Amir A. Schricker

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.

Human Atrial Fibrillation Initiates Via Organized Rather Than Disorganized Mechanisms

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

Modifying Ventricular Fibrillation by Targeted Rotor Substrate Ablation: Proof‐of‐Concept from Experimental Studies to Clinical VF

Recent work has suggested a role for organized sources in sustaining ventricular fibrillation (VF). We assessed whether ablation of rotor substrate could modulate VF inducibility in canines, and used this proof‐of‐concept as a foundation to suppress antiarrhythmic drug‐refractory clinical VF in a patient with structural heart disease.

Frequency analysis of atrial action potential alternans: a sensitive clinical index of individual propensity to atrial fibrillation.

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

Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study

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

Organized Sources Are Spatially Conserved in Recurrent Compared to Pre-Ablation Atrial Fibrillation: Further Evidence for Non-Random Electrical Substrates.

Recurrent atrial fibrillation (AF) after ablation is associated with reconnection of initially isolated pulmonary vein (PV) trigger sites. Substrates are often targeted in addition to PVI, but it is unclear how substrates progress over time. We studied if substrates in recurrent AF are conserved or have developed de novo from pre‐ablation AF.

High-dose loperamide abuse–associated ventricular arrhythmias

Charles W. O’Connell, MD, Amir A. Schricker, MD, MS, Aaron B. Schneir, MD, Imir G. Metushi, PhD, Ulrika Birgersdotter-Green, MD, Alicia B. Minns, MD From the Division of Medical Toxicology, Department of Emergency Medicine, University of California San Diego, San Diego, California, Department of Emergency Medicine, Veterans Association San Diego, La Jolla, California, Division of Cardiovascular Medicine, University of California San Diego, San Diego, California, and Center of Advanced Laboratory Medicine, University of California San Diego, San Diego, California.

Mapping and ablating stable sources for atrial fibrillation: summary of the literature on Focal Impulse and Rotor Modulation (FIRM)

Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common indication for catheter ablation. However, despite substantial technical advances in mapping and energy delivery, ablation outcomes remain suboptimal. A major limitation to AF ablation is that the areas targeted for ablation are rarely of proven mechanistic importance, in sharp contrast to other arrhythmias in which ablation targets demonstrated mechanisms in each patient. Focal impulse and rotor modulation (FIRM) is a new approach to demonstrate the mechanisms that sustain AF (“substrates”) in each patient that can be used to guide ablation then confirm elimination of each mechanism. FIRM mapping reveals that AF is sustained by 2–3 rotors and focal sources, with a greater number in patients with persistent than paroxysmal AF, lying within spatially reproducible 2.2 ± 1.4-cm2 areas in diverse locations. This temporospatial reproducibility, now confirmed by several groups using various methods, changes the concepts regarding AF-sustaining mechanisms, enabling localized rather than widespread ablation. Mechanistically, the role of rotors and focal sources in sustaining AF has been demonstrated by the acute and chronic success of source (FIRM) ablation alone. Clinically, adding FIRM to conventional ablation substantially improves arrhythmia freedom compared with conventional ablation alone, and ongoing randomized trials are comparing FIRM—ablation with and without conventional ablation to conventional ablation alone. In conclusion, ablation of patient-specific AF-sustaining mechanisms (substrates), as exemplified by FIRM, may be central to substantially improving AF ablation outcomes.

Rotors as Drivers of Atrial Fibrillation and Targets for Ablation

Atrial fibrillation (AF) is the most common arrhythmia targeted by catheter ablation. Despite significant advances in our understanding of AF, ablation outcomes remain suboptimal, and this is due in large part to an incomplete understanding of the underlying sustaining mechanisms of AF. Recent developments of patient-tailored and physiology-based computational mapping systems have identified localized electrical spiral waves, or rotors, and focal sources as mechanisms that may represent novel targets for therapy. This report provides an overview of Focal Impulse and Rotor Modulation (FIRM) mapping, which reveals that human AF is often not actually driven by disorganized activity but instead that disorganization is secondary to organized rotors or focal sources. Targeted ablation of such sources alone can eliminate AF and, when added to pulmonary vein isolation, improves long-term outcome compared with conventional ablation alone. Translating mechanistic insights from such patient-tailored mapping is likely to be crucial in achieving the next major advances in personalized medicine for AF.

Multicentre safety of adding Focal Impulse and Rotor Modulation (FIRM) to conventional ablation for atrial fibrillation

Aims Focal Impulse and Rotor Modulation (FIRM) uses 64-electrode basket catheters to identify atrial fibrillation (AF)-sustaining sites for ablation, with promising results in many studies. Accordingly, new basket designs are being tested by several groups. We set out to determine the procedural safety of adding basket mapping and map-guided ablation to conventional pulmonary vein isolation (PVI). Methods and results We collected 30 day procedural safety data in five US centres for consecutive patients undergoing FIRM plus PVI (FIRM-PVI) compared with contemporaneous controls undergoing PVI without FIRM. A total of 625 cases were included in this analysis: 325 FIRM-PVI and 300 PVI-controls. FIRM-PVI patients were more likely than PVI-controls to be male (83% vs. 66%, P < 0.001) and have long-standing persistent AF (26% vs. 13%, P < 0.001) reflecting patients referred for FIRM. Total ablation time was greater for FIRM-PVI (62 ± 22 min) vs. PVI-controls (52 ± 18 min, P = 0.03). The complication rate for FIRM-PVI procedures (4.3%) was similar to controls (4.0%, P = 1) for both major and minor complications; no deaths were reported. The rate of complications potentially attributable to the basket catheter was small and did not differ between basket types (Constellation 2.8% vs. FIRMap 1.8%, P = 0.7) or between cases in which basket catheters were and were not used (P = 0.5). Complication rates did not differ between centres (P = 0.6). Conclusions Procedural complications from the use of the basket catheters for AF mapping are low, and thus procedural safety appears similar between FIRM-PVI and PVI-controls in a large multicentre cohort. Future studies are required to determine the optimal approach to maximize the efficacy of FIRM-guided ablation.