3-Year Outcomes From the Amplatzer Amulet Left Atrial Appendage Occluder Randomized Controlled Trial (Amulet IDE).

BACKGROUND: The Amulet (Abbott) left atrial appendage occluder investigational device exemption trial is the largest randomized trial evaluating the safety and effectiveness of the Amulet left atrial appendage occluder compared with the Watchman 2.5 device (Boston Scientific) through 5 years. OBJECTIVES: This analysis evaluated the device effect on 3-year outcomes in the Amulet investigational device exemption trial. METHODS: The medication regimen and key clinical outcomes were reported through 3 years including: 1) the composite of ischemic stroke or systemic embolism (SE); 2) the composite of all strokes, SE, or cardiovascular (CV) death; 3) major bleeding; and 4) all-cause death and CV death. RESULTS: A total of 1,878 patients at 108 sites were randomized. A significantly higher percentage of patients were free of oral anticoagulation usage at 3 years with Amulet (96.2%) vs Watchman (92.5%) (P < 0.01). Clinical outcomes were comparable for the composite of ischemic stroke or SE (5.0% vs 4.6%; P = 0.69); the composite of all strokes, SE, or CV death (11.1% vs 12.7%; P = 0.31); major bleeding (16.1% vs 14.7%; P = 0.46); all-cause death (14.6% vs 17.9%; P = 0.08); and CV death (6.6% vs 8.5%; P = 0.14) for Amulet and Watchman, respectively. Through 3 years, device factors (device-related thrombus or peridevice leak ≥3 mm) preceded ischemic stroke events and CV deaths more frequently in Watchman compared with Amulet patients. CONCLUSIONS: The Amulet occluder demonstrated continued safety and effectiveness with over 96% free of oral anticoagulation usage through 3 years in a high-risk population compared to the Watchman device. (AMPLATZER Amulet LAA Occluder Trial [Amulet IDE]; NCT02879448).

Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS: Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS: An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION: The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique identifier NCT02879448.

Incidence, Predictors, and Clinical Outcomes of Device-Related Thrombus in the Amulet IDE Trial.

BACKGROUND: Device-related thrombus (DRT) following left atrial appendage occlusion (LAAO) can lead to adverse clinical outcomes. DRT rates and outcomes from randomized trials are limited. OBJECTIVES: This analysis investigated the incidence, predictors, and clinical outcomes of DRT following LAAO in the Amulet IDE (AMPLATZER Amulet LAA Occluder Trial) trial. METHODS: Successful implants occurred in 903 patients with an Amulet occluder (dual occlusive mechanism device) and 885 patients with a Watchman device (single occlusive mechanism device). These patients were then followed through 18 months and DRT was assessed by transesophageal echocardiography. RESULTS: The overall incidence of DRT was 3.9% (n = 70) with 3.4% (n = 30) in dual occlusive mechanism device patients and 4.8% (n = 40) in single occlusive mechanism device patients. Most DRTs (n = 19 of 31) were identified early (≤45 days) on the dual occlusive mechanism device, whereas most of the DRTs (n = 31 of 42) were identified late (>45 days) on the single occlusive mechanism device. Strong predictors of DRT included atrial fibrillation at time of procedure (HR: 2.44; 95% CI: 1.42-4.22; P < 0.01), female sex (HR: 1.65; 95% CI: 1.01-2.71; P = 0.04), and older age (HR: 1.04; 95% CI: 1.01-1.08; P = 0.02). There were no stroke events following DRT in the dual occlusive mechanism device group and 3 stroke events following DRT in the single occlusive mechanism device group. Patients with DRT were at a greater risk for cardiovascular mortality compared with non-DRT patients (8.7% vs 3.9%; HR: 2.33; 95% CI: 1.01-5.39; P = 0.04). CONCLUSIONS: Incidence of DRT following LAAO was low. Early DRTs are seen with the dual occlusive mechanism device and late DRTs are seen with the single occlusive mechanism device. Increased cardiovascular mortality risk in patients with DRT should be further investigated. (AMPLATZER Amulet LAA Occluder Trial; NCT02879448).

Wireless Communication Between Paired Leadless Pacemakers for Dual-Chamber Synchrony.

BACKGROUND: Leadless pacemakers (LPs) can mitigate conventional pacemaker complications related to the transvenous leads and subcutaneous pocket surrounding the pulse generator. Although single-chamber leadless pacing has been established, multichamber pacing requires wireless bidirectional communication across multiple LPs to maintain synchrony. This preclinical study demonstrates the chronic performance of implant-to-implant (i2i) communication that achieves synchronous, dual-chamber pacing with 2 LPs. METHODS: The i2i communication modality employs subthreshold electrical signals conducted between implanted LPs through the blood and myocardial tissue on a beat-by-beat basis. Right atrial and right ventricular LPs were implanted in 9 ovine subjects. The i2i transmission performance was evaluated 13 weeks after implant. RESULTS: Right atrial and right ventricular LPs were implanted successfully and without complication in 9 ovine subjects. A total of 8715±457 right atrial-to-right ventricular and right ventricular-to-right atrial transmissions were sent per hour, with a success rate of 99.2±0.9%. Of periods with i2i communication failure when DDD pacing was not possible, 97.3±1.8% were resolved within 6 s. CONCLUSIONS: For the first time, synchronized, dual-chamber pacing has been demonstrated in a chronic preclinical feasibility study by 2 leadless pacemakers using beat-to-beat, wireless communication, achieving a success rate of 99.2%.

A Blueprint for Productive Maintenance of Certification, But Is the American Board of Internal Medicine up to the Challenge?

The future of the American Board of Internal Medicine Maintenance of Certification (MOC) program is at a crossroads. The current MOC program lacks a clear visible mission, adds to modern health care's onerous bureaucracy, and thus pulls physicians from the most important humanistic aspects of their profession. The aim of the MOC program should be to promote the best patient care by ensuring certified physicians maintain core skills through continuous education and evaluation. The program should focus on education and be designed with the rigorous obligations of practicing physicians in mind. Moving forward, the American Board of Internal Medicine should cocreate MOC with the physician community and apply innovative adult education techniques. Over time, data-driven methods and member feedback should be used to provide continuous program improvement. This review describes the origins of the current state of MOC, explores its evidence base, provides examples of model programs for the maintenance of complex professional skills, and outlines guiding principles for the future of MOC.

Evaluation of Coronary Artery Disease Using Myocardial Elastography with Diverging Wave Imaging: Validation against Myocardial Perfusion Imaging and Coronary Angiography.

Myocardial elastography (ME) is an ultrasound-based technique that can image 2-D myocardial strains. The objectives of this study were to illustrate that 2-D myocardial strains can be imaged with diverging wave imaging and differ, on average, between normal and coronary artery disease (CAD) patients. In this study, 66 patients with symptoms of CAD were imaged with myocardial elastography before a nuclear stress test or an invasive coronary angiography. Radial cumulative strains were estimated in all patients. The end-systolic radial strain in the total cross section of the myocardium was significantly higher in normal patients (17.9 ± 8.7%) than in patients with reversible perfusion defect (6.2 ± 9.3%, p < 0.001) and patients with significant (-0.9 ± 7.4%, p < 0.001) and non-significant (3.7 ± 5.7%, p < 0.01) lesions. End-systolic radial strain in the left anterior descending, left circumflex and right coronary artery territory was found to be significantly higher in normal patients than in CAD patients. These preliminary findings indicate that end-systolic radial strain measured with ME is higher on average in healthy persons than in CAD patients and that ME has the potential to be used for non-invasive, radiation-free early detection of CAD.

Validation of electromechanical wave imaging in a canine model during pacing and sinus rhythm.

BACKGROUND: Accurate determination of regional areas of arrhythmic triggers is of key interest to diagnose arrhythmias and optimize their treatment. Electromechanical wave imaging (EWI) is an ultrasound technique that can image the transient deformation in the myocardium after electrical activation and therefore has the potential to detect and characterize location of triggers of arrhythmias. OBJECTIVES: The objectives of this study were to investigate the relationship between the electromechanical and the electrical activation of the left ventricular (LV) endocardial surface during epicardial and endocardial pacing and during sinus rhythm as well as to map the distribution of electromechanical delays. METHODS: In this study, 6 canines were investigated. Two external electrodes were sutured onto the epicardial surface of the LV. A 64-electrode basket catheter was inserted through the apex of the LV. Ultrasound channel data were acquired at 2000 frames/s during epicardial and endocardial pacing and during sinus rhythm. Electromechanical and electrical activation maps were synchronously obtained from the ultrasound data and the basket catheter, respectively. RESULTS: The mean correlation coefficient between electromechanical and electrical activation was 0.81 for epicardial anterior pacing, 0.79 for epicardial lateral pacing, 0.69 for endocardial pacing, and 0.56 for sinus rhythm. CONCLUSION: The electromechanical activation sequence determined by EWI follows the electrical activation sequence and more specifically in the case of pacing. This finding is of key interest in the role that EWI can play in the detection of the anatomical source of arrhythmias and the planning of pacing therapies such as cardiovascular resynchronization therapy.

Assessing the atrial electromechanical coupling during atrial focal tachycardia, flutter, and fibrillation using electromechanical wave imaging in humans.

Minimally-invasive treatments of cardiac arrhythmias such as radio-frequency ablation are gradually gaining importance in clinical practice but still lack a noninvasive imaging modality which provides insight into the source or focus of an arrhythmia. Cardiac deformations imaged at high temporal and spatial resolution can be used to elucidate the electrical activation sequence in normal and paced human subjects non-invasively and could potentially aid to better plan and monitor ablation-based arrhythmia treatments. In this study, a novel ultrasound-based method is presented that can be used to quantitatively characterize focal and reentrant arrhythmias. Spatio-temporal maps of the full-view of the atrial and ventricular mechanics were obtained in a single heartbeat, revealing with otherwise unobtainable detail the electromechanical patterns of atrial flutter, fibrillation, and tachycardia in humans. During focal arrhythmias such as premature ventricular complex and focal atrial tachycardia, the previously developed electromechanical wave imaging methodology is hereby shown capable of identifying the location of the focal zone and the subsequent propagation of cardiac activation. During reentrant arrhythmias such as atrial flutter and fibrillation, Fourier analysis of the strains revealed highly correlated mechanical and electrical cycle lengths and propagation patterns. High frame rate ultrasound imaging of the heart can be used non-invasively and in real time, to characterize the lesser-known mechanical aspects of atrial and ventricular arrhythmias, also potentially assisting treatment planning for intraoperative and longitudinal monitoring of arrhythmias.

Atrial electromechanical cycle length mapping in paced canine hearts in vivo.

Atrial arrhythmias affect millions of people worldwide. Characterization and study of arrhythmias in the atria in the clinic is currently performed point by point using mapping catheters capable of generating maps of the electrical activation rate or cycle length. In this paper, we describe a new ultrasound-based mapping technique called electromechanical cycle length mapping (ECLM) capable of estimating the electromechanical activation rate, or cycle length, i.e., the rate of the mechanical activation of the myocardium which follows the electrical activation. ECLM relies on frequency analysis of the incremental strain within the atria and can be performed in a single acquisition. ECLM was validated in a canine model paced from the left atrial appendage, against pacing rates within the reported range of cycle lengths previously measured during atrial arrhythmias such as atrial fibrillation. Correlation between the global estimated electromechanical cycle lengths and pacing rates was shown to be excellent (slope = 0.983, intercept = 3.91, r(2) = 0.9999). The effect of the number of cardiac cycles on the performance of ECLM was also investigated and the reproducibility of ECLM was demonstrated (error between consecutive acquisitions for all pacing rates: 6.3 ± 4.3%). These findings indicate the potential of ECLM for noninvasively characterizing atrial arrhythmias and provide feedback on the treatment planning of catheter ablation procedures in the clinic.

Intracardiac myocardial elastography in canines and humans in vivo.

Intracardiac echocardiography (ICE) is a useful imaging modality which is used during RF ablation procedures to identify anatomical structures. Utilizing ICE in conjunction with myocardial elastography (ME) can provide additional information on the mechanical properties of cardiac tissue and provide information on mechanical changes caused by ablation. The objective of this study was to demonstrate that ICE can be used at high frame rate using a diverging beam transmit sequence to image myocardial strain and differentiate myocardial tissue properties before, during, and after ablation for a clinical ablation procedure. In this feasibility study, three normal canines and eight patients with atrial fibrillation (AF) were studied in vivo. A 5.8-MHz ICE transducer was used to image the heart with a diverging beam transmit method achieving 1200 frames per second (fps). Cumulative axial displacement estimation was performed using 1-D cross-correlation with a window size of 2.7 mm and 95% overlap. Axial cumulative strains were estimated in the left atrium (LA) and right atrium (RA) using a least-squares estimator with a kernel of 2 mm on the axial displacements. In the canine case, radial thickening was detected in the lateral wall and in the interatrial septum during LA emptying. For AF patients, the mean absolute strain in the ablated region was lower (6.7 ± 3.1%) than before the ablation (17.4 ± 9.3%) in LA at the end of the LA emptying phase. In the cavotricuspid isthmus (CTI) region, mean absolute strain magnitude at the end of the RA emptying phase was found to be higher during ablation (43.0 ± 18.1%) compared with after ablation (33.7 ± 15.8%). Myocardial strains in the LA of an AF patient were approximately 2.6 times lower in the ablated region than before ablation. This initial feasibility indicates that ME can be used as a new imaging modality in conjunction with ICE in RF ablation guidance and lesion monitoring.

Electromechanical wave imaging of biologically and electrically paced canine hearts in vivo.

Electromechanical wave imaging (EWI) has been show capable of directly and entirely non-invasively mapping the trans mural electromechanical activation in all four cardiac chambers in vivo. In this study, we assessed EWI repeatability and reproducibility, as well as its capability of localizing electronic and, for the first time, biological pacing locations in closed-chest, conscious canines. Electromechanical activation was obtained in six conscious animals during normal sinus rhythm (NSR) and idioventricular rhythms occurring in dogs with complete heart block instrumented with electronic and biologic pacemakers (EPM and BPM respectively). After atrioventricular node ablation, dogs were implanted with an EPM in the right ventricular (RV) endocardial apex (n = 4) and two additionally received a BPM at the left ventricular (LV) epicardial base (n = 2). EWI was performed trans thoracically during NSR, BPM and EPM pacing, in conscious dogs, using an unfocused transmit sequence at 2000 frames/s. During NSR, the EW originated at the right atrium (RA), propagated to the left atrium (LA) and emerged from multiple sources in both ventricles. During EPM, the EW originated at the RV apex and propagated throughout both ventricles. During BPM, the EW originated from the LV basal lateral wall and subsequently propagated throughout the ventricles. EWI differentiated BPM from EPM and NSR and identified the distinct pacing origins. Isochrone comparison indicated that EWI was repeatable and reliable. These findings thus indicate the potential for EWI to serve as a simple, non-invasive and direct imaging technology for mapping and characterizing arrhythmias as well as the treatments thereof.

Ventricular cycle length characteristics estimative of prolonged RR interval during atrial fibrillation.

BACKGROUND: When atrial fibrillation (AF) is incessant, imaging during a prolonged ventricular RR interval may improve image quality. It was hypothesized that long RR intervals could be predicted from preceding RR values. METHODS: From the PhysioNet database, electrocardiogram RR intervals were obtained from 74 persistent AF patients. An RR interval lengthened by at least 250 ms beyond the immediately preceding RR interval (termed T0 and T1, respectively) was considered prolonged. A two-parameter scatterplot was used to predict the occurrence of a prolonged interval T0. The scatterplot parameters were: (1) RR variability (RRv) estimated as the average second derivative from 10 previous pairs of RR differences, T13-T2, and (2) Tm-T1, the difference between Tm, the mean from T13 to T2, and T1. For each patient, scatterplots were constructed using preliminary data from the first hour. The ranges of parameters 1 and 2 were adjusted to maximize the proportion of prolonged RR intervals within range. These constraints were used for prediction of prolonged RR in test data collected during the second hour. RESULTS: The mean prolonged event was 1.0 seconds in duration. Actual prolonged events were identified with a mean positive predictive value (PPV) of 80% in the test set. PPV was >80% in 36 of 74 patients. An average of 10.8 prolonged RR intervals per 60 minutes was correctly identified. CONCLUSIONS: A method was developed to predict prolonged RR intervals using two parameters and prior statistical sampling for each patient. This or similar methodology may help improve cardiac imaging in many longstanding persistent AF patients.

Temporal stability in the spectral representation of complex fractionated atrial electrograms.

BACKGROUND: Although local electrograms during atrial fibrillation (AF) are often spectrally analyzed over 8-second (8s) intervals, changes may be common over intervals as short as 2s. We sought to determine whether averaged 2s measurements of electrogram spectral parameters were similar to 8s measurements, and whether the 2s intervals could provide an estimate of the temporal stability of the signal frequency content in paroxysmal versus persistent AF. METHODS: Complex fractionated atrial electrograms (CFAEs) were acquired outside the pulmonary vein ostia and from free wall sites in nine paroxysmal and 10 longstanding persistent AF patients. Using a 2s sliding calculation window, a frequency spectrum was computed every 100 ms over an interval of 8.4 seconds (82 spectra in total). The dominant frequency (DF), the dominant amplitude (DA), and the mean spectral profile (MP) were measured. The 2s measurements were compared to single 8.4-second interval measurements. Coefficients of variation (COV) were computed from the 82 spectra for each CFAE recording to determine temporal variability of parameters. RESULTS: Over the sliding 2s computation intervals, as for fixed 8.4-second computation intervals, mean DA and DF were significantly higher in longstanding persistent AF while MP was significantly higher in paroxysmal AF (P ≤ 0.001). The COV was significantly higher for the DF parameter in paroxysmal AF (P < 0.001) and significantly higher for the MP parameter in persistent AF (P < 0.02). CONCLUSIONS: For both paroxysmal and persistent AF data, the 2s sliding window averages provide similar results to single 8.4-second intervals, and information regarding temporal stability was additionally obtained in the process.

A clinical feasibility study of atrial and ventricular electromechanical wave imaging.

BACKGROUND: Cardiac resynchronization therapy (CRT) and atrial ablation procedures currently lack a noninvasive imaging modality for reliable treatment planning and monitoring. Electromechanical wave imaging (EWI) is an ultrasound-based method that has previously been shown to be capable of noninvasively and transmurally mapping the activation sequence of the heart in animal studies by estimating and imaging the electromechanical wave, that is, the transient strains occurring in response to the electrical activation, at both high temporal and spatial resolutions. OBJECTIVE: To demonstrate the feasibility of transthoracic EWI for mapping the activation sequence during different cardiac rhythms in humans. METHODS: EWI was perfor`med in patients undergoing CRT and a left bundle branch block (LBBB) during sinus rhythm, left ventricular pacing, and right ventricular pacing, as well as in patients with atrial flutter (AFL) before intervention, EWI findings from patients with AFL were subsequently correlated with results from invasive intracardiac electrical mapping studies during intervention. In addition, the feasibility of single-heartbeat EWI at 2000 frames/s is demonstrated in humans for the first time in a patient with both AFL and right bundle branch block (RBBB). RESULTS: The electromechanical activation maps demonstrated the capability of EWI to localize the pacing sites and characterize the bundle branch block activation sequence transmurally in patients with CRT. In patients with AFL, the EWI propagation patterns obtained with EWI were in excellent agreement with those obtained from invasive intracardiac mapping studies. CONCLUSIONS: Our findings demonstrate the potential capability of EWI to aid in the assessment and follow-up of patients undergoing CRT pacing therapy and atrial ablation, with preliminary validation in vivo.

Spectral profiles of complex fractionated atrial electrograms are different in longstanding and acute onset atrial fibrillation atrial electrogram spectra.

UNLABELLED: Spectral Profiles of CFAE. BACKGROUND: Spectral analysis of complex fractionated atrial electrograms (CFAE) may be useful for gaining insight into mechanisms underlying paroxysmal and longstanding atrial fibrillation (AF). The commonly used dominant frequency (DF) measurement has limitations. METHOD: CFAE recordings were acquired from outside the 4 pulmonary vein ostia and at 2 left atrial free wall sites in 10 paroxysmal and 10 persistent AF patients. Two consecutive 8s-series were analyzed from recordings >16s in duration. Power spectra were computed for each 8s-series in the range 3-12 Hz and normalized. The mean and standard deviation of normalized power spectra (MPS and SPS, respectively) were compared for paroxysmal versus persistent CFAE. Also, the DF and its peak amplitude (ADF) were compared for pulmonary vein sites only. Power spectra were computed using ensemble average and Fourier methods. RESULTS: No significant changes occurred in any parameter from the first to second recording sequence. For both sequences, MPS and SPS were significantly greater, and DF and ADF were significantly less, in paroxysmals versus persistents. The MPS and ADF measurements from ensemble spectra produced the most significant differences in paroxysmals versus persistents (P < 0.0001). DF differences were less significant, which can be attributed to the relatively high variability of DF in paroxysmals. The MPS was correlated to the duration of uninterrupted persistent AF prior to electrophysiologic study (P = 0.01), and to left atrial volume for all AF (P < 0.05). CONCLUSIONS: The MPS and ADF measurements introduced in this study are probably superior to DF for discerning power spectral differences in paroxysmal versus longstanding CFAE. (J Cardiovasc Electrophysiol, Vol. 23, pp. 971-979, September 2012).

Electromechanical wave imaging for arrhythmias.

Electromechanical wave imaging (EWI) is a novel ultrasound-based imaging modality for mapping of the electromechanical wave (EW), i.e. the transient deformations occurring in immediate response to the electrical activation. The correlation between the EW and the electrical activation has been established in prior studies. However, the methods used previously to map the EW required the reconstruction of images over multiple cardiac cycles, precluding the application of EWI for non-periodic arrhythmias such as fibrillation. In this study, new imaging sequences are developed and applied based on flash- and wide-beam emissions to image the entire heart at very high frame rates (2000 fps) during free breathing in a single heartbeat. The methods are first validated by imaging the heart of an open-chest canine while simultaneously mapping the electrical activation using a 64-electrode basket catheter. Feasibility is then assessed by imaging the atria and ventricles of closed-chest, conscious canines during sinus rhythm and during right-ventricular pacing following atrio-ventricular dissociation, i.e., during a non-periodic rhythm. The EW was validated against electrode measurements in the open-chest case, and followed the expected electrical propagation pattern in the closed-chest setting. These results indicate that EWI can be used for the characterization of non-periodic arrhythmias in conditions similar to the clinical setting, in a single heartbeat, and during free breathing.

Differences in repeating patterns of complex fractionated left atrial electrograms in longstanding persistent atrial fibrillation as compared with paroxysmal atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrograms (CFAE) are morphologically more uniform in persistent longstanding as compared with paroxysmal atrial fibrillation (AF). It was hypothesized that this may result from a greater degree of repetitiveness in CFAE patterns at disparate left atrial (LA) sites in longstanding AF. METHODS AND RESULTS: CFAEs were obtained from recording sites outside the 4 pulmonary vein (PV) ostia and at a posterior and an anterior LA site during paroxysmal and longstanding persistent AF (10 patients each, 120 sequences total). To quantify repetitiveness in CFAE, the dominant frequency was measured from ensemble spectra using 8.4-second sequences, and repetitiveness was calculated by 2 novel techniques: linear prediction and Fourier reconstruction methods. Lower prediction and reconstruction errors were considered indicative of increasing repetitiveness and decreasing randomness. In patients with paroxysmal AF, CFAE pattern repetitiveness was significantly lower (randomness higher) at antral sites outside PV ostia as compared with LA free wall sites (P < 0.001). In longstanding AF, repetitiveness increased outside the PV ostia, especially outside the left superior PV ostium, and diminished at the LA free wall sites. The result was that in persistent AF, there were no significant site-specific differences in CFAE repetitiveness at the selected LA locations used in this study. Average dominant frequency magnitude was 5.32 ± 0.29 Hz in paroxysmal AF and higher in longstanding AF, at 6.27 ± 0.13 Hz (P < 0.001), with the frequency of local activation approaching a common upper bound for all sites. CONCLUSIONS: In paroxysmal AF, CFAE repetitiveness is low and randomness high outside the PVs, particularly the left superior PV. As evolution to persistent longstanding AF occurs, CFAE repetitiveness becomes more uniformly distributed at disparate sites, possibly signifying an increasing number of drivers from remote PVs.