Introduction

AF confers a threefold to fivefold increase in the risk of stroke, with 15-20% of all thromboembolic (TE) events in the United States being attributable to AF.¹ Furthermore, mortality rates are higher among patients with AF-related stroke (50%) than those with non-AF-related stroke (27%).¹

Among the various mechanisms reported to contribute to stroke in AF, atrial fibrosis, detected by late gadolinium enhancement (LGE) cardiac magnetic resonance imaging, has been identified as a prominent risk factor.^1-5 Stasis and endocardial changes resulting from myocardial fibrosis are believed to favor thromboembolism.⁶ Daccarett et al. demonstrated independent association of higher degree of fibrosis with prior history of stroke.² In a retrospective analysis by the same group of researchers, left atrial fibrosis was observed to be a significant predictor of appendage thrombus and spontaneous echocardiographic contrast.⁵ In a later study, they reported a direct correlation between severity of left atrial LGE and increased risk of major adverse cerebrovascular events.⁴ Of note in all of the above-mentioned studies, TE risk was evaluated in relation to pre-ablation atrial fibrosis.

Catheter ablation of AF creates scars in the left atrium, with a plausible linear correlation between extent of ablation and degree of scar formation. Thus, it is logical to anticipate more TE events following more extensive ablations. However, no previous study has shown if ablation-induced scarring increases the TE risk and if the risk is incremental with increased scarring as has been reported with pre-ablation fibrosis. In the recently published article, we attempted to address those questions in a large series of patients with AF undergoing catheter ablation.⁷

Study Design

Based on the ablation approach at the first procedure, 6,297 consecutive patients with AF were classified into 2 groups:

• Group 1 (n = 1,713) had limited ablation (isolation of PV, left atrial posterior wall, and superior vena cava)
• Group 2 (n = 4,584) had extensive ablation (limited ablation + ablation of all non-PV triggers except LAA)

Patients were excluded if they received isolation of LAA or had moderate to severe pre-existent left atrial scar detected at the time of first ablation. Oral anticoagulant therapy was continued up to 6 months following the procedure, after which it was discontinued in all patients who remained arrhythmia-free. TE risk was evaluated during the 2-year follow-up period after the first procedure or between the first and the redo procedure if it was performed earlier. Patients were asked to report any occurrence of stroke or transient ischemic attack that were confirmed either from their treating physicians or by reviewing their medical records.

At the time of the redo procedure, post-ablation left atrial scar (bipolar voltage amplitude <0.5 mV) was mapped in sinus rhythm with the CARTO three-dimensional system (Biosense Webster, Inc.; Irvine, CA) and classified as mild (<20%), moderate (≤60%), and severe (>60%) based on the percentage of the estimated left atrial area involved.

Results

Group 2 patients were older (66.0 ± 9.8 vs. 62.6 ± 10.9 years; p < 0.001) and more had non-paroxysmal AF (2,764 [60.3%] vs. 336 [19.6%]; p < 0.001) and coronary artery disease (1,251 [27.3%] vs. 209 [12.2%]; p < 0.001). Additionally, CHA₂DS₂-VASc score was significantly higher in group 2 (2.40 ± 1.49 vs. 1.91 ± 1.34; p < 0.001). Pre-ablation mild scar was similarly distributed across groups (247/1713 [14.4%] vs. 734/4584 [16%]; p = 0.12). At 2 years of follow-up, 831 (48.5%) from group 1 and 2,947 (64.3%) patients from group 2 were arrhythmia-free off antiarrhythmic drugs (p < 0.001).

A total of 19 (0.3%) TE events was reported after the first ablation procedure: 9 (1.02%) in group 1 and 10 (0.61%) in group 2 (p = 0.26). At the time of the TE event, all 19 patients were experiencing arrhythmia, whereas no TE event was reported in patients remaining arrhythmia-free (p < 0.001). Median time to stroke was 14 (9, 20) months in group 1 and 14.5 (8, 18) months in group 2 (p = 1.0). The stroke-free event probabilities were 99.46% and 99.78% at 1 year (p = 0.25) and 99.98% and 99.39% at 2 years (p = 0.26) in groups 1 and 2, respectively. The 19 patients experiencing stroke or transient ischemic attack were off oral anticoagulants at the time of the event, either because of non-compliance or short-term discontinuation due to other medical procedures. Among patients who did not experience stroke, oral anticoagulation therapy was discontinued in all who remained arrhythmia-free and was kept uninterrupted in those with arrhythmia recurrence.

Post-ablation scar was mapped in 882 patients from group 1 and 1,532 from group 2 at the time of the redo procedure. Mean scar area was 67.1 ± 4.6% in group 2 and 34.9 ± 8.8% in group 1 (p < 0.001). Figure 1 demonstrates examples of post-ablation scar in group 2. In the regression analysis, after adjusting for body mass index, left atrial diameter, AF type, and CHA₂DS₂-VASc score, ablation strategy was not associated with TE event rate (p-value = 0.10).

Figure 1: Electroanatomic Maps Showing Extensive Post-Ablation Scar

Discussion

Contrary to the studies reporting increase in the risk of stroke in patients with pre-ablation scarring of the left atrium, we observed similar stroke rate regardless of the extent of the ablation-induced scar. Even though the cohort receiving extensive ablation had higher risk because of older age, predominance of non-paroxysmal AF, comorbidities, and higher CHA₂DS₂-VASc score, they did not experience more TE events compared to those undergoing limited ablation. Therefore, we can safely conclude that scar induced by extensive ablation did not increase the risk of stroke. Thus, extensive ablation can be performed if it is considered necessary for achievement of long-term sinus rhythm. Overall low stroke rate in group 2, despite having significantly higher risk, could be attributed to optimal thromboprophylaxis and arrhythmia monitoring in our study population.

The obvious question that comes to the mind is why scar resulting from catheter ablation does not increase the stroke risk whereas pre-ablation scar does. This is difficult to answer precisely in the absence of documented evidence explaining underlying causative mechanisms. However, it could well be that the same underlying pathology that caused the pre-ablation left atrial fibrosis increased the risk of cerebrovascular disease, resulting in non-AF-related stroke.⁸ It would also be interesting to know if genetic predisposition plays a role in creating a profibrotic and prothrombotic environment at the cellular level in patients with pre-existent left atrial scar.

All our patients experiencing stroke, regardless of the degree of post-ablation scar, were in arrhythmia at the time of the event. Fibrillation promotes stasis and endothelial dysfunction and is associated with a hypercoagulable state as well as chronic inflammation.⁶ However, it may not be AF per se but the atrial cardiomyopathy, a prefibrillatory state, that forms the substrate for AF and predisposes to thrombus formation and stroke.^6,9

Lastly, it is important to mention that stroke risk is high following electrical isolation of LAA, and life-long optimal anticoagulation therapy or LAA occlusion are crucial for effective thromboprophylaxis in this subpopulation.¹⁰ However, the stroke risk reported in this article does not apply to patients with LAA isolation because those patients were excluded from this study.

Conclusion

In our study, stroke rate as well as median time to stroke were comparable in patients with AF undergoing limited versus extensive ablation. Moreover, a significantly higher number of patients remained in sinus rhythm off drugs following extensive ablation compared to the limited ablation cohort. Additionally, no TE events were reported in arrhythmia-free patients. Thus, operators should consider extensive ablation if that is deemed to be the best option to achieve long-term sinus rhythm in specific subsets of the AF population.

References

1. Jagadish PS, Kabra R. Stroke Risk in Atrial Fibrillation: Beyond the CHA 2 DS 2-VASc Score. Curr Cardiol Rep 2019;21:95.
2. Daccarett M, Badger TJ, Akoum N, et al. Association of left atrial fibrosis detected by delayed-enhancement magnetic resonance imaging and the risk of stroke in patients with atrial fibrillation. J Am Coll Cardiol 2011;57:831-8.
3. Fonseca AC, Alves P, Inácio N, et al. Patients With Undetermined Stroke Have Increased Atrial Fibrosis: A Cardiac Magnetic Resonance Imaging Study. Stroke 2018;49:734-7.
4. King JB, Azadani PN, Suksaranjit P, et al. Left Atrial Fibrosis and Risk of Cerebrovascular and Cardiovascular Events in Patients With Atrial Fibrillation. J Am Coll Cardiol 2017;70:1311-21.
5. Akoum N, Fernandez G, Wilson B, Mcgann C, Kholmovski E, Marrouche N. Association of atrial fibrosis quantified using LGE-MRI with atrial appendage thrombus and spontaneous contrast on transesophageal echocardiography in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2013;24:1104-9.
6. D'Souza A, Butcher KS, Buck BH. The Multiple Causes of Stroke in Atrial Fibrillation: Thinking Broadly. Can J Cardiol 2018;34:1503-11.
7. Mohanty S, Trivedi C, Della Rocca DG, et al. Thromboembolic risk in atrial fibrillation patients with left atrial scar post-extensive ablation: a single-center experience. JACC Clin Electrophysiol 2020; in press.
8. Ren JF, Callans DJ, Marchlinski FE. What Is the Biological Relationship Between Left Atrial Fibrosis and Stroke in Atrial Fibrillation? J Am Coll Cardiol 2018;71:1053-4.
9. Goldberger JJ, Arora R, Green D, et al. Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate. Circulation 2015;132:278-91.
10. Di Biase L, Mohanty S, Trivedi C, et al. Stroke Risk in Patients With Atrial Fibrillation Undergoing Electrical Isolation of the Left Atrial Appendage. J Am Coll Cardiol 2019;74:1019-28.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Arrhythmias, Cardiac, Ischemic Attack, Transient, Cicatrix, Anti-Arrhythmia Agents, Contrast Media, Anticoagulants, Coronary Artery Disease, Retrospective Studies, Furylfuramide, Gadolinium, Factor V, Vena Cava, Superior, Atrial Fibrillation, Genetic Predisposition to Disease, Body Mass Index, Risk Factors, Catheter Ablation, Stroke

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