Electrical isolation of the left atrial appendage increases the risk of ischemic stroke and transient ischemic attack regardless of postisolation flow velocity

      Background

      Electrical isolation of the left atrial appendage (LAA) is associated with a lower rate of atrial fibrillation (AF) recurrence in patients undergoing radiofrequency catheter ablation. However, LAA isolation can significantly impair LAA contractility.

      Objective

      This study was performed to evaluate whether electrical isolation of the LAA is associated with an increased risk of ischemic stroke or transient ischemic attack (TIA).

      Methods

      Consecutive patients with AF undergoing radiofrequency catheter ablation at Korea University Medical Center Anam Hospital were analyzed.

      Results

      Of 2352 patients, 39 (1.7%) had LAA isolation. Patients with LAA isolation had a significantly higher rate of ischemic stroke or TIA than did those without LAA isolation (log-rank, P < .001; hazard ratio 23.6; P < .001). There were significant differences in the baseline characteristics of the 2 groups, including type of AF (34 [87.2%] and 911 [39.4%] patients with and without LAA isolation had nonparoxysmal AF, respectively). After multivariate adjustment, LAA isolation was found to be a significant risk factor for ischemic stroke or TIA (adjusted hazard ratio 11.3; P < .001). Propensity score–matched analysis also revealed an increased risk of ischemic stroke or TIA in patients with LAA isolation compared with those without LAA isolation (log-rank, P = .001). The LAA flow velocity of post-LAA isolation status was not significantly different between patients who did and did not experience ischemic stroke or TIA (30.3 ± 17.7 cm/s vs 33.9 ± 17.9 cm/s; P = .608).

      Conclusion

      A significantly increased risk of ischemic stroke or TIA was observed in patients with electrical isolation of the LAA. In addition, postisolation LAA flow velocity is not a reliable marker to predict future ischemic events.

      Keywords

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      Introduction

      Ischemic stroke and transient ischemic attack (TIA) are serious complications of atrial fibrillation (AF).
      • Lip G.Y.
      • Tse H.F.
      • Lane D.A.
      Atrial fibrillation.
      • Petersen P.
      Thromboembolic complications in atrial fibrillation.
      Anticoagulation is an important treatment for patients with AF in order to reduce these thromboembolic events.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
      Warfarin and non–vitamin K oral anticoagulants are particularly effective for the prevention of thrombotic complications in patients with AF. Radiofrequency catheter ablation (RFCA) is the treatment of choice for antiarrhythmic drug refractory symptomatic AF and recent retrospective analyses have also shown that RFCA reduces the risk of ischemic stroke in patients with AF.
      • Karasoy D.
      • Gislason G.H.
      • Hansen J.
      • Johannessen A.
      • Kober L.
      • Hvidtfeldt M.
      • Ozcan C.
      • Torp-Pedersen C.
      • Hansen M.L.
      Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark.
      • Friberg L.
      • Tabrizi F.
      • Englund A.
      Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries.
      • Saliba W.
      • Schliamser J.E.
      • Lavi I.
      • Barnett-Griness O.
      • Gronich N.
      • Rennert G.
      Catheter ablation of atrial fibrillation is associated with reduced risk of stroke and mortality: a propensity score-matched analysis.
      However, thromboembolic event after RFCA is still a challenging issue for electrophysiologists. Although the incidence of periprocedural stroke has decreased dramatically since the introduction of open irrigation ablation catheters, it is one of the most devastating complications of RFCA. Furthermore, ablation lesions, especially if extensive, in the left atrium (LA) and left atrial appendage (LAA) can decrease their contractility and might increase the risk of thromboembolic complications.
      • Wylie Jr., J.V.
      • Peters D.C.
      • Essebag V.
      • Manning W.J.
      • Josephson M.E.
      • Hauser T.H.
      Left atrial function and scar after catheter ablation of atrial fibrillation.
      • Kim Y.G.
      • Shim J.
      • Oh S.K.
      • Park H.S.
      • Lee K.N.
      • Hwang S.H.
      • Choi J.I.
      • Kim Y.H.
      Different responses of left atrium and left atrial appendage to radiofrequency catheter ablation of atrial fibrillation: a follow up MRI study.
      Di Biase et al
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      found that the rate of successful ablation is significantly increased if LAA electrical isolation is achieved in addition to the standard ablation procedure. In this trial, there were no ischemic stroke events in patients who underwent LAA isolation.
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      A recent meta-analysis of LAA isolation also found that LAA isolation is not associated with an increased risk of ischemic stroke, but with significantly improved late recurrence-free survival.
      • Romero J.
      • Michaud G.F.
      • Avendano R.
      • et al.
      Benefit of left atrial appendage electrical isolation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis.
      However, Rillig et al
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      identified an unexpectedly high rate of ischemic stroke or new thrombus formation in the LAA in their retrospective study. This group found that of 50 patients with LAA isolation, 10 and 3 patients experienced new thrombus formation and ischemic stroke or TIA, respectively.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      However, the follow-up duration was not long enough (median 6 months), and the difference between patients with and without LAA isolation was mainly driven by new thrombus formation rather than clinical events.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      It is not clear whether electrical isolation of the LAA is associated with an increased risk of adverse clinical events, such as ischemic stroke or TIA, in patients with AF undergoing RFCA. The LAA is the most frequent place for thrombus formation and subsequent embolization in patients with AF.
      • Holmes D.R.
      • Reddy V.Y.
      • Turi Z.G.
      • Doshi S.K.
      • Sievert H.
      • Buchbinder M.
      • Mullin C.M.
      • Sick P.
      PROTECT AF Investigators
      Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.
      • Blackshear J.L.
      • Odell J.A.
      Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation.
      • Stoddard M.F.
      • Dawkins P.R.
      • Prince C.R.
      • Ammash N.M.
      Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study.
      • Aberg H.
      Atrial fibrillation. I. A study of atrial thrombosis and systemic embolism in a necropsy material.
      Therefore, one might predict that electrical isolation of the LAA, which may decrease its contractility,
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      would increase a patient’s risk of ischemic stroke or TIA. We performed this analysis to test this hypothesis.

      Methods

       Purpose of the study

      We studied the effect of LAA electrical isolation on ischemic stroke or TIA-free survival rate in patients with AF undergoing RFCA. We also evaluated the influence of LAA isolation on transesophageal echocardiographic (TEE) parameters.

       Patients

      Consecutive patients with AF undergoing RFCA at Korea University Medical Center Anam Hospital between June 1998 and May 2016 were analyzed retrospectively. During the study period, a total of 2352 patients underwent their first RFCA procedure for AF. A total of 2997 procedures were performed, with a mean of 1.27 procedures per patient. All patients who underwent RFCA at our institution were included; there were no specific exclusion criteria. This study was approved by the Institutional Review Board of Korea University Medical Center Anam Hospital. Written informed consent was waived because the present study was a retrospective analysis. The study protocol adheres to the ethical guidelines of the 2008 Declaration of Helsinki.

       Definitions

      The primary outcome was ischemic stroke or TIA-free survival after RFCA. In patients without LAA isolation, the index date was the date of the first RFCA procedure. In patients who underwent LAA isolation, the index date was defined as the date of LAA isolation. Ischemic stroke was defined as any neurological symptoms that lasted for >24 hours and could not be explained by other medical conditions. TIA was defined as any neurological symptoms that were not attributable to other medical causes, but resolved completely within 24 hours. If acute infarction was observed on brain computed tomography (CT) or magnetic resonance imaging (MRI), the event was classified as ischemic stroke despite complete restoration of neurological symptoms. The final diagnosis of ischemic stroke and TIA was made after confirmation by neurologists. Late recurrence was defined as any atrial tachycardia lasting for >30 seconds occurring 3 months after RFCA.

       Ablation procedure

      The precise protocol for RFCA at our institution is published elsewhere and is described in the Supplement.
      • Kim Y.G.
      • Shim J.
      • Oh S.K.
      • Park H.S.
      • Lee K.N.
      • Hwang S.H.
      • Choi J.I.
      • Kim Y.H.
      Different responses of left atrium and left atrial appendage to radiofrequency catheter ablation of atrial fibrillation: a follow up MRI study.
      • Kim Y.G.
      • Shim J.
      • Kim D.H.
      • Choi J.I.
      • Park S.W.
      • Pak H.N.
      • Kim Y.H.
      Characteristics of atrial fibrillation patients suffering atrioesophageal fistula after radiofrequency catheter ablation.
      LAA isolation was intentionally performed only if the LAA was thought to be an important focus for triggering or maintaining AF. LAA isolation was documented by inserting a circular mapping catheter into the LAA. Absence of an electrical signal or presence of dissociated potential was used as the criterion to confirm LAA electrical isolation.

       Anticoagulation

      Anticoagulation was administered for at least 2 months after the procedure. After 2 months, anticoagulation therapy was given to patients with CHA2DS2-VASc score ≥2. Anticoagulation was discontinued, at the operator’s discretion, if no AF was documented on regular Holter monitoring (every 3 months for the first year and every 6 months thereafter). Data on post-RFCA anticoagulation prescription were gathered for all patients for the full follow-up duration. The anticoagulants used consisted of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. We calculated anticoagulation coverage as follows: (anticoagulated duration/total follow-up duration) × 100. Therefore, anticoagulation coverage reflects the overall anticoagulation status of each patient. For patients with LAA isolation, anticoagulation coverage was calculated by setting the date of LAA isolation as the index date. The date of the first RFCA procedure was considered an index date for patients without LAA isolation. For patients with ischemic stroke or TIA, the date of the event (ischemic stroke or TIA) was considered to be the end of follow-up.

       Imaging evaluation

      Transthoracic echocardiography and TEE were performed before RFCA to evaluate baseline heart status. We thoroughly examined patients for the presence of thrombus in the LA or LAA. Emptying, filling, and average flow velocity of the LAA were measured during TEE evaluation. The average LAA flow velocity was used for the analysis, and the ΔLAA flow velocity was defined as follows: (1) post-RFCA average LAA flow velocity – pre-RFCA average LAA flow velocity for patients without LAA isolation; (2) post-LAA isolation average LAA flow velocity – pre-LAA isolation average LAA flow velocity for patients with LAA isolation. Either CT or MRI study was performed to assess the anatomy of the pulmonary veins and to create a 3-dimensional reconstruction map using either EnSite NavX (Abbott, Chicago, IL) or CARTO (Johnson & Johnson, New Brunswick, NJ) systems.

       Statistical analysis

      Continuous variables are expressed as mean ± SD. Categorical variables are presented as percentile value. An unpaired t test was used to compare continuous variables. Categorical variables were compared using either the χ2 test or the Fisher exact test, as appropriate. Kaplan-Meier survival curve analysis was performed to depict ischemic stroke or TIA-free survival for each group. The difference between groups was analyzed using the log-rank test. Multivariate Cox regression analysis was performed to evaluate the effect of LAA isolation on ischemic stroke or TIA. Propensity score–matched analysis was also performed to adjust for the influence of covariates. Covariates included in the multivariate Cox regression analysis and propensity score–matched analysis were chosen on the basis of the baseline characteristics of each group and univariate logistic regression analysis. However, the known risk factors of ischemic stroke or TIA, such as individual components of the CHA2DS2-VASc score, were included in multivariate analysis regardless of the results of univariate analysis. The results were considered to be significant if the P value was <.05 on a 2-tailed test. All statistical analyses were performed using SPSS version 24.0 (IBM Corp. Armonk, NY).

      Results

       Patient characteristics

      The study diagram is summarized in Figure 1. A total of 2352 patients underwent first-time RFCA during the study period. LAA was isolated in 39 patients (1.7%). Eleven patients (28.2%) had LAA isolation during their initial RFCA, while 28 patients (71.8%) had LAA isolation during repeat procedures. Thirty-five patients (89.7%) had intentional LAA isolation, and the remaining 4 patients (10.3%) had accidental LAA isolation during ablation. The mean follow-up duration was 4.2 (1.9 when starting from the date of LAA isolation rather than first RFCA date) and 4.3 years for patients with and without LAA isolation, respectively. The baseline demographic characteristics of patients with and without LAA isolation are summarized in Table 1. Patients with LAA isolation vs without LAA isolation had a higher incidence of nonparoxysmal AF (34 [87.2%] vs. 911 [39.4%] patients, respectively; P < .001). Higher incidences of spontaneous echo contrast (SEC) (15 [40.5%] vs 441 [21.1%] patients; P = .004) and dense SEC (4 [10.8%] vs 73 [3.5%] patients; P = .042) were also observed in patients with LAA isolation. The LA diameter was greater (44.1 ± 6.4 mm vs 41.1 ± 5.9 mm; P = .002) and the average LAA flow velocity was lower (31.6 ± 14.7 cm/s vs 48.9 ± 20.9 cm/s; P < .001) in patients with LAA isolation than in those without LAA isolation. Anticoagulation coverage was higher in patients with LAA isolation than in those without LAA isolation (58.4% ± 39.8% vs 29.6% ± 34.3%, respectively; P < .001).
      Figure thumbnail gr1
      Figure 1Flow diagram of the study. LAA = left atrial appendage; RFCA = radiofrequency catheter ablation; TIA = transient ischemic attack.
      Table 1Baseline characteristics
      CharacteristicLAA not isolated (n = 2313)LAA isolated (n = 39)P
      Clinical findings
       Age (y)55.4 ± 11.056.4 ± 9.2.501
       Male sex1837 (79.4)35 (89.7).113
       Body weight (kg)70.6 ± 11.173.8 ± 11.2.079
       Height (cm)168.1 ± 8.2170.9 ± 8.4.031
       Body mass index (kg/m2)24.9 ± 3.025.2 ± 3.1.599
       Heart failure176 (7.6)4 (10.3).536
       Hypertension857 (37.1)8 (20.5).034
       Diabetes mellitus257 (11.1)2 (5.1).309
       Ischemic stroke/TIA/SE184 (8.0)1 (2.6).363
       Vascular disease219 (9.5)1 (2.6).258
       CHA2DS2-VASc score1.3 ± 1.30.7 ± 1.0.009
       Anticoagulation coverage (%)29.6 ± 34.358.4 ± 39.8<.001
       Nonparoxysmal AF911 (39.4)34 (87.2)<.001
       AF duration (y)4.8 ± 4.75.5 ± 3.9.340
      Echocardiographic findings
       LA diameter (mm)41.1 ± 5.944.1 ± 6.4.002
       LV ejection fraction (%)54.9 ± 6.153.0 ± 6.5.061
       E over E′8.9 ± 4.08.5 ± 3.4.501
       LAA emptying velocity (cm/s)47.9 ± 21.930.9 ± 14.9<.001
       LAA filling velocity (cm/s)49.8 ± 22.332.3 ± 15.6<.001
       LAA average velocity (cm/s)48.9 ± 20.931.6 ± 14.7<.001
       SEC441 (21.1)15 (40.5).004
       Dense SEC73 (3.5)4 (10.8).042
       Thrombus4 (0.2)1 (2.7).084
      Laboratory findings
       White blood cell count (103/μL)6.5 ± 3.46.2 ± 1.7.609
       Hemoglobin level (g/dL)14.7 ± 1.415.2 ± 1.2.025
       Platelet count (103/μL)207.8 ± 49.4196.3 ± 33.7.044
       Creatinine level (mg/dL)1.04 ± 0.371.10 ± 0.25.284
      Values are presented as mean ± SD or as n (%).
      AF = atrial fibrillation; LA = left atrium; LAA = left atrial appendage; LV = left ventricle; SE = systemic embolism; SEC = spontaneous echo contrast; TIA = transient ischemic attack.

       LAA isolation

      An example of LAA isolation is shown in Figure 2. In this particular patient, the LAA was isolated at re-do RFCA during LAA anterior neck ablation (Figure 2A). LAA angiography was performed, and LAA contractility was significantly impaired (Figure 2B; video image is presented in Supplemental Video S1). A follow-up TEE evaluation revealed decreased LAA flow velocity (Figure 2C), and the patient experienced ischemic stroke with total occlusion of the right middle cerebral artery (Figure 2D). The patient also experienced hemorrhagic transformation of the infarct zone. He ultimately underwent LAA occlusion therapy to prevent further ischemic stroke (Figure 2E).
      Figure thumbnail gr2
      Figure 2A clinical case of LAA isolation. A: Ablation lesion set of the patient. During first-time ablation, we performed 4 circumferential pulmonary vein isolation, roofline, anterior line, perimitral line, and CFAE-guided ablation. During the re-do procedure, ablation of the LAA anterior neck isolated the LAA. B: Significantly decreased contractility of the LAA was observed after electrical isolation. C: After LAA isolation, the average LAA flow velocity decreased from 41.5 to 25.5 cm/s. D: The patient experienced ischemic stroke with total occlusion of right middle cerebral artery while taking clopidogrel. The patient’s CHA2DS2-VASc score was 0. E: LAA occlusion therapy was performed to prevent further ischemic stroke events. CFAE = complex fractionated atrial electrogram; LAA = left atrial appendage; RFCA = radiofrequency catheter ablation.

       Ischemic stroke and TIA

      During follow-up, a total of 66 (2.8%) ischemic stroke or TIA events occurred. Of 39 patients with LAA isolation, 5 (12.8%) and 4 (10.3%) patients experienced ischemic stroke and TIA, respectively. A summary of these 9 ischemic stroke and TIA events is presented in Table 2. All ischemic stroke and TIA events were confirmed by neurologists. Eight patients underwent brain CT or MRI studies. Before an ischemic stroke or TIA event, 4 patients were treated with anticoagulation, 4 patients were taking antiplatelets, and 1 patient had no such antithrombotic therapy. Seven patients received guideline-directed antithrombotic therapy on the basis of CHA2DS2 -VASc score. One patient received anticoagulation therapy even though CHA2DS2 -VASc score was 0. However, patient 1 did not receive anticoagulation despite a high CHA2DS2-VASc score, because the patient had no AF episodes after the last RFCA. Of 9 patients with thrombotic complications, 6 (66.7%) had LAA isolation during repeat procedures while the remaining 3 (33.3%) demonstrated isolation during the initial RFCA procedure.
      Table 2Presenting symptoms and clinical course of each patient
      Patient no.Type of the eventDate of the eventDate of LAA isolationLAA isolation during the repeat procedureTime interval between LAA isolation and the clinical event (d)Imaging study (CT or MRI)Infarction lesion in the imaging studyNeurologist confirmationCHA2DS2-VASc scoreAntithrombotic therapy before the clinical event
      1Ischemic stroke2016/8/112014/10/20Repeat RFCA661PerformedDocumented infarctionYes3Clopidogrel
      2Ischemic stroke2017/7/112015/6/1Repeat RFCA771PerformedDocumented infarctionYes0Clopidogrel
      3Ischemic stroke2013/8/22012/3/29First-time RFCA491PerformedDocumented infarctionYes1Aspirin + clopidogrel
      4Ischemic stroke2016/5/72014/11/13Repeat RFCA541PerformedDocumented infarctionYes1Warfarin
      5Ischemic stroke2017/3/232016/2/4First-time RFCA413PerformedDocumented infarctionYes1Edoxaban 60 mg
      6TIA2017/8/162014/10/22Repeat RFCA1029PerformedNo infarctionYes0None
      7TIA2015/12/112013/12/31Repeat RFCA710PerformedNo infarctionYes0Aspirin
      8TIA2014/12/22014/3/20Repeat RFCA257Not performedNAYes0Warfarin
      9TIA2017/6/152014/2/12First-time RFCA1219PerformedNo infarctionYes0Edoxaban 60 mg
      CT = computed tomography; LAA = left atrial appendage; MRI = magnetic resonance imaging; NA = not available; RFCA = radiofrequency catheter ablation; TIA = transient ischemic attack.
      In Kaplan-Meier survival curve analysis, patients with LAA isolation had a significantly higher incidence of ischemic stroke or TIA than did those without LAA isolation (log-rank, P < .001; hazard ratio [HR] 23.6; 95% confidence interval 11.0–50.3; P < .001) (Figure 3A). After multivariate adjustment, LAA isolation was a significant risk factor for ischemic stroke or TIA (adjusted HR 11.3; 95% confidence interval 4.5–28.7; P < .001) (Supplemental Table S1). In propensity score–matched analysis, the baseline demographic characteristics were well matched between the 2 groups, including AF type, CHA2DS2-VASc score, transthoracic echocardiographic and TEE parameters, and anticoagulation coverage (Supplemental Table S2). There was a significantly increased risk of ischemic stroke or TIA in patients with LAA isolation in propensity score–matched analysis (log-rank, P = .001) (Figure 3B) than in patients without LAA isolation.
      Figure thumbnail gr3
      Figure 3Electrical isolation of the LAA and the risk of ischemic stroke or TIA. Electrical isolation of the LAA was associated with a significantly increased risk of ischemic stroke or TIA in both raw comparison (A) and propensity score–matched analysis (B). HR = hazard ratio; LAA = left atrial appendage; TIA = transient ischemic attack.
      In patients without LAA isolation, successful maintenance of sinus rhythm was associated with a significantly lower risk of ischemic stroke or TIA (P < .001) (Figure 4A). However, absence of late recurrence had no effect on ischemic stroke or TIA in patients with LAA isolation (P = .142) (Figure 4B). The clinical and echocardiographic findings of patients with LAA isolation did not differ between patients with and without ischemic stroke or TIA (Supplemental Table S3).
      Figure thumbnail gr4
      Figure 4Effect of late recurrence on IS and TIA. Patients without late recurrence had a significantly lower risk of IS only if the LAA was not isolated, which suggests a moderator effect of LAA isolation. IS = ischemic stroke; LAA = left atrial appendage; LR = late recurrence; TIA = transient ischemic attack.
      Two patients had newly developed thrombus formation after LAA isolation. One of these patients subsequently suffered from ischemic stroke after detection of LAA thrombus. The cumulative incidence of ischemic stroke, TIA, or newly detected thrombus was significantly higher in patients with LAA isolation (log-rank, P < .001; HR 26.0; 95% confidence interval 12.6–53.9; P < .001) (Supplemental Figure S1).

       TEE findings

      Post-LAA isolation LAA flow velocity was significantly lower than pre-LAA isolation LAA flow velocity (32.9 ± 17.7 cm/s vs 40.5 ± 16.2 cm/s; P = .025; mean time interval 156.9 ± 141.1 days) (Figure 5A). However, post-LAA isolation LAA flow velocity did not differ between patients with and without ischemic stroke or TIA (30.3 ± 17.7 cm/s vs 33.9 ± 17.9 cm/s; P = .608) (Figure 5B).
      Figure thumbnail gr5
      Figure 5Effect of LAA isolation on LAA flow velocity. A: LAA flow velocity decreased significantly after LAA isolation. B: Post-LAA isolation LAA flow velocity did not differ between patients with and without ischemic stroke or TIA. LAA = left atrial appendage; TIA = transient ischemic attack.
      In patients without LAA isolation, post-RFCA LAA flow velocity was significantly increased in comparison to pre-RFCA LAA flow velocity (Supplemental Figure S2A). The ΔLAA flow velocity was also significantly worse in patients with LAA isolation than in those without LAA isolation (Supplemental Figure S2B).

      Discussion

      Our findings suggest that electrical isolation of the LAA might significantly increase the risk of ischemic stroke and TIA. As previously reported, LAA isolation significantly impaired its contractility.
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      However, in patients with LAA isolation, there were no significant differences in LAA flow velocity between patients who did and did not suffer from ischemic stroke or TIA. This finding suggests that postisolation LAA flow velocity is not a reliable marker to guide antithrombotic treatment in patients with LAA isolation. This is the first study to demonstrate a clear increase in clinical thromboembolic events in patients with electrical isolation of the LAA.

       Ischemic stroke and TIA

      The LAA is a fingerlike projection from the main body of the LA, which actively contracts.
      • Beigel R.
      • Wunderlich N.C.
      • Ho S.Y.
      • Arsanjani R.
      • Siegel R.J.
      The left atrial appendage: anatomy, function, and noninvasive evaluation.
      Active contraction and relaxation of the LAA maintain adequate blood flow in and out of the LAA.
      • Beigel R.
      • Wunderlich N.C.
      • Ho S.Y.
      • Arsanjani R.
      • Siegel R.J.
      The left atrial appendage: anatomy, function, and noninvasive evaluation.
      In patients with AF, LAA contractility is significantly diminished, as manifested by lower LAA flow velocity or SEC in TEE evaluation.
      • Pollick C.
      • Taylor D.
      Assessment of left atrial appendage function by transesophageal echocardiography. implications for the development of thrombus.
      • Nucifora G.
      • Faletra F.F.
      • Regoli F.
      • Pasotti E.
      • Pedrazzini G.
      • Moccetti T.
      • Auricchio A.
      Evaluation of the left atrial appendage with real-time 3-dimensional transesophageal echocardiography: implications for catheter-based left atrial appendage closure.
      As a consequence, blood in the LAA becomes stagnant. Eventually, overt thrombus can develop within the LAA.
      • Kim Y.G.
      • Choi J.I.
      • Kim M.N.
      • et al.
      Non-vitamin K antagonist oral anticoagulants versus warfarin for the prevention of spontaneous echo-contrast and thrombus in patients with atrial fibrillation or flutter undergoing cardioversion: a trans-esophageal echocardiography study.
      In fact, the LAA is the most common site of thrombus formation and embolization, leading to ischemic stroke or TIA in patients with AF.
      • Holmes D.R.
      • Reddy V.Y.
      • Turi Z.G.
      • Doshi S.K.
      • Sievert H.
      • Buchbinder M.
      • Mullin C.M.
      • Sick P.
      PROTECT AF Investigators
      Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.
      • Blackshear J.L.
      • Odell J.A.
      Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation.
      • Stoddard M.F.
      • Dawkins P.R.
      • Prince C.R.
      • Ammash N.M.
      Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study.
      Therefore, electrical isolation of the LAA, which impairs its contractility, should raise concern about the potentially increased risk of ischemic stroke and TIA in patients with AF undergoing RFCA.
      Currently, the risk of ischemic stroke and TIA in patients with AF with LAA isolation is controversial. In the BELIEF trial, Di Biase et al
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      found that the risk of ischemic stroke or TIA was not increased in patients with empirical LAA isolation, despite a substantial proportion of patients having impaired LAA function. Rillig et al,
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      however, published an article showing a detrimental effect of LAA isolation. Of 50 patients with LAA isolation, 10 patients developed new LAA thrombi and 3 patients suffered from ischemic stroke or TIA.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      There was a statistically significant increase in the risk of composite end points (ischemic stroke, TIA, or newly detected thrombus) in the LAA isolation group.
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      However, the main driver for statistical significance in this study was newly detected thrombus rather than clinical events. With an extended follow-up duration of >4 years, we found a clear increase in clinical events, including ischemic stroke or TIA, in patients with LAA isolation compared with that in patients without LAA isolation. Maintenance of sinus rhythm was associated with a decreased risk of stroke or TIA only in patients without LAA isolation, which suggests that regular activation and contraction of LAA are important for stroke prevention. LAA will not contract effectively even in sinus rhythm if it is electrically isolated.
      The reason for discrepancy in the risk of LAA isolation across aforementioned studies including ours is not clear. One major difference between our cohort and that in the BELIEF trial is that a substantial number of our patients had LAA isolated during repeat procedures (28 among 39 patients [71.8%]).
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      In contrast, the BELIEF trial was a randomized clinical trial in which all patients had LAA isolation during the initial RFCA.
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      The BELIEF trial also differs from our cohort in that all LAA isolations were empirical. We performed LAA isolation if the LAA was thought to be a critical focus for triggering or maintaining AF.
      Although recent studies have suggested a decreased risk of ischemic stroke in patients with AF undergoing RFCA, the main purpose of the procedure is still symptomatic relief and improved quality of life.
      • Karasoy D.
      • Gislason G.H.
      • Hansen J.
      • Johannessen A.
      • Kober L.
      • Hvidtfeldt M.
      • Ozcan C.
      • Torp-Pedersen C.
      • Hansen M.L.
      Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark.
      • Friberg L.
      • Tabrizi F.
      • Englund A.
      Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries.
      • Kim Y.G.
      • Shim J.
      • Choi J.I.
      • Kim Y.H.
      Radiofrequency catheter ablation improves the quality of life measured with a Short Form-36 questionnaire in atrial fibrillation patients: A systematic review and meta-analysis.
      The increased risk of ischemic complications after RFCA in patients with AF is an undesired outcome. Therefore, the effect of LAA isolation on ischemic stroke and TIA needs further evaluation.

       TEE findings

      We found that the ΔLAA flow velocity differed significantly between patients with and without LAA isolation. Patients with LAA isolation had a significantly decreased LAA flow velocity after LAA isolation. Two patients were diagnosed with newly detected thrombi after LAA isolation. Interestingly, patients who experienced ischemic stroke or TIA after LAA isolation had a similar LAA flow velocity to those who did not suffer from ischemic stroke or TIA after LAA isolation. These findings suggest that although the LAA flow velocity is significantly impaired after LAA isolation, it is not a reliable predictor of future ischemic stroke or TIA events in patients with LAA isolation. Active contraction of the LAA (including that of the pectinate muscles) might be important to maintain adequate blood flow in the LAA, particularly deep inside its cavity. In fact, previous studies revealed that patients with AF have significantly fewer pectinate muscles than do those without AF.
      • Ernst G.
      • Stollberger C.
      • Abzieher F.
      • Veit-Dirscherl W.
      • Bonner E.
      • Bibus B.
      • Schneider B.
      • Slany J.
      Morphology of the left atrial appendage.
      • Shirani J.
      • Alaeddini J.
      Structural remodeling of the left atrial appendage in patients with chronic non-valvular atrial fibrillation: implications for thrombus formation, systemic embolism, and assessment by transesophageal echocardiography.
      Absence of active LAA contraction due to electrical isolation might predispose the LAA to blood stasis and consequent thrombus formation, especially deep inside its cavity, and the LAA flow velocity might not fully reflect the actual blood flow. The flow velocity of the LAA is determined by the pressure gradient between the LAA and the LA. It does not necessarily fully reflect the actual volume of blood flow. The decision about anticoagulation treatment in patients with LAA isolation should not be solely based on the LAA flow velocity.
      In accordance with our study, previous studies found a profound decrease in LAA flow velocity after electrical isolation of the LAA. In the study performed by Rillig et al,
      • Rillig A.
      • Tilz R.R.
      • Lin T.
      • et al.
      Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
      the median LAA flow velocity decreased from 40 cm/s to 20 cm/s. The BELIEF trial also reported that 56.5% of patients had impaired LAA function after LAA isolation; >80% of patients had an LAA velocity of <40 cm/s.
      • Di Biase L.
      • Burkhardt J.D.
      • Mohanty P.
      • et al.
      Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
      Both decreased LAA flow velocity and absence of active contraction likely contribute to blood stasis in the LAA. Although the exact clinical consequences of LAA isolation differ across studies, aggravation of its hemodynamics after LAA isolation casts serious concerns.

       Study limitations

      We acknowledge that our study has several limitations. First, this was a retrospective analysis. Although both multivariate adjustment and propensity score–matched analysis were performed simultaneously, there may be missing confounders. Second, the sample size of LAA isolation cases was not large. Despite its limitations, however, our study has an advantage of a long follow-up duration and we found that LAA isolated patients, in general, are at increased risk of ischemic stroke and TIA.

      Conclusion

      Electrical isolation of the LAA increases the risk of ischemic stroke or TIA. Postisolation LAA flow velocity did not differ between patients with and without ischemic stroke or TIA. Therefore, flow velocity is probably an unreliable parameter to guide antithrombotic therapy. Our study raises concerns about LAA isolation during RFCA, and the risk of LAA isolation warrants more extensive investigation.

      Appendix. Supplementary data

      Figure thumbnail figs1
      Figure thumbnail figs2

      References

        • Lip G.Y.
        • Tse H.F.
        • Lane D.A.
        Atrial fibrillation.
        Lancet. 2012; 379: 648-661
        • Petersen P.
        Thromboembolic complications in atrial fibrillation.
        Stroke. 1990; 21: 4-13
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • et al.
        2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
        Circulation. 2014; 130: 2071-2104
        • Karasoy D.
        • Gislason G.H.
        • Hansen J.
        • Johannessen A.
        • Kober L.
        • Hvidtfeldt M.
        • Ozcan C.
        • Torp-Pedersen C.
        • Hansen M.L.
        Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long-term follow-up in nationwide cohort of Denmark.
        Eur Heart J. 2015; 36: 307-314a
        • Friberg L.
        • Tabrizi F.
        • Englund A.
        Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries.
        Eur Heart J. 2016; 37: 2478-2487
        • Saliba W.
        • Schliamser J.E.
        • Lavi I.
        • Barnett-Griness O.
        • Gronich N.
        • Rennert G.
        Catheter ablation of atrial fibrillation is associated with reduced risk of stroke and mortality: a propensity score-matched analysis.
        Heart Rhythm. 2017; 14: 635-642
        • Wylie Jr., J.V.
        • Peters D.C.
        • Essebag V.
        • Manning W.J.
        • Josephson M.E.
        • Hauser T.H.
        Left atrial function and scar after catheter ablation of atrial fibrillation.
        Heart Rhythm. 2008; 5: 656-662
        • Kim Y.G.
        • Shim J.
        • Oh S.K.
        • Park H.S.
        • Lee K.N.
        • Hwang S.H.
        • Choi J.I.
        • Kim Y.H.
        Different responses of left atrium and left atrial appendage to radiofrequency catheter ablation of atrial fibrillation: a follow up MRI study.
        Sci Rep. 2018; 8: 7871
        • Di Biase L.
        • Burkhardt J.D.
        • Mohanty P.
        • et al.
        Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF trial.
        J Am Coll Cardiol. 2016; 68: 1929-1940
        • Romero J.
        • Michaud G.F.
        • Avendano R.
        • et al.
        Benefit of left atrial appendage electrical isolation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis.
        EP Europace. 2018; 20: 1268-1278
        • Rillig A.
        • Tilz R.R.
        • Lin T.
        • et al.
        Unexpectedly high incidence of stroke and left atrial appendage thrombus formation after electrical isolation of the left atrial appendage for the treatment of atrial tachyarrhythmias.
        Circ Arrhythm Electrophysiol. 2016; 9: e003461
        • Holmes D.R.
        • Reddy V.Y.
        • Turi Z.G.
        • Doshi S.K.
        • Sievert H.
        • Buchbinder M.
        • Mullin C.M.
        • Sick P.
        • PROTECT AF Investigators
        Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial.
        Lancet. 2009; 374: 534-542
        • Blackshear J.L.
        • Odell J.A.
        Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation.
        Ann Thorac Surg. 1996; 61: 755-759
        • Stoddard M.F.
        • Dawkins P.R.
        • Prince C.R.
        • Ammash N.M.
        Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study.
        J Am Coll Cardiol. 1995; 25: 452-459
        • Aberg H.
        Atrial fibrillation. I. A study of atrial thrombosis and systemic embolism in a necropsy material.
        Acta Med Scand. 1969; 185: 373-379
        • Kim Y.G.
        • Shim J.
        • Kim D.H.
        • Choi J.I.
        • Park S.W.
        • Pak H.N.
        • Kim Y.H.
        Characteristics of atrial fibrillation patients suffering atrioesophageal fistula after radiofrequency catheter ablation.
        J Cardiovasc Electrophysiol. 2018; 29: 1343-1351
        • Beigel R.
        • Wunderlich N.C.
        • Ho S.Y.
        • Arsanjani R.
        • Siegel R.J.
        The left atrial appendage: anatomy, function, and noninvasive evaluation.
        JACC Cardiovasc Imaging. 2014; 7: 1251-1265
        • Pollick C.
        • Taylor D.
        Assessment of left atrial appendage function by transesophageal echocardiography. implications for the development of thrombus.
        Circulation. 1991; 84: 223-231
        • Nucifora G.
        • Faletra F.F.
        • Regoli F.
        • Pasotti E.
        • Pedrazzini G.
        • Moccetti T.
        • Auricchio A.
        Evaluation of the left atrial appendage with real-time 3-dimensional transesophageal echocardiography: implications for catheter-based left atrial appendage closure.
        Circ Cardiovasc Imaging. 2011; 4: 514-523
        • Kim Y.G.
        • Choi J.I.
        • Kim M.N.
        • et al.
        Non-vitamin K antagonist oral anticoagulants versus warfarin for the prevention of spontaneous echo-contrast and thrombus in patients with atrial fibrillation or flutter undergoing cardioversion: a trans-esophageal echocardiography study.
        PLoS One. 2018; 13: e0191648
        • Kim Y.G.
        • Shim J.
        • Choi J.I.
        • Kim Y.H.
        Radiofrequency catheter ablation improves the quality of life measured with a Short Form-36 questionnaire in atrial fibrillation patients: A systematic review and meta-analysis.
        PLoS One. 2016; 11: e0163755
        • Ernst G.
        • Stollberger C.
        • Abzieher F.
        • Veit-Dirscherl W.
        • Bonner E.
        • Bibus B.
        • Schneider B.
        • Slany J.
        Morphology of the left atrial appendage.
        Anat Rec. 1995; 242: 553-561
        • Shirani J.
        • Alaeddini J.
        Structural remodeling of the left atrial appendage in patients with chronic non-valvular atrial fibrillation: implications for thrombus formation, systemic embolism, and assessment by transesophageal echocardiography.
        Cardiovasc Pathol. 2000; 9: 95-101

      Linked Article

      • Left atrial appendage isolation at the time of atrial fibrillation ablation
        Heart RhythmVol. 15Issue 12
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          Since the description of pulmonary vein firing as a trigger for atrial fibrillation (AF),1 pulmonary vein isolation (PVI) has formed the cornerstone of AF ablation. The success rate of PVI has been as high as 65%–70% in patients with paroxysmal AF.2 However, the success rates for persistent AF and long-standing persistent AF ablation have been as low as 40% in some studies.3 This has prompted a search for extra-pulmonary vein targets in order to increase the effectiveness of ablation of persistent and long-standing persistent AF.
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