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C L I N I C A L I N V E S T I G A T I O N S

Predictors of improvement in arrhythmia-specific symptoms

and health-related quality of life after catheter ablation of

atrial fibrillation

Neshro Barmano

1,2

| Emmanouil Charitakis

2,3

| Jan-Erik Karlsson

1,2

|

Fredrik H. Nystrom

2,4

| Håkan Walfridsson

2,3

| Ulla Walfridsson

2,3

1

Department of Internal Medicine, County Hospital Ryhov, Jönköping, Sweden

2

Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

3

Department of Cardiology, Linköping University Hospital, Linköping, Sweden

4

Primary Health Care Centre Centrum, Norrköping, Sweden

Correspondence

Barmano Neshro, MD, Department of Internal Medicine, County Hospital Ryhov, SE-551 85 Jönköping, Sweden.

Email: neshro.barmano@rjl.se Funding information

Biosense Webster; Carldavid Jönsson Research Foundation; County Council of Östergötland, Grant/Award Number: LIO-280731LIO-445511; Heart Foundation, Linköping University

Background: The primary goal of radiofrequency ablation (RFA) of atrial fibrillation (AF) is to improve symptoms and health-related quality of life (HRQoL). However, most studies have focused on predictors of AF recurrence rather than on predictors of improvement in symptoms and HRQoL. Hypothesis: We sought to explore predictors of improvement in arrhythmia-specific symptoms and HRQoL after RFA of AF, and to evaluate the effects on symptoms, HRQoL, anxiety, and depression. Methods: We studied 192 patients undergoing their first RFA of AF. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), arrhythmia-specific questionnaire in tachycar-dia and arrhythmia (ASTA), and hospital anxiety and depression scale (HADS) questionnaires were filled out at baseline, at 4 months, and at a 1-year follow-up.

Results: All questionnaire scale scores improved significantly over time. In the ASTA symptom scale score, female gender and > 10 AF episodes the month before RFA were significant posi-tive predictors of improvement, while diabetes and AF recurrence within 12 months after RFA were significant negative predictors (R2= 0.18; P < 0.001). In the ASTA HRQoL scale score, the presence of heart failure and > 10 AF episodes the month before RFA were significant positive predictors of improvement, while diabetes, maximum left atrial volume and AF recurrence were significant negative predictors (R2= 0.20; P < 0.001).

Conclusion: Left atrial volume, gender, diabetes, heart failure, the frequency of AF attacks prior to RFA, and recurrence of AF after RFA were significant factors affecting improvement in symp-toms and HRQoL after RFA of AF. Future studies are warranted to confirm these findings.

K E Y W O R D S

atrial fibrillation, catheter ablation, health-related quality of life, symptom burden

1 | I N T R O D U C T I O N

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with disabling symptoms and reduced health-related qual-ity of life (HRQoL).1 Anxiety and depression are also common in

patients with AF and are known predictors of reduced HRQoL.2,3 The management of AF aims to improve symptom burden and HRQoL, and to prevent adverse events. Although symptom and HRQoL improvement after radiofrequency ablation (RFA) does not have to be accompanied by AF burden reduction,4many studies have focused on investigating predictors of AF recurrence after RFA,5–10while only a few have investigated predictors of improvement in symptoms and HRQoL.11–15

The aim of this study was to explore possible predictors of improvement in arrhythmia-specific symptoms and HRQoL in patients treated with RFA of AF for the first time, and to evaluate the effect of RFA on symptoms, HRQoL, anxiety and depression.

2 | M E T H O D S

2.1 | Study design and population

This is an observational, single-center cohort study based on data from the SMURF (symptom burden, metabolic profile, ultrasound find-ings, rhythm, neurohormonal activation, hemodynamics, and HRQoL

DOI: 10.1002/clc.23134

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in patients with AF) study.3It was conducted between January 2012

and April 2014. Patients referred for RFA because of AF to the Uni-versity Hospital in Linköping, Sweden, were considered for participa-tion. The inclusion criteria were: (a) age≥ 18 years with paroxysmal or persistent AF, (b) Patients referred for first time RFA, and (c) patients with sufficient knowledge of the Swedish language to fill out the study questionnaires independently.

Exclusion criteria were: (a previous catheter or surgical AF abla-tion, (b) previous or planned heart surgery, (c) left ventricular ejection fraction (EF) <35%, and (d) Acute coronary syndrome during the past 3 months.

2.2 | Informed consent and ethical considerations

The Regional Ethical Review Board of Linköping, Sweden, approved the study (Dnr 2011/40-31, 2012/226-32). All patients gave their written consent and the study complied with the Declaration of Helsinki.16

2.3 | Study flow chart

The protocol of the SMURF study has been published previously by Charitakis et al.17In brief, enrolled patients were subjected to a full

baseline evaluation including medical history, physical examination, 12-lead electrocardiography, and blood sampling. Transthoracic echo-cardiography (TTE) was performed the day before the RFA. All patients were catheterized according to the clinical routine, and addi-tional blood samples were drawn. The ablation procedure has been described previously by Charitakis et al.17Patient-reported outcome measures (PROM) were assessed with three questionnaires, described in the following sections, at baseline, 1-month follow-up (FU) and 1-year FU.

2.4 | Echocardiography and laboratory tests

All patients underwent TTE prior to RFA. GE Vivid 7 or GE Vivid E9 system (GE Healthcare, Horten, Norway) were utilized. Left ventricu-lar EF was calculated by the Simpson biplane method. Left atrial vol-ume (LAV) was calculated as previously described Charitakis et al.17

High sensitive C-reactive protein (hsCRP) was measured as previously described.3

2.5 | Recurrence of atrial fibrillation

AF recurrence was defined as a documented episode of AF or atrial flutter lasting more than 30 seconds, and/or the need for re-ablation, within 1 year from ablation date.

2.6 | Patient-reported outcome measures

2.7 | The medical outcomes study 36-item

short-form health survey

The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a generic questionnaire comprising 36 items, of which 35 items

evaluate eight scales ranging from 0 (worst possible health) to 100 (best possible health).18The eight scales are summarized in

physi-cal and mental component summaries, standardized to a norm with a mean of 50 and an SD of 10.19

2.8 | The arrhythmia-specific questionnaire in

tachycardia and arrhythmia

The disease-specific questionnaire the arrhythmia-specific question-naire in tachycardia and arrhythmia (ASTA) is a validated questionquestion-naire and has been previously described in detail.20,21In brief, nine items assess symptom burden (ASTA symptom scale) and 13 items assess HRQoL (ASTA HRQoL scale), all with a four-point response scale.20,21 The scale scores range from 0 to 100, where higher scores reflect a higher symptom burden and a worse effect on HRQoL, because of the arrhythmia.20,21

2.9 | The hospital anxiety and depression scale

The domain-specific questionnaire hospital anxiety and depression scale (HADS) consists of two subscales, where seven items assess anxiety and seven assess depression. The score for each subscale ranges from 0 to 21. The scores are categorized as normal (0-7), possible,8–10 and probable (≥11) anxiety and depression, respectively.22

2.10 | Statistics

Continuous normally distributed variables were expressed as means SD and non-normally distributed variables as medians with 25th to 75th percentiles within brackets. Categorical data were presented as counts with percentages within brackets.

In order to analyze possible predictors of improvement in arrhythmia-specific symptoms and HRQoL, the difference between the scores at 1-year FU and baseline were calculated for the ASTA symptom scale and the ASTA HRQoL scale, and used as the depen-dent variable in a simple linear regression analysis. The independepen-dent predictors used were: age, gender, body mass index, hypertension, heart failure, diabetes, AF type (paroxysmal or persistent), CHA2DS2

-VASc score, AF episode duration (max AF episode duration of over 1 hour concerning the last 3 months before RFA), frequency of AF episodes (more than 10 episodes of AF the month before RFA), hsCRP, EF, LAV, AF recurrence, and finally possible and probable anxi-ety and depression as assessed with HADS. All variables that turned out to be significant were used in a multiple linear regression analysis, conducted in a stepwise backward elimination fashion. No statistical signs of multicollinearity were found in the final models.

Analysis of the change in all of the questionnaires summary scores, and in each item in ASTA, throughout the three measure points was performed with the Friedman test. In order to analyze between which time points there was a significant change, the Wilcoxon signed rank test was used between two measure points. The magnitude of the change between baseline and 1-year FU was assessed with effect size (ES), which was calculated and interpreted according to standard cri-teria where <0.20 denotes trivial, 0.20 to 0.49 small, 0.50 to 0.79

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moderate, and≥ 0.80 large ES.4All reported P-values were two-sided

and a P-value <0.05 was considered statistically significant. The ana-lyses were performed using the SPSS 24.0 (IBM, Armonk, New York).

3 | R E S U L T S

3.1 | Baseline characteristics

In total, 192 patients were included in the SMURF study. The baseline characteristics are presented in Table 1. Missing PROM summary scores varied between 1% and 19%, 2% and 20%, and 4% and 18% for SF-36, ASTA and HADS, respectively, and were because of not returning the questionnaire or missing answers removing the possibil-ity of calculating a summary score. Figure 1 shows the number of sub-jects included in the different analyses. There were no baseline differences between participants included in the study and those excluded because of logistical difficulties or because they declined participation.23

3.2 | Predictors of improvement in

arrhythmia-specific symptoms and HRQoL

3.2.1 | Predictors of arrhythmia-specific symptoms

In the univariate analysis, female gender and >10 AF episodes in the last month before RFA were significant positive predictors, while dia-betes and AF recurrence were significant negative predictors of improvement in ASTA symptom scale score between baseline and 1-year FU. In the multivariate analysis, these predictors remained sig-nificant (Table 2).

3.2.2 | Predictors of arrhythmia-specific HRQoL

In the univariate analysis, >10 AF episodes in the last month before treatment, heart failure, probable anxiety, and probable depression were significant positive predictors, while diabetes, LAV, and AF recurrence were significant negative predictors of improvement in ASTA HRQoL scale score between baseline and 1-year FU (Table 2). In the multivariate analysis, probable anxiety and probable depression were no longer significant (Table 2 and Figure 2).

3.3 | The effect of catheter ablation on

patient-reported outcome measures

3.3.1 | Arrhythmia-specific symptoms

The most commonly reported symptoms, as assessed with ASTA, were breathlessness during activity, weakness/fatigue, and tiredness, while the least frequently reported symptom was chest pain (Supporting Information Figure S1 in the online version of this article). Each item in the ASTA symptom scale improved significantly over time and there was a significant improvement in the ASTA symptom scale score with a large ES (Table 3 and Figure S1).

3.3.2 | Health-related quality of life

At baseline, the most commonly reported affected arrhythmia-specific HRQoL domains in ASTA were impaired physical activity, deteriorated

life situation, the patient avoiding planning things s/he would have liked to do, and feeling unable to work, study or carry out daily activi-ties (Figure S2). All ASTA HRQoL items improved significantly over time (Figure S2). The arrhythmia-specific HRQoL scale score improved significantly with a large ES (Table 3). General HRQoL, as assessed with SF-36, improved significantly with a small ES in all of the sub-scales (Table 3).

TABLE 1 Baseline patient characteristics

Variables n = 192 Age 60.5 10.2 Female gender 56 (29%) BMI (kg/m2) 28.0 4.2 Paroxysmal AF 71 (37%) Hypertension 82 (43%) Diabetes mellitus 16 (8%) Heart failure 18 (9%) CKD (GFR < 60 mL/min/1.73 m2) 40 (21%) Stroke/TIA 19 (10%) CHA2DS2VASc 2 (0-3)

Systolic blood pressure (mm Hg) 146 20 Diastolic blood pressure (mm Hg) 90 11

Beta blocker 139 (72%) Amiodarone 42 (22%) Flecainide 35 (18%) Dronedarone 23 (12%) ACEi or ARB 77 (40%) Statins 56 (29%) Complicationsa 7 (4%)

AF recurrence within 12 monthsb 119 (62%)

Longest AF episode >1 hour 148 (77%) >10 AF episodes last month 78 (41%)

EF (%) 57 9 LA volume (mL) 56 (46-70) hsCRP>3 mg/L 44 (23%) Anxiety Possible anxiety 35 (18%) Probable anxiety 20 (10%) Depression Possible depression 18 (9%) Probable depression 15 (8%)

Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BMI, body mass index CHA2DS2VASc: congestive heart failure, hypertension, age≥ 75,

diabe-tes, stroke, vascular disease, age 65-74 years, sex category (female); CKD, chronic kidney failure; EF, ejection fraction; hsCRP, high sensitive C-reactive protein; GFR, glomerular filtration rate; LA, left atrium; TIA, transient ischemic attack.

Continuous normally distributed data are presented as means SD and non-normally distributed data as medians with 25th to 75th percentiles within brackets. Categorical data are presented as counts with percent values within brackets.

a

Reported complications were cardiac tamponade (1%), pericardial effu-sion (0.5%), pseudoaneurysm (1.6%), larger than normal hematoma of the groin (0.5%).

bAF recurrence was defined as occurrence of AF or atrial flutter

docu-mented with ECG, or the need for re-ablation, within 1 year from ablation.

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3.3.3 | Anxiety and depression

The mean anxiety and depression scores at baseline, assessed with HADS, indicated normal levels of anxiety and depression (Table 3). How-ever, 55 (29%) had possible or probable anxiety and 33 (17%) had possi-ble or probapossi-ble depression. Both anxiety and depression mean scores improved significantly over time (Table 3). The ES was trivial or small.

4 | D I S C U S S I O N

In contrast to the most previous studies analyzing predictors of AF recurrence, this study analyzed predictors of improvement in symptoms and HRQoL. The most important predictors of improvement in both arrhythmia-specific symptoms and arrhythmia-specific HRQoL were

freedom from AF recurrence, absence of diabetes and > 10 AF epi-sodes in the month before RFA. In addition, female gender was a pre-dictor for symptom improvement, while no dilated left atrium and the presence of heart failure were predictors for HRQoL improvement.

Furthermore, there was a large improvement in arrhythmia-specific symptoms and arrhythmia-arrhythmia-specific HRQoL, and a significant improvement in general HRQoL, anxiety and depression after first time RFA of AF.

4.1 | Predictors of improvement in

arrhythmia-specific symptoms and arrhythmia-arrhythmia-specific HRQoL

The occurrence of frequent attacks of AF before RFA was a pre-dictor of symptom and HRQoL improvement. In a study by Gaita

FIGURE 1 Study inclusion flowchart. Note: Exclusion for logistical reasons was because of the fact that a maximum of four patients per week could be included. AF, atrial fibrillation; ASTA, the arrhythmia-specific questionnaire in tachycardia and arrhythmia; BP, bodily pain; EF, ejection fraction; GH, general health; HADS, hospital anxiety and depression scale; HRQoL, health-related quality of life; MCS, mental component summary; MH, mental health; pats, patients; PCS, physical component summary; PF, physical functioning; RE, role-emotional; RFA, radiofrequency ablation; RP, role-physical; SF, social functioning; SF-36, The Medical Outcomes Study 36-Item Short-Form Health Survey; VT, vitality

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et al, a higher reduction of arrhythmic burden and a higher free-dom from AF recurrence after RFA correlated with significant improvement in HRQoL after 10-year FU.15A high arrhythmic

bur-den prior to RFA is likely to be reduced to a greater extent com-pared to a low arrhythmic burden, explaining why the occurrence of frequent attacks of AF was a significant predictor of improve-ment in symptom burden and HRQoL. Although AF burden is determined by both the frequency and duration of AF episodes, AF frequency, but not duration, was a significant predictor in this study.

There were more patients experiencing >10 AF episodes the month before RFA, than patients classified as having paroxysmal AF. There are possible explanations for this relationship, the most probable one being inaccuracy in patient´s assessment of the prevail-ing rhythm. In a study by Garimella et al,2415% of the study popula-tion were extremely inaccurate in their perceppopula-tion of AF frequency and duration of their AF episodes. Many patients recognize a change in heart rate as an AF episode.24Hence, the patient might inaccurately

recognize a persistent episode as more than one episode. Further-more, classification of AF type can be simple in many patients, but

TABLE 2 Predictors of improvement in arrhythmia-related symptoms and health-related quality of life

Scale Variable Univariate Multivariate Standardized beta P-value Standardized beta P-value Models R2 Models P-value ASTA symptoms scale

score

0.183 <0.001

Female gender −0.179 0.020 −0.181 0.015

>10 AF episodes last month −0.169 0.031 −0.158 0.031

Diabetes 0.210 0.006 0.227 0.002

AF recurrence within 12 months

0.291 <0.001 0.271 <0.001

ASTA HRQoL scale score

0.198 <0.001 >10 AF episodes last month −0.203 0.009 −0.172 0.030

Diabetes 0.197 0.010 0.180 0.018 Heart failure −0.201 0.009 −0.180 0.022 LAV max 0.188 0.018 0.193 0.013 AF recurrence within 12 months 0.259 0.001 0.244 0.002 Probable anxiety −0.182 0.019 Ns. Probable depression −0.157 0.043 Ns.

Abbreviations: AF, atrial fibrillation; ASTA, the arrhythmia-specific questionnaire in tachycardia and arrhythmia; CHA2DS2VASc: congestive heart failure,

hypertension, age≥ 75, diabetes, stroke, vascular disease, age 65-74 years, female gender; HADS, the hospital anxiety and depression scale; HRQoL, health-related quality of life; hsCRP, high sensitive C-reactive protein; LAV, left atrial volume; RFA, radiofrequency ablation.

Univariate linear regression was performed to determine possible predictors of improvement in arrhythmia-related symptoms and health-related quality of life. Only significant variables in the univariate analysis are shown in this table. The dependent variable was the scale score at the 1-year follow-up with the score at baseline subtracted. The independent predictors analyzed were: age, gender, body mass index (BMI), hypertension, heart failure, diabetes, AF type (paroxysmal or persistent), CHA2DS2-VASc score, AF episode duration (max AF episode duration of over 1 hour concerning the last 3 months before

RFA), frequency of AF episodes (more than 10 episodes of AF the month before RFA), hsCRP, EF, LAV, AF recurrence, and finally possible and probable anxiety and depression as assessed with HADS. Variables that were significant in the univariate analysis were imputed in the multivariate analysis, which was conducted in a stepwise backward elimination fashion.

Higher scores reflect a higher symptom burden and a worse HRQoL. The larger the improvement, the larger the decrease in ASTA-score. All reported P-values were two-sided and a P-value <0.05 was considered statistically significant.

FIGURE 2 Mean improvement in ASTA symptom scale score A, and health-related quality of life scale score B, depending on atrial fibrillation (AF) episodes the month before radiofrequency ablation (RFA) and on AF recurrence within 1-year post RFA. Note: Improvement in absolute values.specific questionnaire in tachycardia and arrhythmia

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challenging in patients suffering from both paroxysmal and persistent AF episodes. Some of these patients could have been classified as having persistent AF since persistent episodes dominated over time, but having more paroxysmal AF in the time prior to the ablation.

There was an inverse relationship between recurrence of AF and improvement in symptoms and HRQoL. Although the relationship might be regarded as quite obvious, AF recurrence and improvement

in symptoms and HRQoL do not have to be mutually exclusive. In the study by Wokhlu et al,13a substantial improvement in general HRQoL

was noted also in patients with AF recurrence after RFA. However, despite the improvement in general HRQoL, only minor improvement in arrhythmia-specific symptoms occurred in patients with AF recur-rence. Generic instruments reflect general health, which is influenced by comorbidities, commonly present in patients with AF. A

disease-TABLE 3 Questionnaires summary scores at baseline, 4 months and 1-year follow-up

Friedman´s test Pairwise comparisons

ASTA B 4 M FU 1Y FU ES from B to 1Y FU P-value Time P-value

Symptom scale 37 (26-50) 11 (0-33) 4 (0-30) −1.20 <0.001 B-4 M B-1 Y 4 M-1 Y <0.001 <0.001 0.528 HRQoL scale 36 (21-49) 10 (0-31) 0 (0-28) −1.00 <0.001 B-4 M B-1 Y 4 M-1 Y <0.001 <0.001 0.117 SF-36 PF 75 (55-90) 85 (65-95) 85 (70-95) 0.43 <0.001 B-4 M B-1 Y 4 M-1 Y <0.001 <0.001 0.103 RP 50 (0-100) 75 (25-100) 100 (25–100) 0.43 <0.001 B-4 M B-1Y 4 M-1 Y 0.013 <0.001 0.069 BP 74 (41-100) 74 (51-100) 80 (52-100) 0.16 0,018 B-4 M B-1 Y 4 M-1 Y 0.248 0.040 0.204 GH 60 (45-77) 67 (47-82) 67 (47–82) 0.22 0,020 B-4 M B-1Y 4 M-1 Y 0.108 0.001 0.119 VT 50 (30-70) 65 (45-80) 60 (40-85) 0.40 <0.001 B-4 M B-1 Y 4 M-1 Y <0.001 <0.001 0.574 SF 75 (63-100) 100 (75-100) 100 (63–100) 0.20 0.021 B-4 M B-1 Y 4 M-1 Y 0.005 0.008 0.273 RE 100 (33-100) 100 (67-100) 100 (67–100) 0.31 0.028 B-4 M B-1 Y 4 M-1 Y 0.005 0.001 0.636 MH 76 (60-88) 84 (76-92) 84 (68-92) 0.25 <0.001 B-4 M B-1 Y 4 M-1 Y <0.001 <0.001 0.332 PCS 41 (34-50) 47 (37-52) 48 (39-54) 0.39 <0.001 B-4 M B-1 Y 4 M-1 Y 0.006 <0.001 0.006 MCS 48 (37-55) 53 (44-57) 53 (43-56) 0.28 0,006 B-4 M B-1 Y 4 M-1 Y 0.001 0.002 0.640 HADS Anxiety 5 (2–8) 3 (1–6) 3 (1–7) 0.24 <0.001 B-4 M B-1 Y 4 M-1 Y 0.001 <0.001 0.743 Depression 3 (1–6) 2 (1-5) 2 (1-6) 0.18 <0.001 B-4 M B-1 Y 4 M-1 Y 0.002 0.001 0.819 Abbreviations: 1 Y, 1 year; 4 M: 4 months; B, Baseline; ASTA, the arrhythmia-specific questionnaire in tachycardia and arrhythmia; BP, bodily pain; ES, effect size; FU, follow-up; GH, general health; HADS, hospital anxiety and depression scale; HRQoL, health-related quality of life; MCS, mental component summary; MH, mental health; PCS, physical component summary; PF, physical functioning; RE, role-emotional; RP, role-physical; SF, social functioning; SF-36, the medical outcomes study 36-item short-form health survey; VT, vitality.

Summary scores are presented as medians (25th to 75th percentiles).

ASTA and SF-36 scores range from 0 to 100 and HADS from 0 to 21. In SF-36, a higher score reflects better health status while the opposite is the case in ASTA and HADS.

ES was calculated by dividing the mean difference between baseline and 1-year follow-up by the SD at baseline. A result <0.20 denotes trivial, 0.20-0.49 small, 0.50-0.79 moderate and≥ 0.80 large ES.

Analysis of development in questionnaire scores was performed using the Friedman test. Analysis of change between two time points was performed using Wilcoxon signed rank test.

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specific instrument, on the other hand, allows both the detection and reflection of disease-specific changes between patients with a specific disease and over time. Björkenheim et al.4 showed that an

arrhythmia-specific questionnaire is more sensitive to changes related to AF burden than a generic questionnaire and more accurately reflects the effect of RFA, indicating the importance of using a disease-specific instrument when evaluating the effects of RFA. Hence, in this study, in which an arrhythmia-specific instrument was used, AF recurrence was one of the strongest inverse predictors of symptom and HRQoL improvement.

Diabetes was a negative predictor of both symptom and HRQoL improvement. In contrast to our study, Mohanty et al.11reported a higher post-ablation improvement in generic HRQoL in patients with the metabolic syndrome. In the present study, both diabetes and AF recurrence remained as significant predictors in the multivariate regression analysis, indicating that diabetes per se, regardless of whether AF recurred or not, was a negative predictor of improvement in symptoms and HRQoL.

Both diabetes and heart failure are chronic conditions that can affect HRQoL negatively, but in the present study, they had an oppo-site effect on HRQoL improvement after RFA. In the recently pub-lished catheter ablation vs standard conventional therapy in patients with left ventricular dysfunction and atrial fibrillation (CASTLE-AF) study, RFA for AF in patients with heart failure was associated with a significantly lower rate of the composite end point of death or hospi-talization, and also with an improved EF and 6-minute walk test, com-pared to medical therapy.25 Although the CASTLE-AF study only

included patients with an EF < 35%, which was an exclusion criterion in the present study, the diagnosis of heart failure in our study was also associated with improvement after RFA. While reduced HRQoL in diabetic patients may be because of affection of several organs, car-diac dysfunction is most probably the primary cause of reduced HRQoL in heart failure patients. Restoring atrial function and thus improving cardiac function, consequently has a greater effect on HRQoL in patients with heart failure than in patients with diabetes.

LAV was a negative predictor of HRQoL improvement. LAV is a known predictor of AF recurrence post RFA,26 and AF recurrence

reduces the likelihood of improvement in HRQoL, especially when assessed by a disease-specific instrument.4 However, although an

arrhythmia-specific instrument was used in the present study, both LAV and AF recurrence remained as significant negative predictors of HRQoL improvement, indicating that larger LAV per se is negatively associated with HRQoL improvement. Larger LAV might be an indica-tor of more severe and longstanding AF, affecting HRQoL negatively, even after a successful RFA.

Female gender was a significant predictor of symptom improve-ment. In a previous study by Forleo et al, there was a trend towards a greater improvement in HRQoL, assessed with SF-36, in women com-pared to men, although not statistically significant.27 The authors

pointed out the small number of women in their study as a reason for the failure to detect a significant difference. Women are reported to have higher symptom burden and to be referred for RFA less often and later than men, despite that both men and women had equal results after RFA concerning clinical outcomes, such as treatment suc-cess rate, complications, AF recurrences, and hospitalizations.27,28

There are not any obvious explanations for these gender-related inequalities.

The predictors discussed above are not required in order for any improvement to occur and should rather be reviewed in relation to their counterpart. For example, men with≤10 AF episodes the month before RFA may very well benefit from RFA, however, probably not as much as women with >10 AF episodes. Thus, the predictors do not have to be present in order for RFA to be meaningful. However, if they are, a greater improvement in symptoms and HRQoL can proba-bly be expected, should these findings be confirmed in future studies.

4.2 | The effect of catheter ablation on

patient-reported outcome measures

4.2.1 | Arrhythmia-specific symptoms

As in the medical antiarrhythmic treatment or radiofrequency ablation in paroxysmal atrial fibrillation (MANTRA-PAF) trial, in which the ASTA questionnaire also was used, breathlessness during activity and tiredness were the most commonly reported symptoms.29After RFA, all the symptoms, as well as the ASTA symptom scale score, improved. The large ES implies a large effect of RFA on symptom improvement, which is in line with other studies.29–31

4.2.2 | Health-related quality of life

There was a large improvement in the disease-specific ASTA HRQoL score, which is in line with previous studies.32 General HRQoL, assessed with SF-36, improved also, but to a lesser extent. The lesser degree of improvement was probably because of the above men-tioned differences between generic and disease-specific instruments.

4.2.3 | Anxiety and depression

Anxiety and depression are common in patients with AF.2 Thrall

et al showed that approximately one-third of patients with AF have elevated levels of anxiety and depression,2as was the case for anxiety

in the present study. Anxiety and depression are also known predic-tors of HRQoL,2,3and are associated with AF recurrence after RFA.33 Although several possible mechanisms have been suggested, such as correlation with systemic inflammation and elevated sympathetic tone,33the mechanisms behind this relationship remain unclear. Both anxiety and depression improved after RFA, which is in line with pre-vious studies.33,34

4.3 | Limitations

One potential limitation to this study is that it is a single-center obser-vational cohort study with a moderate sample size and no control group. Another is that it examined a heterogenic group of patients including people with both paroxysmal and persistent AF. Furthermore, the assessment of AF recurrence was made through examination of medical records and the local RFA register, and by 24-hour Holter monitoring. An implantable loop recorder could have been an alternative method, but was not within the scope of this study. Hence, the number of patients with AF recurrence was proba-bly underestimated. Finally, the Friedman test requires valid scores at all measure points, which was not the case for all study participants.

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5 | C O N C L U S I O N S

The most important predictors of improvement in arrhythmia-specific symptoms and HRQoL were frequent AF attacks before RFA, freedom from AF recurrence after RFA, and no diabetes, and additionally female gender for symptom improvement and heart failure and no enlarged left atrium for HRQoL improvement. Future studies are war-ranted to confirm these findings.

A C K N O W L E D G M E N T S

We would like to thank all the study participants and all personnel involved in the study. We would also like to thank Lars Valter and Mats Fredrikson, statisticians at Forum Östergötland, for their help with the statistical analyses, and Futurum—the Academy for Health-care, Region Jönköping County, for granting research time. The SMURF study is supported by grants from the County Council of Östergötland, the Carldavid Jönsson Research Foundation, the Heart Foundation, Linköping University and by unrestricted grants from Bio-sense Webster, Johnson & Johnson.

C O N F L I C T S O F I N T E R E S T

The authors declare no potential conflict of interests.

O R C I D

Neshro Barmano https://orcid.org/0000-0002-2012-7346

R E F E R E N C E S

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S U P P O R T I N G I N F O R M A T I O N

Additional supporting information may be found online in the Sup-porting Information section at the end of the article.

How to cite this article: Barmano N, Charitakis E, Karlsson J-E, Nystrom FH, Walfridsson H, Walfridsson U. Pre-dictors of improvement in arrhythmia-specific symptoms and health-related quality of life after catheter ablation of atrial fibrillation. Clin Cardiol. 2019;42:247–255.https://doi.org/10. 1002/clc.23134

References

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