History of hyperthyroidism and long-term outcome of catheter ablation of drug-refractory atrial fibrillation

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History of Hyperthyroidism and Long-Term Outcome of Catheter Ablation of Drug-Refractory Atrial Fibrillation Wanwarang Wongcharoen M.D., Yenn-Jiang Lin M. D., PH.D., Shih-Lin Chang M.D., Li-Wei Lo M.D., Yu-Feng Hu M.D., Fa-Po Chung M.D., Eric Chong M.D., Tzu-Fan Chao M.D., Da-Chuan Duan M.D., Yao-Ting Chang M.D., Chin-Yu Lin M.D., Jo-Nan Liao M.D., Yi-Chun Lin M.D., Yun-Yu Chen M.P. H., Shih-Ann Chen M.D.

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S1547-5271(15)00694-3 http://dx.doi.org/10.1016/j.hrthm.2015.06.004 HRTHM6303

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Cite this article as: Wanwarang Wongcharoen M.D., Yenn-Jiang Lin M.D., PH.D., ShihLin Chang M.D., Li-Wei Lo M.D., Yu-Feng Hu M.D., Fa-Po Chung M.D., Eric Chong M.D., Tzu-Fan Chao M.D., Da-Chuan Duan M.D., Yao-Ting Chang M.D., Chin-Yu Lin M.D., Jo-Nan Liao M.D., Yi-Chun Lin M.D., Yun-Yu Chen M.P.H., Shih-Ann Chen M. D., History of Hyperthyroidism and Long-Term Outcome of Catheter Ablation of DrugRefractory Atrial Fibrillation, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.06.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

History of Hyperthyroidism and Long-Term Outcome of Catheter Ablation of Drug-Refractory Atrial Fibrillation Wanwarang Wongcharoen, M.D.1; Yenn-Jiang Lin, M.D., PH.D.2,3,*; Shih-Lin Chang, M.D.2,3; Li-Wei Lo, M.D.2,3; Yu-Feng Hu, M.D.2,3; Fa-Po Chung, M.D.2,3; Eric Chong, M.D.2,5; Tzu-Fan Chao, M.D.2,3; Da-Chuan Duan, M.D.2,3; Yao-Ting Chang, M.D.2,3, Chin-Yu Lin, M.D.2,3; Jo-Nan Liao, M.D.2,3; Yi-Chun Lin, M.D.4; Yun-Yu Chen, M.P.H. 2; Shih-Ann Chen, M.D.2,3. 1

Department of Internal Medicine, Faculty of Medicine, Chiang Mai University,

Chiang Mai, Thailand; 2

Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan;

3

Faculty of Medicine, Institute of Clinical Medicine, and Cardiovascular Research

Institute, National Yang-Ming University, Taipei, Taiwan; 4

Division of Endocrinology and Metabolism, Taipei Veterans General Hospital,

Taipei, Taiwan; 5

Division of Cardiology, Medicine Department, Jurong Health, Singapore.

No conflict of interest to declare Short title: Hyperthyroidism and AF ablation

*Corresponding author: Yenn-Jiang Lin, M.D. PhD. Division of Cardiology, Taipei Veterans General Hospital, Taiwan; Faculty of Medicine, Institute of Clinical Medicine, and Cardiovascular Research Institute, National Yang-Ming University, Taipei, Taiwan E-mail: [email protected] Fax: 886-2-2875

1

Abstract BACKGROUND: Hyperthyroidism is a known reversible cause of atrial fibrillation (AF). However, some patients remain in AF despite restoration of euthyroid status. OBJECTIVE: This study compared electrophysiological characteristics and long-term ablation outcome in AF patients with and without history of hyperthyroidism. METHODS: The study enrolled 717 consecutive patients with AF who underwent first AF ablation, which involved pulmonary vein isolation (PVI) in paroxysmal AF and additional substrate modification in non-paroxysmal AF patients. Eighty-four patients (12%) with hyperthyroidism history were compared to those without. Euthyroid status was achieved for ≥3 months before ablation in hyperthyroid patients. RESULTS: Patients with hyperthyroid history were associated with older age, more female gender, lower mean right atrial voltage, higher number of PV ectopic foci (1.3±0.4 vs. 1.0±0.2, P<0.01) and higher prevalence of non-PV foci (42% vs. 23%, P<0.01). Ectopic foci from ligament of Marshall (LOM) were demonstrated more often in hyperthyroid patients (7.1% vs. 1.6%, P<0.01) in whom alcohol ablations were required. After propensity score matching for potential covariates, history of hyperthyroidism was an independent predictor of AF recurrence after single procedure (hazard ratio=2.07, 95% confidence interval=1.27-3.38). AF recurrence rates after multiple procedures were not different between patients with and without hyperthyroid history. . CONCLUSIONS: Patients with hyperthyroid history had significantly higher number of PV ectopies and higher prevalence of non-PV ectopic foci comparing to euthyroid patients which resulted in the higher AF recurrence rate after single procedure. KEYWORDS: Atrial fibrillation; Ablation; Hyperthyroidism; Ligament of Marshall; Pulmonary vein isolation.

Abbreviations AAD: antiarrhythmic drug; AFL: atrial fultter; APD: action potential duration; AT: atrial tachycardia; 2

BMI: body mass index; FT3: free triiodothyronine; FT4: free thyroxine; IVS: inverventricular septum; LA: left atrium; LOM: ligament of Marshall; PVs: pulmonary veins; RA: right atrial (atrium); SVC: superior vena cava; TIA: transient ischemic attack; TSH: thyroid stimulating hormone.

Introduction Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and it is associated with significant morbidity and mortality.1,2 Overt and subclinical hyperthyroidism has been shown to increase risk of AF occurrence. 3,4 The reported incidence of AF in hyperthyroidism ranged from 13-20%, compared to 4% in the general population.5 Mechanism of AF in hyperthyroidism is multifactorial. Several potential mechanisms have been described which include electrophysiological changes of pulmonary veins (PVs) and atria, atrial electromechanical delay and alteration of sympathovagal balance.5-7 It is recommended in the guidelines that the treatment of AF during hyperthyroidism should aim at restoring euthyroid state, which usually leads to spontaneous reversion of AF to sinus rhythm. However, a significant number of patients remain in AF despite euthyroid restoration after treatment.8,9 Commonly, 3

catheter ablations are required to treat drug-refractory AF in hyperthyroid patients even after euthyroid restoration. Previous small studies have reported conflicting results in the outcome of AF ablation in patients with hyperthyroidism.10-13 Therefore, we compared the outcome of catheter ablation between euthyroid AF patients with history of hyperthyroidism and normal thyroid AF patients. The electrophysiological characteristics of PVs and atria were compared between the two groups.

Methods Study population Patients with symptomatic drug refractory AF who received radiofrequency catheter ablation for the first time during the period of 2004 to 2010 were studied. Those who failed to attend regular follow up for at least 1 year after ablation were excluded. Finally, there were 535 paroxysmal AF (75%) and 182 persistent AF patients (25%) enrolled in the study. Among 717 patients with drug-refractory AF, 84 patients (12%) with history of hyperthyroidism were compared with the remaining patients who were free from thyroid disease. Due to the differences in baseline characteristics between patients with and without history of hyperthyroidism, the propensity score matching with potential covariates was performed (Table 1). Euthyroid status was restored for at least 3 months before ablation in all patients with history of hyperthyroidism. Euthyroid status was defined when the patients had normal levels of thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). No patients received amiodarone at the time of ablation. This study complied with the Declaration of Helsinki. The Institutional Review Board of the Taipei Veterans General Hospital, Taipei, Taiwan approved the study protocol. 4

Catheter ablation of AF After

giving

written

informed

consent,

each

patient

underwent

an

electrophysiological study and catheter ablation in the fasting, non-sedative state. The details have been described in previously publications.14-16 In brief, after completing the left atrium (LA) geometry, continuous circumferential lesions were created encircling the right and left PV ostia guided by the NavX system using either a conventional 4-mm tip or irrigated-tip catheter. The intention was to place the radiofrequency lesions at least 1–2 cm away from the angiographically defined ostia. Successful circumferential PV isolation was demonstrated by the absence of any PV activity or dissociated PV activity. If persistent AF did not stop after completing PV isolations, additional linear ablation was performed at both the anterior roof and lateral mitral isthmus. For paroxysmal AF patients, the additional linear ablation was only performed when the AF was still inducible with programmed stimulation.17 If persistent AF persisted after PV isolations and linear ablations, an additional complex fractionated electrographically guided substrate ablation was performed sequentially based on complex fractionated electrographic maps after PVs isolation. Complex fractionated electrographic ablation was confined to the continuous complex fractionated electrograms (>5 seconds) in LA and proximal coronary sinus.18,19 The end point of complex fractionated electrographic site ablation was to obtain a prolongation of cycle length, eliminate complex fractionated electrograms, or abolish local fractionated potentials (bipolar voltage <0.05 mV). After sinus rhythm was restored by procedural AF termination or electric cardioversion, mapping and ablation were applied only to spontaneously initiating focal atrial tachycardias and non-PV ectopies that initiated AF. If any non-PV ectopies initiating AF from the superior vena cava (SVC) was identified, isolation of SVC was guided by the circular catheter 5

recordings from the SVC–atrial junction. In patients with recurrence of triggers from ligament of Marshall (LOM) refractory to endocardial ablation/coronary sinus ablation in the first procedure,20 alcoholic ablation via coronary sinus was performed in the repeated procedure.21 After LOM ablation, reassessment of LOM triggers was performed. Bidirectional conduction block of mitral lines was also required.

Post-ablation follow up After the catheter ablation, all patients received antiarrhythmic drugs for 8 weeks to prevent any early recurrence of AF. Patients underwent regular follow-up (2 weeks after the catheter ablation, then every 1–3 months) at our cardiology clinic or with the referring physicians. During the follow-up, 24-hour Holter monitoring and/or cardiac event recording with a recording duration of one week were performed. The recurrence was defined as an episode of atrial arrhythmias lasting more than 30 seconds and confirmed by electrocardiograms 3 months after the ablation (blanking period). Freedom of recurrence was defined as the absence of atrial arrhythmias without using any antiarrhythmic agents after the catheter ablation. The long-term efficacy was assessed clinically on the basis of the clinical symptoms, resting surface 12-lead electrocardiogram, 24-hour Holter monitoring and/or 1 week cardiac event recordings. Statistical analysis Differences between continuous variables were assessed using a Student's t-test for normally distributed continuous variables. Proportions were compared by Chi-square test or Fisher exact test when appropriate. This study employed matching technique to minimize confounding from hyperthyroidism, one-to-four pairs under identical propensity scores with a 0.01 caliper width for age, gender, hypertension, diabetes mellitus, congestive heart failure, coronary artery disease, and previous 6

stroke or transient ischemic attack were matched. The recurrence free survival curve was examined via the Kaplan-Meier (KM) method with the log-rank test. We performed the log minus log plot to test if the model fit proportional hazard assumption without crossing effect. Multivariate Cox proportional hazards regression was performed if variables with a P-value of less than 0.2 in univariate model for hazard ratio.22 All statistical significances were set at p value < 0.05 which were carried out by SPSS 17.0 (SPSS Inc. USA) and SAS version 9.3 (SAS Institute, Cary, NC).

Results Baseline characteristics The prevalence of patients with history of hyperthyroidism undergoing AF ablation was 11.7% in the present study. The medical history of hyperthyroidism was available in 57 of the overall 84 patients. Graves’ disease was diagnosed in 26 patients (46%, duration: 17±15 years), thyroiditis was diagnosed in 15 patients (26%, duration: 3.5±5.7 years), amiodarone related hyperthyroidism was diagnosed in 16 patients (28%, duration: 1.5±0.8 years). Baseline characteristics are shown in Table 1. Patients with history of hyperthyroidism were associated with older age (57±10 vs. 54±11 years, P<0.01), more female gender (50% vs. 22%, P<0.001), no history of stroke (0% vs. 4.2%, P=0.04), and lower body mass index (BMI) (24.5±3.4 vs. 25.3±3.4, P=0.03). There was trend towards higher prevalence of hypertension (60% vs. 48%, P=0.05) and congestive heart failure (11% vs. 6%, P=0.06) in hyperthyroid patients than normal thyroid patients. The other baseline characteristics were comparable between the two groups. After propensity score matching, a total of 81 AF patients with 7

hyperthyroidism and 309 AF patients without hyperthyroidism were retained for further analyses, baseline characteristics were similar between the hyperthyroidism and non-hyperthyroidism groups (Table 1).

Electrophysiological characteristics The LA size and LA substrate characteristics did not differ between the two groups with and without history of hyperthyroidism. However, the mean right atrial (RA) voltage was significantly lower in patients with history of hyperthyroidism (1.48±0.54 vs. 1.76± 0.57 mV, P=0.001; Table 2). The number of PV ectopic foci were significantly higher in the hyperthyroid patients (1.3±0.4 vs. 1.0±0.2, P=0.01). The higher prevalence of non-PV ectopic foci was also observed in those with hyperthyroid history (42% vs. 23%, P<0.01). In addition, the higher prevalence of non-PV ectopic foci was noted in non-paroxysmal AF group as compared with paroxysmal AF (30% vs. 14%, P<0.001). Interestingly, the ectopic foci from LOM were observed more frequently in patients with hyperthyroid history compared to the normal thyroid patients (7.1% vs. 1.6%, P<0.01). Among patients with LOM triggers, alcohol ablations were required to eliminate these foci in two-thirds of patients with history of hyperthyroidism. In addition, the prevalence of ectopic foci from coronary sinus, LA posterior wall and mitral valve annulus appeared to be higher in patients with history of hyperthyroidism (Table 3). AF ablation outcomes After propensity score matching, the mean follow-up duration was 32±14 months (up to 48 months) for the matched cohort. Higher AF recurrence rate was observed after single procedure in patients with hyperthyroidism (49% vs 37%, log 8

rank test by KM survival analysis: P=0.04; Figure 1). After multiple procedures, the recurrence rate of AF was similar between two matched groups (14% vs 11%, long rank test: P=0.62). The recurrence rate of atrial tachycardia and atypical atrial flutter was similar between the two matched groups. We demonstrated that history of hyperthyroidism, congestive heart failure, higher body mass index (BMI), larger LA size, lower LA voltage, and presence of non-PV ectopies were significantly associated with higher recurrence of AF after single procedure in univariate Cox models. After adjusting by the multivariate Cox models for potential covariates, the results showed that history of hyperthyroidism, lower LA voltage, and presence of non-PV ectopies were still the independent predictors of AF recurrence after single procedure (hazard ratio [HR] of thyroid history=2.07, 95% confidence interval [CI]=1.27-3.38, P<0.01; Table 4). Furthermore, history of congestive heart failure, larger LA size and lower LA voltage were found to correlate with higher rate of AF recurrence after multiple procedures in univariate Cox models. Multivariate Cox models showed that the only independent predictor of AF recurrence after multiple procedures was the LA diameter (HR=1.05, 95% CI=1.01-1.10, P=0.03; Table 5). Notably, history of hyperthyroidism was not associated with AF recurrence after multiple procedures (HR=1.43, 95% CI=0.68-3.01, P=0.34).

9

Discussion Main findings Our study demonstrated that (1) history of hyperthyroidism was associated with older age, female gender, advanced remodeling of RA in patients undergoing AF ablation. (2) Higher number of PVs ectopies and higher prevalence of non-PV ectopies, particularly from the LOM, were demonstrated in patients with history of hyperthyroidism. (3) History of hyperthyroidism was an independent predictor of AF recurrence after single procedure at 3-year follow-up. Thyroid disease and AF It is well established that hyperthyroidism is an important risk factor of AF occurrence.3,4 There was a high prevalence of patients with history of hyperthyroidism in our study population. The PV is important source for AF initiation and it plays critical roles in AF maintenance.23,24 We demonstrated a higher number of PV ectopies in patients with history of hyperthyroidism compared to the normal thyroid patients. Several mechanisms of increased PV arrhythmogenicity in hyperthyroidism have been proposed. Previous studies showed that excess thyroid hormone increased calcium currents and potassium currents of PV cardiomyocytes resulting in shortening of action potential duration (APD) and the increased automaticity of PVs.25 Subsequent study demonstrated presence of higher titer of autoantibodies to β1-adrenergic and M2 muscarinic receptors in AF patients with hyperthyroidism when compared to sinus rhythm patients with hyperthyroidism and normal control patients. It has been demonstrated that these autoantibodies induced hyperpolarization, decreased APD, enhanced early after-depolarization formation and facilitated triggered firing in the PVs. The co-existence of autoantibodies to β1-adrenergic and

10

M2 muscarinic receptors lead to simultaneous activation of sympathetic and parasympathetic outflow which may enhance PVs arrhythmogenicity.26 Hyperthyroidism and non-PVs triggers Although PVs are the major site of ectopic foci which are capable of initiating AF, non-PV foci also play important role in initiating and maintaining AF in 20-35% of patients.27,28 The presence of non-PV foci is closely related to the recurrence of paroxysmal AF after PV isolation.29,30 In the present study, the prevalence of non-PV ectopic foci was significantly higher in patients with history of hyperthyroidism. One of the common sites of non-PV foci in patients with hyperthyroid history was LOM. The foci from coronary sinus, LA posterior wall and mitral valve annulus were also more frequently identified in patients with history of hyperthyroidism, although the differences were not statistically significant when compared with normal thyroid patients. We postulated that hyperthyroidism affected the electrophysiological changes of non-PV ectopies in a similar fashion to the PVs. Previous study from our group showed that female gender could predict presence of SVC ectopies initiating AF, and LA enlargement could predict LA posterior wall ectopies.29 To the best of our knowledge, this is the first study to demonstrate the significant association between history of hyperthyroidism and presence of LOM ectopies in patients undergoing AF ablation. Several echocardiographic studies demonstrated the presence of atrial electromechanical delay and increased atrial size in patients with hyperthyroidism.31-33 However, we did not find any differences in terms of LA size and LA voltage between patients with history of hyperthyroidism and those without. Nevertheless, we demonstrated that the mean RA voltage was significantly lower in patients with history of hyperthyroidism. As all patients with history of hyperthyroidism were in 11

euthyroid state at the time of ablation, it was possible that the left atrial function could have improved after euthyroid restoration.32 Outcome of catheter ablation Previous small studies have reported the outcomes of AF ablation in patients with history of hyperthyroidism. Machino and colleagues showed similar success rates of PVs isolation in those with and without history of hyperthyroidism. Almost one-third of patients in their study received additional roof linear ablation and SVC isolation.11 On the contrary, a case-control study by Milkhaylov and colleagues demonstrated that patients with history of amiodarone-induced hyperthyroidism had higher AF recurrence rate after PVs isolation.12 Similarly, another study showed that patient with high-normal thyroid function was associated with an increased risk of AF recurrence after catheter ablation.13 Nevertheless, none of these studies have thoroughly examined the presence of PVs and non-PV ectopic foci in patients with history of hyperthyroidism undergoing AF ablation. In the present study, we demonstrated higher prevalence of PVs and non-PVs ectopic foci in patients with hyperthyroidism, which may explain the higher recurrence rate after single procedure. Nevertheless, the recurrence rate of AF after multiple procedures was similar between patients with and without history of hyperthyroidism. Our ablation protocol aims to eliminate all the AF initiating ectopic foci from both PVs and non-PVs, this strategy would have contributed to the favorable long-term outcome of AF ablation after multiple procedures in patients with history of hyperthyroidism.

The prevalence of overt hyperthyroidism in our AF population was 11.7%. This was much higher than the reported range of 1-3% in published studies from China, Sweden, New Zealand and Canada.34-37 The possible explanation for the difference

12

could be the frequent referral of complex AF cases with concurrent thyroid disease to our center.

Limitations This study was based on a retrospective analysis. The underlying mechanisms of hyperthyroidism were different among the patients. However, our study was based on a large AF ablation database in a tertiary referral center. All patients were in euthyroid status before ablation.

Conclusion Patients with hyperthyroid history had significantly higher number of PV ectopies and higher prevalence of non-PV ectopic foci comparing to euthyroid patients which resulted in the higher AF recurrence rate after single procedure. Elimination of these ectopic foci during subsequent procedures may have accounted for the comparable AF recurrence rates after multiple procedures between those with and without hyperthyroid history.

13

Tables Table 1: Baseline characteristics Original cohort

Baseline characteristics

Without hyperthyroidism (N =633) Age (year) Male (%) Persistent AF (%) Hypertension (%) Diabetes mellitus (%) Congestive heart failure (%) Coronary artery disease (%) Previous stroke/TIA (%) Body mass index (kg/m2) AADs use before ablation (%) History of amiodarone (%) History of procanamide (%) History of propafenone (%) CHADS2 score Left atrial diameter (mm) Left ventricular ejection fraction (%) IVS thickness (mm)

After propensity score matching

History of hyperthyroidism (N=84)

P value

57±10 42 (50%) 23 (27.4%) 50 (59.5%) 10 (11.9%) 9 (10.7%) 18 (21.4%) 0 (0.0%) 24.5±3.36 55 (65.4%) 26 (30.9%)

<0.01 <0.001 0.74 0.05 0.83 0.06 0.48 0.04 0.03 0.94 0.53

8 (1.3%) 239 (37.8%)

0 (0%) 28 (33.3%)

0.61 0.40

0.90±0.94 38.9±6.27 58.5±7.52

1.08±0.90 38.9±6.30 59.6±8.05

9.74±1.82

9.42±2.14

54±11 493 (77.9 %) 159 (25.1%) 302 (47.7%) 68 (10.7%) 36 (5.7%) 152 (24 %) 27 (4.3%) 25.3±3.37 421 (66.5%) 215 (33.9%)

0.06 0.69 0.20

Without hyperthyroidism (N =309) 56±9 160 (51.8%) 73 (23.6%) 174 (56.3%) 41 (13.3%) 27 (8.7%) 65 (21%) 0 (0.0%) 24.7±3.35 208 (67.3%) 109 (35.3%) 7 (2.3%) 120 (38.8%) 0.96±0.85 38.8±6.42 58.2±59.8

History of hyperthyroidism (N=81) 57±10 39 (48.1 %) 20 (24.7 %) 47 (58%) 11 (13.6%) 8 (9.9%) 18 (22.2 %) 0 (0.0%) 24.7±3.4 55 (67.9%) 26 (32.1%) 0 (0%) 27 (33.3%) 1.06±0.9 38.4±6.41 59.8±8.02

0.14 0.56 0.84 0.80 0.94 0.83 0.82 >0.99 0.97 0.92 0.59 0.19 0.36 0.37 0.71 0.10

0.13

9.6±1.96

9.42±2.15

0.48

Table 2: Electrophysiologic characteristics in patients with and without history of hyperthyroidism Clinical variables

Without hyperthyroidism (N =633)

History of hyperthyroidism (N=84)

P value

Mean LA voltage (mV)

1.80±0.77

1.70±0.64

0.31

LA total activation time (ms)

116±54.9

116±54.9

0.74

Mean RA voltage (mV)

1.76±0.57

1.48±0.54

0.001

RA total activation time (ms)

116±43.4

120±35.7

0.58

1.0±0.2

1.3±0.4

0.01

146 (23.1%)

35 (41.6%)

<0.01

Number of PV ectopies Prevalence of non-PV ectopies (%)

14

P value

Table 3: Location of non-pulmonary vein ectopic foci Location of Non-PV foci

Without hyperthyroidism (N =633) 78 (12.3%)

History of hyperthyroidism (N=84) 11 (13.1%)

value

19 (3%)

6 (7.14%)

0.06

Ligament of marshall (%)

10 (1.58%)

6 (7.14%)

0.01

Atrial septum (%)

17 (2.66%)

4 (4.76%)

0.29

Left atrial posterior wall (%)

5 (0.78%)

3 (3.57%)

0.06

Mitral annulus (%)

5 (0.78%)

3 (3.57%)

0.06

Other atrial regions (%)

10 (1.58%)

2 (2.38%)

0.64

Total (%)

146 (22.7%)

35 (41.7%)

<0.001

Superior vena cava (%) Coronary sinus (%)

P

0.86

Table 4: Predictor of AF recurrence after single procedure Clinical variables

Univariate Analysis (Hazard ratio, 95% CI) 1.50 (1.02-2.21)

P value

Multivariate Analysis (Hazard ratio, 95% CI) 2.07 (1.27-3.38)

History of 0.04 hyperthyroidism Age 0.97 (0.98-1.02) 0.68 Male 1.30 (0.85-1.99) 0.22 Hypertension 0.93 (0.66-1.32) 0.70 Diabetes mellitus 1.01 (0.61-1.68) 0.97 Congestive heart failure 2.10 (1.29-3.42) <0.01 1.67 (0.89-3.11) Coronary artery disease 1.16 (0.77-1.74) 0.47 Body mass index, kg/m2 1.06 (1.01-1.12) 0.02 1.07 (0.99-1.15) LA diameter (mm) 1.05 (1.02-1.08) <0.001 1.03 (0.99-1.07) IVS thickness (mm) 1.05 (0.97-1.14) 0.24 Mean LA voltage (mV) 0.61 (0.42-0.89) 0.01 0.68 (0.47-0.98) Non-PV ectopies 1.44 (0.93-2.22) 0.11 1.73 (1.03-2.92) †Hazard ratio changes per unit as the increment of each clinical continuous variable.

P value

<0.01 0.11 0.07 0.13 0.04 0.04

Table 5: Predictor of AF recurrence after multiple procedures Clinical variables

History of hyperthyroidism Age Male Hypertension Diabetes mellitus Congestive heart failure Coronary artery disease Body mass index, kg/m2

Univariate Analysis (Hazard ratio, 95% CI)

P value

1.01 (0.56-1.82)

0.98

1.00 (0.98-1.03) 1.31 (0.81-2.14) 0.96 (0.59-1.56) 1.32 (0.69-2.52) 2.68 (1.46-4.92) 1.05 (0.59-1.87) 1.04 (0.97-1.12)

0.86 0.27 0.87 0.40 0.001 0.86 0.29 15

Multivariate Analysis (Hazard ratio, 95% CI) 1.43 (0.68-3.01) 1.82 (0.81-4.11) -

P value 0.34

0.15 -

-

LA diameter (mm) 1.07 (1.03-1.11) <0.001 1.05 (1.01-1.10) IVS thickness (mm) 1.02 (0.91-1.15) 0.74 Mean LA voltage (mV) 0.56 (0.34-0.94) 0.03 0.70 (0.41-1.19) Prevalence of non-PV 1.69 (0.95-3.00) 0.08 1.41 (0.66-3.01) ectopies †Hazard ratio changes per unit as the increment of each clinical continuous variable.

0.03 0.19 0.34

Figure Legends Figure 1: Kaplan-Meier analysis of (A) time to first atrial fibrillation recurrence after single procedure in patients with history of hyperthyroidism (green line) and those without history of hyperthyroidism (blue line)

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Clinical Perspectives Hyperthyroidism is an important risk factor of AF occurrence. The treatment of AF during hyperthyroidism is generally aimed at restoring euthyroid state, which usually results in spontaneous reversion of AF to sinus rhythm. However, a significant number of patients remain in AF despite euthyroid restoration after treatment. The catheter ablation is currently the main therapy in patients with symptomatic AF refractory to medical treatment. However, the outcome after catheter AF ablation in patients with history of hyperthyroidism after euthyroid state remains unclear. Our study showed that history of hyperthyroidism was an independent predictor of AF recurrence after single ablation procedure. In addition, we demonstrated for the first time that patients with hyperthyroid history had higher number of PV ectopies and higher prevalence of non-PV ectopic foci as compared to those without. Interestingly, ectopic foci from LOM were demonstrated more often in patients with history of hyperthyroidism in whom alcohol ablations were required in most patients. Nevertheless, we found that history of hyperthyroidism was not associated with AF recurrence after multiple procedures. This may be due to the fact that our ablation protocol aims to eliminate all the AF initiating ectopic foci from both PVs and non-PVs. This strategy would have contributed to the satisfactory outcome of AF ablation after multiple procedures in our patients. Therefore, our findings reinforced that elimination of these ectopic foci during AF ablation was essential to achieve favorable long-term outcomes in patients with history of hyperthyroidism.

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Figure 1