incomplete segments of partial rotations coincided with areas of slow conduction characterized by complex, multicomponent electrograms, and variations in assigning activation times at such sites substantially altered mapped mechanisms.Local activation mapping at sites of termination of persistent AF showed repetitive patterns of rotational or focal activity. In computer simulations, complete rotational activation sequence was observed but was sensitive to assignment of activation timing particularly in segments of slow conduction. The observed phenomena of repetitive localized activation and the mechanism by which local ablation terminates putative AF drivers require further investigation.

View details for PubMedID 29330332

View details for PubMedCentralID PMC5769709
Ablation of Atrial Fibrillation Drivers ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW Baykaner, T., Zaman, J. B., Wang, P. J., Narayan, S. M. 2017; 6 (4): 195?201
Abstract

Pulmonary vein isolation (PVI) is central to ablation approaches for atrial fibrillation (AF), yet many patients still have arrhythmia recurrence after one or more procedures, despite evolving technologies for PVI. Ablation of localised AF drivers, which lie outside the pulmonary veins in many patients, is a practical approach that has been shown to improve success by many groups. Such localised drivers lie in atrial regions shown mechanistically to sustain AF in optical mapping and clinical studies of human AF, as well as computational and animal studies. Clinical studies now verify rotational activation by multiple mapping approaches in the same patients, at sites where ablation terminates persistent AF. This review article provides a mechanistic and clinical rationale to ablate localised drivers, and describes successful techniques for their ablation as well as pitfalls to avoid, which may explain discrepancies between results from some centres. We hope that this review will serve as a platform for future improvements in the patient-tailored ablation for complex arrhythmias.

View details for PubMedID 29326835

View details for PubMedCentralID PMC5739904
Rotational Drivers in Atrial Fibrillation: Are Multiple Techniques Circling Similar Mechanisms? Circulation. Arrhythmia and electrophysiology Zaman, J. A., Rogers, A. J., Narayan, S. M. 2017; 10 (12)
View details for PubMedID 29254949
Synergistic Anti-arrhythmic Effects in Human Atria with Combined Use of Sodium Blockers and Acacetin FRONTIERS IN PHYSIOLOGY Ni, H., Whittaker, D. G., Wang, W., Giles, W. R., Narayan, S. M., Zhang, H. 2017; 8: 946
Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Developing effective and safe anti-AF drugs remains an unmet challenge. Simultaneous block of both atrial-specific ultra-rapid delayed rectifier potassium (K+) current (IKur) and the Na+ current (INa) has been hypothesized to be anti-AF, without inducing significant QT prolongation and ventricular side effects. However, the antiarrhythmic advantage of simultaneously blocking these two channels vs. individual block in the setting of AF-induced electrical remodeling remains to be documented. Furthermore, many IKur blockers such as acacetin and AVE0118, partially inhibit other K+ currents in the atria. Whether this multi-K+-block produces greater anti-AF effects compared with selective IKur-block has not been fully understood. The aim of this study was to use computer models to (i) assess the impact of multi-K+-block as exhibited by many IKur blokers, and (ii) evaluate the antiarrhythmic effect of blocking IKur and INa, either alone or in combination, on atrial and ventricular electrical excitation and recovery in the setting of AF-induced electrical-remodeling. Contemporary mathematical models of human atrial and ventricular cells were modified to incorporate dose-dependent actions of acacetin (a multichannel blocker primarily inhibiting IKur while less potently blocking Ito, IKr, and IKs). Rate- and atrial-selective inhibition of INa was also incorporated into the models. These single myocyte models were then incorporated into multicellular two-dimensional (2D) and three-dimensional (3D) anatomical models of the human atria. As expected, application of IKur blocker produced pronounced action potential duration (APD) prolongation in atrial myocytes. Furthermore, combined multiple K+-channel block that mimicked the effects of acacetin exhibited synergistic APD prolongations. Synergistically anti-AF effects following inhibition of INa and combined IKur/K+-channels were also observed. The attainable maximal AF-selectivity of INa inhibition was greatly augmented by blocking IKur or multiple K+-currents in the atrial myocytes. This enhanced anti-arrhythmic effects of combined block of Na+- and K+-channels were also seen in 2D and 3D simulations; specially, there was an enhanced efficacy in terminating re-entrant excitation waves, exerting improved antiarrhythmic effects in the human atria as compared to a single-channel block. However, in the human ventricular myocytes and tissue, cellular repolarization and computed QT intervals were modestly affected in the presence of actions of acacetin and INa blockers (either alone or in combination). In conclusion, this study demonstrates synergistic antiarrhythmic benefits of combined block of IKur and INa, as well as those of INa and combined multi K+-current block of acacetin, without significant alterations of ventricular repolarization and QT intervals. This approach may be a valuable strategy for the treatment of AF.

View details for PubMedID 29218016
The continuous challenge of AF ablation: From foci to rotational activity. Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology Narayan, S. M., Vishwanathan, M. N., Kowalewski, C. A., Baykaner, T., Rodrigo, M., Zaman, J. A., Wang, P. J. 2017; 36 Suppl 1: 9?17
Abstract

Pulmonary vein isolation (PVI) is central to ablation approaches for atrial fibrillation (AF), yet many patients still have arrhythmia recurrence after one or more procedures despite the latest technology for PVI. Ablation of rotational or focal sources for AF, which lie outside the pulmonary veins in many patients, is a practical approach that has been shown to improve success by many groups. Localized sources lie in atrial regions shown mechanistically to sustain AF in optical mapping and clinical studies of human AF, as well as computational and animal studies. Because they arise in localized atrial regions, AF sources may explain central paradoxes in clinical practice - such as how limited ablation in patient specific sites can terminate persistent AF yet extensive anatomical ablation at stereotypical locations, which should extinguish disordered waves, does not improve success in clinical trials. Ongoing studies may help to resolve many controversies in the field of rotational sources for AF. Studies now verify rotational activation by multiple mapping approaches in the same patients, at sites where ablation terminates persistent AF. However, these studies also show that certain mapping methods are less effective for detecting AF sources than others. It is also recognized that the success of AF source ablation is technique dependent. This review article provides a mechanistic and clinical rationale to ablate localized sources (rotational and focal), and describes successful techniques for their ablation as well as pitfalls to avoid. We hope that this review will serve as a platform for future improvements in the patient-tailored ablation for complex arrhythmias.

View details for PubMedID 29126896
Treating Specialty and Outcomes in Newly Diagnosed Atrial Fibrillation From the TREAT-AF Study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Perino, A. C., Fan, J., Schmitt, S. K., Askari, M., Kaiser, D. W., Deshmukh, A., Heidenreich, P. A., Swan, C., Narayan, S. M., Wang, P. J., Turakhia, M. P. 2017; 70 (1): 78?86
Abstract

Atrial fibrillation (AF) occurs in many clinical contexts and is diagnosed and treated by clinicians across�many specialties. This approach has resulted in treatment variations.The goal of this study was to evaluate the association between treating specialty and AF outcomes among�patients newly diagnosed with AF.Using data from the TREAT-AF (Retrospective Evaluation and Assessment of Therapies in AF) study from�the Veterans Health Administration, patients with newly diagnosed, nonvalvular AF between 2004 and 2012�were identified who had at least 1 outpatient encounter with primary care or cardiology within 90 days of the AF diagnosis. Cox proportional hazards regression was used to evaluate the association between treating specialty and AF outcomes.Among 184,161 patients with newly diagnosed AF (age 70 � 11 years; 1.7% women; CHA2DS2-VASc score 2.6�� 1.7), 40% received cardiology care and 60% received primary care only. After adjustment for covariates, cardiology�care was associated with reductions in stroke (hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.86 to 0.96; p�<�0.001) and death (HR: 0.89; 95% CI: 0.88 to 0.91; p�< 0.0001) and increases in hospitalizations for AF/supraventricular�tachycardia (HR: 1.38; 95% CI: 1.35 to 1.42; p�< 0.0001) and myocardial infarction (HR: 1.03; 95% CI: 1.00 to 1.05; p�< 0.04). The propensity-matched cohort had similar results. In mediation analysis, oral anticoagulation prescription within 90 days of diagnosis may have mediated reductions in stroke but did not mediate reductions in�survival.In patients with newly diagnosed AF, cardiology care was associated with improved outcomes, potentially mediated by early prescription of oral anticoagulation therapy. Although hypothesis-generating, these data�warrant serious consideration and study of health care system interventions at the time of new AF diagnosis.

View details for PubMedID 28662810
Multicentre safety of adding Focal Impulse and Rotor Modulation (FIRM) to conventional ablation for atrial fibrillation. Europace Krummen, D. E., Baykaner, T., Schricker, A. A., Kowalewski, C. A., Swarup, V., Miller, J. M., Tomassoni, G. F., Park, S., Viswanathan, M. N., Wang, P. J., Narayan, S. M. 2017; 19 (5): 769-774
Abstract

Focal Impulse and Rotor Modulation (FIRM) uses 64-electrode basket catheters to identify atrial fibrillation (AF)-sustaining sites for ablation, with promising results in many studies. Accordingly, new basket designs are being tested by several groups. We set out to determine the procedural safety of adding basket mapping and map-guided ablation to conventional pulmonary vein isolation (PVI).We collected 30?day procedural safety data in five US centres for consecutive patients undergoing FIRM plus PVI (FIRM-PVI) compared with contemporaneous controls undergoing PVI without FIRM. A total of 625 cases were included in this analysis: 325 FIRM-PVI and 300 PVI-controls. FIRM-PVI patients were more likely than PVI-controls to be male (83% vs. 66%, P?
View details for DOI 10.1093/europace/euw377

View details for PubMedID 28339546
Spatial relationship of organized rotational and focal sources in human atrial fibrillation to autonomic ganglionated plexi. International journal of cardiology Baykaner, T., Zografos, T. A., Zaman, J. A., Pantos, I., Alhusseini, M., Navara, R., Krummen, D. E., Narayan, S. M., Katritsis, D. G. 2017
Abstract

One approach to improve ablation for atrial fibrillation (AF) is to focus on physiological targets including focal or rotational sources or ganglionic plexi (GP). However, the spatial relationship between these potential mechanisms has never been studied. We tested the hypothesis that rotors and focal sources for AF may co-localize with ganglionated plexi (GP).We prospectively identified locations of AF rotors and focal sources, and correlated these to GP sites in 97 consecutive patients (age 59.9�11.4, 73% persistent AF). AF was recorded with 64-pole catheters with activation/phase mapping, and related to anatomic GP sites on electroanatomic maps.AF sources arose in 96/97 (99%) patients for 2.6�1.4 sources per patient (left atrium: 1.7�0.9 right atrium: 1.1�0.8), each with an area of 2-3cm(2). On area analyses, the probability of an AF source randomly overlapping a GP area was 26%. Left atrial sources were seen in 94 (97%) patients, in whom ?1 source co-localized with GP in 75 patients (80%; p<0.05). AF sources were more likely to colocalize with left vs right GPs (p<0.05), and colocalization was more likely in patients with higher CHADS2VASc scores (age>65, diabetes; p<0.05).This is the first study to demonstrate that clinically detected AF focal and rotational sources in the left atrium often colocalize with regions of autonomic innervation. Studies should define if the role of AF sources differs by their anatomical location.

View details for DOI 10.1016/j.ijcard.2017.02.152

View details for PubMedID 28433558
Two Independent Mapping Techniques Identify Rotational Activity Patterns at Sites of Local Termination during Persistent Atrial Fibrillation. Journal of cardiovascular electrophysiology Alhusseini, M., Vidmar, D., Meckler, G. L., Kowalewski, C., Shenasa, F., Wang, P. J., Narayan, S. M., Rappel, W. 2017
Abstract

The mechanisms for atrial fibrillation (AF) are unclear in part because diverse mapping techniques yield diverse maps, ranging from stable organized sources to highly disordered waves. We hypothesized that AF mechanisms may be clarified if mapping techniques were compared in the same patients, and referenced to a clinical endpoint. We compared two independent AF mapping techniques in patients in whom ablation terminated persistent AF before pulmonary vein isolation (PVI).We identified 12 patients with persistent AF (61.2 � 10.8 years, four female) in whom mapping with 64 pole baskets and technique 1 (activation/phase mapping, FIRM) identified rotational activation patterns during at least 50% of the 4-second mapping interval and targeted ablation at these rotational sites terminated AF to sinus rhythm (n = 10) or atrial tachycardia. We analyzed the unipolar electrograms of these patients to determine phase maps of activation by an independent technique 2 (Kuklik, Schotten et�al., IEEE Trans Biomed Eng 2015). Compared to technique 1, technique 2 revealed a source in 12 of 12 (100%) cases with spatial concordance in all cases (P <0.05) and similar rotational characteristics.At sites where ablation terminated persistent AF, two independent mapping techniques identified stable rotational activation for multiple cycles that drove peripheral disorder. Future comparative studies referenced to a clinical endpoint may help reconcile if discrepancies between AF mapping studies reports represent techniques, patient populations or models of AF, and improve mapping to better guide ablation.

View details for DOI 10.1111/jce.13177

View details for PubMedID 28185348
Electrocardiographic spatial loops indicate organization of atrial fibrillation minutes before ablation-related transitions to atrial tachycardia. Journal of electrocardiology Baykaner, T., Trikha, R., Zaman, J. A., Krummen, D. E., Wang, P. J., Narayan, S. M. 2017
Abstract

During ablation for atrial fibrillation (AF), it is challenging to anticipate transitions to organized tachycardia (AT). Defining indices of this transition may help to understand fibrillatory conduction and help track therapy.To determine the timescale over which atrial fibrillation (AF) organizes en route to atrial tachycardia (AT) using the ECG referenced to intracardiac electrograms.In 17 AF patients at ablation (58.7�9.6years; 53% persistent AF) we analyzed spatial loops of atrial activity on the ECG and intracardiac electrograms over successive timepoints. Loops were tracked at precisely 15, 10, 5, 3 and 1min prior to defined transitions of AF to AT.Organizational indices reliably quantified changes from AF to AT. Spatiotemporal AF organization on the ECG was identifiable at least 15min before AT was established (p=0.02).AF shows anticipatory global organization on the ECG minutes before AT is clinically evident. These results offer a foundation to establish when AF therapy is on an effective path, and for a quantitative classification separating AT from AF.

View details for DOI 10.1016/j.jelectrocard.2017.01.007

View details for PubMedID 28108014
Mapping Ripples or Waves in Atrial Fibrillation? Journal of cardiovascular electrophysiology Zaman, J. A., Kowalewski, C. A., Narayan, S. M. 2017; 28 (4): 383?85
View details for PubMedID 28185356

View details for PubMedCentralID PMC5398913
Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study. JACC. Clinical electrophysiology Zaman, J. A., Baykaner, T., Clopton, P., Swarup, V., Kowal, R. C., Daubert, J. P., Day, J. D., Hummel, J., Schricker, A. A., Krummen, D. E., Mansour, M., Tomassoni, G. F., Wheelan, K. R., Vishwanathan, M., Park, S., Wang, P. J., Narayan, S. M., Miller, J. M. 2017; 3 (4): 393?402
Abstract

The role of atrial fibrillation (AF) substrates is unclear in patients with paroxysmal AF (PAF) that recurs after pulmonary vein isolation (PVI). We hypothesized that patients with recurrent post-ablation (redo) PAF despite PVI have electrical substrates marked by rotors and focal sources, and structural substrates that resemble persistent AF more than patients with (de novo) PAF at first ablation.In 175 patients at 11 centers, we compared AF substrates in both atria using 64 pole-basket catheters and phase mapping, and indices of anatomical remodeling between patients with de novo or redo PAF and first ablation for persistent AF.Sources were seen in all patients. More patients with de novo PAF (78.0%) had sources near PVs than patients with redo PAF (47.4%, p=0.005) or persistent AF (46.9%, p=0.001). The total number of sources per patient (p=0.444), and number of non-PV sources (p=0.701) were similar between groups, indicating that redo PAF patients had residual non-PV sources after elimination of PV sources by prior PVI. Structurally, left atrial size did not separate de novo from redo PAF (49.5�9.5 vs. 49.0�7.1mm, p=0.956) but was larger in patients with persistent AF (55.2�8.4mm, p=0.001).Patients with paroxysmal AF despite prior PVI show electrical substrates that resemble persistent AF more closely than patients with paroxysmal AF at first ablation. Notably, these subgroups of paroxysmal AF are indistinguishable by structural indices. These data motivate studies of trigger versus substrate mechanisms for patients with recurrent paroxysmal AF after PVI.

View details for PubMedID 28596994
Spatial relationship of sites for atrial fibrillation drivers and atrial tachycardia in patients with both arrhythmias. International journal of cardiology Baykaner, T., Zaman, J. A., Rogers, A. J., Navara, R., AlHusseini, M., Borne, R. T., Park, S., Wang, P. J., Krummen, D. E., Sauer, W. H., Narayan, S. M. 2017; 248: 188?95
Abstract

Atrial fibrillation (AF) often converts to and from atrial tachycardia (AT), but it is undefined if these rhythms are mechanistically related in such patients. We tested the hypothesis that critical sites for AT may be related to regional AF sources in patients with both rhythms, by mapping their locations and response to ablation on transitions to and from AF.From 219 patients undergoing spatial mapping of AF prior to ablation at 3 centers, we enrolled 26 patients in whom AF converted to AT by ablation (n=19) or spontaneously (n=7; left atrial size 42�6cm, 38% persistent AF). Both atria were mapped in both rhythms by 64-electrode baskets, traditional activation maps and entrainment.Each patient had a single mapped AT (17 reentrant, 9 focal) and 3.7�1.7 AF sources. The mapped AT spatially overlapped one AF source in 88% (23/26) of patients, in left (15/23) or right (8/23) atria. AF transitioned to AT by 3 mechanisms: (a) ablation anchoring AF rotor to AT (n=13); (b) residual, unablated AF source producing AT (n=6); (c) spontaneous slowing of AF rotor leaving reentrant AT at this site without any ablation (n=7). Electrogram analysis revealed a lower peak-to-peak voltage at overlapping sites (0.36�0.2mV vs 0.49�0.2mV p=0.03).Mechanisms responsible for AT and AF may arise in overlapping atrial regions. This mechanistic inter-relationship may reflect structural and/or functional properties in either atrium. Future work should delineate how acceleration of an organized AT may produce AF, and whether such regions can be targeted a priori to prevent AT recurrence post AF ablation.

View details for PubMedID 28733070
Spatiotemporal Progression of Early Human Ventricular Fibrillation. JACC. Clinical electrophysiology Vidmar, D., Krummen, D. E., Hayase, J., Narayan, S. M., Ho, G., Rappel, W. J. 2017; 3 (12): 1437?46
Abstract

The objective of this study was to evaluate the spatio-temporal organization and progression of human ventricular fibrillation (VF) in the left (LV) and right (RV) ventricles.Studies suggest that localized sources contribute to VF maintenance, but the evolution of VF episodes has not been quantified.Synchrony between electrograms recorded from 25 patients with induced VF is computed and used to define the Asynchronous Index (ASI), indicating regions which are out-of-step with surrounding tissue. Computer simulations show that ASI can identify the location of VF-maintaining sources, where larger values of ASImax correlate with more stable sources.Automated synchrony analysis shows elevated values of ASI in a majority of self-terminating episodes (LV: 8/9, RV: 7/8) and sustained episodes (LV: 11/11, RV: 12/12). The locations of ASImax in sustained episodes co-localize with rotor cores when rotational activity is simultaneously present in phase maps (LV: 8/8, RV: 5/7, p<.05). The distribution of ASImax differentiates self-terminating from sustained episodes (mean ASImax = 0.60�0.14 and 0.70�0.16, respectively; p=0.01). Across sustained episodes the LV exhibits an increase in ASImax with time.Quantitative analysis identifies localized asynchronous regions that correlate with sources in VF, with sustained episodes evolving to exhibit more stable activation in the LV. This successive increase in stability indicates a stabilizing agent may be responsible for perpetuating fibrillation in a "migrate-and-capture" mechanism in the LV.

View details for PubMedID 29238755

View details for PubMedCentralID PMC5725953
Mechanistic targets for the ablation of atrial fibrillation. Global cardiology science & practice Zaman, J. A., Baykaner, T., Schricker, A. A., Krummen, D. E., Narayan, S. M. 2017; 2017 (1): e201707
Abstract

The mechanisms responsible for sustaining atrial fibrillation are a key debate in cardiovascular pathophysiology, and directly influence the approach to therapy including ablation Clinical and basic studies have split AF mechanisms into two basic camps: 'spatially distributed disorganization' and 'localized sources'. Recent data suggest that these mechanisms can also be separated by the method for mapping -�with nearly all traditional electrogram analyses showing spatially distributed disorganization and nearly all optical mapping studies showing localized sources We will review this dichotomy in light of these recently identified differences in mapping, and in the context of recent clinical studies in which localized ablation has been shown to impact AF, also lending support to the localized source hypothesis. We will conclude with other concepts on mechanism-based ablation and areas of ongoing research that must be addressed to continue improving our knowledge and treatment of AF.

View details for PubMedID 28971106

View details for PubMedCentralID PMC5621726
Editorial commentary: What can lung transplantation teach us about the mechanisms of atrial arrhythmias? Trends in cardiovascular medicine Baykaner, T., Rogers, A. J., Zaman, J. A., Narayan, S. M. 2017
View details for PubMedID 28893519
Determining conduction patterns on a sparse electrode grid: Implications for the analysis of clinical arrhythmias PHYSICAL REVIEW E Vidmar, D., Narayan, S. M., Krummen, D. E., Rappel, W. 2016; 94 (5)
View details for DOI 10.1103/PhysRevE.94.050401

View details for Web of Science ID 000387541400001
Determining conduction patterns on a sparse electrode grid: Implications for the analysis of clinical arrhythmias. Physical review. E Vidmar, D., Narayan, S. M., Krummen, D. E., Rappel, W. 2016; 94 (5-1): 050401-?
Abstract

We present a general method of utilizing bioelectric recordings from a spatially sparse electrode grid to compute a dynamic vector field describing the underlying propagation of electrical activity. This vector field, termed the wave-front flow field, permits quantitative analysis of the magnitude of rotational activity (vorticity) and focal activity (divergence) at each spatial point. We apply this method to signals recorded during arrhythmias in human atria and ventricles using a multipolar contact catheter and show that the flow fields correlate with corresponding activation maps. Further, regions of elevated vorticity and divergence correspond to sites identified as clinically significant rotors and focal sources where therapeutic intervention can be effective. These flow fields can provide quantitative insights into the dynamics of normal and abnormal conduction in humans and could potentially be used to enhance therapies for cardiac arrhythmias.

View details for PubMedID 27967050
Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2016
Abstract

Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (? = -0.48, P < 0.001), lateral E/e' (? = -0.24, P < 0.001), age (? = -0.21, P < 0.001), and heart rate (? = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.

View details for PubMedID 27638850
Mechanisms linking electrical alternans and clinical ventricular arrhythmia in human heart failure. Heart rhythm Bayer, J. D., Lalani, G. G., Vigmond, E. J., Narayan, S. M., Trayanova, N. A. 2016; 13 (9): 1922-1931
Abstract

Mechanisms of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure (HF) are undefined.The purpose of this study was to elucidate VT/VF mechanisms in HF by using a computational-clinical approach.In 53 patients with HF and 18 control patients, we established the relationship between low-amplitude action potential voltage alternans (APV-ALT) during ventricular pacing at near-resting heart rates and VT/VF on long-term follow-up. Mechanisms underlying the transition of APV-ALT to VT/VF, which cannot be ascertained in patients, were dissected with multiscale human ventricular models based on human electrophysiological and magnetic resonance imaging data (control and HF).For patients with APV-ALT k-score >1.7, complex action potential duration (APD) oscillations (?2.3% of mean APD), rather than APD alternans, most accurately predicted VT/VF during long-term follow-up (+82%; -90% predictive values). In the failing human ventricular models, abnormal sarcoplasmic reticulum (SR) calcium handling caused APV-ALT (>1 mV) during pacing with a cycle length of 550 ms, which transitioned into large magnitude (>100 ms) discordant repolarization time alternans (RT-ALT) at faster rates. This initiated VT/VF (cycle length <400 ms) by steepening apicobasal repolarization (189 ms/mm) until unidirectional conduction block and reentry. Complex APD oscillations resulted from nonstationary discordant RT-ALT. Restoring SR calcium to control levels was antiarrhythmic by terminating electrical alternans.APV-ALT and complex APD oscillations at near-resting heart rates in patients with HF are linked to arrhythmogenic discordant RT-ALT. This may enable novel physiologically tailored, bioengineered indices to improve VT/VF risk stratification, where SR calcium handling and spatial apicobasal repolarization are potential therapeutic targets.

View details for DOI 10.1016/j.hrthm.2016.05.017

View details for PubMedID 27215536

View details for PubMedCentralID PMC4996715
Can Cardiac Conduction System Disease Be Prevented? JAMA internal medicine Narayan, S. M., Baykaner, T., Maron, D. J. 2016; 176 (8): 1093-1094
View details for DOI 10.1001/jamainternmed.2016.2863

View details for PubMedID 27367299
Comparison of Detailed and Simplified Models of Human Atrial Myocytes to Recapitulate Patient Specific Properties. PLoS computational biology Lombardo, D. M., Fenton, F. H., Narayan, S. M., Rappel, W. 2016; 12 (8)
Abstract

Computer studies are often used to study mechanisms of cardiac arrhythmias, including atrial fibrillation (AF). A crucial component in these studies is the electrophysiological model that describes the membrane potential of myocytes. The models vary from detailed, describing numerous ion channels, to simplified, grouping ionic channels into a minimal set of variables. The parameters of these models, however, are determined across different experiments in varied species. Furthermore, a single set of parameters may not describe variations across patients, and models have rarely been shown to recapitulate critical features of AF in a given patient. In this study we develop physiologically accurate computational human atrial models by fitting parameters of a detailed and of a simplified model to clinical data for five patients undergoing ablation therapy. Parameters were simultaneously fitted to action potential (AP) morphology, action potential duration (APD) restitution and conduction velocity (CV) restitution curves in these patients. For both models, our fitting procedure generated parameter sets that accurately reproduced clinical data, but differed markedly from published sets and between patients, emphasizing the need for patient-specific adjustment. Both models produced two-dimensional spiral wave dynamics for that were similar for each patient. These results show that simplified, computationally efficient models are an attractive choice for simulations of human atrial electrophysiology in spatially extended domains. This study motivates the development and validation of patient-specific model-based mechanistic studies to target therapy.

View details for DOI 10.1371/journal.pcbi.1005060

View details for PubMedID 27494252

View details for PubMedCentralID PMC4975409
Organized Sources Are Spatially Conserved in Recurrent Compared to Pre-Ablation Atrial Fibrillation: Further Evidence for Non-Random Electrical Substrates JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Lalani, G. G., Coysh, T., Baykaner, T., Zaman, J., Hopper, K., Schricker, A. A., Trikha, R., Clopton, P., Krummen, D. E., Narayan, S. M. 2016; 27 (6): 661-669
Abstract

CONSERVED ROTORS IN RECURRENT AF.Recurrent atrial fibrillation (AF) after ablation is associated with reconnection of initially isolated pulmonary vein (PV) trigger sites. Substrates are often targeted in addition to PVI, but it is unclear how substrates progress over time. We studied if substrates in recurrent AF are conserved or have developed de novo from pre-ablation AF.Of 137 patients undergoing Focal Impulse and Rotor Mapping (FIRM) at their index procedure for AF, 29 consecutive patients (60�8 years, 79% persistent) recurred and were also mapped at repeat procedure (21�20 months later) using carefully placed 64-pole baskets and RhythmView(TM) (Topera, Menlo Park, CA) to identify AF sources and disorganized zones. Compared to index AF, recurrent AF had a longer cycle length (177�21 vs. 167�19ms, p = 0.01). All patients (100%) had one or more conserved AF rotors between procedures with surrounding disorganization. The number of sources was similar for recurrent AF post-PVI versus index AF (3.2�1.4 vs. 3.1�1.0, p = 0.79), but was lower for recurrent AF after FIRM+PVI versus index AF (4.4�1.4 vs. 2.9�1.7, p = 0.03). Overall, 81% (61/75) of AF sources lay in conserved regions, while 19% (14/75) were detected de novo.Electrical propagation patterns for recurrent AF after unsuccessful ablation are similar in individual patients to their index AF. These data support temporospatial stability of AF substrates over 1-2 years. Trials should determine the relative benefit of adding substrate-mapping and ablation to PVI for recurrent AF. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/jce.12964

View details for Web of Science ID 000378396900001

View details for PubMedID 26918971
Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial. JAMA cardiology Hammond, H. K., Penny, W. F., Traverse, J. H., Henry, T. D., Watkins, M. W., Yancy, C. W., Sweis, R. N., Adler, E. D., Patel, A. N., Murray, D. R., Ross, R. S., Bhargava, V., Maisel, A., Barnard, D. D., Lai, N. C., Dalton, N. D., Lee, M. L., Narayan, S. M., Blanchard, D. G., Gao, M. H. 2016; 1 (2): 163-171
Abstract

Gene transfer has rarely been tested in randomized clinical trials.To evaluate the safety and efficacy of intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) in heart failure.A randomized, double-blind, placebo-controlled, phase 2 clinical trial was conducted in US medical centers (randomization occurred from July 19, 2010, to October 30, 2014). Participants 18 to 80 years with symptomatic heart failure (ischemic and nonischemic) and an ejection fraction (EF) of 40% or less were screened; 86 individuals were enrolled, and 56 were randomized. Data analysis was of the intention-to-treat population. Participants underwent exercise testing and measurement of left ventricular EF (echocardiography) and then cardiac catheterization, where left ventricular pressure development (+dP/dt) and decline (-dP/dt) were recorded. Participants were randomized (3:1 ratio) to receive 1 of 5 doses of intracoronary Ad5.hAC6 or placebo. Participants underwent a second catheterization 4 weeks later for measurement of dP/dt. Exercise testing and EF were assessed 4 and 12 weeks after randomization.Intracoronary administration of Ad5.hAC6 (3.2?�?109 to 1012 virus particles) or placebo.Primary end points included exercise duration and EF before and 4 and 12 weeks after randomization and peak rates of +dP/dt and -dP/dt before and 4 weeks after randomization. Fourteen placebo participants were compared (intention to treat) with 24 Ad5.hAC6 participants receiving the highest 2 doses (D4?+?5).Fifty-six individuals were randomized and monitored for up to 1 year. Forty-two participants (75%) received Ad5.hAC6 (mean [SE] age, 63 [1] years; EF, 30% [1%]), and 14 individuals (25%) received placebo (age, 62 [1] years; EF, 30% [2%]). Exercise duration showed no significant group differences (4 weeks, P?=?.27; 12 weeks, P?=?.47, respectively). The D4?+?5 participants had increased EF at 4 weeks (+6.0 [1.7] EF units; n?=?21; P?
View details for DOI 10.1001/jamacardio.2016.0008

View details for PubMedID 27437887
Mechanistically based mapping of human cardiac fibrillation JOURNAL OF PHYSIOLOGY-LONDON Narayan, S. M., Zaman, J. A. 2016; 594 (9): 2399-2415
Abstract

The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 treatise on 'Dynamic Equilibrium in the Heart', Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from 2 fundamental mechanisms - sources in preferred cardiac regions or spatially diffuse self-sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non-uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non-coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, that are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. This article is protected by copyright. All rights reserved.

View details for DOI 10.1113/JP270513

View details for Web of Science ID 000375601400006

View details for PubMedID 26607671
The precise timing of tachycardia entrainment is determined by the postpacing interval, the tachycardia cycle length, and the pacing rate: Theoretical insights and practical applications HEART RHYTHM Kaiser, D. W., Hsia, H. H., Dubin, A. M., Liem, L. B., Viswanathan, M. N., Zei, P. C., Wang, P. J., Narayan, S. M., Turakhia, M. P. 2016; 13 (3): 695-703
Abstract

Previous observations have reported that the number of pacing stimuli required to entrain a tachycardia varies on the basis of arrhythmia type and location, but a quantitative formulation of the number needed to entrain (NNE) that unifies these observations has not been characterized.We sought to investigate the relationship between the number of pacing stimulations, the tachycardia cycle length (TCL), the overdrive pacing cycle length (PCL), and the postpacing interval (PPI) to accurately estimate the timing of tachycardia entrainment.First, we detailed a mathematical derivation unifying electrophysiological parameters with empirical confirmation in 2 patients undergoing catheter ablation of typical atrial flutter. Second, we validated our formula in 44 patients who underwent various catheter ablation procedures. For accuracy, we corrected for rate-related changes in conduction velocity.We derived the equations NNE = |(PPI - TCL)/(TCL - PCL)| + 1 and Tachycardia advancement = (NNE - 1) � (TCL - PCL) - (PPI - TCL), which state that the NNE and the amount of tachycardia advancement on the first resetting stimulation are determined using regularly measured intracardiac parameters. In the retrospective cohort, the observed PPI - TCL highly correlated with the predicted PPI - TCL (mean difference 5.8 ms; r = 0.97; P < .001), calculated as PPI - TCL = (NNE - 1) � (TCL - PCL) - tachycardia advancement.The number of pacing stimulations required to entrain a reentrant tachycardia is predictable at any PCL after correcting for cycle length-dependent changes in conduction velocity. This relationship unifies established empirically derived diagnostic and mapping criteria for supraventricular tachycardia and ventricular tachycardia. This relationship may help elucidate when antitachycardia pacing episodes are ineffective or proarrhythmic and could potentially serve as a theoretical basis to customize antitachycardia pacing settings for improved safety and effectiveness.

View details for DOI 10.1016/j.hrthm.2015.11.032

View details for Web of Science ID 000372367800012

View details for PubMedCentralID PMC4770895
The precise timing of tachycardia entrainment is determined by the postpacing interval, the tachycardia cycle length, and the pacing rate: Theoretical insights and practical applications. Heart rhythm Kaiser, D. W., Hsia, H. H., Dubin, A. M., Liem, L. B., Viswanathan, M. N., Zei, P. C., Wang, P. J., Narayan, S. M., Turakhia, M. P. 2016; 13 (3): 695-703
Abstract

Previous observations have reported that the number of pacing stimuli required to entrain a tachycardia varies on the basis of arrhythmia type and location, but a quantitative formulation of the number needed to entrain (NNE) that unifies these observations has not been characterized.We sought to investigate the relationship between the number of pacing stimulations, the tachycardia cycle length (TCL), the overdrive pacing cycle length (PCL), and the postpacing interval (PPI) to accurately estimate the timing of tachycardia entrainment.First, we detailed a mathematical derivation unifying electrophysiological parameters with empirical confirmation in 2 patients undergoing catheter ablation of typical atrial flutter. Second, we validated our formula in 44 patients who underwent various catheter ablation procedures. For accuracy, we corrected for rate-related changes in conduction velocity.We derived the equations NNE = |(PPI - TCL)/(TCL - PCL)| + 1 and Tachycardia advancement = (NNE - 1) � (TCL - PCL) - (PPI - TCL), which state that the NNE and the amount of tachycardia advancement on the first resetting stimulation are determined using regularly measured intracardiac parameters. In the retrospective cohort, the observed PPI - TCL highly correlated with the predicted PPI - TCL (mean difference 5.8 ms; r = 0.97; P < .001), calculated as PPI - TCL = (NNE - 1) � (TCL - PCL) - tachycardia advancement.The number of pacing stimulations required to entrain a reentrant tachycardia is predictable at any PCL after correcting for cycle length-dependent changes in conduction velocity. This relationship unifies established empirically derived diagnostic and mapping criteria for supraventricular tachycardia and ventricular tachycardia. This relationship may help elucidate when antitachycardia pacing episodes are ineffective or proarrhythmic and could potentially serve as a theoretical basis to customize antitachycardia pacing settings for improved safety and effectiveness.

View details for DOI 10.1016/j.hrthm.2015.11.032

View details for PubMedID 26611239
New Mechanism-based Approaches to Ablating Persistent AF: Will Drug Therapy Soon Be Obsolete? JOURNAL OF CARDIOVASCULAR PHARMACOLOGY Zaman, J. A., Baykaner, T., Narayan, S. M. 2016; 67 (1): 1-8
View details for DOI 10.1097/FJC.0000000000000270

View details for Web of Science ID 000368504500001
Terminating atrial fibrillation by cooling the heart. Heart rhythm Narayan, S. M., Baykaner, T., Sahli Costabal, F., Kuhl, E. 2016; 13 (11): 2259?60
View details for PubMedID 27435588
Comparative efficacy of stellate ganglion block with bupivacaine vs pulsed radiofrequency in a patient with refractory ventricular arrhythmias. Journal of clinical anesthesia Hayase, J., Vampola, S., Ahadian, F., Narayan, S. M., Krummen, D. E. 2016; 31: 162?65
Abstract

There is increasing interest in interventional therapies targeting the cardiac sympathetic nervous system to suppress ventricular arrhythmias. In this case report, we describe an 80-year-old patient with ischemic cardiomyopathy and multiple implantable cardioverter-defibrillator shocks due to refractory ventricular tachycardia and ventricular fibrillation who was unable to continue biweekly stellate ganglion block procedures using bupivacaine 0.25% for suppression of his arrhythmias. He had previously failed antiarrhythmic drug therapy with amiodarone, catheter ablation, and attempted surgical autonomic denervation. He underwent pulsed radiofrequency treatment (3 lesions, 2 minutes each, temperature 42�C, 2-Hz frequency, 20-millisecond pulse width) of the left stellate ganglion resulting in persistent arrhythmia suppression for more than 12 months duration. This represents the first report of a pulsed radiofrequency stellate ganglion lesion providing long-term suppression of ventricular arrhythmias. Further study of this technique in patients with refractory ventricular tachycardia or ventricular fibrillation is warranted.

View details for PubMedID 27185701
New Mechanism-based Approaches to Ablating Persistent AF: Will Drug Therapy Soon Be Obsolete? Journal of cardiovascular pharmacology Zaman, J. A., Baykaner, T., Narayan, S. M. 2016; 67 (1): 1-8
Abstract

Persistent atrial fibrillation (AF) represents a major public health and medical challenge. The progressive nature of the disease, high morbidity and increasing health-economic costs ensure it remains at the forefront of novel research into mechanisms and potential therapies. These are largely divided into pharmacological (drugs) and electrical (ablation), with patients often going from former to latter. AF ablation has improved sufficiently to be offered as first line for paroxysmal AF, but there is uncertainty on whether drug therapy will improve from its current role or be relegated to niche status. In this review we shall outline the progress in mechanistic understanding of AF that may allow results from ablation to diverge dramatically from drug therapy, to identify populations in whom drug therapy may become less relevant. We end by looking ahead to future developments which we hope will spur on therapeutic efficacy in both fields.

View details for DOI 10.1097/FJC.0000000000000270

View details for PubMedID 25923323
Phase synchrony reveals organization in human atrial fibrillation AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vidmar, D., Narayan, S. M., Rappel, W. 2015; 309 (12): H2118-H2126
View details for DOI 10.1152/ajpheart.00407.2015

View details for Web of Science ID 000367288700013
Mechanisms for the Termination of Atrial Fibrillation by Localized Ablation Computational and Clinical Studies CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Rappel, W., Zaman, J. A., Narayan, S. M. 2015; 8 (6): 1325-1333
View details for DOI 10.1161/CIRCEP.115.002956

View details for Web of Science ID 000366604600007

View details for PubMedID 26359479
Mechanisms for the Termination of Atrial Fibrillation by Localized Ablation: Computational and Clinical Studies. Circulation. Arrhythmia and electrophysiology Rappel, W., Zaman, J. A., Narayan, S. M. 2015; 8 (6): 1325-1333
Abstract

-Human atrial fibrillation (AF) can terminate after ablating localized regions, that supports the existence of localized rotors (spiral waves) or focal drivers. However, it is unclear why ablation near a spiral wave tip would terminate AF and not anchor reentry. We addressed this question by analyzing competing mechanisms for AF termination in numerical simulations, referenced to clinical observations.-Spiral wave reentry was simulated in monodomain 2D myocyte sheets using clinically realistic rate-dependent values for repolarization and conduction. Heterogeneous models were created by introduction of parameterized variations in tissue excitability. Ablation lesions were applied as non-conducting circular regions. Computational models confirmed localized ablation may anchor spiral wave reentry, producing organized tachycardias. Several mechanisms also explained termination of AF to sinus rhythm. First, lesions may create an excitable gap vulnerable to invasion by fibrillatory waves. Second, ablation of rotors in regions of low-excitability (from remodeling) produced reentry in more excitable tissue allowing collision of wave-front and back. Conversely, ablation of rotors in high-excitability regions migrated spiral waves to less excitable tissue, where they detached to collide with non-conducting boundaries. Third, ablation may connect rotors to non-conducting anatomic orifices. Fourth, reentry through slow conducting channels may terminate if ablation closes these channels.-Limited ablation can terminate AF by several mechanisms. These data shed light on how clinical AF may be sustained in patients' atria, emphasizing heterogeneities in tissue excitability, slow-conducting channels and obstacles that are increasingly detectable in patients and should be the focus of future translational studies.

View details for DOI 10.1161/CIRCEP.115.002956

View details for PubMedID 26359479
Modifying Ventricular Fibrillation by Targeted Rotor Substrate Ablation: Proof-of-Concept from Experimental Studies to Clinical VF JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Krummen, D. E., Hayase, J., Vampola, S. P., Ho, G., Schricker, A. A., Lalani, G. G., Baykaner, T., Coe, T. M., Clopton, P., Rappel, W., Omens, J. H., Narayan, S. M. 2015; 26 (10): 1117-1126
View details for DOI 10.1111/jce.12753

View details for PubMedID 26179310
Ablation of atrial fibrillation TRENDS IN CARDIOVASCULAR MEDICINE Wright, M., Narayan, S. M. 2015; 25 (5): 409-419
View details for DOI 10.1016/j.tcm.2014.11.009

View details for Web of Science ID 000356997800007
Ablating Atrial Fibrillation: Customizing Lesion Sets Guided by Rotor Mapping. Methodist DeBakey cardiovascular journal Zaman, J. A., Narayan, S. M. 2015; 11 (2): 76-81
Abstract

Ablation occupies an increasing role in the contemporary management of atrial fibrillation (AF), but results are suboptimal, particularly for persistent AF. While an anatomic approach to ablation is a highly efficacious and safe method to isolate pulmonary vein (PV) triggers, recurrence of AF is not always associated with PV reconnection, and there is compelling evidence that non-PV sites sustain AF after it is triggered. Recent developments in wide-area mapping and signal processing now identify rotors in the vast majority of AF patients that sustain AF and whose elimination improves long-term freedom from AF in multicenter studies. Investigators have now demonstrated rotor and focal sources for AF that show many analogous properties between approaches: they lie in spatially reproducible regions temporally over hours to days, and they are amenable to targeted ablation. This review outlines the rationale and technical developments supporting this mechanistic paradigm for human AF, and discusses how rotor mapping may be implemented for individual patient customization of lesion sets. Mechanistic studies are required to explain why rotor elimination (or other ablation approaches) producing long-term elimination of AF may not always terminate AF acutely, how AF correlates with structural changes on magnetic resonance imaging, and how these findings can be integrated clinically with current ablation strategies to improve patient outcomes.

View details for DOI 10.14797/mdcj-11-2-76

View details for PubMedID 26306123

View details for PubMedCentralID PMC4547681
The role of rotors in atrial fibrillation. Journal of thoracic disease Krummen, D. E., Swarup, V., Narayan, S. M. 2015; 7 (2): 142-151
Abstract

Despite significant advances in our understanding of atrial fibrillation (AF) mechanisms in the last 15 years, ablation outcomes remain suboptimal. A potential reason is that many ablation techniques focus on anatomic, rather than patient-specific functional targets for ablation. Panoramic contact mapping, incorporating phase analysis, repolarization and conduction dynamics, and oscillations in AF rate, overcomes many prior difficulties with mapping AF. This approach provides evidence that the mechanisms sustaining human AF are deterministic, largely due to stable electrical rotors and focal sources in either atrium. Ablation of such sources (Focal Impulse and Rotor Modulation: FIRM ablation) has been shown to improve ablation outcome compared with conventional ablation alone; independent laboratories directly targeting stable rotors have shown similar results. Clinical trials examining the role of stand-alone FIRM ablation are in progress. Looking forward, translating insights from patient-specific mapping to evidence-based guidelines and clinical practice is the next challenge in improving patient outcomes in AF management.

View details for DOI 10.3978/j.issn.2072-1439.2014.11.15

View details for PubMedID 25713729

View details for PubMedCentralID PMC4321066
Rotor mapping and ablation to treat atrial fibrillation CURRENT OPINION IN CARDIOLOGY Zaman, J. A., Peters, N. S., Narayan, S. M. 2015; 30 (1): 24-32
Abstract

Rotors have long been postulated to drive atrial fibrillation, but evidence has been limited to animal models. This changed recently with the demonstration using focal impulse and rotor modulation (FIRM) mapping that rotors act as human atrial fibrillation sources. This mechanistic approach to diagnosing the causes of atrial fibrillation in individual patients has been supported by substantially improved outcomes from FIRM-guided ablation, resulting in increased attention to rotors as therapeutic targets.In this review, we outline the pathophysiology of rotors in animal and in-silico studies of fibrillation, and how this motivated FIRM mapping in humans. We highlight the characteristics of rotors in human atrial fibrillation, now validated by several techniques, with discussion on similar and discrepant findings between techniques. The interventional approaches to eliminate atrial fibrillation rotors are explained and the ablation results in latest studies using FIRM are discussed.We propose that mapping localized sources for human atrial fibrillation, specifically rotors, is moving the field towards a unifying hypothesis that explains several otherwise contradictory observations in atrial fibrillation management. We conclude by suggesting areas of potential research that may reveal more about these critical sites and how these may lead to better and novel treatments for atrial fibrillation.

View details for DOI 10.1097/HCO.0000000000000123

View details for Web of Science ID 000346157200004

View details for PubMedID 25389649
Ablation of atrial fibrillation. Trends in cardiovascular medicine Wright, M., Narayan, S. M. 2015; 25 (5): 409?19
Abstract

Ablation is increasingly used to treat AF, since recent trials of pharmacological therapy for AF have been disappointing. Ablation has been shown to improve maintenance of sinus rhythm compared to pharmacological therapy in many multicenter trials, although success rates remain suboptimal. This review will discuss several trends in the field of catheter ablation, including studies to advance our understanding of AF mechanisms in different patient populations, innovations in detecting and classifying AF, use of this information to improve strategies for ablation, technical innovations that have improved the ease and safety of ablation, and novel approaches to surgical therapy and imaging. These trends are likely to further improve results from AF ablation in coming years as it becomes an increasingly important therapeutic option for many patients.

View details for PubMedID 25572010

View details for PubMedCentralID PMC4764083
Is Human Long-Standing Persistent Atrial Fibrillation More Stable Than Assumed? JACC. Clinical electrophysiology Verma, A., Narayan, S. M. 2015; 1 (1-2): 25?28
View details for PubMedID 29759335
Phase synchrony reveals organization in human atrial fibrillation. American journal of physiology. Heart and circulatory physiology Vidmar, D., Narayan, S. M., Rappel, W. J. 2015; 309 (12): H2118?26
Abstract

It remains unclear if human atrial fibrillation (AF) is spatially nonhierarchical or exhibits a hierarchy of organization sustained by sources. We utilize activation times obtained at discrete locations during AF to compute the phase synchrony between tissue regions, to examine underlying spatial dynamics throughout both atria. We construct a binary synchronization network and show that this network can accurately define regions of coherence in coarse-grained in silico data. Specifically, domains controlled by spiral waves exhibit regions of high phase synchrony. We then apply this analysis to clinical data from patients experiencing cardiac arrhythmias using multielectrode catheters to simultaneously record from a majority of both atria. We show that pharmaceutical intervention with ibutilide organizes activation by increasing the size of the synchronized domain in AF and quantify the increase in temporal organization when arrhythmia changes from fibrillation to tachycardia. Finally, in recordings from 24 patients in AF we show that the level of synchrony is spatially broad with some patients showing large spatially contiguous regions of synchronization, while in others synchrony is localized to small pockets. Using computer simulations, we show that this distribution is inconsistent with distributions obtained from simulations that mimic multiwavelet reentry but is consistent with mechanisms in which one or more spatially conserved spiral waves is surrounded by tissue in which activation is disorganized.

View details for PubMedID 26475585

View details for PubMedCentralID PMC4698428
When is Structure, Function? Revisiting an Old Concept in Atrial Fibrillationx. Journal of cardiovascular electrophysiology Zaman, J. A., Narayan, S. M. 2015
Abstract

The mechanistic role of cardiac structure is central to the conceptualization and therapy of arrhythmias, yet it is poorly understood in all but the simplest cases. A century after Mines first conceptualized reentry based on structural pathways, (1,2) it is common to dichotomize reentry into 'anatomical' and 'functional'. However, in many ways this is an uneasy distinction. This article is protected by copyright. All rights reserved.

View details for PubMedID 26359793
Ablation of Atrial Fibrillation: How Can Less Be More? Circulation. Arrhythmia and electrophysiology Zaman, J. A., Narayan, S. M. 2015; 8 (6): 1303?5
View details for PubMedID 26671931
Atrial Fibrillation: Can Electrograms Be Interpreted Without Repolarization Information? Heart rhythm : the official journal of the Heart Rhythm Society Narayan, S. M., Zaman, J., Baykaner, T., Franz, M. R. 2015
View details for PubMedID 26711801
Progress toward the prevention and treatment of atrial fibrillation: A summary of the Heart Rhythm Society Research Forum on the Treatment and Prevention of Atrial Fibrillation, Washington, DC, December 9-10, 2013. Heart rhythm Van Wagoner, D. R., Piccini, J. P., Albert, C. M., Anderson, M. E., Benjamin, E. J., Brundel, B., Califf, R. M., Calkins, H., Chen, P., Chiamvimonvat, N., Darbar, D., Eckhardt, L. L., Ellinor, P. T., Exner, D. V., Fogel, R. I., Gillis, A. M., Healey, J., Hohnloser, S. H., Kamel, H., Lathrop, D. A., Lip, G. Y., Mehra, R., Narayan, S. M., Olgin, J., Packer, D., Peters, N. S., Roden, D. M., Ross, H. M., Sheldon, R., Wehrens, X. H. 2015; 12 (1): e5-e29
View details for DOI 10.1016/j.hrthm.2014.11.011

View details for PubMedID 25460864
Stability of Rotors and Focal Sources for Human Atrial Fibrillation: Focal Impulse and Rotor Mapping (FIRM) of AF Sources and Fibrillatory Conduction JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Swarup, V., Baykaner, T., Rostamian, A., Daubert, J. P., Hummel, J., Krummen, D. E., Trikha, R., Miller, J. M., Tomassoni, G. F., Narayan, S. M. 2014; 25 (12): 1284-1292
Abstract

Several groups report electrical rotors or focal sources that sustain atrial fibrillation (AF) after it has been triggered. However, it is difficult to separate stable from unstable activity in prior studies that examined only seconds of AF. We applied phase-based focal impulse and rotor mapping (FIRM) to study the dynamics of rotors/sources in human AF over prolonged periods of time.We prospectively mapped AF in 260 patients (169 persistent, 61 � 12 years) at 6 centers in the FIRM registry, using baskets with 64 contact electrodes per atrium. AF was phase mapped (RhythmView, Topera, Menlo Park, CA, USA). AF propagation movies were interpreted by each operator to assess the source stability/dynamics over tens of minutes before ablation.Sources were identified in 258 of 260 of patients (99%), for 2.8 � 1.4 sources/patient (1.8 � 1.1 in left, 1.1 � 0.8 in right atria). While AF sources precessed in stable regions, emanating activity including spiral waves varied from collision/fusion (fibrillatory conduction). Each source lay in stable atrial regions for 4,196 � 6,360 cycles, with no differences between paroxysmal versus persistent AF (4,290 � 5,847 vs. 4,150 � 6,604; P = 0.78), or right versus left atrial sources (P = 0.26).Rotors and focal sources for human AF mapped by FIRM over prolonged time periods precess ("wobble") but remain within stable regions for thousands of cycles. Conversely, emanating activity such as spiral waves disorganize and collide with the fibrillatory milieu, explaining difficulties in using activation mapping or signal processing analyses at fixed electrodes to detect AF rotors. These results provide a rationale for targeted ablation at AF sources rather than fibrillatory spiral waves.

View details for DOI 10.1111/jce.12559

View details for Web of Science ID 000346020800004

View details for PubMedID 25263408
Rotors and Focal Sources for Human Atrial Fibrillation - Mechanistic Paradigm With Direct Clinical Relevance CIRCULATION JOURNAL Lalani, G. G., Trikha, R., Krummen, D. E., Narayan, S. M. 2014; 78 (10): 2357-2366
View details for DOI 10.1253/circj.CJ-14-0478

View details for Web of Science ID 000343249600003
Human Atrial Fibrillation Initiates via Organized Rather Than Disorganized Mechanisms CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Schricker, A. A., Lalani, G. G., Krummen, D. E., Rappel, W., Narayan, S. M. 2014; 7 (5): 816-U94
View details for DOI 10.1161/CIRCEP.113.001289

View details for Web of Science ID 000344156200010
Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM) JOURNAL OF INTERVENTIONAL CARDIAC ELECTROPHYSIOLOGY Baykaner, T., Lalani, G. G., Schricker, A., Krummen, D. E., Narayan, S. M. 2014; 40 (3): 237-244
Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common indication for catheter ablation. However, despite substantial technical advances in mapping and energy delivery, ablation outcomes remain suboptimal. A major limitation to AF ablation is that the areas targeted for ablation are rarely of proven mechanistic importance, in sharp contrast to other arrhythmias in which ablation targets demonstrated mechanisms in each patient. Focal impulse and rotor modulation (FIRM) is a new approach to demonstrate the mechanisms that sustain AF ("substrates") in each patient that can be used to guide ablation then confirm elimination of each mechanism. FIRM mapping reveals that AF is sustained by 2-3 rotors and focal sources, with a greater number in patients with persistent than paroxysmal AF, lying within spatially reproducible 2.2?�?1.4-cm(2) areas in diverse locations. This temporospatial reproducibility, now confirmed by several groups using various methods, changes the concepts regarding AF-sustaining mechanisms, enabling localized rather than widespread ablation. Mechanistically, the role of rotors and focal sources in sustaining AF has been demonstrated by the acute and chronic success of source (FIRM) ablation alone. Clinically, adding FIRM to conventional ablation substantially improves arrhythmia freedom compared with conventional ablation alone, and ongoing randomized trials are comparing FIRM-ablation with and without conventional ablation to conventional ablation alone. In conclusion, ablation of patient-specific AF-sustaining mechanisms (substrates), as exemplified by FIRM, may be central to substantially improving AF ablation outcomes.

View details for DOI 10.1007/s10840-014-9889-8

View details for Web of Science ID 000341693100006

View details for PubMedID 24647673
Initial Independent Outcomes from Focal Impulse and Rotor Modulation Ablation for Atrial Fibrillation: Multicenter FIRM Registry JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Miller, J. M., Kowal, R. C., Swarup, V., Daubert, J. P., Daoud, E. G., Day, J. D., Ellenbogen, K. A., Hummel, J. D., Baykaner, T., Krummen, D. E., Narayan, S. M., Reddy, V. Y., Shivkumar, K., Steinberg, J. S., Wheelan, K. R. 2014; 25 (9): 921-929
Abstract

The success of pulmonary vein isolation (PVI) for atrial fibrillation (AF) may be improved if stable AF sources identified by Focal Impulse and Rotor Mapping (FIRM) are also eliminated. The long-term results of this approach are unclear outside the centers where FIRM was developed; thus, we assessed outcomes of FIRM-guided AF ablation in the first cases at 10 experienced centers.We prospectively enrolled n = 78 consecutive patients (61 � 10 years) undergoing FIRM guided ablation for persistent (n = 48), longstanding persistent (n = 7), or paroxysmal (n = 23) AF. AF recordings from both atria with a 64-pole basket catheter were analyzed using a novel mapping system (Rhythm View(TM) ; Topera Inc., CA, USA). Identified rotors/focal sources were ablated, followed by PVI.Each institution recruited a median of 6 patients, each of whom showed 2.3 � 0.9 AF rotors/focal sources in diverse locations. 25.3% of all sources were right atrial (RA), and 50.0% of patients had ?1 RA source. Ablation of all sources required a total of 16.6 � 11.7 minutes, followed by PVI. On >1 year follow-up with a 3-month blanking period, 1 patient lost to follow-up (median time to 1st recurrence: 245 days, IQR 145-354), single-procedure freedom from AF was 87.5% (patients without prior ablation; 35/40) and 80.5% (all patients; 62/77) and similar for persistent and paroxysmal AF (P = 0.89).Elimination of patient-specific AF rotors/focal sources produced freedom-from-AF of ?80% at 1 year at centers new to FIRM. FIRM-guided ablation has a rapid learning curve, yielding similar results to original FIRM reports in each center's first cases.

View details for DOI 10.1111/jce.12474

View details for Web of Science ID 000341821200003

View details for PubMedID 24948520
CrossTalk proposal: Rotors have been demonstrated to drive human atrial fibrillation JOURNAL OF PHYSIOLOGY-LONDON Narayan, S. M., Jalife, J. 2014; 592 (15): 3163-3166
View details for DOI 10.1113/jphysiol.2014.271031

View details for Web of Science ID 000340404100001

View details for PubMedID 25085968
Defining Arrhythmic Risk and Defibrillator Therapy in ARVC Shocking Rhythm? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McGarry, T. J., Narayan, S. M. 2014; 64 (2): 126-128
View details for DOI 10.1016/j.jacc.2014.05.010

View details for Web of Science ID 000340238400002

View details for PubMedID 25011715
Rotor Stability Separates Sustained Ventricular Fibrillation From Self-Terminating Episodes in Humans JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Krummen, D. E., Hayase, J., Morris, D. J., Ho, J., Smetak, M. R., Clopton, P., Rappel, W., Narayan, S. M. 2014; 63 (24): 2712-2721
Abstract

This study mapped human ventricular fibrillation (VF) to define mechanistic differences between episodes requiring defibrillation versus those that spontaneously terminate.VF is a leading cause of mortality; yet, episodes may also self-terminate. We hypothesized that the initial maintenance of human VF is dependent upon the formation and stability of VF rotors.We enrolled 26 consecutive patients (age 64 � 10 years, n = 13 with left ventricular dysfunction) during ablation procedures for ventricular arrhythmias, using 64-electrode basket catheters in both ventricles to map VF prior to prompt defibrillation per the institutional review board-approved protocol. A total of 52 inductions were attempted, and 36 VF episodes were observed. Phase analysis was applied to identify biventricular rotors in the first 10 s or until VF terminated, whichever came first (11.4 � 2.9 s to defibrillator charging).Rotors were present in 16 of 19 patients with VF and in all patients with sustained VF. Sustained, but not self-limiting VF, was characterized by greater rotor stability: 1) rotors were present in 68 � 17% of cycles in sustained VF versus 11 � 18% of cycles in self-limiting VF (p < 0.001); and 2) maximum continuous rotations were greater in sustained (17 � 11, range 7 to 48) versus self-limiting VF (1.1 � 1.4, range 0 to 4, p < 0.001). Additionally, biventricular rotor locations in sustained VF were conserved across multiple inductions (7 of 7 patients, p = 0.025).In patients with and without structural heart disease, the formation of stable rotors identifies individuals whose VF requires defibrillation from those in whom VF spontaneously self-terminates. Future work should define the mechanisms that stabilize rotors and evaluate whether rotor modulation may reduce subsequent VF risk.

View details for DOI 10.1016/j.jacc.2014.03.037

View details for Web of Science ID 000337358800010

View details for PubMedID 24794115
Ablation of Rotor and Focal Sources Reduces Late Recurrence of Atrial Fibrillation Compared With Trigger Ablation Alone Extended Follow-Up of the CONFIRM Trial (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Narayan, S. M., Baykaner, T., Clopton, P., Schricker, A., Lalani, G. G., Krummen, D. E., Shivkumar, K., Miller, J. M. 2014; 63 (17): 1761-1768
Abstract

The aim of this study was to determine if ablation that targets patient-specific atrial fibrillation (AF)-sustaining substrates (rotors or focal sources) is more durable than trigger ablation alone at preventing late AF recurrence.Late recurrence substantially limits the efficacy of pulmonary vein isolation for AF and is associated with pulmonary vein reconnection and the emergence of new triggers.Three-year follow-up was performed of the CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial, in which 92 consecutive patients with AF (70.7% persistent) underwent novel computational mapping. Ablation comprised source (focal impulse and rotor modulation [FIRM]) and then conventional ablation in 27 patients (FIRM guided) and conventional ablation alone in 65 patients (FIRM blinded). Patients were followed with implanted electrocardiographic monitors when possible (85.2% of FIRM-guided patients, 23.1% of FIRM-blinded patients).FIRM mapping revealed a median of 2 (interquartile range: 1 to 2) rotors or focal sources in 97.7% of patients during AF. During a median follow-up period of 890 days (interquartile range: 224 to 1,563 days), compared to FIRM-blinded therapy, patients receiving FIRM-guided ablation maintained higher freedom from AF after 1.2 � 0.4 procedures (median 1; interquartile range: 1 to 1) (77.8% vs. 38.5%, p�= 0.001) and a single procedure (p < 0.001) and higher freedom from all atrial arrhythmias (p�= 0.003). Freedom from AF was higher when ablation directly or coincidentally passed through sources than when it missed sources (p < 0.001).FIRM-guided ablation is more durable than conventional trigger-based ablation in preventing 3-year AF recurrence. Future studies should investigate how ablation of patient-specific AF-sustaining rotors and focal sources alters the natural history of arrhythmia recurrence. (The Dynamics of Human Atrial Fibrillation; NCT01008722).

View details for DOI 10.1016/j.jacc.2014.02.543

View details for Web of Science ID 000335312200011

View details for PubMedID 24632280
Lone Atrial Fibrillation Does it Exist? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Wyse, D. G., van Gelder, I. C., Ellinor, P. T., Go, A. S., Kalman, J. M., Narayan, S. M., Nattel, S., Schotten, U., Rienstra, M. 2014; 63 (17): 1715-1723
Abstract

The historical origin of the term "lone atrial fibrillation" (AF) predates by 60 years our current understanding of the pathophysiology of AF, the multitude of known etiologies for AF, and our ability to image and diagnose heart disease. The term was meant to indicate AF in patients for whom subsequent investigations could not demonstrate heart disease, but for many practitioners has become synonymous with "idiopathic AF." As the list of heart diseases has expanded and diagnostic techniques have improved, the prevalence of lone AF has fallen. The legacy of the intervening years is that definitions of lone AF in the literature are inconsistent so that studies of lone AF are not comparable. Guidelines provide a vague definition of lone AF but do not provide direction about how much or what kind of imaging and other testing are necessary to exclude heart disease. There has been an explosion in the understanding of the pathophysiology of AF in the last 20 years in particular. Nevertheless, there are no apparently unique mechanisms for AF in patients categorized as having lone AF. In addition, the term "lone AF" is not invariably useful in making treatment decisions, and other tools for doing so have been more thoroughly and carefully validated. It is, therefore, recommended that use of the term "lone AF" be avoided.

View details for DOI 10.1016/j.jacc.2014.01.023

View details for Web of Science ID 000335312200004

View details for PubMedID 24530673
Intermittent Atrial Tachycardia Promotes Repolarization Alternans and Conduction Slowing During Rapid Rates, and Increases Susceptibility to Atrial Fibrillation in a Free-Behaving Sheep Model JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY Monigatti-Tenkorang, J., Jousset, F., Pascale, P., Vesin, J., Ruchat, P., Fromer, M., Narayan, S. M., Pruvot, E. 2014; 25 (4): 418-427
Abstract

Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood.Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF.This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

View details for DOI 10.1111/jce.12353

View details for Web of Science ID 000334165500013

View details for PubMedID 24383960
Highlights of the Year in JACC 2013 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY DeMaria, A. N., Adler, E. D., Bax, J. J., Ben-Yehuda, O., Feld, G. K., Greenberg, B. H., Hall, J. L., Hlatky, M. A., Lew, W. Y., Lima, J. A., Mahmud, E., Maisel, A. S., Narayan, S. M., Nissen, S. E., Sahn, D. J., Tsimikas, S. 2014; 63 (6): 570-602
View details for DOI 10.1016/j.jacc.2014.01.002

View details for Web of Science ID 000331081700015
Highlights of the year in JACC 2013. Journal of the American College of Cardiology DeMaria, A. N., Adler, E. D., Bax, J. J., Ben-Yehuda, O., Feld, G. K., Greenberg, B. H., Hall, J. L., Hlatky, M. A., Lew, W. Y., Lima, J. A., Mahmud, E., Maisel, A. S., Narayan, S. M., Nissen, S. E., Sahn, D. J., Tsimikas, S. 2014; 63 (6): 570-602
View details for DOI 10.1016/j.jacc.2014.01.002

View details for PubMedID 24524815
Structural contributions to fibrillatory rotors in a patient-derived computational model of the atria. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology Gonzales, M. J., Vincent, K. P., Rappel, W. J., Narayan, S. M., McCulloch, A. D. 2014; 16 Suppl 4: iv3?iv10
Abstract

The aim of this study was to investigate structural contributions to the maintenance of rotors in human atrial fibrillation (AF) and possible mechanisms of termination.A three-dimensional human biatrial finite element model based on patient-derived computed tomography and arrhythmia observed at electrophysiology study was used to study AF. With normal physiological electrical conductivity and effective refractory periods (ERPs), wave break failed to sustain reentrant activity or electrical rotors. With depressed excitability, decreased conduction anisotropy, and shorter ERP characteristic of AF, reentrant rotors were readily maintained. Rotors were transiently or permanently trapped by fibre discontinuities on the lateral wall of the right atrium near the tricuspid valve orifice and adjacent to the crista terminalis, both known sites of right atrial arrhythmias. Modelling inexcitable regions near the rotor tip to simulate fibrosis anchored the rotors, converting the arrhythmia to macro-reentry. Accordingly, increasing the spatial core of inexcitable tissue decreased the frequency of rotation, widened the excitable gap, and enabled an external wave to impinge on the rotor core and displace the source.These model findings highlight the importance of structural features in rotor dynamics and suggest that regions of fibrosis may anchor fibrillatory rotors. Increasing extent of fibrosis and scar may eventually convert fibrillation to excitable gap reentry. Such macro-reentry can then be eliminated by extending the obstacle or by external stimuli that penetrate the excitable gap.

View details for DOI 10.1093/europace/euu251

View details for PubMedID 25362167
Human Atrial Fibrillation Initiates via Organized Rather Than Disorganized Mechanisms. Circulation. Arrhythmia and electrophysiology Schricker, A. A., Lalani, G. G., Krummen, D. E., Rappel, W. J., Narayan, S. M. 2014; 7 (5): 816?24
Abstract

It is unknown how atrial fibrillation (AF) is actually initiated by triggers. Based on consistencies in atrial structure and function in individual patients between episodes of AF, we hypothesized that human AF initiates when triggers interact with deterministic properties of the atria and may engage organized mechanisms.In 31 patients with AF, we mapped AF initiation after spontaneous triggers or programmed stimulation. We used 64-pole basket catheters to measure regional dynamic conduction slowing and to create biatrial activation maps during transitions to AF. Sixty-two AF initiations were recorded (spontaneous, n=28; induced, n=34). Notably, AF did not initiate by disorganized mechanisms, but by either a dominant reentrant spiral wave (76%) or a repetitive focal driver. Both mechanisms were located 21�17 mm from their triggers. AF-initiating spirals formed at the site showing the greatest rate-dependent slowing in each patient. Accordingly, in 10 of 12 patients with multiple observed AF episodes, AF initiated using spatially conserved mechanisms despite diverse triggers.Human AF initiates from triggers by organized rather than disorganized mechanisms, either via spiral wave re-entry at sites of dynamic conduction slowing or via repetitive focal drivers. The finding that diverse triggers initiate AF at predictable, spatially conserved functional sites in each individual provides a novel deterministic paradigm for AF with therapeutic implications.

View details for DOI 10.1161/CIRCEP.113.001289

View details for PubMedID 25217042
Rotors and focal sources for human atrial fibrillation: mechanistic paradigm with direct clinical relevance. Circulation journal : official journal of the Japanese Circulation Society Lalani, G. G., Trikha, R., Krummen, D. E., Narayan, S. M. 2014; 78 (10): 2357?66
Abstract

Outcomes for patients with atrial fibrillation (AF) have changed little despite many advances in technology. In large part, this reflects fundamental uncertainty about the mechanisms for AF in humans, which must reconcile diverse observations. Despite the complexity of AF, many electrophysiologists have witnessed modulation of 'chaotic' AF after the first few ablation lesions, or before lines are complete or trigger sites are isolated, and numerous analyses demonstrate temporospatial stability in AF. These common observations challenge the concept that AF is driven by spatially disorganized, widespread mechanisms. Using mathematical techniques applied to other complex systems, evidence is rapidly accumulating that human AF is largely sustained by localized rotors and focal sources. Elimination of sources by Focal Impulse and Rotor Modulation (FIRM)-guided ablation has been shown by independent laboratories to substantially improve success compared with pulmonary vein isolation alone. These data advance our mechanistic understanding of AF. Randomized trials are underway to verify the relative efficacy of ablation at AF sources (substrate) vs. conventional trigger ablation. The renewed focus on AF substrates is a paradigm shift, but also a re-alignment of concepts for AF towards those for other cardiac arrhythmias that are generally defined by sustaining mechanisms (substrates).

View details for PubMedID 25213002
Rhythm control in heart failure patients with atrial fibrillation: contemporary challenges including the role of ablation. Journal of the American College of Cardiology Trulock, K. M., Narayan, S. M., Piccini, J. P. 2014; 64 (7): 710?21
Abstract

Because nonpharmacological interventions likely alter the risks and benefits associated with rhythm control, this paper reviews the role of current rhythm control strategies in atrial fibrillation. This report also focuses on the specific limitations of pharmacological interventions and the utility of percutaneous ablation in this growing population of patients with concomitant atrial fibrillation and heart failure.

View details for DOI 10.1016/j.jacc.2014.06.1169

View details for PubMedID 25125304
A case of a human ventricular fibrillation rotor localized to ablation sites for scar-mediated monomorphic ventricular tachycardia HEART RHYTHM Hayase, J., Tung, R., Narayan, S. M., Krummen, D. E. 2013; 10 (12): 1913-1916
View details for DOI 10.1016/j.hrthm.2013.07.049

View details for Web of Science ID 000327767600035

View details for PubMedID 23911894
Frequency Analysis of Atrial Action Potential Alternans A Sensitive Clinical Index of Individual Propensity to Atrial Fibrillation CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Lalani, G. G., Schricker, A. A., Clopton, P., Krummen, D. E., Narayan, S. M. 2013; 6 (5): 859-867
Abstract

Few clinical indices identify the propensity of patients to atrial fibrillation (AF) when not in AF. Repolarization alternans has been shown to indicate AF vulnerability, but is limited in its sensitivity to detect changes in action potential (AP) duration (APD), which may be subtle. We hypothesized that spectral analysis would be a more sensitive and robust marker of AP alternans and thus a better clinical index of individual propensity to AF than APD alternans.In 31 patients (12 persistent AF, 15 paroxysmal AF, 4 controls with no AF), we recorded left (n=27) and right (n=6) atrial monophasic APs during incremental pacing from cycle length 500 ms (120 beats per minute) to AF onset. Alternans was measured by APD and spectral analysis. At baseline pacing (median cycle length [1st, 3rd quartiles], 500 ms [500, 500]), APD alternans was detected in only 7 of 27 AF patients (no controls), whereas spectral AP alternans was detected in 18 of 27 AF patients (no controls; P=0.003); AP alternans was more prevalent in persistent than paroxysmal AF, and absent in controls (P=0.018 APD; P=0.042 spectral). Spectral AP alternans magnitude at baseline was highest in persistent AF, with modest rate-dependent amplification, followed by paroxysmal AF, with marked rate dependence, and undetectable in controls until just before induced AF.Spectral AP alternans near baseline rates can identify patients with, versus those without, clinical histories and pathophysiological substrates for AF. Future studies should examine whether the presence of spectral AP alternans during sinus rhythm may obviate the need to actually demonstrate AF, such as on ambulatory ECG monitoring.

View details for DOI 10.1161/CIRCEP.113.000204

View details for Web of Science ID 000329923700014

View details for PubMedID 23995250
Targeted Ablation at Stable Atrial Fibrillation Sources Improves Success Over Conventional Ablation in High-Risk Patients: A Substudy of the CONFIRM Trial CANADIAN JOURNAL OF CARDIOLOGY Baykaner, T., Clopton, P., Lalani, G. G., Schricker, A. A., Krummen, D. E., Narayan, S. M. 2013; 29 (10): 1218-1226
Abstract

Pulmonary vein (PV) isolation has disappointing results in patients with obesity, heart failure, obstructive sleep apnea (OSA) and enlarged left atria (LA), for unclear reasons. We hypothesized that these comorbidities may cause higher numbers or non-PV locations of atrial fibrillation (AF) sources, where targeted source ablation (focal impulse and rotor modulation [FIRM]) should improve the single-procedure success of ablation.The Conventional Ablation of AF With or Without Focal Impulse and Rotor Modulation (CONFIRM) trial prospectively enrolled 92 patients at 107 AF ablation procedures, in whom computational mapping identified AF rotors or focal sources. Patients underwent FIRM plus conventional ablation (FIRM-guided), or conventional ablation only, and were evaluated for recurrent AF quarterly with rigourous, often implanted, monitoring. We report the n = 73 patients undergoing first ablation in whom demographic information was available (n = 52 conventional, n = 21 FIRM-guided).Stable sources for AF were found in 97.1% of patients. The numbers of concurrent sources per patient (2.1 � 1.1) rose with LA diameter (P = 0.021), lower left ventricular ejection fraction (P = 0.039), and the presence of OSA (P = 0.002) or hypomagnesemia (P = 0.017). Right atrial sources were associated with obesity (body mass index ? 30; P = 0.015). In patients with obesity, hypertension, OSA, and LA diameter > 40 mm, single-procedure freedom from AF was > 80% when FIRM-guided was used vs. < 50% when conventional ablation was used (all; P < 0.05).Patients with "difficult to treat" AF exhibit more concurrent AF sources in more widespread biatrial distributions than other patients. These mechanisms explain the disappointing results of PV isolation, and how FIRM can identify patient-specific AF sources to enable successful ablation in this population.

View details for DOI 10.1016/j.cjca.2013.07.672

View details for Web of Science ID 000324858700011

View details for PubMedID 23993247
Direct or Coincidental Elimination of Stable Rotors or Focal Sources May Explain Successful Atrial Fibrillation Ablation On-Treatment Analysis of the CONFIRM Trial (Conventional Ablation for AF With or Without Focal Impulse and Rotor Modulation) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Narayan, S. M., Krummen, D. E., Clopton, P., Shivkumar, K., Miller, J. M. 2013; 62 (2): 138-147
Abstract

This study sought to determine whether ablation of recently described stable atrial fibrillation (AF) sources, either directly by Focal Impulse and Rotor Modulation (FIRM) or coincidentally when anatomic ablation passes through AF sources, may explain long-term freedom from AF.It is unclear why conventional anatomic AF ablation can be effective in some patients yet ineffective in others with similar profiles.The CONFIRM (Conventional Ablation for AF With or Without Focal Impulse and Rotor Modulation) trial prospectively revealed stable AF rotors or focal sources in 98 of 101 subjects with AF at 107 consecutive ablation cases. In 1:2 fashion, subjects received targeted source ablation (FIRM) followed by conventional ablation, or conventional ablation alone. We determined whether ablation lesions on electroanatomic maps passed through AF sources on FIRM maps.Subjects who completed follow-up (n = 94; 71.2% with persistent AF) showed 2.3 � 1.1 concurrent AF rotors or focal sources that lay near pulmonary veins (22.8%), left atrial roof (16.0%), and elsewhere in the left (28.2%) and right (33.0%) atria. AF sources were ablated directly in 100% of FIRM cases and coincidentally (e.g., left atrial roof) in 45% of conventional cases (p < 0.05). During a median (interquartile range) of 273 days (138 to 636 days) after one procedure, AF was absent in 80.3% of patients if sources were ablated but in only 18.2% of patients if sources were missed (p < 0.001). Freedom from AF was highest if all sources were ablated, intermediate if some sources were ablated, and lowest if no sources were ablated (p < 0.001).Elimination of stable AF rotors and focal sources may explain freedom from AF after diverse approaches to ablation. Patient-specific AF source distributions are consistent with the reported success of specific anatomic lesion sets and of widespread ablation. These results support targeting AF sources to reduce unnecessary ablation, and motivate studies on FIRM-only ablation.

View details for DOI 10.1016/j.jacc.2013.03.021

View details for Web of Science ID 000321338600010

View details for PubMedID 23563126
Panoramic Electrophysiological Mapping but not Electrogram Morphology Identifies Stable Sources for Human Atrial Fibrillation Stable Atrial Fibrillation Rotors and Focal Sources Relate Poorly to Fractionated Electrograms CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Narayan, S. M., Shivkumar, K., Krummen, D. E., Miller, J. M., Rappel, W. 2013; 6 (1): 58-67
Abstract

The foundation for successful arrhythmia ablation is the mapping of electric propagation to identify underlying mechanisms. In atrial fibrillation (AF), however, mapping is difficult so that ablation has often targeted electrogram features, with mixed results. We hypothesized that wide field-of-view (panoramic) mapping of both atria would identify causal mechanisms for AF and allow interpretation of local electrogram features, including complex fractionated atrial electrograms (CFAE).Contact mapping was performed using biatrial multipolar catheters in 36 AF subjects (29 persistent). Stable AF rotors (spiral waves) or focal sources were seen in 35 of 36 cases and targeted for ablation (focal impulse and rotor modulation) before pulmonary vein isolation. In 31 of 36 subjects (86.1%), AF acutely terminated (n=20; 16 to sinus rhythm) or organized (n=11; 19�8% slowing) with 2.5 minutes focal impulse and rotor modulation (interquartile range, 1.0-3.1) at one source, defined as the primary source. Subjects exhibited 2.1�1.0 concurrent AF sources of which the primary, by phase mapping, precessed in limited areas (persistent 2.5�1.7 versus paroxysmal 1.7�0.5 cm(2); P=0.30). Notably, source regions showed mixed electrogram amplitudes and CFAE grades that did not differ from surrounding atrium (P=NS). AF sources were not consistently surrounded by CFAE (P=0.67).Stable rotors and focal sources for human AF were revealed by contact panoramic mapping (focal impulse and rotor modulation mapping), but not by electrogram footprints. AF sources precessed within areas of ?2 cm(2), with diverse voltage characteristics poorly correlated with CFAE. Most CFAE sites lie remote from AF sources and are not suitable targets for catheter ablation of AF.

View details for DOI 10.1161/CIRCEP.111.977264

View details for Web of Science ID 000320670700013

View details for PubMedID 23392583
What Tissue Does Circumferential PV Isolation Actually Modulate? Journal of cardiovascular electrophysiology McGarry, T. J., Narayan, S. M. 2013
View details for DOI 10.1111/jce.12310

View details for PubMedID 24152088

View details for PubMedCentralID PMC3997629
HRS Policy Statement: Clinical Cardiac Electrophysiology Fellowship Curriculum: Update 2011 HEART RHYTHM Link, M. S., Exner, D. V., Anderson, M., Ackerman, M., Al-Ahmad, A., Knight, B. P., Markowitz, S. M., Kaufman, E. S., Haines, D., Asirvatham, S. J., Callans, D. J., Mounsey, J. P., Bogun, F., Narayan, S. M., Krahn, A. D., Mittal, S., Singh, J., Fisher, J. D., Chugh, S. S. 2011; 8 (8): 1340-1356
View details for DOI 10.1016/j.hrthm.2011.06.008

View details for Web of Science ID 000293013600033

View details for PubMedID 21699868
Highlights of the Year in JACC 2010 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY DeMaria, A. N., Bax, J. J., Ben-Yehuda, O., Feld, G. K., Greenberg, B. H., Hall, J., Hlatky, M., Lew, W. Y., Lima, J. A., Maisel, A. S., Narayan, S. M., Nissen, S., Sahn, D. J., Tsimikas, S. 2011; 57 (4): 480-514
View details for DOI 10.1016/j.jacc.2010.12.007

View details for Web of Science ID 000286376500015

View details for PubMedID 21251590
Highlights of the Year in JACC 2009 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY DeMaria, A. N., Bax, J. J., Ben-Yehuda, O., Feld, G. K., Greenberg, B. H., Hall, J., Hlatky, M., Lew, W. Y., Lima, J. A., Maisel, A. S., Narayan, S. M., Nissen, S., Sahn, D. J., Tsimikas, S. 2010; 55 (4): 380-407
View details for DOI 10.1016/j.jacc.2009.12.007

View details for Web of Science ID 000273802200023

View details for PubMedID 20117446

Sanjiv Narayan

Professor of Medicine (Cardiovascular Medicine) at the Stanford University Medical Center

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