Incidental left atrial appendage isolation after catheter ablation of persistent atrial fibrillation: Mechanisms and long‐term risk of thromboembolism

Incidental left atrial appendage (LAA) isolation may occur during radiofrequency ablation of persistent atrial fibrillation (AF). The study aims to describe the mechanisms and long‐term thromboembolic risk related to incidental LAA isolation.


| INTRODUCTION
Adjunctive electrical isolation of the left atrial appendage (LAA) has been shown to improve outcomes in patients with persistent atrial fibrillation (AF). 1 However, mechanical stasis imparted by an electrically disconnected appendage may predispose to thromboembolism. Landmark studies that described this technique utilized an empiric LAA isolation strategy. In other words, the LAA was electrically isolated without necessarily showing its participation in the maintenance of AF or related arrhythmias. However, LAA isolation may occur incidentally while targeting clinical arrhythmias. 2 Further, since LAA isolation may occur despite energy delivery at anatomically remote sites, the operator may not anticipate such an occurrence, possibly exposing the patient to risk of thromboembolism. The study aims to describe the mechanisms of incidental LAA isolation, and the long-term thromboembolic risk in such patients as compared to matched controls without appendage disconnection.

| METHODS
This is a retrospective study of consecutive patients undergoing an ablation procedure between 2010 and 2020 for AF, or post-AF atrial tachycardia (AT) in whom incidental LAA isolation was noted. The incidence of thromboembolism postablation in these patients was

| Electrophysiology study
All patients provided informed written consent. All antiarrhythmic drugs except amiodarone were discontinued at least 4 to 5 half-lives before the study; amiodarone was discontinued at least 2 months before the procedure. Oral anticoagulation with warfarin was not interrupted. Patients taking a direct oral anticoagulant (DOAC) were asked to withhold the medication on the day of the procedure. The ablation procedure was performed using deep conscious sedation or general anesthesia. All patients underwent a transesophageal echocardiogram to rule out LA thrombus. Vascular access was obtained through a femoral vein. A multipolar catheter was positioned in the coronary sinus (CS) and was used for recording and atrial pacing. After the transseptal puncture, systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time of >350 s. A 3-D mapping system was used to guide catheter navigation and ablation (CARTO 3; Biosense Webster).
An open-irrigation, 3.5-mm-tip deflectable catheter was used for mapping and ablation. Bipolar electrograms were recorded at a band pass of 30 to 500 Hz (EPMedSystems). The esophagus was delineated with a radio-opaque marker. Radiofrequency (RF) energy was applied at a maximum power output of 35 W at a flow rate of 30 mL/min and a maximum temperature of 45°C. When ablation was performed near the pulmonary vein (PV) ostia, or in the posterior LA, the power was reduced to 25 W at a flow rate of 17 mL/min. Power was limited to 20 W during energy application in the CS.

| Ablation protocol
The ablation procedure was performed during AF. PV isolation was performed in all patients, followed by linear ablation at the LA roof.
Over the last 6 years, the ablation protocol has evolved to include the posterior LA, with the endpoint of complete electrical isolation. This step is followed by ablation of the inferior LA and lateral LA guided by rapid activity (not complexity) as compared to the global CL in the LAA. 3 In addition, the left and possibly the right atrial (RA) appendage are targeted based on analysis of AF cycle length. 3 Importantly, the endpoint of appendage ablation during the initial ablation procedure was not complete electrical isolation but slowing of the AF cycle length by at least two-fold, for example, from an average cycle length of 160 ms to greater than 320 ms. If LAA isolation was noted, RF energy was immediately discontinued. If AF terminates to AT at any time, these organized arrhythmias are mapped and ablated. If AF persists after these steps, transthoracic CV is performed.
If the LAA had fully reconnected in a patient presenting for a repeat procedure for atrial fibrillation, and it was clear that the endpoint of local slowing could not be achieved without electrical isolation, RF energy was not interrupted. If LAA isolation was incidentally noted during RF ablation at the critical isthmus/site of origin of an atrial tachycardia, energy delivery was not interrupted, for example, during ablation of perimitral atrial flutter. 2,4 In the case of AF, the rationale is that AF is unlikely to be eliminated if a putative source in the LAA continues to harbor rapid activity, typically in the range of 150-170 ms. In the case of AT, the risk of LAA isolation is accepted if it is clear that the clinical tachycardia cannot be eliminated without concomitant electrical disconnection of the appendage. LAA conduction was monitored by placing a multipolar catheter into the appendage.

| Postablation management and follow-up
Patients were monitored on a telemetry unit overnight, and prescribed oral anticoagulation, and rate-controlling medications.
Antiarrhythmic medications were not prescribed unless the patient developed recurrence associated with hospitalization or severe symptoms such as heart failure. Patients were seen in an outpatient clinic 3 months after the ablation procedure and every 3 to 6 months thereafter. Patients on long-term anticoagulation were enrolled in a GHANNAM ET AL. | 1153 pharmacist-led anticoagulation clinic for monitoring. Rhythm status was assessed via device interrogation in patients with an implantable device, or a 30-day, auto-trigger event monitor (Lifestar AF Express, Life Watch Inc) at 12 months after the ablation procedure, in the absence of antiarrhythmic medications. Recurrence was defined as sustained (>30 s) symptomatic or asymptomatic AF/AT after the 3month blinding period. Oral anticoagulation was continued in patients with CHA 2 DS 2 -VASc score >2, including those with electrical isolation, or conduction delay into the LAA during sinus rhythm, defined as local activation occurring after the QRS complex. Patients with LAA isolation were advised to undergo bridging with low molecular weight heparin should they require temporary discontinuation of oral anticoagulation for medical/surgical procedures.
Patients who experienced thromboembolism or those who were unable to tolerate long-term anticoagulation were recommended to undergo implantation of a LAA occlusion device. This information was also communicated to the referring physician.

| Statistical analysis
Continuous variables are expressed as mean± standard deviation, categorical variables were expressed as counts and percentages. Data were compared using the Fisher's t-test or χ 2 test for categorical variables and the Student's t-test or Mann-Whitney test for continuous variables as appropriate. Based upon their established association with long-term stroke risk, the variables for propensity matching were components of the CHA 2 DS 2 -VASc score (age, sex, congestive heart failure, hypertension, prior stroke/transient ischemic attach/thromboembolism, vascular disease, or diabetes). Propensity scoring was performed using the nearest neighbor matching method in the MatchIt package within R. Cox proportional hazard modeling and Kaplan-Meier analyses were performed to examine the incidence of stroke between the group with and without LAA isolation. Among patients with LAA isolation, cox proportional hazard modeling was used to identify patient and procedural characteristics associated with the risk of thromboembolism. Index procedure was defined as the procedure during which LAA isolation occurred for the study group, and the ablation which occurred at the time of propensity matching in the control arm. A 2-tailed p < .05 indicated statistical significance. All statistical analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing).

| RESULTS
Eight hundred and five patients underwent ablation for atrial fibrillation over the study period, the study group consisted of 41 patients with LAA isolation, and 82 control patients without LAA isolation. The average age was 64 ± 11 years, and 36 of the 123 (29%) patients were female. All patients were taking oral anticoagulants: 85 (70%) on DOAC, and 38 (30%) on warfarin. There were no significant differences in patient age, sex, LA size, ejection fraction or CHA 2 DS 2 -VASc score, the use of DOACs versus warfarin, or ASA use between the two groups (Table 1). Total follow-up time was 4.2 ± 3.6 years and was similar between the control and study group

| LAA isolation group
LAA isolation was not observed in any patient during an initial ablation procedure, and patients had undergone 2.5 ± 1.2 prior procedures before the ablation resulting in LAA isolation. Among the 41 patients who sustained LAA isolation during the redo procedure, the presenting rhythm was persistent AF, AT, or sinus, in 12, 23, and 6 patients, respectively. PVs were found to be isolated   Complete isolation was not pursued. At the redo session, there was full reconnection of the LAA (172 ms). A single radiofrequency (RF) lesion caused complete isolation of the LAA. In this case, it was not possible to simply slow the putative AF source without complete LAA isolation. The patient has been arrhythmia-free without antiarrhythmic medications for more than 4 years. Abl, ablation. CS, coronary sinus; RAA, right atrial appendage; "v", far-field ventricular electrogram.
F I G U R E 2 Mode of LAA isolation. Circumferential LAA ablation in this patient led to a limited area of isolation that was confined to the distal aspect of the appendage. Slight withdrawal of the mapping catheter (green catheter icon/arrow) showed ongoing conduction proximal to the level of isolation. As compared to the extensive linear ablation that might lead to isolation of the entire LAA (Figure 4), the prevalence of thrombus in patients with distal isolation may be lower. LI, left inferior; LS, left superior; RI, right inferior; RS, right superior. F I G U R E 5 LAA isolation during RF ablation within the CS from the same patient whose electroanatomic map is shown in Figures 3D. Despite extensive endocardial and alcohol ablation (not shown), there was ongoing conduction across the mitral isthmus (arrow). RF ablation within the CS during LAA pacing ("S") caused exit block from the appendage, mimicking loss-of-capture. However, the stimulus is followed by local capture (red asterisks) that does not conduct to the atrium or the CS. To prevent recurrent perimitral reentry, RF energy was continued as it was not possible to attain isthmus block without LAA isolation. Note the long conduction time to the CS, and fragmented/long-duration electrograms (red asterisks/bracket). LAA, left atrial appendage; "P", p-wave during sinus rhythm; RF, radiofrequency.
F I G U R E 6 This patient presented with recurrent AT that could not be eliminated during the prior session. Contrast injection into the vein of Marshall (VoM) terminated the tachycardia. Note the very delayed LAA activation occurring after the QRS complex ("A"). Thereafter, 1 cubic centimeter (cc) of ethyl alcohol (EtOH) was slowly infused into the VoM causing complete isolation of the LAA, and rendering the patient noninducible. In the left anterior oblique (LAO) view, the myocardial blush corresponds to the course of the VoM, and a not a vein responsible for draining the LAA. Note, that the small deflection in the ST segment (asterisks) is also eliminated coincidentally with LAA isolation, confirming that its inscription on the surface lead was due to very late LAA activation. AP, anteroposterior.

| Comparison to control group
Over the follow-up period, 3 of the 82 patients (4%) without LAA isolation experienced a stroke: one patient while compliant with oral anticoagulation, and two others due to noncompliance or interruption of anticoagulation for hemoptysis. One patient was in AF at the time of stroke, and the other two were in sinus rhythm. Patients with LAA isolation were more likely to experience thromboembolism as compared to controls without isolation (log rank p < .009; HR 5.14 95% CI [1.32-19.94], p = .02) (Figure 8). After allowing for multiple procedures,

| Rationale for targeting the LAA
A randomized trial found that empiric LAA isolation helped eliminate longstanding persistent AF in 76% of patients. 1 An advantage of such an approach is that it does not rely on demonstration of LAA ectopy/ triggers, and thus, can be executed in sinus rhythm, simplifying the ablation procedure. A recent observational study also found supporting evidence for LAA ablation. 3 In contradistinction to the randomized study, mapping and ablation was performed during AF in the latter study, with the endpoint of slowing of the LAA cycle length (or AF termination) as opposed to complete appendage isolation. In addition, the LAA has also been implicated in perpetuating LA reentry after catheter ablation of AF. 5

| Anatomic basis of incidental LAA isolation
It follows that circumferential ablation around the ostium of the LAA akin to PV isolation, may lead electrical isolation of the appendage. In contradistinction, LAA isolation may also occur unexpectedly during RF ablation at a number of sites that lie remote from the appendage.
F I G U R E 7 A large LAA thrombus after appendage isolation. This patient was referred for a repeat procedure for AT. A prior procedure in 2017 consisted of both lateral and anterior approaches for perimitral reentry, resulting in LAA isolation. A computed tomography scan before the procedure in 2017 showed no thrombus (panels A, B). A repeat scan in 2022 showed a large thrombus (panels C, D; blue arrows). The thrombus was also demonstrated on echocardiography (panel E; blue arrows). Ao, aorta; LAR, left atrial ridge; MV, mitral valve.
Recall that myocardial fibers that "embrace" the anterior and posterior bases of the LAA emerge from Bachmann's bundle, an epicardial structure located outside the anterior antrum of the right superior PV. 6 In the vulnerable patient, that is, one in whom there is evidence of spontaneous and/or ablation-induced scarring, LAA isolation may occur during RF ablation at Bachmann's bundle, which might be located >5 cm away from the LAA. 2 RF ablation at this site (to anchor the anterior lesion) is often required in patients with perimitral reentry who do not respond to a lateral approach. In addition, LAA isolation may occur during RF energy delivery in the distal CS, for example, for mitral isthmus block, at the inferolateral LA, or during alcohol ablation of the vein of Marshall. 4 In the context of extensive endocardial ablation or intrinsic remodeling, these epicardial structures may be solely responsible for maintaining conduction into the lateral LA and the appendage.

| Mode of LAA isolation
Inadvertent LAA isolation was initially described in the context of extensive LA ablation, including linear ablation at the lateral mitral isthmus and possibly anterior LA. 2,7 Additional studies have shown that purposeful LAA isolation can be achieved in 82% of cases through linear lesions at the mitral isthmus, roof, and anterior line. 8 LAA isolation can then be explained as a result of disruption of myocardial fibers destined for the LAA 6 during the course of ablation of for perimitral and related tachycardias. These fibers may be targeted both from the left atrial endocardium as well as epicardially within the coronary venous system. 9 During purposeful LAA isolation for AF, the appendage is targeted in a circumferential fashion but at a level that is more distal, closer to the ostium of the appendage as compared to the linear lesions described above. It has been speculated 10 that the high risk of thrombus reported in some studies 7 might be related to multiple linear lesions that transect the LA (Figure 4) as opposed to more focused or distal ablation around the ostium of the LAA itself ( Figure 2). Despite the differences in the lesion set and possibly the thrombogenic potential, management of resultant LAA isolation is probably similar, that is, the recommendation of indefinite anticoagulation, and consideration of appendage occlusion.

| LAA isolation as a thromboembolic risk
While the importance of the LAA as a source of AF is being increasingly recognized, the thromboembolic risk of an electrically isolated appendage is also gaining attention. Chan

| Risk mitigation
As discussed previously, the operator may have an opportunity to make a real-time decision as to the risks and benefits of LAA isolation during the ablation procedure. The thromboembolic risk associated with an isolated LAA may not be familiar to the patient's cardiologist or primary care physician. As such, it is in the patient's best interest that the operator include a specific plan in the medical record, such as bridging with heparin should oral anticoagulation need to be interrupted, and indications for an appendage occlusion device.
With increasing experience and decreasing risk of complications, appendage occlusion devices may be considered upfront in such patients to prevent not only thrombotic but also possibly hemorrhagic complications. Patients who are tolerating anticoagulation and remain free of neurological events may, however, elect to continue oral anticoagulation as opposed to submitting to yet another procedure. It is important to note that even among motivated patients, interruption in anticoagulation may occur due to bleeding, in preparation for surgical procedures, and under financial and accessto-care constraints. Even a well informed and compliant patient with LAA isolation may be vulnerable to thromboembolism in these reallife situations. These considerations should be part of an informeddecision making conversation when discussing left atrial appendage occlusion. The number of patients with LAA isolation at a given institution, the financial and coverage ramifications may also figure into the decision-making process. A strategy of utilizing LAA emptying velocity to guide long-term anticoagulation may seem intuitive. 12,13 However, these echocardiographic measures may not be sufficiently discriminating in identifying at-risk patients. 14-16

| Limitations
This was a single-center, retrospective report in a relatively small number of patients. Routine postablation transesophageal, or cerebral imaging (to evaluate for subclinical thromboembolism) was not obtained, which may have the potential to identify high-risk patients. High-power, shorter duration ablation was not utilized in this study which may have impacted long-term ablation outcomes.
The results of this study may not apply to a population of patients in whom LAA isolation was performed intentionally.

| Conclusions and clinical implications
LAA isolation may occur even when RF ablation is being performed at sites relatively distant from the appendage, owing to disruption of long myocardial fibers. Patients who experience incidental LAA isolation during the course of persistent AF ablation appear to be at heightened risk for thromboembolism during long-term follow-up. Neither CHA 2 DS 2 -VASc score nor rhythm status seems to be able to identify high-risk patients, calling for indefinite anticoagulation in all such patients. Since oral anticoagulation is inevitably interrupted at some point, for example, for medical procedures, patients may be particularly vulnerable to thromboembolism even during this brief period. Bridging with low molecular weight heparin may be an option in some patients but may be associated with bleeding complications. A LAA occlusion device offers protection against thromboembolism, but involves another invasive procedure.
Given these challenges, it seems reasonable to focus on prevention of LAA isolation when possible.