Low resting heart rate is associated with recurrence in persistent atrial fibrillation after catheter ablation

doi:10.21203/rs.3.rs-8468599/v1

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Research Article

Low resting heart rate is associated with recurrence in persistent atrial fibrillation after catheter ablation

https://doi.org/10.21203/rs.3.rs-8468599/v1

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Background: Resting heart rate (RHR)is critical for identifying high-risk patients with atrial fibrillation (AF). However, the association between resting heart rate (RHR) and AF recurrence after catheter ablation remains unknown.

Objective: This study was to evaluate the association between RHR and recurrence in patients with persistent atrial fibrillation (PeAF) after catheter ablation.

Methods: Data from the China-AF registry (ChiCTR-OCH-13003729) from January 2018 to December 2023 at Beijing Anzhen Hospital were retrospectively analyzed. The primary outcome was the recurrence of AF, defined as an episode of atrial tachyarrhythmia lasting >30 seconds after a 3-month blanking period. The secondary outcome was the composite of heart failure, ischemic stroke, and cardiovascular death. Cox regression was used to assess the association between RHR and outcomes.

Results: Our study included 2,432 patients with PeAF undergoing catheter ablation. Cox regression demonstrated that RHR of 40-60 bpm was associated with an increased risk of recurrence after adjusting the confounders (HR=2.08, 95% CI:1.16-3.74, P=0.014). Additionally, we showed that patients with low RHR (40-60 bpm) had a higher risk of the composite of heart failure, ischemic stroke, and cardiovascular death (HR=11.69, 95% CI:3.01-45.43, P<0.001).

Conclusion: Low RHR is associated with recurrence in PeAF after catheter ablation, where RHR of 40-60 bpm exhibits a higher risk.

Atrial fibrillation

resting heart rate

catheter ablation

recurrence

prognosis

Atrial fibrillation (AF) represents the most common sustained cardiac arrhythmia in clinical practice, posing a significant risk of stroke and heart failure. Heart rate control constitutes a fundamental component of AF management even for patients who will get rhythm control. Particularly, resting heart rate (RHR) serves as a vital, readily accessible clinical indicator for assessing the adequacy of heart rate control and for identifying individuals with AF who may be at an elevated risk.

Previous investigations have demonstrated an association between an increased RHR and unfavorable outcomes in the general AF population(1, 2). However, their applicability to patients after catheter ablation is not straightforward, as the ablation induces significant physiological changes to cardiac autonomic innervation, a key determinant of RHR. Catheter ablation could have direct impact on the auto nervous system by decreasing the parasympathetic activity(3). This provides a strong physiological rationale for expecting alterations in RHR following ablation, and suggests that the changes of RHR could potentially correlate with recurrence. Detecting the relationship between RHR and AF recurrence after catheter ablation is important since the catheter ablation has emerged as an increasingly recommended and effective rhythm control intervention for AF.

Despite the escalating use and success of catheter ablation, AF recurrence remains a significant clinical challenge. Ideally, using the RHR to predict the recurrence of AF is easily accessible and could provide therapeutic indication of the management of RHR. The relationship between RHR and recurrence after catheter ablation may theoretically follow the same pattern with the relationship between RHR and the initial development of AF in the general population. Previous study showed there was a U-shaped relationship between RHR and the risk of developing AF, with both low and high RHR being associated with the development of AF. However, some research indicates that an increase in RHR following ablation may be associated with a lower likelihood of AF recurrence but the detailed relationship is still unknown. This counterintuitive finding, contrasting with the general cardiovascular principle that a lower RHR is often preferable strongly underscores the necessity for more definitive research. Therefore, in the study we used the large sample size data of patients with persistent AF (PeAF) undergoing catheter ablation to detect the relationship between RHR and the recurrence of AF.

This study was a single-center, retrospective analysis derived from China-AF registry (ChiCTR-OCH-13003729) which is a prospective observational study of patients with AF. Patients with PeAF undergoing catheter ablation at Beijing Anzhen Hospital from January 2018 to December 2023 were enrolled. Ethics approval was obtained from the Human Research Ethics Committees at Beijing Anzhen Hospital. All participants in the cohort obtained written informed consent.

The primary outcome was the recurrence of AF, defined as an episode of atrial tachyarrhythmia lasting > 30 seconds after a 3-month blanking period. The secondary outcome was the composite of heart failure, ischemic stroke, and cardiovascular death. Cardiovascular death includes death caused by acute myocardial infarction, sudden cardiac death, heart failure, stroke, or other cardiovascular causes. Follow-up surveys were conducted at the third, sixth, and twelfth month after treatment through telephone interviews and out-patients.

Detection of AF recurrence was performed using a three-component strategy. Firstly, patients adhered to a scheduled follow-up protocol involving electrocardiograms (ECGs) and 24-hour Holter monitoring. Secondly, symptom-driven ECGs were conducted whenever a patient reported episodes of tachycardia. Thirdly, any incidental ECG or Holter recordings obtained for unrelated clinical indications were also analyzed.

All antiarrhythmic drugs (AADs) were stopped for at least five half-lives before ablation. Patients with a history of pacemaker implantation were excluded. Radiofrequency ablation guided by a three-dimensional electroanatomic mapping system (CARTO, Biosense-Webster, Inc.) were performed. All patients underwent pulmonary vein isolation (PVI) and the majority of patients were treated with an optimized linear ablation and ethanol infusion via the vein of Marshall, known as the '2C3L' procedure(4). This technique has been previously published and was demonstrated to significantly increase the success rate compared to PVI alone(5). Cardioversion was performed if AF persisted or converted to an organized atrial tachyarrhythmia following the ablation.

The RHR was measured in a resting state on the morning of the first day after ablation. Only the patients with successfully converted to sinus rhythm and with RHR recorded in sinus rhythm were included. RHR was categorized into five different groups: 40–60 bpm, 61–70 bpm, 71–80 bpm, 81–90 bpm and 91–100 bpm.

Continuous variables are summarized as mean ± standard deviation (SD) or median with interquartile range, as appropriate based on data distribution. Comparisons among the five groups were performed using one-way analysis of variance (ANOVA) for normally distributed data or the Kruskal-Wallis H test for non-normally distributed data. To further explore inter-group differences, pairwise post-hoc comparisons were performed for all baseline variables. Following ANOVA, Tukey's Honestly Significant Difference test was applied. For variables analyzed with the Kruskal-Wallis test, Dunn's test for multiple comparisons was utilized. For categorical variables, pairwise comparisons were conducted using the Chi-squared test. To account for multiple comparisons in these pairwise analyses, all p-values were adjusted using the Benjamini-Hochberg method to control the False Discovery Rate.

Cumulative incidence curves were visualized using the Kaplan–Meier analyses, and the log-rank test was performed. Multivariable Cox proportional hazard analyses were performed to compute the hazard ratio with a 95% confidence interval by adjusting for age, gender, history of hypertension, diabetes, coronary heart disease, valvular AF, heart failure, cerebrovascular disease, chronic kidney disease, smoking, drinking, left atrial anteroposterior diameter, left ventricular ejection fraction, AF duration, AADs (moracizine, propafenone, sotalol, amiodarone), rate control agents (β blocker, calcium channel blocker, digoxin), oral anticoagulant (warfarin, rivaroxaban, dabigatran, edoxaban), antiplatelet (aspirin, clopidogrel, ticagrelor), glucose lowering agents (oral hypoglycemic drugs, insulin), and angiotensin converting enzyme inhibitors/angiotensin 2 receptor blockers (ACEI/ARB). A two-sided adjusted p-value of less than 0.05 was considered statistically significant. The statistical analyses were performed using R version 4.5.0 (The R Project for Statistical Computing, Vienna, Austria).

A total of 2,432 patients were included in the final analysis, with a median follow-up of 375 (346–741) days. Among them, 72.1% were men and the mean age was 63 years. At baseline, the distribution of RHR was as follows: 22 patients (0.9%) had an RHR of 40–60 bpm, 326 (13.4%) had an RHR of 61–70 bpm, 1,625 (66.8%) had an RHR of 71–80 bpm, 390 (16.0%) had an RHR of 81–90 bpm, and 69 (2.9%) had an RHR of 91–100 bpm. Baseline characteristics of these groups are shown in Table 1. Patients with RHR of 40–60 bpm were more likely to be female (72.7%; P < 0.001). During the follow-up period, a total of 817 (33.6%) patients experienced AF recurrence. The recurrence rate significantly differed across groups (P = 0.027). Patients with RHR of 40–60 bpm exhibited the highest recurrent rate (63.6%), followed by those with 91–100 bpm (39.1%). Post-hoc analysis showed patients with 40–60 bpm group had a significantly lower proportion of male patients compared to the 61–70 bpm group (27.3% vs. 70.6%, respectively; adjusted P < 0.001). Regarding the primary outcome, patients in the 40–60 bpm group experienced a significantly higher rate of AF recurrence than those in the 61–70 bpm group (63.6% vs. 33.4%; adjusted P = 0.0278) (Supplemental Table 1).

Table 1

Baseline characteristics of the study population
Variables	Total (n = 2432)	40–60 bpm (n = 22)	61–70 bpm (n = 326)	71–80 bpm (n = 1625)	81–90 bpm (n = 390)	91–100 bpm (n = 69)	P
Male sex, n (%)	1754 (72.1)	6 (27.3)	230 (70.6)	1175 (72.3)	288 (73.8)	55 (79.7)	< 0.001
Age (years)	63.0 [56.0–69.0]	69.0 [62.0-75.5]	63.0 [56.0–69.0]	63.0 [56.0–69.0]	63.0 [56.0–69.0]	63.0 [54.0–68.0]	0.144
Previous history, n (%)
Smoking	159 (6.5)	1 (4.5)	22 (6.7)	98 (6.0)	34 (8.7)	4 (5.8)	0.413
Drinking	218 (9.0)	0 (0.0)	22 (6.7)	143 (8.8)	44 (11.3)	9 (13.0)	0.086
Hypertension	1397 (57.4)	12 (54.5)	200 (61.3)	936 (57.6)	218 (55.9)	31 (44.9)	0.140
Diabetes	449 (18.5)	2 (9.1)	57 (17.5)	304 (18.7)	73 (18.7)	13 (18.8)	0.813
Coronary artery disease	345 (14.2)	4 (18.2)	49 (15.0)	225 (13.8)	59 (15.1)	8 (11.6)	0.862
Heart failure	423 (17.4)	5 (22.7)	66 (20.2)	283 (17.4)	60 (15.4)	9 (13.0)	0.369
Cerebrovascular disease	258 (10.6)	2 (9.1)	36 (11.0)	173 (10.6)	39 (10.0)	8 (11.6)	0.987
CKD	64 (2.6)	1 (4.5)	13 (4.0)	43 (2.6)	7 (1.8)	0 (0.0)	0.232
Valvular AF, n (%)	33 (1.4)	1 (4.5)	6 (1.8)	21 (1.3)	3 (0.8)	2 (2.9)	0.340
Left atrium diameter (mm)	44.0 [40.0–47.0]	45.0 [41.3–47.8]	44.0 [40.0–48.0]	44.0 [41.0–47.0]	44.0 [40.0–48.0]	43.0 [40.0–47.0]	0.714
LVEF (%).	60.0 [56.0–65.0]	60.0 [58.0–64.0]	60.0 [55.0–64.0]	60.0 [56.0–65.0]	60.0 [56.0–64.0]	63.0 [57.0-66.3]	0.236
Duration of AF diagnosis (years)	2.0 [0.5-5.0]	3.0 [0.5–6.8]	2.0 [0.5-5.0]	2.0 [0.5-5.0]	2.0 [0.5-5.0]	3.0 [0.3-7.0]	0.807
AF recurrence, n (%)	817 (33.6)	14 (63.6)	109 (33.4)	546 (33.6)	121 (31.0)	27 (39.1)	0.027
AADs, n (%)	1625 (66.8)	12 (54.5)	208 (63.8)	1090 (67.1)	267 (68.5)	48 (69.6)	0.464
Rate control agents, n (%)	808 (33.2)	11 (50.0)	102 (31.3)	539 (33.2)	126 (32.3)	30 (43.5)	0.149
Oral anticoagulant, n (%)	2196 (90.3)	22 (100.0)	284 (87.1)	1474 (90.7)	355 (91.0)	61 (88.4)	0.138
Antiplatelet, n (%)	121 (5.0)	0 (0.0)	17 (5.2)	73 (4.5)	28 (7.2)	3 (4.3)	0.195
Glucose lowering agents, n (%)	410 (16.9)	2 (9.1)	49 (15.0)	279 (17.2)	68 (17.4)	12 (17.4)	0.746
ACEI/ARB, n (%)	806 (33.1)	6 (27.3)	115 (35.3)	534 (32.9)	131 (33.6)	20 (29.0)	0.801
CKD chronic kidney disease, AF atrial fibrillation, LVEF left ventricular ejection fraction, AADs antiarrhythmic drugs, ACEI angiotensin converting enzyme inhibitors, ARB angiotensin 2 receptor blockers.

For the primary outcome, univariable Cox regression (61–70 bpm reference) revealed a significantly elevated HR in 40–60 bpm (HR = 2.57, 95% CI:1.47–4.49, P < 0.001). Additionally, there was a trend of increased HR in 91–100 bpm (HR = 1.52, 95% CI:1.00-2.32, P = 0.052). Multivariable Cox regression revealed that RHR of 40–60 bpm was significantly associated with AF recurrence (HR = 2.08, 95% CI:1.16–3.74, P = 0.014) (Table 2). Kaplan-Meier curves showed lower recurrence-free survival in RHR of 40–60 bpm, indicating higher AF recurrent risk (Fig. 1).

Table 2

Univariable and multivariable regression analyses according to the RHR
	Events (n, %)	Unadjusted HR	(95% CI)	P	Adjusted HR	(95% CI)	P
Primary outcome
40–60 bpm	14 (63.6%)	2.57	1.47–4.49	< 0.001	2.08	1.16–3.74	0.014
61–70 bpm	109 (33.4%)	Reference
71–80 bpm	546 (33.6%)	1.07	0.87–1.31	0.536	1.05	0.85–1.29	0.668
81–90 bpm	121 (31.0%)	1.03	0.80–1.34	0.812	1.00	0.77–1.31	0.971
91–100 bpm	27 (39.1%)	1.52	1.00-2.32	0.052	1.47	0.96–2.25	0.077
Secondary outcome
40–60 bpm	4 (18.2%)	2.71	4.03–55.94	< 0.001	11.69	3.01–45.43	< 0.001
61–70 bpm	5 (1.5%)
71–80 bpm	41 (2.5%)	1.73	0.69–4.39	0.246	2.00	0.78–5.10	0.149
81–90 bpm	16 (4.1%)	3.12	1.14–8.52	0.027	3.79	1.36–10.52	0.001
91–100 bpm	2 (2.9%)	2.34	0.45–12.06	0.311	2.01	0.36–11.11	0.422
Multivariable regression was adjusted for age, gender, history of hypertension, diabetes, coronary heart disease, valvular AF, heart failure, cerebral infarction, chronic kidney disease, smoking, drinking, left atrial anteroposterior diameter, left ventricular ejection fraction, AF duration, AADs, rate control agents, oral anticoagulant, antiplatelet, glucose lowering agents and angiotensin converting enzyme inhibitors / angiotensin 2 receptor blockers.

For the secondary outcome, univariable Cox regression (61–70 bpm reference) revealed a significantly elevated HRs in 40–60 bpm (HR = 2.71, 95% CI:4.03–55.94, P < 0.001) and 81–90 bpm (HR = 3.12, 95% CI:1.14–8.52, P = 0.027), whereas the other two groups showed no significant differences (P = 0.246 and 0.311, respectively). Multivariable Cox regression also revealed that RHR of 40–60 bpm (HR = 11.69, 95% CI:3.01–45.43, P < 0.001) and 81–90 bpm (HR = 3.79, 95% CI:1.36–10.52, P = 0.001) maintained a significantly positive association with the secondary outcome (Table 2). Kaplan-Meier curves showed patients with RHR of 40–60 bpm were more susceptible to secondary outcomes (Fig. 2).

The findings of this study elucidate a significant association between low RHR and recurrence for PeAF patients after catheter ablation. Specifically, RHR in the range of 40–60 bpm confers an elevated risk of recurrence. There is also a trend of recurrence in patients with high RHR of 91–100 bpm (P = 0.077). Postoperative RHR represented a non-invasive and readily accessible reliable predictor for AF recurrence, enabling early screening of high-risk populations. We identified specific ranges of RHR associated with elevated recurrence risk, which highlights the clinical imperative to prioritize comprehensive management for patients with low RHR of 40–60 bpm, including more intensive or prolonged heart rate monitoring for this individual. Additionally, timely intervention for patients with high-risk RHR after ablation is essential to reduce recurrence and improve long-term outcomes.

Regarding the selection of RHR acquisition time, most current studies rely on preoperative or long-term RHR, overlooking the critical immediate postoperative period. Postoperative RHR, as a non-invasive and readily accessible predictive marker for AF recurrence, exhibits substantial clinical value, particularly for patients with PeAF who inherently have a higher propensity for recurrence. Postoperative RHR can more intuitively reflect the patient's postoperative status, establish a reliable correlation between RHR and recurrence, and screen out patients with high risk of recurrence in the early postoperative period, enabling timely interventions to reduce the recurrence rate.

Some studies analyzed the change in RHR before and after ablation. Killu AM et al.'s self-controlled study found a weak correlation between the relative change in overall RHR after ablation and AF recurrence (P = 0.067). Patients were further divided into quartiles based on the relative change in RHR, and the upper quartile with the largest relative increase in RHR had a significantly lower AF recurrence rate than the lower quartile. Nilsson B et al. conducted an RCT on RHR changes after PVI in AF patients, showing that PVI may lead to RHR increase, which is positively correlated with ablation success(6). Goff ZD et al. more precisely indicated that an increase in RHR ≥ 15 bpm after PVI was associated with 1-year freedom from AF(7). These prior investigations have unequivocally established that an elevated postoperative RHR confers a protective effect against recurrence(6–8). However, they failed to delineate the association between the exact RHR range in the immediate postoperative period and AF recurrence after ablation.

Our study revealed that patients with postoperative RHR maintained within 61–90 bpm exhibit a diminished risk of recurrence and superior long-term prognosis. Meanwhile, by explicitly selecting RHR within 24 hours after ablation for analysis, our study excludes the interference of preoperative RHR monitoring methods compared with previous studies analyzing RHR changes before and after ablation, which not only can better represent the AF population after catheter ablation, but also can reflect the immediate postoperative status more intuitively.

The relationship between RHR and recurrence in this study may involve multiple mechanisms. Ablation directly influences the autonomic nervous system by reducing parasympathetic activity(9, 10). Low RHR (40–60 bpm) may reflect autonomic dysfunction after ablation, particularly excessive vagal tone, which impacts atrial electrophysiological characteristics. This may increase atrial vulnerability to reentry by shortening action potential duration and enhancing conduction heterogeneity, thereby promoting AF recurrence. Conversely, higher RHR with shortening of myocardial action potential duration may be accompanied by calcium handling abnormalities (such as calcium overload), which in turn facilitates ectopic electrical activity associated with delayed after depolarization. This mechanism provides the electrophysiological substrate for the recurrence of AF. Additionally, extreme RHR may impair atrial mechanical function, leading to hemodynamic instability and further exacerbating AF recurrence(11–13).

Previous studies have documented a non-linear correlation between RHR and the occurrence of AF. Consistently, our study identified a similar pattern of association between RHR and recurrence of AF, which may suggest a shared underlying mechanism for AF development and recurrence. Morten W. Skov et al. found a U-shaped association between RHR and incident AF using electrocardiograms from 281,451 primary care patients excluding AF/atrial flutter, with this association being strongest for the outcome lone AF(14). A previous meta-analysis using 68–80 bpm as the reference showed that both low and high RHR were associated with an increased risk of AF(15). Although there are differences in the RHR ranges defining high AF risk across these studies(14–16), the U/J-shaped association between RHR and AF incidence has shown high consistency. This bears similarity to the association established in our study between RHR and recurrence of AF, suggesting shared underlying mechanisms for incidence and recurrence, such as autonomic dysfunction or electrical remodeling.

Previous study with a 1.5-year follow-up has shown that the progression of paroxysmal or persistent AF to a more sustained form was closely associated with faster heart rates(17). This indicates that RHR is valuable not only for predicting AF incidence but also for forecasting disease progression. However, the optimal target range for RHR control in clinical practice remains undefined. The 2020 European Society of Cardiology guidelines recommend a standard heart rate control target of < 110 bpm(18), yet the validity of this range and the necessity for strict heart rate control require further validation(9, 19–21). Undeniably, RHR demonstrates critical observational value in the progression of AF. Our cohort study further extends this to AF recurrence, highlighting the role of RHR in maintaining the arrhythmogenic substrate. The findings to some extent demonstrate the consistency of disease characteristics across different stages.

RHR has been demonstrated to facilitate the screening of AF patients at high risk of cardiovascular adverse events. Both elevated and depressed RHR correlate with poor long-term prognosis(22, 23). Higher RHR is associated with an increased long-term risk of cardiovascular events (especially heart failure) and all-cause mortality, while lower RHR is associated with a greater risk of future permanent pacemaker implantation(24). A retrospective analysis of the Atrial Fibrillation Rhythm Management (AFFIRM) study showed that RHR ≥ 80 bpm was associated with increased mortality risk in AF patients(10). During a median follow-up of 24 months, Benjamin A. Steinberg et al. found a non-linear relationship between longitudinally measured RHR and mortality in patients with permanent AF, with an inflection point at 65 bpm. All-cause mortality increased as RHR deviated from 65 bpm(19). In patients with AF and heart failure with reduced ejection fraction, high RHR (> 81 bpm) was associated with a progressive increase in mortality risk(25, 26). By contrast, in patients with AF and heart failure with preserved ejection fraction, RHR exhibited a U-shaped association with cardiovascular adverse events, where lower RHR also elevated mortality(26). Collectively, these findings fully confirm that both excessively high and low RHR portend poor outcomes in AF.

Study limitations

Although this study enhanced the reliability of findings by employing a large sample size (2,468 patients) and multivariate models (adjusting for clinical confounders), robustly validating the relationship between RHR and AF recurrence, several limitations still remain: (1) As an observational cohort study, it cannot establish a causal relationship between RHR and AF recurrence. (2) Without continuous monitoring via insertable cardiac monitor, single RHR measurement within 24 hours postoperatively may fail to capture temporal variability. (3) Although the study used a large sample size so far, the sample size is still relatively small, with fewer secondary outcomes in certain RHR intervals (e.g., 91–100 bpm). Notwithstanding statistical significance was not achieved, the risk in this subgroup should not be overlooked.

This study confirms that low RHR is associated with recurrence in PeAF after catheter ablation, where RHR of 40–60 bpm exhibits a higher risk. Prospective studies are warranted to validate RHR as a therapeutic target and optimize individualized management strategies for preventing AF recurrence.

AF: Atrial fibrillation

PeAF: Persistent atrial fibrillation

RHR: Resting heart rate

AADs: Antiarrhythmic drugs

ACEI: Angiotensin converting enzyme inhibitors

ARB: Angiotensin 2 receptor blockers

PVI: Pulmonary vein isolation

ECGs: Electrocardiograms

SD: Standard deviation

ANOVA: One-way analysis of variance

HR: Hazard ratio

CI: Confidence interval

CKD: Chronic kidney disease

LVEF: Left ventricular ejection fraction

RCT: Randomized controlled trial

AFFIRM: Atrial Fibrillation Rhythm Management study

RACE II: Rate control efficacy in permanent atrial fibrillation II study

Data Availability Statement

Data are available from the authors upon reasonable request and with permission of Beijing Anzhen Hospital, Capital Medical University.

Funding Statement

This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0504200).

Conflict of Interest Disclosure

The authors declare no conflict of interests.

Ethics Approval Statement

Ethics approval was obtained from the Human Research Ethics Committees at Beijing Anzhen Hospital. (NCT06987825). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent Statement

Informed consent was obtained from all patients.

Author Contributions

WQ, KH: investigation, original draft preparation, and formal analysis. WQ: data curation. KH: visualization. KH, XL, BF: methodology. LH, WW, TL, CJ, RT, CS, CM: supervision. DL: conceptualization and funding acquisition. All authors have read and agreed to the published version of the manuscript.

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No competing interests reported.

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Low resting heart rate is associated with recurrence in persistent atrial fibrillation after catheter ablation

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