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Background: Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of phase singularities (PS) in cardiac fibrillation. We hypothesized PS formation/destruction in fibrillation could be modeled as self-regenerating Poisson renewal processes, producing exponential distributions of interevent times governed by constant rate parameters defined by the prevailing properties of each system., Methods: PS formation/destruction were studied in 5 systems: (1) human persistent atrial fibrillation (n=20), (2) tachypaced sheep atrial fibrillation (n=5), (3) rat atrial fibrillation (n=4), (5) rat ventricular fibrillation (n=11), and (5) computer-simulated fibrillation. PS time-to-event data were fitted by exponential probability distribution functions computed using maximum entropy theory, and rates of PS formation and destruction (λ f /λ d ) determined. A systematic review was conducted to cross-validate with source data from literature., Results: In all systems, PS lifetime and interformation times were consistent with underlying Poisson renewal processes (human: λ f , 4.2%/ms±1.1 [95% CI, 4.0-5.0], λ d , 4.6%/ms±1.5 [95% CI, 4.3-4.9]; sheep: λ f , 4.4%/ms [95% CI, 4.1-4.7], λ d , 4.6%/ms±1.4 [95% CI, 4.3-4.8]; rat atrial fibrillation: λ f , 33%/ms±8.8 [95% CI, 11-55], λ d , 38%/ms [95% CI, 22-55]; rat ventricular fibrillation: λ f , 38%/ms±24 [95% CI, 22-55], λ f , 46%/ms±21 [95% CI, 31-60]; simulated fibrillation λ d , 6.6-8.97%/ms [95% CI, 4.1-6.7]; R 2 ≥0.90 in all cases). All PS distributions identified through systematic review were also consistent with an underlying Poisson renewal process., Conclusions: Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation.

Aims: Contact force (CF) catheters provide catheter-tissue contact information to improve outcome of pulmonary vein isolation (PVI) in paroxysmal atrial fibrillation (PAF). We evaluated different target-CF values for achievement of the additional endpoint of an unexcitable ablation line., Methods: A total of 106 patients undergoing PVI were randomized into three groups (G) (G1: target-CF 15 g, G2: target-CF 10 g, G3: CF concealed from operator). The PVI encircling line was divided into predefined sections. Excitable tissue along the PVI-line identified by high output pacing (10 V, 2 ms) was targeted for further ablation., Results: Mean average CF was 17.4 ± 4.7 g (G1) vs. 12.3 ± 6.0 g (G2) vs. 11.1 ± 6.5 g (G 3) (p < 0.001). Primary unexcitable ablation lines were found in 38.6, 19.4 and 5.7% (G1, G2, G3 respectively; G1 vs. G2 p < 0.05, G1 vs. G3 p < 0.001, G2 vs. G3 ns). Additional radiofrequency (RF)-energy to achieve unexcitability was lowest in G1 (3.6 ± 3.1 kJ vs. 8.6 ± 7.2 kJ (G2) and 10.4 ± 6.7 (G3), p ≤ 0.001, G2 vs. G3 ns) with accordingly lowest additional RF applications in G1 (3.0 ± 2.6 vs. 7.0 ± 5.4 in G2 and 8.4 ± 4.0 in G3; G1 vs. G2 and G3, p < 0.001, G 2 vs. G 3 ns). Sections along ablation lines with low initial CF were most likely to reveal excitability. Single procedure success was 81.9 vs. 73.5 vs. 71.4% (G 1, 2 and 3, p = 0.6) during 437 ± 254 day follow-up., Conclusion: Higher tip-to-tissue CF during PVI facilitates the achievement of an unexcitable ablation line, requiring less additional RF-energy.

Background: Current phase mapping systems for atrial fibrillation create 2-dimensional (2D) maps. This process may affect the accurate detection of rotors. We developed a 3-dimensional (3D) phase mapping technique that uses the 3D locations of basket electrodes to project phase onto patient-specific left atrial 3D surface anatomy., Objective: We sought to determine whether rotors detected in 2D phase maps were present at the corresponding time segments and anatomical locations in 3D phase maps., Methods: One-minute left atrial atrial fibrillation recordings were obtained in 14 patients using the basket catheter and analyzed off-line. Using the same phase values, 2D and 3D phase maps were created. Analysis involved determining the dominant propagation patterns in 2D phase maps and evaluating the presence of rotors detected in 2D phase maps in the corresponding 3D phase maps., Results: Using 2D phase mapping, the dominant propagation pattern was single wavefront (36.6%) followed by focal activation (34.0%), disorganized activity (23.7%), rotors (3.3%), and multiple wavefronts (2.4%). Ten transient rotors were observed in 9 of 14 patients (64%). The mean rotor duration was 1.1 ± 0.7 seconds. None of the 10 rotors observed in 2D phase maps were seen at the corresponding time segments and anatomical locations in 3D phase maps; 4 of 10 corresponded with single wavefronts in 3D phase maps, 2 of 10 with 2 simultaneous wavefronts, 1 of 10 with disorganized activity, and in 3 of 10 there was no coverage by the basket catheter at the corresponding 3D anatomical location., Conclusion: Rotors detected in 2D phase maps were not observed in the corresponding 3D phase maps. These findings may have implications for current systems that use 2D phase mapping., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions (‘breakthroughs’). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability., Methods and Results: In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges., Conclusion: Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.

Introduction: Conventional mapping of complex atrial tachycardias (ATs) can be challenging. Thus, we evaluated feasibility and utility of a novel, ultra high-density 3D mapping approach to characterize and map AT in these cases., Methods and Results: Overall, 21 patients (67.4 ± 7.6 years; male: 52.4%, 1.9 ± 1.4 previous ablation procedures) with documented AT referred to our center underwent catheter ablation including ultra high-density mapping using a novel 64-electrode mini-basket catheter and an adjunctive 3D mapping system. A total of 24 AT (20 left atrial, 4 right atrial AT) were analyzed in 19 cases. In 2 patients, map acquisition failed due to scarce local electrograms and unstable AT cycle length, respectively. Underlying mechanisms were focal (n = 3), as well as local (n = 8) and macro (n = 13) reentry tachycardias with a mean cycle length of 311.8 ± 67.7 milliseconds. The analysis of propagation waves, activation and voltage revealed complex activation patterns and allowed for the identification of critical sites of AT initiation or maintenance without the need for further mapping techniques. In all cases critical sites could be verified by successful consecutive ablation. Mean mapping time was 19.4 ± 7.6 minutes, mean number of mapping points was 19,217 ± 10,270. Radiofrequency application until first effect was 165.1 ± 374.2 seconds; total procedure time was 157.6 ± 51.4 minutes, fluoroscopy time 21.7 ± 13.8 minutes, and total radiofrequency duration 1,016 ± 951.9 seconds, respectively. No severe complications occurred., Conclusion: Ultra high-density mapping of complex AT is safe and feasible. Further, it enables detailed insight into AT mechanisms. Critical AT sites can be identified precisely in order to guide successful catheter ablation., (© 2016 Wiley Periodicals, Inc.)

Background: The success rate of catheter ablation for persistent atrial fibrillation (AF) is still far from satisfactory. Identification of patients who will benefit from ablation is highly desirable. We investigated the predictive value of noninvasive AF complexity parameters derived from standard 12-lead ECGs for AF termination and long-term success of catheter ablation and compared them with clinical predictors., Methods and Results: The study included a training (93 patients) and a validation set (81 patients) of patients with persistent AF undergoing stepwise radiofrequency ablation. In the training set AF terminated in 81% during catheter ablation, 77% were in sinus rhythm after 6 years and multiple ablations. ECG-derived complexity parameters were determined from a baseline 10-s 12-lead ECG. Prediction of AF termination was similar using only ECG (cross-validated mean area under the curve [AUC], 0.76±0.15) or only clinical parameters (mean AUC, 0.75±0.16). The combination improved prediction to a mean AUC of 0.79±0.13. Using a combined model of ECG and clinical parameters, sinus rhythm at long-term follow-up could be predicted with a mean AUC of 0.71±0.12. In the validation set AF terminated in 57%, 61% were in sinus rhythm after 4.6 years. The combined models predicted termination with an AUC of 0.70 and sinus rhythm at long-term follow-up with an AUC of 0.61. Overall, fibrillation-wave amplitude provided the best rhythm prediction., Conclusions: The predictive performance of ECG-derived AF complexity parameters for AF termination and long-term success of catheter ablation in patients with persistent AF is at least as good as known clinical predictive parameters, with fibrillation-wave amplitude as the best predictor., (© 2016 American Heart Association, Inc.)

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients., (© 2015 Wiley Publishing Asia Pty Ltd.)

Background: Temporal dynamics of electrical wave propagation during AF is unknown. There are reports of transient linking of atrial activation. We aim to characterize temporal dynamics of wave propagation patterns during AF in an established chronically remodeled substrate., Methods: Bi-atrial epicardial mapping of AF (mean duration 62±61s) was performed in 13 sheep with induced hypertension using custom-designed plaques. Wave propagation patterns were classified into periods of repetitive activity termed modes., Results: In total, we identified 9241 distinct depolarization events which were classified as: passing wave (69% occurrence, 68.6% of total time), point source (20.4%, 13.1%), wave collision (4%, 2.8%), re-entrant wave (0.7%, 6.3%), half-rotation (2.9%, 4.4%), wave splitting (2.7%, 4.3%), conduction block (0.05%, 0.03%) and figure of eight reentry (0.05%, 0.05%). Episodes of re-entrant activity had mean length 701±1012ms. A total of 435 modes of distinct periods of repetitive activity were detected (121 in LA and 314 in RA). Looking at temporal changes between modes, we found a preferential transition: change between train of waves propagating from direction of coronary sinus and reentrant activity. High density mapping of the hypertensive fibrillating atria observed 20% point sources and 0.7% of reentrant activation which may have served as drivers of AF. Remaining activations were peripheral waves. Majority of the activation was organized into events of transient linking with existence of preferential types of transitions., Conclusions: These findings support the importance of substrate based regions of anatomically or functionally determined preferential conduction in the maintenance of AF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Recently, a new image integration module (IIM, CartoUnivu™ Module) has been introduced to combine and merge fluoroscopy images with 3-dimensional-(3D)-electroanatomical maps (Carto® 3 System) into an accurate 3D view. The aim of the study was to investigate the influence of IIM on the fluoroscopy exposure during pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) in a prospective randomized trial., Methods and Results: Between June and November 2014, a total of 60 patients with PAF (73.3% male, 64.0 ± 9.2 years), who underwent PVI with the endpoint of unexcitability of the ablation line, were randomized to either a conventional 3D mapping system (Carto® 3 System) or to an additional IIM on the basis of an assumed reduction of fluoroscopy exposure by the use of IIM. There were no significant differences in baseline characteristics. The median ablation procedure time was identical in both groups (140.7 ± 27.8 minutes vs. 140.8 ± 39.5 minutes; P = 0.851). A significant decrease of mean fluoroscopy time from 11.9 ± 2.1 to 7.4 ± 2.6 minutes (P < 0.0006) and median fluoroscopy dose from 882.9 to 476.5 cGycm(2) (P < 0.001) was achieved. The main reduction of radiation could be realized during creation of the 3D-map. No major complications occurred during the procedures. After a median follow-up of 125.7 ± 45.6 days 80% of the patients were free from any atrial arrhythmias., Conclusion: CartoUnivu™ module easily integrates into the workflow of PVI with the endpoint of unexcitability of the ablation line without prolonging the procedure time. It is associated with a marked reduction in fluoroscopic dose when compared to a conventional 3D mapping system., (© 2015 Wiley Periodicals, Inc.)

Background: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood., Objective: The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF., Methods: Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined., Results: All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block., Conclusion: The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the divergent and limited success rates of catheter ablation strategies targeting CFAE., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: Mapping and interpretation of wave conduction patterns recorded during simultaneous mapping of the electrical activity on both endocardial and epicardial surfaces are challenging because of the difficulty of reconstruction of reciprocal alignment of electrodes in space. Here, we suggest a method to overcome this difficulty using a concept of maximized endo-epicardial phase coherence., Methods and Results: Endo-epicardial mapping was performed in six humans during induced atrial fibrillation (AF) in right atria using two sets of 8 × 8 electrode plaques. For each electrode, mean phase coherence (MPC) with all electrodes on the opposite side of the atrial wall was calculated. Localization error was defined as a distance between the directly opposing electrode and the electrode with the maximal MPC. Overall, there was a linear correlation between MPC and distance between electrodes with R(2) = 0.34. Localization error obtained for electrodes of the plaque in six patients resulted in a mean 2.3 ± 1.9 mm for 25 s electrogram segment length. Eighty-four per cent of the measurements resulted in error smaller than 3.4 mm. The duration of the recording used to compute MPC was negatively correlated with localization error; however, the effect reached plateau for segment durations longer than 15 s., Conclusion: Application of the concept of maximized endo-epicardial phase coherence to electrograms during AF allows reconstruction of reciprocal alignment of the electrodes on the opposite side of the atrial wall. This approach may be especially useful in settings where the spatial position of endo- and epicardial electrodes for intracardiac mapping cannot otherwise be determined., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Surviving myocytes within scar may form channels that support ventricular tachycardia (VT) circuits. There are little data on the properties of channels that comprise VT circuits and those that are non-VT supporting channels., Methods and Results: In 22 patients with ischemic cardiomyopathy and VT, high-density mapping was performed with the PentaRay catheter and Ensite NavX system during sinus rhythm. A channel was defined as a series of matching pace-maps with a stimulus (S) to QRS time of ≥40 ms. Sites were determined to be part of a VT channel if there were matching pace-maps to the VT morphology. This was confirmed with entrainment mapping when possible. Of the 238 channels identified, 57 channels corresponded to an inducible VT. Channels that were part of a VT circuit were more commonly located within dense scar than non-VT channels (97% versus 82%; P=0.036). VT supporting channels were of greater length (mean±SEM, 53±5 versus 33±4 mm), had higher longest S-QRS (130±12 versus 82±12 ms), longer conduction time (103±14 versus 43±13 ms), and slower conduction velocity (0.87±0.23 versus 1.39±0.21 m/s) than non-VT channels (P<0.001). Of all the fractionated, late, and very late potentials located in scar, only 21%, 26%, and 29%, respectively, were recorded within VT channels., Conclusions: High-density mapping shows substantial differences among channels in ventricular scar. Channels supporting VT are more commonly located in dense scar, longer than non-VT channels, and have slower conduction velocity. Only a minority of scar-related potentials participate in the VT supporting channels.

Background: The pivot is critical to rotors postulated to maintain atrial fibrillation (AF). We reasoned that wavefronts circling the pivot should broaden the amplitude distribution of bipolar electrograms because of directional information encoded in these signals. We aimed to determine whether Shannon entropy (ShEn), a measure of signal amplitude distribution, could differentiate the pivot from surrounding peripheral regions and thereby assist clinical rotor mapping., Methods and Results: Bipolar electrogram recordings were studied in 4 systems: (1) computer simulations of rotors in a 2-dimensional atrial sheet; (2) isolated rat atria recorded with a multi-electrode array (n=12); (3) epicardial plaque recordings of induced AF in hypertensive sheep (n=11); and (4) persistent AF patients (n=10). In the model systems, rotation episodes were identified, and ShEn calculated as an index of amplitude distribution. In humans, ShEn distribution was analyzed at AF termination sites and with respect to complex fractionated electrogram mean. We analyzed rotation episodes in simulations (4 cycles) and animals (rats: 14 rotors, duration 80±81 cycles; sheep: 13 rotors, 4.2±1.5 cycles). The maximum ShEn bipole was consistently colocated with the pivot zone. ShEn was negatively associated with distance from the pivot zone in simulated spiral waves, rats, and sheep. ShEn was modestly inversely associated with complex fractionated electrogram; however, there was no relationship at the sites of highest ShEn., Conclusions: ShEn is a mechanistically based tool that may assist AF rotor mapping.

Various forms of heart disease are associated with remodeling of the heart muscle, which results in a perturbation of cell-to-cell electrical coupling. These perturbations may alter the trajectory of spiral wave drift in the heart muscle. We investigate the effect of spatially extended inhomogeneity of transverse cell coupling on the spiral wave trajectory using a simple active media model. The spiral wave was either attracted or repelled from the center of inhomogeneity as a function of cell excitability and gradient of the cell coupling. High levels of excitability resulted in an attraction of the wave to the center of inhomogeneity, whereas low levels resulted in an escape and termination of the spiral wave. The spiral wave drift velocity was related to the gradient of the coupling and the initial position of the wave. In a diseased heart, a region of altered transverse coupling corresponds with local gap junction remodeling that may be responsible for stabilization-destabilization of spiral waves and hence reflect potentially important targets in the treatment of heart arrhythmias.

Aims: There is increasing evidence of the role direction-dependent conduction plays in the arrhythmogenic interaction between ectopic triggers and abnormal atrial substrates. We thus sought to characterize direction-dependent conduction in chronically stretched atria., Methods and Results: Twenty-four patients with chronic atrial stretch due to mitral stenosis and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, and coronary sinus (CS) characterized direction-dependent conduction along linear catheters and across the crista terminalis. Bi-atrial electroanatomic maps were created in both sinus rhythm and an alternative wavefront direction by pacing from the distal CS. This allowed an assessment of conduction velocities, electrogram, and voltage characteristics during wavefronts propagating in different directions.  While differing wavefront directions caused changes in both chronic atrial stretch and reference patients (P< 0.001 for all), these direction-dependent changes were greater in chronic atrial stretch compared with reference patients, who exhibited greater slowing in conduction velocities (P= 0.09), prolongation of bi-atrial activation time (P= 0.04), increase in number (P< 0.001) and length (P< 0.001) of lines of conduction block, increase in fractionated electrograms (P< 0.001), and decrease in voltage (P= 0.08) during left-to-right compared with right-to-left atrial activation. These direction-dependent changes were associated with a greater propensity for chronically stretched atria to develop atrial fibrillation (P= 0.02)., Conclusions: Atrial remodelling in chronic atrial stretch exacerbates physiological direction-dependent conduction characteristics. Our data suggest that the greater direction-dependent conduction seen in patients with chronic atrial stretch may promote arrhythmogenesis due to ectopic triggers from the left atrium.

Introduction: All preclinical studies of atrial remodeling in heart failure (HF) have been confined to a single model of rapid ventricular pacing. To evaluate whether the atrial changes were specific to the model or represented an end result of HF, this study aimed to characterize atrial remodeling in an ovine model of doxorubicin-induced cardiomyopathy., Methods and Results: Fourteen sheep, 7 with cardiomyopathy induced by repeated intracoronary doxorubicin infusions and 7 controls, were studied. The development of HF was monitored by cardiac imaging and hemodynamic parameters. Open chest electrophysiological study was performed using custom-made 128-electrode epicardial plaque assessing effective refractory period (ERP) and conduction velocity. Atrial tissues were harvested for structural analysis. The HF group had demonstrable moderate global HF (left ventricular ejection fraction [LVEF]: 37.1 vs 46.4%; P = 0.003) and showed the following compared to controls: left atrial dilatation (P = 0.02) and dysfunction (P = 0.005); longer P-wave duration (P < 0.05); higher ERP at all cycle lengths (P ≤ 0.002) and locations (P < 0.001); slower conduction velocity (P < 0.001); increased conduction heterogeneity index (P < 0.001); increased atrial fibrosis (right atrial [RA]: 5.9 ± 2.6 vs 2.8 ± 0.9%; P < 0.0001, left atrial [LA]: 3.7 ± 2.2 vs 2.4 ± 1.1%; P = 0.002), and longer induced atrial fibrillation (AF) episodes (16 ± 22 vs 2 ± 3 seconds; P = 0.04)., Conclusion: In this model of HF, there was significant atrial remodeling characterized by atrial enlargement/dysfunction, increased fibrosis, slowed/heterogeneous conduction, and increased refractoriness associated with more sustained AF. These findings appear the "same sort" to previous models of HF implicating a final common substrate leading to the development of AF in HF., (© 2010 Wiley Periodicals, Inc.)

Background: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor., Objective: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension., Methods: Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters., Results: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis., Conclusion: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with lone atrial fibrillation (AF) have an abnormal atrial substrate., Objective: The purpose of this study was to determine the role of direction-dependent conduction in patients with lone AF., Methods: Twenty-four patients with paroxysmal lone AF and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, coronary sinus (CS), and left atrial roof were used to determine direction-dependent conduction characteristics. Biatrial electroanatomic maps were created during sinus rhythm and with distal CS pacing to characterize direction-dependent differences in conduction velocities, electrogram complexity, and voltage., Results: Differing wavefront directions caused changes in conduction velocity (P <.001), biatrial activation times (P <.001), electrogram fragmentation (P <.001), site-specific conduction delays (P <.001), and voltage (P <.001) in both lone AF and reference patients. These direction-dependent abnormalities were amplified in lone AF patients compared to reference patients, who exhibited greater slowing in conduction velocities (P = .02), prolongation of biatrial activation time (P = .04), increase in number (P <.001) and length (P <.001) of lines of conduction block, increase in proportion of fractionated electrograms (P <.001), and decrease in voltage (P = .03) during distal CS pacing compared to sinus rhythm., Conclusion: This study demonstrates the marked direction-dependent conduction abnormalities present in patients with lone AF. These results provide further insights into the critical interplay between the underlying abnormal substrate and differing wavefront directions. The study suggests that direction-dependent conduction abnormalities may explain in part the greater arrhythmogenicity of ectopic triggers from the left atrium rather than the right atrium., (Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.)

The left atrium is a complex chamber, which plays an integral role in the maintenance of physiologic hemodynamic and electrical stability of the heart and is involved in many disease states, most commonly atrial fibrillation. Preserving regions of the left atrium that contribute the greatest to atrial mechanical function during curative strategies for atrial fibrillation are important. We present here a new application of the CARTO electroanatomical mapping system in the assessment of the left atria mechanical function. Electroanatomical data were collected in course of the electrophysiological procedure in 11 control patients and 12 patients with paroxysmal atrial fibrillation. The three-dimensional geometry of the left atria was reconstructed in 10 ms intervals and segmented into distinct regions. For each segment, a regional ejection fraction was calculated. We found that anterior, septal and lateral segments have significantly greater regional ejection fraction than atria roof, inferior and posterior segments. Therefore, we hypothesize that in order to minimize the impact on atrial mechanical function, an important determinant of thromboembolic risk, damage should be minimized to these atrial regions.

Introduction: Sites of complex fractionated atrial electrograms (CFAE) and dominant frequency (DF) have been implicated in maintaining atrial fibrillation (AF); however, their relationship is poorly understood., Methods and Results: Twenty patients underwent biatrial high-density contact mapping (507 +/- 150 points/patient) during AF. CFAE were characterized using software to quantify electrogram complexity (CFE-mean). Spectral analysis determined the frequency with greatest power and sites of high DF with a frequency gradient. CFE-mean was higher (less fractionated) for right compared with left atria (P < 0.001) and in paroxysmal compared with persistent AF (P < 0.001). DF was lower for right compared with left atria (P = 0.02) and in paroxysmal compared with persistent AF (P < 0.001). There was significant regional variation in DF in paroxysmal (P < 0.001) but not persistent AF. Highest DF points clustered together with 5.2 +/- 1.7 clusters/patient. Correlation between CFE-mean and DF was poor on a point-by-point basis (r =-0.17, P < 0.001), but moderate on an individual basis (r =-0.50, P = 0.03). Exploration of their spatial relationship demonstrated CFAE areas in close proximity (median 5 mm, IQR 2-10) to high DF sites; within 10 mm in 80% and 10-20 mm in 10%. Simultaneous activation mapping at these sites further supports this observation., Conclusion: Greater fractionation and higher DF are seen in persistent AF and left atria during AF. Preferential areas of high DF are observed in paroxysmal but not persistent AF. CFAE and DF correlate within an individual but not point-by-point. Exploration of their spatial relationship demonstrates CFAE in areas adjacent to high DF, and this is supported by activation mapping at these sites.

Background: QRS abnormalities may not be apparent in sinus rhythm in electrically stable cardiomyopathy patients who can have quiescent but highly arrhythmogenic substrate. Here, we test the hypothesis that differential changes in QRS construction during right‐ventricular apex pacing (RVP) as opposed to atrial pacing (AP) will identify latent substrate for ventricular arrhythmias (VA) and death. Methods: Forty patients with cardiomyopathy free of VA underwent baseline 114‐electrode body‐surface electrocardiogram during AP (100 beats per minute [bpm]) and RVP (100 and 120 bpm). The filtered‐averaged QRS at each electrode was deconstructed into individual intra‐QRS and post‐QRS ventricular myopotentials (VMP). The primary outcome was VA or death. Prognostic accuracy of VMP was validated using V1 to V6 leads in another prospective cohort of 44‐cardiomyopathy patients. Results: Twenty‐six patients were eligible for initial analysis. After 5 ± 2 years of follow‐up, eight (31%) patients had VA (VAPos) while rest were uneventful (VANeg). During AP100, VAPos patients expressed more VMP than VANeg patients (16 ± 1 vs 12 ± 1, P = 0.02). RVP100 and RVP120 in VAPos patients introduced an additional 5.5 ± 0.5 and 6.0 ± 0.5 VMP (P < 0.0001 vs AP100). The relative change with RVP120 versus AP100 in VANeg patients exceeded VAPos patients by 1.2 ± 0.5 VMP (P = 0.03). Increment in VMP count of <8 in lead‐V5 with RVP120 compared to AP100 best predicted VA (area under curve 0.81, P = 0.01). In the validation cohort, primary outcome occurred in 13 (33%) patients. Native QRS features and AP100 alone failed to predict primary outcome. Patients with increment in VMP count of <8 in lead‐V5 with RVP120 versus AP100 had 7.9‐fold increased risk of primary outcome (95% confidence interval 1.01, 61.61; P = 0.049). Conclusion: Cardiomyopathy patients at risk of VA or death perturb the QRS less than low‐risk patients with differential pacing. This functional response may be useful to identify arrhythmogenic substrate. [ABSTRACT FROM AUTHOR]

Aims: Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions (‘breakthroughs’). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability.Methods and Results: In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges.Conclusion: Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections. [ABSTRACT FROM AUTHOR]

Background: Electrogram-based identification of the regions maintaining persistent Atrial Fibrillation (AF) is a subject of ongoing debate. Here, we explore the concept of local electrical dyssynchrony to identify AF drivers. Methods and Results: Local electrical dyssynchrony was calculated using mean phase coherence. High-density epicardial mapping along with mathematical model were used to explore the link between local dyssynchrony and properties of wave conduction. High-density mapping showed a positive correlation between the dyssynchrony and number of fibrillatory waves (R2 = 0.68, p<0.001). In the mathematical model, virtual ablation at high dyssynchrony regions resulted in conduction regularization. The clinical study consisted of eighteen patients undergoing catheter ablation of persistent AF. High-density maps of left atrial (LA) were constructed using a circular mapping catheter. After pulmonary vein isolation, regions with the top 10% of the highest dyssynchrony in LA were targeted during ablation and followed with ablation of complex atrial electrograms. Catheter ablation resulted in termination during ablation at high dyssynchrony regions in 7 (41%) patients. In another 4 (24%) patients, transient organization was observed. In 6 (35%) there was no clear effect. Long-term follow-up showed 65% AF freedom at 1 year and 22% at 2 years. Conclusions: Local electrical dyssynchrony provides a reasonable estimator of regional AF complexity defined as the number of fibrillatory waves. Additionally, it points to regions of dynamical instability related with action potential alternans. However, despite those characteristics, its utility in guiding catheter ablation of AF is limited suggesting other factors are responsible for AF persistence. [ABSTRACT FROM AUTHOR]

Loss of Pace Capture and Dormant Conduction in PVI Introduction Permanent pulmonary vein isolation (PVI) remains an essential goal of ablation therapy in patients with atrial fibrillation. Aim of this study was the intraindividual comparison of unexcitability to pacing along the ablation line versus dormant conduction (DC) as additional procedural endpoints. Methods A total of 58 patients with paroxysmal atrial fibrillation (PAF) underwent PVI by circumferential ablation of ipsilateral pulmonary veins (PVs), followed by testing for DC by adenosine administration. Irrespective of the presence of DC, pacing along the ablation line for left atrium capture was performed and additional radio frequency energy applied if necessary. PVs with initial DC were retested after achieving unexcitability. Results PVI was achieved in 224 of 224 PVs. In 33 of 224 PVs (15%) DC was revealed. At 92 of 112 ablation lines (82%) sites of excitability were found. Three (9%) of the initial 33 PVs with DC showed further DC after achieving unexcitability at repeated testing. Thirty-two of 33 assumed areas of unmasked PV-LA reconduction as revealed by DC-testing showed a corresponding site of excitability on the ablation line. After a follow-up of 11.6 ± 3.4 months 79% of patients were free of arrhythmia. Conclusions Pacing for unexcitability can safely identify potential sites of DC and even sites that would have not been detected by testing for DC. Unexcitability, therefore, serves as a suitable and safe procedural endpoint not only for patients with contraindications to adenosine administration. Our data suggest that adenosine may be expendable when achieving unexcitability along the ablation line. [ABSTRACT FROM AUTHOR]

Sinus Node Mapping. Introduction: The area of the functional sinus node complex exceeds that of the anatomical sinus node; however, reasons for this discrepancy are unknown. We aimed to characterize the functional sinus node complex in health and disease with high-density simultaneous mapping. Methods and Results: Sinus node activity was characterized in 15 reference patients after ablation for supraventricular tachycardia. A further 16 patients were studied following ablation of chronic atrial flutter to determine effects of atrial remodeling. High-density simultaneous mapping of the sinus node complex was performed using a multi-electrode array. In reference patients, distance from superior vena cava-right atrial (SVC-RA) junction to earliest activation (EA) was 4 ± 4 mm and sinus break-out (SBO) 9 ± 6 mm. Preferential pathways of conduction were observed between EA and SBO. For patients with flutter, these distances were greater (EA: 15 ± 12 mm, P = 0.003; SBO: 23 ± 11 mm, P < 0.001). Conduction time along preferential pathways was 15 ± 5 ms for reference patients and 23 ± 8 ms for patients with flutter (P = 0.005). Following pacing, distance from SVC–RA junction to EA and SBO lengthened to 13 ± 8 mm (P = 0.006) and 16 ± 10 mm (P = 0.02), respectively, in reference patients, and 19 ± 12 mm (P = 0.045), 28 ± 9 mm (P = 0.02) in patients with flutter. This resulted in caudal shifts in EA and SBO of 10 ± 9 mm and 7 ± 8 mm in reference patients but diminished shifts in patients with flutter; 4 ± 7 mm and 4 ± 6 mm. Conclusion: The functional sinus node complex demonstrates dynamic changes in activation. There are preferential pathways of conduction from sinus node to atrial myocardium. The remodeled atria demonstrate longer conduction times along preferential pathways and a restricted functional sinus node complex. (J Cardiovasc Electrophysiol, Vol. 21, pp. 532-539, May 2010) [ABSTRACT FROM AUTHOR]