Long-term clinical outcomes of catheter ablation in patients with atrial fibrillation predisposing to tachycardia-bradycardia syndrome: a long pause predicts implantation of a permanent pacemaker

Long-term clinical outcomes of catheter ablation in patients with atrial fibrillation... Background: There is a controversy as to whether catheter ablation should be the first-line therapy for tachycardia- bradycardia syndrome (TBS) in patients with atrial fibrillation (AF). Methods: We aimed to investigate long-term clinical outcomes of catheter ablation in patients with TBS and AF. Among 145 consecutive patients who underwent catheter ablation of AF with TBS, 121 patients were studied. Results: Among 121 patients, 11 (9.1%) received implantation of a permanent pacemaker during a mean 21 months after ablation. Length of pause on termination of AF was significantly greater in patients who received pacemaker implantation after ablation than those who underwent ablation only (7.9 ± 3.5 vs. 5.1 ± 2.1 s, p < 0.001). Using a multivariate model, a long pause of 6.3 s or longer after termination of AF was associated with the requirement to implant a permanent pacemaker after ablation (HR 1.332, 95% CI 1.115-1.591, p = 0.002). Conclusion: This study suggests that, in patients with AF predisposing to TBS, long pause on termination of AF predicts the need to implant a permanent pacemaker after catheter ablation. Keywords: Atrial fibrillation, Tachycardia, Bradycardia, Catheter ablation, Pacemaker Background device-related complications (e.g. infection, endocarditis, Tachycardia-bradycardia syndrome (TBS) is literally a vascular complications, need for generator change) may two-fold disease that is characterized by prolonged sinus also occur. pause on termination of atrial tachyarrhythmias, includ- Catheter ablation has been widely performed in pa- ing atrial fibrillation (AF). Implantation of a permanent tients with AF, and its clinical benefits and safety in pa- pacemaker plus antiarrhythmic drug (AAD) prescription tients with AF have been well documented. Catheter is the mainstay therapy for patients with TBS due to ablation is also known to be curative for TBS, especially sinus pause or its aggravation on AAD [1]. However, in PV-triggered AF [5], through elimination of triggers AF-related problems (e.g. AF symptoms, progression to for tachycardia. Recent studies demonstrated that abla- persistent AF [2], tachycardia-mediated cardiomyopathy tion, compared to pacemaker implantation, decreased [3, 4], AAD use, anticoagulation) may remain even after tachycardia-related hospitalization and was effective at implantation of a permanent pacemaker. Furthermore, controlling AF and prolonged sinus pause [6]. However, long term follow-up data are needed because some pop- ulations of patients are likely to have intrinsic sinus node * Correspondence: jongilchoi@korea.ac.kr Division of Cardiology, Department of Internal Medicine, Korea University dysfunction (SND) even in the clinical setting of TBS, College of Medicine and Korea University Medical Center, 73, Inchon-ro, and SND can gradually progress in those patients who Seongbuk-gu, Seoul 02841, Republic of Korea © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 2 of 8 require a pacemaker after catheter ablation of AF [7, 8]. was determined at the physicians’ discretion based on Thus, whether catheter ablation should be considered symptoms of palpitations, dizziness, syncope, and history the first line therapy for TBS in AF remains debated. In of stroke. this study, we investigated the long-term clinical out- Among the 145 patients, 24 patients were excluded; 20 comes of catheter ablation in patients with TBS on with a pause of less than three seconds, 3 because of no termination of AF. Furthermore, we determined predic- documented electrocardiography (ECG) of pause, and 1 tors for triage of patients in whom catheter ablation is due to follow-up loss. Finally, 121 patients with catheter expected to be more beneficial than implantation of a ablation were studied. A permanent pacemaker was im- permanent pacemaker. planted in 11 patients who were highly symptomatic due to a long pause after ablation. This study was approved Methods by the institutional review board in Korea University Patient population Medical Center. Figure 1 shows the study populations. Patients who visited Korea University Medical Center and underwent Procedures for catheter ablation catheter ablation of AF or pacemaker implantation After written informed consent was obtained, all the pa- during June 2004-June 2015 were retrospectively exam- tients underwent electrophysiology study and catheter ined. Definitions of AF type and catheter ablation of AF ablation. Prior to the procedure, all antiarrhythmic drugs followed the Guidelines for the management of atrial were discontinued, and more than 5 half-lives were fibrillation and the 2014 consensus documents of the allowed to pass before the study was performed. Amio- American Heart Association/American College of darone was discontinued at least 1 month before the ab- Cardiology/Heart Rhythm Society [9, 10]. TBS was de- lation procedure. All catheters were inserted via the fined as in previous studies, namely a ventricular pause femoral vein. A duodecapolar catheter (St. Jude Medical following termination of atrial tachyarrhythmia (e.g. AF) Inc., Lowell, MA, USA) was placed in the coronary sinus [11, 12]. TBS was defined when more than 3 s of sinus (CS) to record both the low right atrium (RA) and CS pause was documented on ECG immediately after ter- electrograms, and a decapolar catheter (Bard Electro- mination of AF leading to related symptoms, such as physiology Inc., Lowell, MA, USA) was positioned at the dizziness and syncope. If long sinus pause more than 3 s high RA. A quadripolar catheter was placed at either the after termination of tachyarrhythmia could not be docu- His bundle or superior vena cava (SVC). Intracardiac mented, we checked Holter ECG or event ECG recorder electrograms were recorded using a Prucka CardioLab™ repeatedly. Although ECG with long pause more than electrophysiology system (General Electric Health Care 3 s was documented, TBS was not diagnosed if there System Inc., Milwaukee, WI, USA) or EP Workmate sys- were no symptoms related to the ECG documentation. tem (EP MedSystem, Inc./St. Jude Medical Inc., St. Paul, Catheter ablation of AF in patients with AF and TBS MN, USA). After double transseptal puncture, the Fig. 1 Study population and flow chart Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 3 of 8 patients were administered anticoagulants such as intra- considered statistically significant. Statistical analyses venous heparin to maintain an activated clotting time of were performed using SPSS Statistics 19.0 software between 300 and 400 s. Three-dimensional geometries (SPSS Inc., Armonk, NY, USA). of the LA and PVs were reconstructed using Ensite- NavX mapping system (St. Jude Medical Inc., St. Paul, Results MN, USA). Trigger was defined as initiation of AF be- Clinical characteristics fore PV isolation. When non-PV trigger was detected, Total 121 patients underwent catheter ablation and clin- and then was also ablated [13, 14]. Circumferential pul- ical characteristics at baseline are summarized in Table 1. monary vein isolation (CPVI) with electrical PV isolation Mean longest pause following termination of AF were 5. was performed. When AF followed CPVI, either linear 4 s. After ablation, anticoagulant and antiplatelet therapy ablation or complex fractionated atrial electrogram- was continued according to CHADS score or CHA DS - guided ablation was performed additionally. When AF 2 2 2 VASc score: warfarin 37.2%, anti-platelet drug 49.6%, and converted into atrial tachycardia (AT), AT was ablated NOAC 3.3% (Table 1). according to the mechanisms of AT. For focal AT, RF en- ergy was delivered at the focus; for macroreentrant AT, a line of block was created at the critical isthmus. The end- points of the ablation were AF or AT termination. Each Complications after ablation and clinical outcomes radiofrequency energy application was performed using After AF ablation, 9 complications were noted: cardiac tam- an open-irrigated ablation catheter with a maximum ponade (n = 6, 4.9%), groin hematoma (n =2, 1.6%), and temperature of 48 °C and a power of 25-35 W. atrial esophageal fistula (n = 1, 0.8%). One patient (0.8%) died among total 121 patients. Four patients (3.3%) experi- enced stroke. Outcome measurements and patient follow-up Primary outcome measurement was freedom from atrial Table 1 Demographics and clinical characteristics of the study tachyarrhythmia(s), AF or AT, after the procedures. After participants ablation, patients were asked to visit the outpatient clinic Factors n = 121 at 1, 3, 6, 9, and 12 months and then every 6 months Age, years old 61.1 ± 10.4 thereafter or whenever they experienced tachycardia- Male, n (%) 64 (52.9) related symptoms. ECG was performed at every visit. Longest pause, seconds 5.4 ± 2.4 Holter monitor recording was performed in patients who were thought to have arrhythmia-related inter- Time of AF symptom onset, months 36.5 ± 32.3 mittent symptoms. Recurrence of atrial tachyarrhyth- Type of persistent AF, n (%) 17 (14.0) mia was defined as an event lasting more than 30 s AAD before procedure, n (%) 77 (63.6) after a 3-month blanking period. Antiarrhythmic Class I drug 66 (54.5) drugs (AADs) were taken during the first 3 months Class III drug 11 (9.1) after the ablation. Discontinuation of AADs was de- Antithrombotic drug, n (%) 109 (90.1) termined at the physicians’ discretion. Warfarin 45 (37.2) Anti-platelet drug 60 (49.6) Statistical analysis NOAC 4 (3.3) All values are expressed as means ± SD or as num- bers and percentages where appropriate. Categorical LVEF 57.8 ± 7.9 data were compared by the χ test. Continuous LA size, mm 41.0 ± 5.6 variable data were compared by independent samples E/e′ 9.6 ± 5.2 t-test when the distribution was normal or by the Hypertension, n (%) 66 (54.5) Mann-Whitney test if it the distribution was not nor- Diabetes mellitus, n (%) 16 (13.2) mal. Kaplan-Meier analysis with the log-rank test was CHAS DS -VASc score 1.9 ± 1.3 2 2 used to determine the probability of freedom from re- current atrial tachyarrhythmia. Receiver operating 0, n (%) 15 (12.4) characteristic (ROC) analysis was used to calculate 1, n (%) 39 (32.2) sensitivity and specificity, and the area-under-the- ≥ 2, n (%) 67 (55.4) curve (AUC) was used to compare accuracy for differ- HAS-BLED score 1.6 ± 1.1 ent lengths of pause. Cox regression analysis was used Values are expressed as means±SDs and numbers (percentages). AF atrial for the predictor model. Variables were selected on fibrillation, AAD anti-arrhythmic drug, NOAC non-vitamin K antagonist anti- the basis of univariate significance. P <0.05 was coagulant, LVEF left ventricular ejection fraction, LA left atrium Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 4 of 8 Recurrence of atrial tachyarrhythmia after catheter ablation longer in patients who underwent pacemaker implant- After catheter ablation, the rate of any atrial tachyar- ation after catheter ablation compared to those who rhythmia (AF or AT) recurrence is 19.0% (23 of 121) underwent catheter ablation alone (7.9 ± 3.5 vs. 5.1 ± 2.1 s, during mean 29.3 months of follow up. We investigate p< 0.001) (Fig. 2). ROC curve analysis showed that the factors affecting recurrence according to age and trigger optimal cutoff point for predicting implantation of a per- sites. Thirty-one patients (25.6%) were 70-year-old or manent pacemaker following catheter ablation was 6.3 s more. Atrial tachyarrhythmia recurrence was not signifi- (sensitivity 72.7%, specificity 79.1%, AUC = 0.75). The lon- cantly different between patients with 70-year-old or gest pause was associated with a need for implantation of more and those with younger than 70-year-old (18.9% a permanent pacemaker using both univariate analyses vs. 19.4%, log-rank test p = 0.732). During the ablation (HR 1.287, 95% CI 1.101-1.506, p = 0.002) and a multivari- procedures, triggers were identified in 73 patients (60. ate model (HR 1.576, 95% CI 1.060-2.343, p =0.025) 3%) and no trigger was identified in 48 patients (39.7%). adjusted by age, sex, time of AF symptom onset, HTN, There was no significant difference of atrial tachyarrhyth- DM, use of post-procedural AAD, LVEF, LA diameter, and mia recurrence between patients with triggers and those trigger (Table 3). Antiplatelet therapy (aspirin, n = 1) was with no trigger (17.8% vs. 20.8%, log-rank test p =0.559, continued during pacemaker implantation. Anticoagula- Additional file 1: Figure S1). Among total patients, sixty- tion therapy with warfarin (n = 9) was continued without three patients (52.1%) had a pulmonary vein (PV) trigger; heparin bridge during pacemaker implantation. One left superior PVs, left inferior PVs, right superior PVs, patient did not receive any antithrombotic therapy be- right middle PV, right inferior PV, and multiple PVs fore the procedure. Among total 11 patients with accounted for 27 (22.3%), 7 (5.8%), 13 (10.7%), 1 (0.8%), 2 pacemaker implantation after ablation, there was no (1.7%), and 13 (10.7%) trigger sites, respectively. Ten pa- pocket hematoma. tients (8.3%) had non-PV triggers; eight (6.6%) at SVC and two (1.7%) at the high RA septum. There was no signifi- cant difference of atrial tachyarrhythmia recurrence Discussion between patients with PV trigger and those with non-PV Main findings trigger (18.6% vs. 14.3%, log-rank test p =0.817, This study demonstrated that recurrence rate after cath- Additional file 2:FigureS2). eter ablation were 19% in patients with AF predisposing to TBS during mean 29 months of follow up, 9.1% of Pacemaker implantation after catheter ablation patients were required implantation of a permanent Following catheter ablation of AF, eleven patients (9.1%) pacemaker after catheter ablation, and they had a longer received implantation of permanent pacemaker. Mean pause on termination of AF compared to those with time interval from catheter ablation to pacemaker im- catheter ablation alone. Multivariate analysis showed plantation was 21 months. The patients’ characteristics that a pause of 6.3 s or longer at baseline was associated are shown in Table 2. Mean longest pause on termin- with the need to implant a permanent pacemaker after ation of AF prior to catheter ablation was significantly catheter ablation. Table 2 Patients who underwent implantation of permanent pacemaker after RFCA No. Age Sex Longest LA size CHA DS Trigger AAD or AF Symptom PM Pause after Time interval PM mode 2 2 (years) pause (mm) –VASc NB after recur after indication ablation from RFCA (seconds) score ablation ablation (seconds) to PM (days) 1 71 M 10.1 39.5 1 None None recur dizziness SP 4.2 2422 DDD 2 60 F 5.2 49.5 1 None None SR dizziness SP 5.1 14 DDDR 3 67 M 12.8 37.8 1 LSPV None SR syncope SP 5.2 7 DDDR 4 49 F 13.6 47.9 1 SVC None SR syncope SP 8.5 70 DDDR 5 59 M 6.3 40.7 1 LSPV None SR dizziness SP 7.2 566 DDDR 6 52 F 6.9 36.0 2 SVC None recur dizziness SP 5.3 1504 DDDR 7 58 F 3.4 43.3 2 LSPV None SR dizziness SP 7.0 1269 DDDR 8 70 M 8.2 43.1 2 LSPV None SR dizziness SP 6.8 27 DDDR 9 61 F 7.2 60.8 2 None None SR dizziness SP 6.8 1126 DDDR 10 70 F 9.8 32.2 3 SVC None SR dizziness SP 5.2 51 DDDR 11 69 F 3.1 39.7 3 None None SR dizziness SP 4.7 250 DDDR No. patients number, M male, F female, RFCA radiofrequency catheter ablation, PM pacemaker, AAD anti-arrhythmic drug, NB nodal blocker, SR sinus rhythm, AF atrial fibrillation, SP sinus pause Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 5 of 8 Fig. 2 Comparison and the longest pause between patients who did not receive a pacemaker and those who received a pacemaker after catheter ablation Mechanisms of TBS with AF demonstrated that altered C-linker interaction in SND is frequently associated with AF [11], and is caused hyperpolarized-activated ion channel HCN4 is associated by inhomogeneous refractoriness [15]. A study in a with familial TBS and AF, indicating that funny channel chronic pacing-induced AF dog model demonstrated dysfunction contributes to the development of atrial sinus node remodeling as a result of AF that was charac- tachyarrhythmias [20]. Ectopic activities that elicit trig- terized by prolongation of corrected sinus node recovery gers for initiation of AF may also be induced in HCN4- time and P-wave duration and a decrease in maximal K530 N by the switch from enforced inhibition of gating and intrinsic heart rate [2]. Sick sinus syndrome can be to stimulation of gating due to binding of cAMP under regarded as an atrial disease rather than as sinus node adrenergic stress. Furthermore, slow heart rates may in- disease per se [16–18]. The mechanism of TBS, where crease susceptibility to ectopic beats. Therefore, molecu- the pause is manifested just after AF terminates, remains lar and structural remodeling of the sinus node increases to be determined. Yeh et al. suggested that funny current arrhythmogenesis, promoting the vicious cycle of “AF (I ) down-regulation may contribute to the clinically begets AF” [21]. Thus, early ablation for TBS likely de- significant association between SND and supraventricu- creases the rate of implantation of permanent pace- lar tachyarrhythmias [19]. Recently, Duhme et al. makers before predisposition to SND by AF burden. Table 3 Factors associated with pacemaker implantation after ablation Factors HR (univariate analysis) P value HR (multivariate analysis) P value Age, years 1.014 (0.954-1.078) 0.657 Female sex 0.488 (0.142-1.676) 0.254 Longest pause, seconds 1.287 (1.101-1.506) 0.002 1.576 (1.060-1.343) 0.025 Time of AF symptom onset, months 0.978 (0.933-1.025) 0.357 AAD after ablation 1.459 (0.308-6.904) 0.634 LVEF, % 1.024 (0.952-1.102) 0.525 LA diameter, mm 1.086 (0.990-1.191) 0.080 1.230 (0.860-1.757) 0.257 Trigger (vs. no-trigger) 0.753 (0.217-2.614) 0.655 Values are expressed as hazard ratios (HRs) with CI 95%. AAD anti-arrhythmic drug, LVEF left ventricular ejection fraction, LA left atrium Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 6 of 8 Catheter ablation for TBS with AF comorbidity in patients who undergo implantation of Catheter ablation has been used to treat patients with pacemaker. Moreover, AF itself may lead to medical AF for several decades. Clinical outcome is better in par- problems (e.g. progression to persistent AF, tachycardia- oxysmal AF than in persistent AF. The reasons for this mediated cardiomyopathy, proarrhythmic events due to include the lower severity of the remodeling process in uses of AAD, bleeding due to maintenance of antithrom- paroxysmal AF than persistent AF, and the main cause botic therapy), and the management for AF is also of AF onset being ectopic beats that can be eliminated needed indefinitely. In contrast to pacemaker implant- by catheter ablation. Catheter ablation may also improve ation, catheter ablation of AF has several strengths in sinus node function in patients with TBS and AF by in- patients with TBS including eradication of AF and no ducing reverse remodeling. Hocini et al. demonstrated need for a device. However, it was not clear whether that successful ablation of AF was followed by marked catheter ablation or pacemaker implantation was better recovery in sinus atrial node function when AF patients for treating paroxysmal AF-related TBS. Furthermore, showed prolonged sinus pauses on AF termination [7]. recent studies demonstrated that maintenance of sinus These concepts suggest that TBS that manifests as trigger- rhythm following catheter ablation might reduce the risk AF may be cured by catheter ablation. Premature beat or of stroke compared with AAD therapy alone [27–29]. In activity originating from the PV is well-known and is the our study, two patients were hospitalized due to stroke most common trigger in patients with AF [22, 23]. after catheter ablation. Further study is required to ad- Miyazaki et al. demonstrated that SVC plays a role in AF dress whether ablation is more beneficial than implant- not only as a trigger, but also as a perpetuator [24]. We ation of permanent pacemaker for preventing stroke. identified triggers in 60.3% of patients. PV trigger activity was 86% and the most common non-PV trigger originated Prediction for implantation of a pacemaker in TBS: TBS or from the SVC (8 of 10). However, there was no significant intrinsic SND? difference in the rate of freedom from atrial tachyarrhyth- Miyanaga et al. reported that mean heart rate did not in- mia between PV trigger and non-PV trigger patients. crease in TBS patients, probably due to pre-existing SND, although parasympathetic modulation was signifi- Permanent pacemaker or catheter ablation? cantly attenuated after CPVI [30]. Inada et al. reported Whether catheter ablation or implantation of a perman- that a pacemaker was required in 8% of patients with ent pacemaker should be the first-line treatment remains paroxysmal AF and prolonged sinus pauses following debated. Prior to the AF-ablation era, pacing was the catheter ablation, but gradual progression of SND oc- only option for treatment of TBS because tachycardia curred after long-term follow-up of over 3 years [8]. In therapy using AAD aggravated bradycardia. Patients our study, a pacemaker had to be implanted in 9.1% of with drug-resistant tachycardia were considered to be patients who underwent catheter ablation due to candidates for catheter ablation even at that time [25]. bradycardia-related symptoms, such as syncope. Mean However, the treatment strategy of pacemaker plus AAD time interval from catheter ablation to implantation of a has many weaknesses, including pacemaker- and AF- permanent pacemaker was 21 months, which suggests related problems. In patients who receive a pacemaker, that intrinsic SND was progressive. Nevertheless, it is various device-related complications may occur, such as difficult to differentiate between patients who have AF infection, endocarditis, vascular injury, lead extraction, with TBS or intrinsic SND because the characteristics of and pocket hematoma. In our study, there was no pocket intrinsic SND are similar to those of TBS. We found that hematoma in 11 patients who underwent pacemaker im- implantation of a permanent pacemaker after catheter ab- plantation. Recently, Malagù M et al. demonstrated that lation was required in patients with a long pause (≥ 6.3 s). uninterrupted antiplatelet therapy or continued anticoa- This finding suggests that a pacemaker should primarily be gulation therapy without heparin bridge based on considered in patients with a long pause on AF termin- thromboembolic risk stratification was associated with a ation. Of course, SND might be caused or accelerated by reduced incidence of clinically significant pocket the ageing process [31, 32]. However, this still remains un- hematoma [26]. The incidence of pocket hematoma was clear [33]. The ages of patients who received pacemaker 1.6% in no-bridge protocol group and 6.5% in conven- implantation and those who did not after catheter ablation tional management group. Pacing-induced heart failure were similar. In addition, the rates of freedom from atrial may be a potential comorbidity. Need for generator tachyarrhythmia following catheter ablation were similar change will increase as average life expectancy increases between patients who were 70 years or older versus those compared to device longevity. Because the risk of stroke younger than 70 years. Recently, Nademanee et al. demon- increases in elderly patients with AF, use of certain diag- strated that elderly patients with AF benefited from AF ab- nostic tools, such as magnetic resonance imaging, be- lation, which was safe and effective at maintaining sinus comes problematic. Furthermore, AF still remains as a rhythm and was associated with lower mortality and stroke Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 7 of 8 risk [34]. Thus, the ageing process may not be the sole Ethics approval and consent to participate The study protocol was approved both by the Research Committee and the mechanism affecting the pathophysiology of TBS and AF. Ethics in Research Committee of in Korea University Medical Center. Written informed consent was obtained. All procedures were conducted based on the Declaration of Helsinki and local regulations. Study limitations This was not a randomized trial that was designed to de- Competing interests termine whether ablation was superior to pacemaker im- The authors declare that they have no competing interests. plantation. In this retrospective study, the decision of whether to perform catheter ablation or to implant a Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published permanent pacemaker as the first-line treatment was at maps and institutional affiliations. the physicians’ discretion based on clinical manifesta- tions. Rates of recurrence of atrial tachyarrhythmias Received: 9 August 2017 Accepted: 9 May 2018 might also have been underestimated because we did not use a continuous rhythm monitoring device, such as References an implantable loop recorder, for detection of AF [35]. 1. 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Long-term clinical outcomes of catheter ablation in patients with atrial fibrillation predisposing to tachycardia-bradycardia syndrome: a long pause predicts implantation of a permanent pacemaker

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Medicine & Public Health; Cardiology; Cardiac Surgery; Angiology; Blood Transfusion Medicine; Internal Medicine; Medicine/Public Health, general
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Abstract

Background: There is a controversy as to whether catheter ablation should be the first-line therapy for tachycardia- bradycardia syndrome (TBS) in patients with atrial fibrillation (AF). Methods: We aimed to investigate long-term clinical outcomes of catheter ablation in patients with TBS and AF. Among 145 consecutive patients who underwent catheter ablation of AF with TBS, 121 patients were studied. Results: Among 121 patients, 11 (9.1%) received implantation of a permanent pacemaker during a mean 21 months after ablation. Length of pause on termination of AF was significantly greater in patients who received pacemaker implantation after ablation than those who underwent ablation only (7.9 ± 3.5 vs. 5.1 ± 2.1 s, p < 0.001). Using a multivariate model, a long pause of 6.3 s or longer after termination of AF was associated with the requirement to implant a permanent pacemaker after ablation (HR 1.332, 95% CI 1.115-1.591, p = 0.002). Conclusion: This study suggests that, in patients with AF predisposing to TBS, long pause on termination of AF predicts the need to implant a permanent pacemaker after catheter ablation. Keywords: Atrial fibrillation, Tachycardia, Bradycardia, Catheter ablation, Pacemaker Background device-related complications (e.g. infection, endocarditis, Tachycardia-bradycardia syndrome (TBS) is literally a vascular complications, need for generator change) may two-fold disease that is characterized by prolonged sinus also occur. pause on termination of atrial tachyarrhythmias, includ- Catheter ablation has been widely performed in pa- ing atrial fibrillation (AF). Implantation of a permanent tients with AF, and its clinical benefits and safety in pa- pacemaker plus antiarrhythmic drug (AAD) prescription tients with AF have been well documented. Catheter is the mainstay therapy for patients with TBS due to ablation is also known to be curative for TBS, especially sinus pause or its aggravation on AAD [1]. However, in PV-triggered AF [5], through elimination of triggers AF-related problems (e.g. AF symptoms, progression to for tachycardia. Recent studies demonstrated that abla- persistent AF [2], tachycardia-mediated cardiomyopathy tion, compared to pacemaker implantation, decreased [3, 4], AAD use, anticoagulation) may remain even after tachycardia-related hospitalization and was effective at implantation of a permanent pacemaker. Furthermore, controlling AF and prolonged sinus pause [6]. However, long term follow-up data are needed because some pop- ulations of patients are likely to have intrinsic sinus node * Correspondence: jongilchoi@korea.ac.kr Division of Cardiology, Department of Internal Medicine, Korea University dysfunction (SND) even in the clinical setting of TBS, College of Medicine and Korea University Medical Center, 73, Inchon-ro, and SND can gradually progress in those patients who Seongbuk-gu, Seoul 02841, Republic of Korea © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 2 of 8 require a pacemaker after catheter ablation of AF [7, 8]. was determined at the physicians’ discretion based on Thus, whether catheter ablation should be considered symptoms of palpitations, dizziness, syncope, and history the first line therapy for TBS in AF remains debated. In of stroke. this study, we investigated the long-term clinical out- Among the 145 patients, 24 patients were excluded; 20 comes of catheter ablation in patients with TBS on with a pause of less than three seconds, 3 because of no termination of AF. Furthermore, we determined predic- documented electrocardiography (ECG) of pause, and 1 tors for triage of patients in whom catheter ablation is due to follow-up loss. Finally, 121 patients with catheter expected to be more beneficial than implantation of a ablation were studied. A permanent pacemaker was im- permanent pacemaker. planted in 11 patients who were highly symptomatic due to a long pause after ablation. This study was approved Methods by the institutional review board in Korea University Patient population Medical Center. Figure 1 shows the study populations. Patients who visited Korea University Medical Center and underwent Procedures for catheter ablation catheter ablation of AF or pacemaker implantation After written informed consent was obtained, all the pa- during June 2004-June 2015 were retrospectively exam- tients underwent electrophysiology study and catheter ined. Definitions of AF type and catheter ablation of AF ablation. Prior to the procedure, all antiarrhythmic drugs followed the Guidelines for the management of atrial were discontinued, and more than 5 half-lives were fibrillation and the 2014 consensus documents of the allowed to pass before the study was performed. Amio- American Heart Association/American College of darone was discontinued at least 1 month before the ab- Cardiology/Heart Rhythm Society [9, 10]. TBS was de- lation procedure. All catheters were inserted via the fined as in previous studies, namely a ventricular pause femoral vein. A duodecapolar catheter (St. Jude Medical following termination of atrial tachyarrhythmia (e.g. AF) Inc., Lowell, MA, USA) was placed in the coronary sinus [11, 12]. TBS was defined when more than 3 s of sinus (CS) to record both the low right atrium (RA) and CS pause was documented on ECG immediately after ter- electrograms, and a decapolar catheter (Bard Electro- mination of AF leading to related symptoms, such as physiology Inc., Lowell, MA, USA) was positioned at the dizziness and syncope. If long sinus pause more than 3 s high RA. A quadripolar catheter was placed at either the after termination of tachyarrhythmia could not be docu- His bundle or superior vena cava (SVC). Intracardiac mented, we checked Holter ECG or event ECG recorder electrograms were recorded using a Prucka CardioLab™ repeatedly. Although ECG with long pause more than electrophysiology system (General Electric Health Care 3 s was documented, TBS was not diagnosed if there System Inc., Milwaukee, WI, USA) or EP Workmate sys- were no symptoms related to the ECG documentation. tem (EP MedSystem, Inc./St. Jude Medical Inc., St. Paul, Catheter ablation of AF in patients with AF and TBS MN, USA). After double transseptal puncture, the Fig. 1 Study population and flow chart Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 3 of 8 patients were administered anticoagulants such as intra- considered statistically significant. Statistical analyses venous heparin to maintain an activated clotting time of were performed using SPSS Statistics 19.0 software between 300 and 400 s. Three-dimensional geometries (SPSS Inc., Armonk, NY, USA). of the LA and PVs were reconstructed using Ensite- NavX mapping system (St. Jude Medical Inc., St. Paul, Results MN, USA). Trigger was defined as initiation of AF be- Clinical characteristics fore PV isolation. When non-PV trigger was detected, Total 121 patients underwent catheter ablation and clin- and then was also ablated [13, 14]. Circumferential pul- ical characteristics at baseline are summarized in Table 1. monary vein isolation (CPVI) with electrical PV isolation Mean longest pause following termination of AF were 5. was performed. When AF followed CPVI, either linear 4 s. After ablation, anticoagulant and antiplatelet therapy ablation or complex fractionated atrial electrogram- was continued according to CHADS score or CHA DS - guided ablation was performed additionally. When AF 2 2 2 VASc score: warfarin 37.2%, anti-platelet drug 49.6%, and converted into atrial tachycardia (AT), AT was ablated NOAC 3.3% (Table 1). according to the mechanisms of AT. For focal AT, RF en- ergy was delivered at the focus; for macroreentrant AT, a line of block was created at the critical isthmus. The end- points of the ablation were AF or AT termination. Each Complications after ablation and clinical outcomes radiofrequency energy application was performed using After AF ablation, 9 complications were noted: cardiac tam- an open-irrigated ablation catheter with a maximum ponade (n = 6, 4.9%), groin hematoma (n =2, 1.6%), and temperature of 48 °C and a power of 25-35 W. atrial esophageal fistula (n = 1, 0.8%). One patient (0.8%) died among total 121 patients. Four patients (3.3%) experi- enced stroke. Outcome measurements and patient follow-up Primary outcome measurement was freedom from atrial Table 1 Demographics and clinical characteristics of the study tachyarrhythmia(s), AF or AT, after the procedures. After participants ablation, patients were asked to visit the outpatient clinic Factors n = 121 at 1, 3, 6, 9, and 12 months and then every 6 months Age, years old 61.1 ± 10.4 thereafter or whenever they experienced tachycardia- Male, n (%) 64 (52.9) related symptoms. ECG was performed at every visit. Longest pause, seconds 5.4 ± 2.4 Holter monitor recording was performed in patients who were thought to have arrhythmia-related inter- Time of AF symptom onset, months 36.5 ± 32.3 mittent symptoms. Recurrence of atrial tachyarrhyth- Type of persistent AF, n (%) 17 (14.0) mia was defined as an event lasting more than 30 s AAD before procedure, n (%) 77 (63.6) after a 3-month blanking period. Antiarrhythmic Class I drug 66 (54.5) drugs (AADs) were taken during the first 3 months Class III drug 11 (9.1) after the ablation. Discontinuation of AADs was de- Antithrombotic drug, n (%) 109 (90.1) termined at the physicians’ discretion. Warfarin 45 (37.2) Anti-platelet drug 60 (49.6) Statistical analysis NOAC 4 (3.3) All values are expressed as means ± SD or as num- bers and percentages where appropriate. Categorical LVEF 57.8 ± 7.9 data were compared by the χ test. Continuous LA size, mm 41.0 ± 5.6 variable data were compared by independent samples E/e′ 9.6 ± 5.2 t-test when the distribution was normal or by the Hypertension, n (%) 66 (54.5) Mann-Whitney test if it the distribution was not nor- Diabetes mellitus, n (%) 16 (13.2) mal. Kaplan-Meier analysis with the log-rank test was CHAS DS -VASc score 1.9 ± 1.3 2 2 used to determine the probability of freedom from re- current atrial tachyarrhythmia. Receiver operating 0, n (%) 15 (12.4) characteristic (ROC) analysis was used to calculate 1, n (%) 39 (32.2) sensitivity and specificity, and the area-under-the- ≥ 2, n (%) 67 (55.4) curve (AUC) was used to compare accuracy for differ- HAS-BLED score 1.6 ± 1.1 ent lengths of pause. Cox regression analysis was used Values are expressed as means±SDs and numbers (percentages). AF atrial for the predictor model. Variables were selected on fibrillation, AAD anti-arrhythmic drug, NOAC non-vitamin K antagonist anti- the basis of univariate significance. P <0.05 was coagulant, LVEF left ventricular ejection fraction, LA left atrium Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 4 of 8 Recurrence of atrial tachyarrhythmia after catheter ablation longer in patients who underwent pacemaker implant- After catheter ablation, the rate of any atrial tachyar- ation after catheter ablation compared to those who rhythmia (AF or AT) recurrence is 19.0% (23 of 121) underwent catheter ablation alone (7.9 ± 3.5 vs. 5.1 ± 2.1 s, during mean 29.3 months of follow up. We investigate p< 0.001) (Fig. 2). ROC curve analysis showed that the factors affecting recurrence according to age and trigger optimal cutoff point for predicting implantation of a per- sites. Thirty-one patients (25.6%) were 70-year-old or manent pacemaker following catheter ablation was 6.3 s more. Atrial tachyarrhythmia recurrence was not signifi- (sensitivity 72.7%, specificity 79.1%, AUC = 0.75). The lon- cantly different between patients with 70-year-old or gest pause was associated with a need for implantation of more and those with younger than 70-year-old (18.9% a permanent pacemaker using both univariate analyses vs. 19.4%, log-rank test p = 0.732). During the ablation (HR 1.287, 95% CI 1.101-1.506, p = 0.002) and a multivari- procedures, triggers were identified in 73 patients (60. ate model (HR 1.576, 95% CI 1.060-2.343, p =0.025) 3%) and no trigger was identified in 48 patients (39.7%). adjusted by age, sex, time of AF symptom onset, HTN, There was no significant difference of atrial tachyarrhyth- DM, use of post-procedural AAD, LVEF, LA diameter, and mia recurrence between patients with triggers and those trigger (Table 3). Antiplatelet therapy (aspirin, n = 1) was with no trigger (17.8% vs. 20.8%, log-rank test p =0.559, continued during pacemaker implantation. Anticoagula- Additional file 1: Figure S1). Among total patients, sixty- tion therapy with warfarin (n = 9) was continued without three patients (52.1%) had a pulmonary vein (PV) trigger; heparin bridge during pacemaker implantation. One left superior PVs, left inferior PVs, right superior PVs, patient did not receive any antithrombotic therapy be- right middle PV, right inferior PV, and multiple PVs fore the procedure. Among total 11 patients with accounted for 27 (22.3%), 7 (5.8%), 13 (10.7%), 1 (0.8%), 2 pacemaker implantation after ablation, there was no (1.7%), and 13 (10.7%) trigger sites, respectively. Ten pa- pocket hematoma. tients (8.3%) had non-PV triggers; eight (6.6%) at SVC and two (1.7%) at the high RA septum. There was no signifi- cant difference of atrial tachyarrhythmia recurrence Discussion between patients with PV trigger and those with non-PV Main findings trigger (18.6% vs. 14.3%, log-rank test p =0.817, This study demonstrated that recurrence rate after cath- Additional file 2:FigureS2). eter ablation were 19% in patients with AF predisposing to TBS during mean 29 months of follow up, 9.1% of Pacemaker implantation after catheter ablation patients were required implantation of a permanent Following catheter ablation of AF, eleven patients (9.1%) pacemaker after catheter ablation, and they had a longer received implantation of permanent pacemaker. Mean pause on termination of AF compared to those with time interval from catheter ablation to pacemaker im- catheter ablation alone. Multivariate analysis showed plantation was 21 months. The patients’ characteristics that a pause of 6.3 s or longer at baseline was associated are shown in Table 2. Mean longest pause on termin- with the need to implant a permanent pacemaker after ation of AF prior to catheter ablation was significantly catheter ablation. Table 2 Patients who underwent implantation of permanent pacemaker after RFCA No. Age Sex Longest LA size CHA DS Trigger AAD or AF Symptom PM Pause after Time interval PM mode 2 2 (years) pause (mm) –VASc NB after recur after indication ablation from RFCA (seconds) score ablation ablation (seconds) to PM (days) 1 71 M 10.1 39.5 1 None None recur dizziness SP 4.2 2422 DDD 2 60 F 5.2 49.5 1 None None SR dizziness SP 5.1 14 DDDR 3 67 M 12.8 37.8 1 LSPV None SR syncope SP 5.2 7 DDDR 4 49 F 13.6 47.9 1 SVC None SR syncope SP 8.5 70 DDDR 5 59 M 6.3 40.7 1 LSPV None SR dizziness SP 7.2 566 DDDR 6 52 F 6.9 36.0 2 SVC None recur dizziness SP 5.3 1504 DDDR 7 58 F 3.4 43.3 2 LSPV None SR dizziness SP 7.0 1269 DDDR 8 70 M 8.2 43.1 2 LSPV None SR dizziness SP 6.8 27 DDDR 9 61 F 7.2 60.8 2 None None SR dizziness SP 6.8 1126 DDDR 10 70 F 9.8 32.2 3 SVC None SR dizziness SP 5.2 51 DDDR 11 69 F 3.1 39.7 3 None None SR dizziness SP 4.7 250 DDDR No. patients number, M male, F female, RFCA radiofrequency catheter ablation, PM pacemaker, AAD anti-arrhythmic drug, NB nodal blocker, SR sinus rhythm, AF atrial fibrillation, SP sinus pause Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 5 of 8 Fig. 2 Comparison and the longest pause between patients who did not receive a pacemaker and those who received a pacemaker after catheter ablation Mechanisms of TBS with AF demonstrated that altered C-linker interaction in SND is frequently associated with AF [11], and is caused hyperpolarized-activated ion channel HCN4 is associated by inhomogeneous refractoriness [15]. A study in a with familial TBS and AF, indicating that funny channel chronic pacing-induced AF dog model demonstrated dysfunction contributes to the development of atrial sinus node remodeling as a result of AF that was charac- tachyarrhythmias [20]. Ectopic activities that elicit trig- terized by prolongation of corrected sinus node recovery gers for initiation of AF may also be induced in HCN4- time and P-wave duration and a decrease in maximal K530 N by the switch from enforced inhibition of gating and intrinsic heart rate [2]. Sick sinus syndrome can be to stimulation of gating due to binding of cAMP under regarded as an atrial disease rather than as sinus node adrenergic stress. Furthermore, slow heart rates may in- disease per se [16–18]. The mechanism of TBS, where crease susceptibility to ectopic beats. Therefore, molecu- the pause is manifested just after AF terminates, remains lar and structural remodeling of the sinus node increases to be determined. Yeh et al. suggested that funny current arrhythmogenesis, promoting the vicious cycle of “AF (I ) down-regulation may contribute to the clinically begets AF” [21]. Thus, early ablation for TBS likely de- significant association between SND and supraventricu- creases the rate of implantation of permanent pace- lar tachyarrhythmias [19]. Recently, Duhme et al. makers before predisposition to SND by AF burden. Table 3 Factors associated with pacemaker implantation after ablation Factors HR (univariate analysis) P value HR (multivariate analysis) P value Age, years 1.014 (0.954-1.078) 0.657 Female sex 0.488 (0.142-1.676) 0.254 Longest pause, seconds 1.287 (1.101-1.506) 0.002 1.576 (1.060-1.343) 0.025 Time of AF symptom onset, months 0.978 (0.933-1.025) 0.357 AAD after ablation 1.459 (0.308-6.904) 0.634 LVEF, % 1.024 (0.952-1.102) 0.525 LA diameter, mm 1.086 (0.990-1.191) 0.080 1.230 (0.860-1.757) 0.257 Trigger (vs. no-trigger) 0.753 (0.217-2.614) 0.655 Values are expressed as hazard ratios (HRs) with CI 95%. AAD anti-arrhythmic drug, LVEF left ventricular ejection fraction, LA left atrium Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 6 of 8 Catheter ablation for TBS with AF comorbidity in patients who undergo implantation of Catheter ablation has been used to treat patients with pacemaker. Moreover, AF itself may lead to medical AF for several decades. Clinical outcome is better in par- problems (e.g. progression to persistent AF, tachycardia- oxysmal AF than in persistent AF. The reasons for this mediated cardiomyopathy, proarrhythmic events due to include the lower severity of the remodeling process in uses of AAD, bleeding due to maintenance of antithrom- paroxysmal AF than persistent AF, and the main cause botic therapy), and the management for AF is also of AF onset being ectopic beats that can be eliminated needed indefinitely. In contrast to pacemaker implant- by catheter ablation. Catheter ablation may also improve ation, catheter ablation of AF has several strengths in sinus node function in patients with TBS and AF by in- patients with TBS including eradication of AF and no ducing reverse remodeling. Hocini et al. demonstrated need for a device. However, it was not clear whether that successful ablation of AF was followed by marked catheter ablation or pacemaker implantation was better recovery in sinus atrial node function when AF patients for treating paroxysmal AF-related TBS. Furthermore, showed prolonged sinus pauses on AF termination [7]. recent studies demonstrated that maintenance of sinus These concepts suggest that TBS that manifests as trigger- rhythm following catheter ablation might reduce the risk AF may be cured by catheter ablation. Premature beat or of stroke compared with AAD therapy alone [27–29]. In activity originating from the PV is well-known and is the our study, two patients were hospitalized due to stroke most common trigger in patients with AF [22, 23]. after catheter ablation. Further study is required to ad- Miyazaki et al. demonstrated that SVC plays a role in AF dress whether ablation is more beneficial than implant- not only as a trigger, but also as a perpetuator [24]. We ation of permanent pacemaker for preventing stroke. identified triggers in 60.3% of patients. PV trigger activity was 86% and the most common non-PV trigger originated Prediction for implantation of a pacemaker in TBS: TBS or from the SVC (8 of 10). However, there was no significant intrinsic SND? difference in the rate of freedom from atrial tachyarrhyth- Miyanaga et al. reported that mean heart rate did not in- mia between PV trigger and non-PV trigger patients. crease in TBS patients, probably due to pre-existing SND, although parasympathetic modulation was signifi- Permanent pacemaker or catheter ablation? cantly attenuated after CPVI [30]. Inada et al. reported Whether catheter ablation or implantation of a perman- that a pacemaker was required in 8% of patients with ent pacemaker should be the first-line treatment remains paroxysmal AF and prolonged sinus pauses following debated. Prior to the AF-ablation era, pacing was the catheter ablation, but gradual progression of SND oc- only option for treatment of TBS because tachycardia curred after long-term follow-up of over 3 years [8]. In therapy using AAD aggravated bradycardia. Patients our study, a pacemaker had to be implanted in 9.1% of with drug-resistant tachycardia were considered to be patients who underwent catheter ablation due to candidates for catheter ablation even at that time [25]. bradycardia-related symptoms, such as syncope. Mean However, the treatment strategy of pacemaker plus AAD time interval from catheter ablation to implantation of a has many weaknesses, including pacemaker- and AF- permanent pacemaker was 21 months, which suggests related problems. In patients who receive a pacemaker, that intrinsic SND was progressive. Nevertheless, it is various device-related complications may occur, such as difficult to differentiate between patients who have AF infection, endocarditis, vascular injury, lead extraction, with TBS or intrinsic SND because the characteristics of and pocket hematoma. In our study, there was no pocket intrinsic SND are similar to those of TBS. We found that hematoma in 11 patients who underwent pacemaker im- implantation of a permanent pacemaker after catheter ab- plantation. Recently, Malagù M et al. demonstrated that lation was required in patients with a long pause (≥ 6.3 s). uninterrupted antiplatelet therapy or continued anticoa- This finding suggests that a pacemaker should primarily be gulation therapy without heparin bridge based on considered in patients with a long pause on AF termin- thromboembolic risk stratification was associated with a ation. Of course, SND might be caused or accelerated by reduced incidence of clinically significant pocket the ageing process [31, 32]. However, this still remains un- hematoma [26]. The incidence of pocket hematoma was clear [33]. The ages of patients who received pacemaker 1.6% in no-bridge protocol group and 6.5% in conven- implantation and those who did not after catheter ablation tional management group. Pacing-induced heart failure were similar. In addition, the rates of freedom from atrial may be a potential comorbidity. Need for generator tachyarrhythmia following catheter ablation were similar change will increase as average life expectancy increases between patients who were 70 years or older versus those compared to device longevity. Because the risk of stroke younger than 70 years. Recently, Nademanee et al. demon- increases in elderly patients with AF, use of certain diag- strated that elderly patients with AF benefited from AF ab- nostic tools, such as magnetic resonance imaging, be- lation, which was safe and effective at maintaining sinus comes problematic. Furthermore, AF still remains as a rhythm and was associated with lower mortality and stroke Kim et al. BMC Cardiovascular Disorders (2018) 18:106 Page 7 of 8 risk [34]. Thus, the ageing process may not be the sole Ethics approval and consent to participate The study protocol was approved both by the Research Committee and the mechanism affecting the pathophysiology of TBS and AF. Ethics in Research Committee of in Korea University Medical Center. Written informed consent was obtained. All procedures were conducted based on the Declaration of Helsinki and local regulations. Study limitations This was not a randomized trial that was designed to de- Competing interests termine whether ablation was superior to pacemaker im- The authors declare that they have no competing interests. plantation. In this retrospective study, the decision of whether to perform catheter ablation or to implant a Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published permanent pacemaker as the first-line treatment was at maps and institutional affiliations. the physicians’ discretion based on clinical manifesta- tions. Rates of recurrence of atrial tachyarrhythmias Received: 9 August 2017 Accepted: 9 May 2018 might also have been underestimated because we did not use a continuous rhythm monitoring device, such as References an implantable loop recorder, for detection of AF [35]. 1. 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BMC Cardiovascular DisordersSpringer Journals

Published: May 30, 2018

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