Wouter-Jan Rappel

Treatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial

OBJECTIVES We hypothesized that human atrial fibrillation (AF) may be sustained by localized sources (electrical rotors and focal impulses), whose elimination (focal impulse and rotor modulation [FIRM]) may improve outcome from AF ablation. BACKGROUND Catheter ablation for AF is a promising therapy, whose success is limited in part by uncertainty in the mechanisms that sustain AF. We developed a computational approach to map whether AF is sustained by several meandering waves (the prevailing hypothesis) or localized sources, then prospectively tested whether targeting patient-specific mechanisms revealed by mapping would improve AF ablation outcome. METHODS We recruited 92 subjects during 107 consecutive ablation procedures for paroxysmal or persistent (72%) AF. Cases were prospectively treated, in a 2-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n = 36), or conventional ablation alone (n = 71; FIRM-blinded). RESULTS Localized rotors or focal impulses were detected in 98 (97%) of 101 cases with sustained AF, each exhibiting 2.1 ± 1.0 sources. The acute endpoint (AF termination or consistent slowing) was achieved in 86% of FIRM-guided cases versus 20% of FIRM-blinded cases (p < 0.001). FIRM ablation alone at the primary source terminated AF in a median 2.5 min (interquartile range: 1.0 to 3.1 min). Total ablation time did not differ between groups (57.8 ± 22.8 min vs. 52.1 ± 17.8 min, p = 0.16). During a median 273 days (interquartile range: 132 to 681 days) after a single procedure, FIRM-guided cases had higher freedom from AF (82.4% vs. 44.9%; p < 0.001) after a single procedure than FIRM-blinded cases with rigorous, often implanted, electrocardiography monitoring. Adverse events did not differ between groups. CONCLUSIONS Localized electrical rotors and focal impulse sources are prevalent sustaining mechanisms for human AF. FIRM ablation at patient-specific sources acutely terminated or slowed AF, and improved outcome. These results offer a novel mechanistic framework and treatment paradigm for AF. (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation [CONFIRM]; NCT01008722).

Expedited PublicationTreatment of Atrial Fibrillation by the Ablation of Localized Sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) Trial

OBJECTIVES We hypothesized that human atrial fibrillation (AF) may be sustained by localized sources (electrical rotors and focal impulses), whose elimination (focal impulse and rotor modulation [FIRM]) may improve outcome from AF ablation. BACKGROUND Catheter ablation for AF is a promising therapy, whose success is limited in part by uncertainty in the mechanisms that sustain AF. We developed a computational approach to map whether AF is sustained by several meandering waves (the prevailing hypothesis) or localized sources, then prospectively tested whether targeting patient-specific mechanisms revealed by mapping would improve AF ablation outcome. METHODS We recruited 92 subjects during 107 consecutive ablation procedures for paroxysmal or persistent (72%) AF. Cases were prospectively treated, in a 2-arm 1:2 design, by ablation at sources (FIRM-guided) followed by conventional ablation (n = 36), or conventional ablation alone (n = 71; FIRM-blinded). RESULTS Localized rotors or focal impulses were detected in 98 (97%) of 101 cases with sustained AF, each exhibiting 2.1 ± 1.0 sources. The acute endpoint (AF termination or consistent slowing) was achieved in 86% of FIRM-guided cases versus 20% of FIRM-blinded cases (p < 0.001). FIRM ablation alone at the primary source terminated AF in a median 2.5 min (interquartile range: 1.0 to 3.1 min). Total ablation time did not differ between groups (57.8 ± 22.8 min vs. 52.1 ± 17.8 min, p = 0.16). During a median 273 days (interquartile range: 132 to 681 days) after a single procedure, FIRM-guided cases had higher freedom from AF (82.4% vs. 44.9%; p < 0.001) after a single procedure than FIRM-blinded cases with rigorous, often implanted, electrocardiography monitoring. Adverse events did not differ between groups. CONCLUSIONS Localized electrical rotors and focal impulse sources are prevalent sustaining mechanisms for human AF. FIRM ablation at patient-specific sources acutely terminated or slowed AF, and improved outcome. These results offer a novel mechanistic framework and treatment paradigm for AF. (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation [CONFIRM]; NCT01008722).

Self-organization in systems of self-propelled particles

We investigate a discrete model consisting of self-propelled particles that obey simple interaction rules. We show that this model can self-organize and exhibit coherent localized solutions in one- and in two-dimensions. In one-dimension, the self-organized solution is a localized flock of finite extent in which the density abruptly drops to zero at the edges. In two-dimensions, we focus on the vortex solution in which the particles rotate around a common center and show that this solution can be obtained from random initial conditions, even in the absence of a confining boundary. Furthermore, we develop a continuum version of our discrete model and demonstrate that the agreement between the discrete and the continuum model is excellent.

Clinical mapping approach to diagnose electrical rotors and focal impulse sources for human atrial fibrillation.

Computational Mapping of Rotors and Focal Impulses in Human AF. Introduction: The perpetuating mechanisms for human atrial fibrillation (AF) remain undefined. Localized rotors and focal beat sources may sustain AF in elegant animal models, but there has been no direct evidence for localized sources in human AF using traditional methods. We developed a clinical computational mapping approach, guided by human atrial tissue physiology, to reveal sources of human AF.

Phase-field model of dendritic sidebranching with thermal noise.

We investigate dendritic sidebranching during crystal growth in an undercooled melt by simulation of a phase-field model which incorporates thermal noise of microscopic origin. As a nontrivial quantitative test of this model, we first show that the simulated fluctuation spectrum of a one-dimensional interface in thermal equilibrium agrees with the exact sharp-interface spectrum up to an irrelevant short-wavelength cutoff comparable to the interface thickness. Simulations of dendritic growth are then carried out in two dimensions to compute sidebranching characteristics (root-mean-square amplitude and sidebranch spacing) as a function of distance behind the tip. These quantities are compared quantitatively to the predictions of the existing linear WKB theory of noise amplification. The extension of this study to three dimensions remains needed to determine the origin of noise in experiments.

Repolarization and Activation Restitution Near Human Pulmonary Veins and Atrial Fibrillation Initiation: A Mechanism for the Initiation of Atrial Fibrillation by Premature Beats

OBJECTIVES The authors sought to study mechanisms to explain why single premature atrial complexes (PACs) from the pulmonary veins (PVs) may initiate human atrial fibrillation (AF). BACKGROUND Theoretically, single PACs may initiate AF if the rate response of action potential duration (APD) restitution has a slope >1. However, human left atrial APD restitution and its relationship to AF have not been studied. We hypothesized that an APD restitution slope >1 near PVs explains the initiation of clinical AF. METHODS We studied 27 patients with paroxysmal and persistent (n = 13) AF. We advanced monophasic action potential catheters transseptally to superior PVs. Restitution was plotted as APD of progressively early PACs against their diastolic interval (DI) from prior beats. Activation time restitution was measured using the time from the pacing artifact to each PAC. RESULTS Compared with paroxysmal AF, patients with persistent AF had shorter left atrial APD and effective refractory period (p = 0.01). In paroxysmal AF, maximum left atrial APD restitution slope was 1.5 +/- 0.4; and 12 of 13 patients had slope >1 (p < 0.001). In persistent AF, PACs encountered prolonged activation for a wider range of beats than in paroxysmal AF (p = 0.01), which prolonged DI and flattened APD restitution (slope 0.7 +/- 0.2; p < 0.001); no patient had APD restitution slope >1. A single PAC produced AF in 5 patients; in all, an APD restitution slope >1 caused extreme APD oscillations after the PAC, then AF. CONCLUSIONS In patients with paroxysmal AF, maximum APD restitution slope >1 near the PVs enables single PACs to initiate AF. However, patients with persistent AF show marked dynamic activation delay near PVs that flattens APD restitution. Studies should determine how regional APD and conduction dynamics contribute to the substrates of persistent AF.

Incoherent Feedforward Control Governs Adaptation of Activated Ras in a Eukaryotic Chemotaxis Pathway

Rapid adaptation to changes in chemoattractant concentration involves an incoherent feedforward structure of the underlying signaling network. Adapting Incoherently The model organism Dictyostelium moves toward higher concentrations of the chemoattractant cAMP (cyclic adenosine monophosphate), which activates a receptor that then stimulates effector proteins of the Ras family. Takeda et al. sought to understand how Dictyostelium adapts to rapid changes in chemoattractant by measuring the kinetics of Ras activation in cells exposed to cAMP. Mathematical modeling indicated that a signaling network in which the chemoattractant activates two components, which respectively activate and inhibit a third component, accurately described the data obtained from cAMP-stimulated cells. This type of network, called incoherent feedforward control, may be conserved in other chemotactic signaling networks. Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein–coupled receptors. The response of an activated Ras showed near-perfect adaptation, leading us to attempt to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only the incoherent feedforward network accurately described the experimental results. This analysis revealed that adaptation in this Ras pathway is achieved through the proportional activation of upstream components and not through negative feedback loops. Furthermore, these results are consistent with a local excitation, global inhibition mechanism for gradient sensing, possibly with a Ras guanosine triphosphatase–activating protein acting as a global inhibitor.

Coupling actin flow, adhesion, and morphology in a computational cell motility model

Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites which can be in a “gripping” or “slipping” mode and integrates the adhesion dynamics with the dynamics of the actin filaments, modeled as a viscous network. To test this model, we apply it to fish keratocytes, fast moving cells that maintain their morphology, and show that we are able to reproduce recent experimental results on actin flow and stress patterns. Furthermore, we explore the phase diagram of cell motility by varying myosin II activity and adhesion strength. Our model suggests that the pattern of the actin flow inside the cell, the cell velocity, and the cell morphology are determined by the integration of actin polymerization, myosin contraction, adhesion forces, and membrane forces.

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

Background—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). Methods and Results—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 cm2; 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). Conclusions—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 cm2, 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.Background— 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). Methods and Results— 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 cm2; 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). Conclusions— 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 cm2, 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.

Modeling wave propagation in realistic heart geometries using the phase-field method

We present a novel algorithm for modeling electrical wave propagation in anatomical models of the heart. The algorithm uses a phase-field approach that represents the boundaries between the heart muscle and the surrounding medium as a spatially diffuse interface of finite thickness. The chief advantage of this method is to automatically handle the boundary conditions of the voltage in complex geometries without the need to track the location of these boundaries explicitly. The algorithm is shown to converge accurately in nontrivial test geometries with no-flux (zero normal current) boundary conditions as the width of the diffuse interface becomes small compared to the width of the cardiac action potential wavefront. Moreover, the method is illustrated for anatomically realistic models of isolated rabbit and canine ventricles as well as human atria.