Inhibition of Atrial Fibrillation by Elimination of Transitional Mechanisms

1. Patient Enrollment:

UCSD will enroll subjects with symptomatic AF undergoing clinically-indicated ablation at the Sulpizio Cardiovascular Center.

1. Research Study Data UCSD will record patient demographics (e.g. age, gender, echocardiographic information), AF history (AF duration, previous and current antiarrhythmic medications, prior ablations), medical history (current medication regimen, lab values, etc.), and other relevant history. All recorded digital data such as electrocardiograms and intracardiac recordings will be exported from the recorder stripped of patient identifying information.
2. Electrophysiology (EP) Study and Catheter Placement:

EP study will be performed in the fasting state and after antiarrhythmic medications are discontinued for 5 half-lives (>60 days for amiodarone). Catheters are advanced to the right atrium (RA), coronary sinus, and transseptally to left atrium (LA). A 64-pole basket catheter (FIRMap, Topera, Menlo Park, CA) will map the LA. RA recordings are made using a second basket, simultaneously when possible. Heparin will be infused to maintain activated clotting time >350 seconds.

1. Data Acquisition:

Creating an Electroanatomic Map Digital electroanatomical maps ("shells") will be created of each atrium's using mapping software (Ensite NavX, St Jude, St. Paul, MN or Biosense-Webster, Carto, Diamond Bar, CA.) Each shell is created by sampling atrial and venous points (Figure 3), and when available, referenced to preprocedural computed tomographic scans.

Recording Electrograms All AF electrograms will be recorded in a wide field-of-view using the 64-pole basket catheters. Unipolar and bipolar electrograms are filtered at 0.05 Hz to 500 Hz and recorded at 1 kHz (Bard, Lowell, MA) as described in prior work9.

Inducing AF Induction will be performed systematically first with programmed premature atrial contractions (PACs) using single extrastimuli at shortening coupling intervals after an 8-beat drive of cycle length (CL) 500ms (120 bpm). Next, burst pacing will be done at CL 500ms, reducing in 50ms steps to 300ms, then in 10ms steps to AF from the proximal coronary sinus as a stable reference point. If AF still does not initiate, isoproterenol (≤ 10mcg/min)10 will be infused. Each patient's induction threshold will be documented.

Recording Transitional and Sustained AF AF from induction until >5 minutes will be recorded, at which point prior work suggests AF is sustained, 6 whether spontaneous or induced. The first few seconds of AF will then be analyzed as described below.

9.2 Data Analysis A. AF initiation will be mapped and transitional mechanisms identified Phase mapping will be used to analyze AF initiation, defined as the first 5 seconds of AF. Biatrial phase movies will be created to visualize spatial distribution of activation times across the LA and RA. These phase movies illustrate the rotor phase singularities, which are defined as the point about which the integral of phase is 0, and visualized as the intersection of depolarization and repolarization isolines.

In patients with multiple AF initiations, the investigators will determine whether AF initiation occurs at conserved sites, defined as a separation in location ≤1 electrode distance. Other initiating mechanisms will be noted, including rapidly-firing focal impulses (focal activation is defined as centrifugal emanation from an origin that drives the atrium into fibrillatory conduction.)

1. Transitional rotors will be ablated After identifying transitional AF rotors, they will be targeted for localized ablation. Rotor location within the atria will be noted, both in the electroanatomic map and relative to the basket catheter splines. Radiofrequency (RF) energy will be applied to the core of the rotor, as described previously6, 9. RF energy will be delivered with a 3.5 mm tip irrigated catheter (ThermoCool, Biosense-Webster) at 25-35 W or, in patients with heart failure, an 8 mm tip catheter (Blazer, Boston Scientific, Marlborough, MA) at 50 to 55 W, with a target temperature of 52˚C. Each lesion is applied for approximately 30-60 seconds, with a predetermined goal of 5-10 minutes of RF energy being placed to cover the ≈2 cm2 area of AF rotor precession.
2. Induction thresholds will be compared Post-ablation, AF will again be induced systematically using the same protocol as before, and this threshold will be compared to the pre-ablation one. The threshold will be considered as increased if the post-ablation induction protocol entails a more aggressive pacing protocol (e.g. a protocol with faster pacing [shorter cycle length]). Figure 4 summarizes the workflow for Specific Aim 2.
3. Sustained AF will be mapped and ablated FIRM maps of ongoing AF will be created and analyzed using RhythmView (Topera, Menlo Park, CA). Rotors and focal impulses are considered AF sources only if stable in repeated samples, to distinguish from transient fibrillatory activity. The focal source origin or rotor core (center of rotational activity) will be located by its electrode coordinates and localized digitally within each patient-specific anatomic shell at the time of each FIRM map to eliminate errors from subsequent possible movement.

Patients begin in sinus rhythm. If induction threshold is higher after ablating initiating mechanisms, rotor ablation will proceed as per standard. If induction threshold is not higher, AF initiation is re-mapped once to confirm elimination of initiating mechanism; if present, it will be ablated again and again re-mapped to confirm. DCCV: Direct-current cardioversion.

In this trial, the only aspects of the procedure that are specifically done for research are the mapping and ablating of the initiating rotors that are identified within the first minute of inducing AF. The mapping and ablating of the sustaining rotors and the following PVI ablation are all standard of care ablation procedures.

9.3 Study Follow-up Schedule

Enrolled subjects will be followed for 1 year in this study by one of the sub-investigators or the principle investigator. All study visits are considered standard of care and these clinic visits will be expected of patients that receive ablation, regardless of whether they enroll in the trial or not. This study will entail three in-clinic follow-up visits at 1month, 6month, and 12 months post-ablation. At these visits, the following information will be collected:

• Cardiovascular symptoms (such as shortness of breath, fatigue, palpitations)
• Physical exam
• Cardiac medications, including anti arrhythmics, and changes in prescriptions
• 12-lead ECG recordings
• Cardiac monitoring, including Holter monitor (of any duration) or event monitor (or any duration), should be reviewed for any arrhythmias. If present, implanted devices will be interrogated at this time, evaluating for the same.

A study visit window of +/- 2 weeks will be put into effect during study follow-up in order to better schedule and accommodate enrolled subjects' schedules.

9.4 Expected Results and Endpoints A. Ablation of transitional AF mechanisms will increase AF induction threshold. Preliminary work in the UCSD lab has found that ablation of a transitional rotor in a patient with paroxysmal AF increased the AF induction threshold. If this finding holds true for the proposed study, this will be an important mechanistic finding, of interest to the general electrophysiology community.

1. Ablation of transitional AF mechanisms will improve ablation success The secondary endpoint is 1-year survival free of AF, with follow-up as per guidelines (i.e. 24-hour Holter monitor every 6 months with 12-lead ECG at every follow-up visit.) The investigators expect ablation of transitional mechanisms will improve success versus historical controls matched by age, AF duration, LA size, and EF.