David E. Krummen

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).

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.

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)

OBJECTIVES 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. BACKGROUND It is unclear why conventional anatomic AF ablation can be effective in some patients yet ineffective in others with similar profiles. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation

Background— The substrates for human atrial fibrillation (AF) are poorly understood, but involve abnormal repolarization (action potential duration [APD]). We hypothesized that beat-to-beat oscillations in APD may explain AF substrates, and why vulnerability to AF forms a spectrum from control subjects without AF to patients with paroxysmal then persistent AF. Methods and Results— In 33 subjects (12 with persistent AF, 13 with paroxysmal AF, and 8 controls without AF), we recorded left (n=33) and right (n=6) atrial APD on pacing from cycle lengths 600 to 500 ms (100 to 120 bpm) up to the point where AF initiated. Action potential duration alternans required progressively faster rates for patients with persistent AF, patients with paroxysmal AF, and controls (cycle length 411±94 versus 372±72 versus 218±33 ms; P<0.01). In AF patients, APD alternans occurred at rates as slow as 100 to 120 bpm, unrelated to APD restitution (P>0.10). In this milieu, spontaneous ectopy initiated AF. At fast rates, APD alternans disorganized to complex oscillations en route to AF. Complex oscillations also arose at progressively faster rates for persistent AF, paroxysmal AF, and controls (cycle length: 316±99 versus 266±19 versus 177±16 ms; P=0.02). In paroxysmal AF, APD oscillations amplified before AF (P<0.001). In controls, APD alternans arose only at very fast rates (cycle length <250 ms; P<0.001 versus AF groups) just preceding AF. In 4 AF patients in whom rapid pacing did not initiate AF, APD alternans arose transiently then extinguished. Conclusions— Atrial APD alternans reveals dynamic substrates for AF, arising most readily (at lower rates and higher magnitudes) in persistent AF then paroxysmal AF, and least readily in controls. APD alternans preceded all AF episodes and was absent when AF did not initiate. The cellular mechanisms for APD alternans near resting heart rates require definition.

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.

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.

Patient-specific models of cardiac biomechanics

Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veterans Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

Patient-Specific Modeling of Dyssynchronous Heart Failure: A Case Study

The development and clinical use of patient-specific models of the heart is now a feasible goal. Models have the potential to aid in diagnosis and support decision-making in clinical cardiology. Several groups are now working on developing multi-scale models of the heart for understanding therapeutic mechanisms and better predicting clinical outcomes of interventions such as cardiac resynchronization therapy. Here we describe the methodology for generating a patient-specific model of the failing heart with a myocardial infarct and left ventricular bundle branch block. We discuss some of the remaining challenges in developing reliable patient-specific models of cardiac electromechanical activity, and identify some of the main areas for focusing future research efforts. Key challenges include: efficiently generating accurate patient-specific geometric meshes and mapping regional myofiber architecture to them; modeling electrical activation patterns based on cellular alterations in human heart failure, and estimating regional tissue conductivities based on clinically available electrocardiographic recordings; estimating unloaded ventricular reference geometry and material properties for biomechanical simulations; and parameterizing systemic models of circulatory dynamics from available hemodynamic measurements.

Atrial conduction slows immediately before the onset of human atrial fibrillation: a bi-atrial contact mapping study of transitions to atrial fibrillation.

OBJECTIVES The aim of this study was to determine whether onset sites of human atrial fibrillation (AF) exhibit conduction slowing, reduced amplitude, and/or prolonged duration of signals (i.e., fractionation) immediately before AF onset. BACKGROUND Few studies have identified functional determinants of AF initiation. Because conduction slowing is required for reentry, we hypothesized that AF from pulmonary vein triggers might initiate at sites exhibiting rate-dependent slowing in conduction velocity (CV restitution) or local slowing evidenced by signal fractionation. METHODS In 28 patients with AF (left atrial size 43 ± 5 mm; n = 13 persistent) and 3 control subjects (no AF) at electrophysiological study, we measured bi-atrial conduction time (CT) electrogram fractionation at 64 or 128 electrodes with baskets in left (n = 17) or both (n = 14) atria during superior pulmonary vein pacing at cycle lengths (CL) accelerating from 500 ms (120 beats/min) to AF onset. RESULTS Atrial fibrillation initiated in 19 of 28 AF patients and no control subjects. During rate acceleration, conduction slowed in 23 of 28 AF patients (vs. no control subjects, p = 0.01) at the site of AF initiation (15 of 19) or latest activated site (20 of 28). The CT lengthened from 79 ± 23 ms to 107 ± 39 ms (p < 0.001) on acceleration, in a spectrum from persistent AF (greatest slowing) to control subjects (least slowing; p < 0.05). Three patterns of CV restitution were observed: 1) broad (gradual CT prolongation, 37% patients); 2) steep (abrupt prolongation, at CL 266 ± 62 ms, 42%); and 3) flat (no prolongation, 21% AF patients, all control subjects). The AF initiation was more prevalent in patients with CV restitution (17 of 23 vs. 2 of 8; p = 0.03) and immediately followed abrupt re-orientation of the activation vector in patients with broad but not steep CV restitution (p < 0.01). Patients with broad CV restitution had larger atria (p = 0.03) and were more likely to have persistent AF (p = 0.04). Notably, neither amplitude nor duration (fractionation) of the atrial signal at the AF initiation site were rate-dependent (both p = NS). CONCLUSIONS Acceleration-dependent slowing of atrial conduction (CV restitution) precedes AF initiation, whereas absence of CV restitution identifies inability to induce AF. Conduction restitution, but not fractionated electrograms, may thus track the functional milieu enabling AF initiation and has implications for guiding AF ablation and pharmacological therapy.