One-Year Change in the H2FPEF Score After Catheter Ablation of Atrial Fibrillation in Patients With a Normal Left Ventricular Systolic Function

Background: It is unclear whether atrial fibrillation (AF) catheter ablation (AFCA) improves the left ventricular (LV) diastolic function. We evaluated the 1-year change in the H2FPEF score, which reflects the degree of LV diastolic function, after AFCA among patients with a normal LV systolic function. Methods and Results: We included 1,471 patients (30.7% female, median age 60 years, paroxysmal-type AF 68.6%) who had available H2FPEF scores at baseline and at 1-year after AFCA to evaluate the 1-year change in the H2FPEF score (ΔH2FPEF score[1−yr]) after AFCA. Baseline high H2FPEF scores (≥6) were independently associated with the female sex, left atrium (LA) diameter, LV mass index, pericardial fat volume, and a low estimated glomerular filtration rate. One year after AFCA, decreased ΔH2FPEF scores[1−yr] were associated with baseline H2FPEF scores of ≥6 [OR, 4.19 (95% CI, 2.88–6.11), p < 0.001], no diabetes [OR, 0.60 (95% CI, 0.37–0.98), p = 0.04], and lower pericardial fat volume [OR, 0.99 (95% CI, 0.99–1.00), p = 0.003]. Increased ΔH2FPEF scores[1−yr] were associated with a baseline H2FPEF score of <6 [OR, 3.54 (95% CI, 2.08–6.04), p < 0.001] and sustained AF after a recurrence within 1 year [SustainAF[1−yr]; OR, 1.89 (95% CI, 1.01–3.54), p = 0.048]. Throughout a 56-month median follow-up, an increased ΔH2FPEF score[1−yr] resulted in a poorer rhythm outcome of AFCA (at 1 year, log-rank p = 0.003; long-term, log-rank p = 0.010). Conclusions: AFCA appears to improve LV diastolic dysfunction. However, SustainAF[1−yr] may contribute to worsening LV diastolic dysfunction, and it was shown by increased ΔH2FPEF scores[1−yr], which was independently associated with higher risk of AF recurrence rate after AFCA. Clinical Trial Registration:ClinicalTrials.gov Identifier: NCT02138695.


INTRODUCTION
Atrial fibrillation (AF) and underlying heart failure (HF) have been emerging topics of importance in the field of cardiovascular disease over the past 3 decades and frequently overlap (1,2). Specifically, AF has been shown to follow HF with preserved ejection fraction (HFpEF) more frequently than HF with reduced ejection fraction (HFrEF) due to the differences in the left ventricular (LV) diastolic dysfunction and the left atrial (LA) remodeling process (2,3). Prior studies have shown improvements in the LV systolic function (4), performance and quality of life (5), and mortality (6) after AF catheter ablation (AFCA) in HFrEF patients, suggesting that a reduction in AF may be sufficient for a clinical benefit. Nevertheless, there are no specific recommendations for the management of AF in HFpEF patients, and data regarding the efficacy of AFCA in patients with a normal LV systolic function and LV diastolic dysfunction are relatively limited. Although there have been a few studies reporting an improvement in the LV diastolic function after AFCA by maintaining sinus rhythm (7,8), they adopted conventional approaches that used mainly symptoms and the LV ejection fraction (LVEF) for the diagnosis of HFpEF with various diagnostic accuracies (9). Recently, a novel scoring system has been developed, the H 2 FPEF score (10), which can estimate the probability of the underlying HFpEF through six clinical and echocardiographic characteristics, and can be feasibly applied in clinical practice. The aim of this study was to better understand the factors by which LV diastolic function worsens or improves after AF rhythm control by AFCA. In this study, we used the H 2 FPEF score at two time points, before and 1 year after the AFCA. We aimed to compare the cardiac structural and functional changes within a year and to evaluate the rhythm outcomes both within a year and over the long-term using the H 2 FPEF score.

Study Subjects
The study protocol adhered to the Declaration of Helsinki and was approved by the institutional review board of the Yonsei University Health system. All patients provided written informed consent for inclusion in the Yonsei AF Ablation Cohort Database (ClinicalTrials.gov Identifier: NCT02138695). From January 2009 to September 2019, 1,471 patients with a diagnosis of AF and a normal LVEF were identified as having clinical and echocardiographic information for the calculation of the H 2 FPEF score before AFCA and 1 year after AFCA. All patients underwent AFCA, and the indications for the AFCA complied with the latest guidelines (11). The exclusion criteria for the study were as follows: (1) a reduced LVEF, defined as <50%; (2) a follow-up duration <12 months; and (3) a repeat ablation within a year (Figure 1).

Calculating the H 2 FPEF Score at Baseline and 1 Year After the Atrial Fibrillation Catheter Ablation
The H 2 FPEF score has six domains based on clinical and echocardiographic values: heaviness (body mass index >30 kg/m 2 , 2 points), hypertension (on two or more antihypertensive medicines, 1 point), atrial fibrillation (paroxysmal or persistent, 3 points), pulmonary hypertension (Doppler echocardiographic estimated pulmonary artery systolic pressure >35 mmHg, 1 point), elderly status (age >60 years, 1 point), and filling pressure (Doppler echocardiographic E/Em > 9, 1 point). The baseline H 2 FPEF scores were obtained within 3 months prior to the AFCA, and the 1-year H 2 FPEF scores were obtained 1 year after the AFCA with all clinical and echocardiographic values.

Echocardiographic Measurement and Three-Dimensional Computed Tomography
Transthoracic echocardiography was conducted in all patients using commercially available devices (Vivid 7 or Vivid E9 from GE Healthcare, Chicago, IL, USA, or iE 33 from Philips, Amsterdam, the Netherlands) as recommended by the American Society of Echocardiography (12). Standard images were obtained in the parasternal and apical views through twodimensional (2D), Doppler, and M-mode imaging, including the LA anteroposterior diameter and the LV end-systolic and end-diastolic dimensions (LVESD and LVEDD). The early Doppler mitral inflow (E) was recorded using pulsed waves from the apical window, with a 1-to 3-mm pulsed Doppler sample volume placed between the tips and mitral leaflets during diastole. The early diastolic mitral annular velocity (Em) was recorded as the peak early diastolic tissue velocity using color Doppler tissue imaging of the septal mitral annulus. The ratio of the early diastolic mitral inflow velocity to the early diastolic mitral annular velocity (E/Em) was calculated. Tricuspid regurgitation (TR) and estimated right atrial (RA) pressure were evaluated using the recommended methods, and the right ventricular systolic pressure (RVSP) was calculated as 4 × (TR jet) 2 + estimated RA pressure (13). The initial and 1 year after AFCA, the echocardiographies used to estimate the H 2 FPEF scores were those performed during an elective visit on stable medication.
Three-dimensional spiral computed tomography (CT) (64-channel, Light Speed Volume CT from GE Healthcare, Chicago, IL, USA, or Brilliance 63 from Philips, Amsterdam, the Netherlands) was performed in all patients, and the scans were analyzed using an imagingprocessing workstation (Aquarius; TeraRecon, Inc., Foster City, CA, USA). The LA volume and pericardial fat volume measurements have been described in previous studies (14,15).

Electrophysiologic Characterization and Radiofrequency Catheter Ablation
Intracardiac electrograms were obtained using the Prucka CardioLab TM Electrophysiology system (GE Healthcare, Chicago, IL, USA). A 3D electro-anatomical map (Ensite NavX; Abbott Laboratories, Chicago, IL, USA; CARTO3; Johnson & Johnson Inc., USA) was generated using a circumferential pulmonary vein-mapping catheter through a long sheath (Schwartz left 1; Abbott Laboratories, Chicago, IL, USA) and by merging the 3D geometry generated by the electroanatomic mapping system with the corresponding 3D spiral CT images. Left atrium electrogram voltage maps were generated during high right atrial pacing at 500 ms to prevent rate-dependent activation changes and by measuring mean peak-to-peak voltage as previously described (16). All patients underwent a de novo procedure with a circumferential pulmonary vein isolation (CPVI). The endpoint of the CPVI was the electric isolation of the PV potentials and bidirectional block of the PVs. We tested whether there was an immediate recurrence of AF within 10 min after cardioversion with an isoproterenol infusion (5-20 µg/min depending on the ß-blocker used with a target sinus heart rate of 120 bpm) to find extra-PV foci triggers, then confirmed successful CPVI 30 min after the initial isolation. Extra-PV foci triggers under an isoproterenol infusion were ablated as much as possible if they were consistent and reproducible. Then, we ended the de novo procedure. The detailed procedural techniques and strategies for the AFCA have been presented in our previous studies (17,18).

Post-ablation Management and Rhythm Follow-Up
The patients were discharged without any antiarrhythmic drugs (AADs) with the exception of those who had symptomatic frequent atrial premature beats, non-sustained atrial tachycardia (AT), early recurrence of AF on telemetry during the admission period, or recurrent extra-PV foci triggers after the AFCA procedure (13.7%). The clinical and cardiac rhythm information was obtained regularly from an outpatient clinic at 1, 3, 6, and 12 months, and every 6 months thereafter (or whenever symptoms developed). All patients underwent electrocardiogram recordings at every visit, and 24-h Holter monitoring was performed at 3 and 6 months, and every 6 months thereafter, according to the latest guidelines (11). AF recurrence was defined as any episode of AF or AT of at least 30 s in duration. Any ECG documentation of an AF recurrence within the 3-month blanking period was diagnosed as an early recurrence, and an AF recurrence of more than 3 months after the AFCA was diagnosed as a clinical recurrence. We evaluated the time point of the clinical recurrence as follows: within 1 year as a short-term and beyond 1 year as a long-term recurrence. We also estimated the quality of the AF control after the AFCA. We defined patients with sustained AF/AT as those who remained in a sustaining AF/AT rhythm (>30 s) on the final follow-up after the AFCA despite AADs or electrical cardioversion.

Statistical Analysis
The baseline characteristics of the patients were compared using descriptive statistics and presented as median (interquartile interval) values for continuous variables and as numbers (percentages) for categorical variables. To compare the baseline characteristics according to the baseline H 2 FPEF and the 1-year change in the H 2 FPEF score ( H 2 FPEF score [1−yr] ) categories, the Mantel-Haenszel chi-squared test was used for categorical variables, and the Kruskal-Wallis H test was used for continuous variables. To identify the factors associated with the baseline H 2 FPEF and H 2 FPEF score [1−yr] , univariate and multivariable logistic regression analyses were performed. Multivariable Cox   H 2 FPEF Score [1-yr] One year after the AFCA, the H 2 FPEF scores decreased in 17.1% of the patients (252), were maintained in 61.5% (905), and increased in 21.4% (314) ( Table 2). A reduction in the H 2 FPEF score [1−yr] was more commonly observed in patients with high baseline H 2 FPEF scores (Figure 2A)

Rhythm Outcomes After Atrial Fibrillation Catheter Ablation and the H 2 FPEF Score
Because we evaluated the H 2 FPEF score before and 1 year after the procedure, we compared the 1-year and long-term clinical recurrence rates of AF separately, depending on the baseline H 2 FPEF scores and H 2 FPEF scores [1−yr] . In contrast, the baseline H 2 FPEF scores did not affect the 1-year rhythm outcome (log rank, p = 0.82; Figure 3A), and the clinical recurrence of AF was significantly higher in the patients with an increased H 2 FPEF scores [1−yr] (log rank, p = 0.003; Figure 3B). In the multivariate Cox regression analysis, increased H 2 FPEF scores [ Table 5). The rhythm outcomes in the overall duration were consistent with the 1-year rhythm outcome depending on the baseline H 2 FPEF score (log rank, p = 0.57; Figure 3C) or H 2 FPEF score [1−yr] (log rank, p = 0.01; Figure 3D). In the subgroup of patients with baseline H 2 FPEF scores of ≥5, the risk of an AF recurrence was significantly higher in the patients with increased H 2 FPEF scores [1−yr] than in those with reduced H 2 FPEF scores [1−yr] (Supplementary Figure 1).

Failed Rhythm Control and the H 2 FPEF
Score [1-yr] Among the 1,471 patients, 257 (17.5%) had an AF recurrence within a year, and 201 (13.7%) had sinus rhythm restored after using antiarrhythmic drugs, but 56 (3.8%) patients had sustained AF under antiarrhythmic drugs even after cardioversion. The proportion of patients with reduced H 2 FPEF scores [1−yr] tended to be higher without a statistical significance among those with no recurrence (p = 0.118, Figure 2C). However, the proportion of patients with increased H 2 FPEF scores [1−yr] was significantly higher in the group with sustained AF after a recurrence than in those with sinus rhythm maintained at a year after the AFCA (p = 0.007, Figure 2D).

Main Findings
In this study, we observed a change in the H 2 FPEF score 1 year after the AFCA in AF patients with a normal LV systolic function. The H 2 FPEF score [1−yr] decreased in 17% of the patients but increased in 21% a year after the AFCA. A high baseline H 2 FPEF score, which is related to LV diastolic dysfunction, was independently associated with a reduced H 2 FPEF score [1−yr] .
On the other hand, low baseline scores or sustained AF after a recurrence were significantly associated with an increase in the H 2 FPEF scores [1−yr] after the AFCA. Patients with an increased H 2 FPEF score [1−yr] had higher rates of recurrence within a year or longer. Therefore, AFCA improved the H 2 FPEF scores [1−yr] in patients with baseline LV diastolic dysfunction; however, patients with a poor rhythm control and sustained AF despite AFCA had a significant increase in the H 2 FPEF scores [1−yr] .

Atrial Fibrillation and the Ventricular Diastolic Function
AF and LV diastolic dysfunction are closely related and have important features in common, such as age, obesity, hypertension, and diabetes (19). LV diastolic dysfunction has deteriorative effects on the atrial function and structure, which contributes to the development, progression, and maintenance of AF (20). Consequently, AF has an influence on the LV function and LA remodeling (21), and can lead to increasingly sustained AF episodes. Therefore, these two conditions have pathophysiological effects on the occurrence and aggravation of each, and coexistence is associated with a poor prognosis (2,22,23). Furthermore, as the AF burden increases chronically, the right ventricular function progressively worsens (24). Reddy et al. (10) proposed a novel risk score, the H 2 FPEF score, which includes all of the abovementioned factors, to diagnose HFpEF patients. We adopted this score to evaluate the prognostic utility in AF patients with a normal LVEF after AFCA.

Effects of Atrial Fibrillation Catheter Ablation on the Left Venticular Diastolic Function
The data to support the clinical benefits of catheter ablation in symptomatic AF patients with HFrEF are strong and compatible with those from previous clinical trials and meta-analyses (6,25). However, AF is more potently associated with HFpEF (2) with the prevalence of HFpEF increasing by almost half in AF patients (26). The benefits of AFCA in symptomatic AF patients with HFpEF have been investigated in previous studies (7,8), but the effects seem less favorable than those in HFrEF patients. Machino-Ohtsuka et al. (7) showed that the longstanding persistent-type AF and a lack of hypertension were factors associated with an improvement in the LV systolic and diastolic indices when sinus rhythm was maintained. Black-Maier et al. (8) showed equivalent rhythm outcomes, all-cause hospitalization, and cardiovascular hospitalization in patients with both HFpEF and HFrEF after AFCA over a median follow-up of 10 months. However, previous studies adopted conventional diagnostic approaches that mainly consisted of symptoms and the LVEF for an HFpEF diagnosis, which show a heterogeneity in terms of the inclusion (9). Thus, we used the H 2 FPEF scores that were newly developed for identifying HFpEF patients and which were superior to the previous diagnostic algorithms. Although the baseline H 2 FPEF scores do not have prognostic value for rhythm outcomes after AFCA, which is consistent with a recent study (27), increased H 2 FPEF scores [1−yr] were independently associated with the rhythm outcomes in this study. Although the cause-result relationship was unclear, sustained AF despite AFCA had a significant correlation with an increased H 2 FPEF score [1−yr] .

Heart Failure With Preserved Ejection Fraction, a Good Candidate for Atrial Fibrillation Catheter Ablation
Among the patients with a normal LV systolic function, which subgroup is the most helpful based on the H 2 FPEF scores after AFCA? Those with the most significant decrease in the H 2 FPEF scores [1−yr] were those with a baseline HFpEF score of ≥6, i.e., successful rhythm control by AFCA can significantly improve the LV diastolic function in patients with HFpEF. Furthermore, the absence of diabetes, a higher LVEF, and a lower pericardial fat volume were associated with decreased H 2 FPEF scores [1−yr] , which suggested that metabolic factors may have influenced the recovery of the LV diastolic function.

Limitations
This study had several limitations. First, since the current study was conducted in a single center and included a relatively small number of patients, the findings cannot be generalized to all patients with a normal LV systolic function. However, there was also an advantage of this single-center cohort in that the ablation and rhythm follow-up protocols were consistent. Second, although we performed a regular rhythm followup in all included patients, the exact AF burden could not be assessed by the Holter monitoring. Third, we excluded patients who did not have both baseline and 1-year followup echocardiograms with all parameters taken from the same institute, to calculate appropriate H 2 FPEF scores. Fourth, there was some discrepancy between the HF clinically judged by the CH 2 A 2 DS-VASc and H 2 FPEF scores because the clinical HF was classified mainly by the LV systolic function. Finally, because of the limited follow-up duration, we could not determine the long-term changes in the biventricular function and other clinical outcomes in this study. Future prospective and controlled studies are warranted.

CONCLUSION
The H 2 FPEF scores decreased in 17% and increased in 21% of the patients with a normal LV function at 1 year after the AFCA. AFCA has shown a tendency to improve the H 2 FPEF scores [1−yr] in the patients with an abnormal diastolic function. However, a poor rhythm control and sustained AF after the AFCA were significantly associated with an increase in the H 2 FPEF score [1−yr] . An increased H 2 FPEF score [1−yr] was an independent prognostic factor for poorer rhythm outcomes after the AFCA.

DATA AVAILABILITY STATEMENT
Data supporting the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by The institutional review board of the Yonsei University Health system. The patients/participants provided their written informed consent to participate in this study.

AUTHOR CONTRIBUTIONS
HN-P and MK designed the study, analyzed and interpreted the data, drafted the manuscript, and did the final approval of the manuscript submission. HTY, T-HK, J-SU, BYJ, and M-HL interpreted data and contributed to acquiring patients' clinical data. All authors contributed to the article and approved the submitted version.