Metabolic syndrome (MS), a proinflammatory state, is a cluster of cardiovascular risk factors including obesity, hypertension, diabetes, and dyslipidemia (1). As earlier studies have implicated many components of MS, namely, hypertension, diabetes, and obesity, to be prominent risk factors for atrial fibrillation (AF), a strong association between MS and AF is well evident (2). A fully efficient treatment strategy for AF is yet to be established, because of limited understanding of the complex pathophysiology of the disease (3). The most commonly used therapeutic options are antiarrhythmic drugs (AADs) and catheter ablation using radiofrequency (RF) energy. Catheter ablation provides an alternative therapy in patients with symptomatic drug-refractory AF. However, the rate of success in maintaining long-term sinus rhythm after ablation seems to vary widely, ranging from <30% to 85% (4- 5). Both MS and AF, as stand-alone conditions, trigger physical, mental, and psychosocial problems, which greatly impair quality of life (QoL) (6). In this prospective study, we aimed to analyze the impact of coexistent MS on long-term outcomes of catheter ablation, such as recurrence-free survival and QoL, in patients with AF.

Inflammation is a common denominator for both MS and AF. It is known to play a significant role in AF genesis and perpetuation. Moreover, a proinflammatory state evidenced by elevated levels of C-reactive protein (CRP) is commonly observed in patients with MS. Therefore, we additionally sought to explore the role of inflammatory markers such as CRP and total white blood cell (WBC) count at baseline in predicting AF recurrence after RF catheter ablation.

A total of 1,496 consecutive patients with AF (439 [29%] with paroxysmal atrial fibrillation [PAF], 393 [26%] with persistent AF, and 664 [44%] with long-standing persistent AF) undergoing their first catheter ablations were enrolled in this prospective study. Patients were classified into 2 groups: group 1, those with MS (n = 485; mean age 64 ± 8 years; 77% men; mean left ventricular ejection fraction, 55 ± 12%), and group 2, those without MS (n = 1,011; mean age 62 ± 11 years; 72% men; mean left ventricular ejection fraction 57 ± 9%). Baseline fasting blood samples were obtained from all patients for the measurement of blood glucose, lipid profile, CRP (Dimension RXL, Siemens Healthcare, Erlangen, Germany), and total WBC count (DXH 800, Beckman-Coulter, Brea, California). The CRP cutoff value was set at 0.9 mg/dl, with values below and above this cutoff considered normal and high, respectively. Follow-up event recording and 7-day Holter monitoring were performed at 3, 6, 9, and 12 months to check AF recurrence.

The Medical Outcomes Study SF-36 Health Survey was used to assess QoL at baseline and 12 months after ablation. Self-administration mode was strictly followed for QoL surveys; patients completed the survey in the privacy of their homes, without any interference or help from the hospital staff members or physicians.

The SF-36 Health Survey assesses 8 different domains of health status, namely physical functioning, role limitations due to physical health, mental health, role limitations due to emotional problem, social functioning, bodily pain, general health, and vitality.

Two composite scores, physical component summary (PCS) and mental component summary (MCS), were computed from the SF-36 Health Survey subscales (PCS included physical functioning, role limitations due to physical health, bodily pain, and general health, and MCS included vitality, social functioning, role limitations due to emotional problem, and mental health). All responses were scored on a scale ranging from 0 to 100, with 100 representing the best possible functional status.

The following criteria were used to define different components of MS (1,7): hypertension (blood pressure 130/85 mm Hg or current antihypertensive medication use), diabetes (fasting blood glucose ≥ 100 mg/dl or antidiabetic medication use), dyslipidemia (high-density lipoprotein 40 mg/dl in men and <50 mg/dl in women and serum triglycerides ≥150 mg/dl), and obesity (body mass index [BMI] ≥25 kg/m² or abdominal obesity, defined as waist circumference >102 cm in men and >88 cm in women). According to the World Health Organization, diabetes plus any 2 other risk factors is sufficient for the diagnosis of MS (1).

AF type was categorized into 2 main groups for the study purpose: PAF and nonparoxysmal atrial fibrillation (NPAF), which included persistent and long-standing persistent AF.

A standard catheter ablation protocol was followed, as described in previous publications from our group (8- 9). Periprocedural anticoagulation management was done with continuous warfarin therapy before, during, and after the procedure, with the aim of maintaining the international normalized ratio at >2 to 3.

AADs were discontinued 4 to 5 half-lives before ablation. A circular mapping catheter (Lasso, Biosense Webster, Diamond Bar, California) and a 3.5-mm open–irrigation tip catheter (Thermocool, Biosense Webster) were used for ablation. In patients with PAF, the pulmonary vein (PV) antrum, the posterior wall between the PVs, and the area anterior to the right PVs along the left atrial septum were ablated using RF energy. The superior vena cava was also isolated if PV-like potentials were recorded in that region. In patients with NPAF, the PV antrum, the posterior wall down to the coronary sinus, and the left septal wall were isolated using RF energy. Additionally, the left atrium was mapped to identify complex fractionated atrial electrograms, which were ablated as well. Complex fractionated atrial electrograms were defined as electrograms composed of 2 or more deflections and/or with continuous baseline activity or electrograms with cycle lengths ≤120 ms.

After ablation, in all patients, isoproterenol (up to 30 μg/min) challenge was performed to locate any non-PV triggers or to ensure electrical disconnection. All sites showing firings were ablated.

Non-PV triggers were defined as any firing sites outside the PV antrum.

Improvement in QoL and long-term procedural success were the 2 primary end points in this study. Procedural success was defined as freedom from arrhythmia (AF, atrial flutter [AFL], or atrial tachycardia [AT]) of >30 s in duration without AADs at follow-up. Any episodes that occurred during the first 12 weeks (the blanking period) after the procedure were not considered recurrence (7- 8).

Patients were discharged after overnight observation following ablation. They were discharged on their previously ineffective AADs, which were continued during the blanking period (12 weeks). After the blanking period, AADs were discontinued. In case of recurrences after the blanking period, patients were given previously ineffective AADs.

All patients were followed for 21 ± 7 months after ablation. Follow-up was performed at 3, 6, 9, and 12 months after the procedure, with a cardiologic evaluation, 12-lead electrocardiography, and 7-day Holter monitoring.

Patients were given event recorders for 5 months after ablation and were asked to transmit their rhythms every time they had symptoms compatible with arrhythmias and at least twice a week even if asymptomatic. Any episode of AF or AT lasting >30 s was considered a recurrence.

QoL surveys were administered before ablation (baseline) and at 12-month follow-up.

Continuous data are described as mean ± SD and categorical data as counts and percents. Student t tests, chi-square tests, and Fisher exact tests were used to compare groups. Paired t tests were used to compare QoL scores at baseline and 12-month follow-up. Pearson linear correlation coefficients (r values) and Spearman rank correlation coefficients (rho values) were calculated to assess correlations between individual scales. Multivariate general linear modeling was used to identify significant predictors of QoL improvement, and multivariate Cox models were used to determine predictors of AF recurrence. All covariates were entered into the model on the basis of known or expected clinical relevance. Variables included in the model were age, sex, comorbidities, baseline ejection fraction, and left atrial diameter. The proportional hazards assumption for the covariates was tested using Schoenfeld residual analysis. Tests were run to examine the presence of any significant interactions and to identify possible multicollinearity of the covariates. The hazard ratio (HR) and 95% confidence interval (CI) of AF or AT recurrence were computed and are presented in the results. Time to event was calculated from the procedure date and the date of recurrence. Recurrence-free survival over time was calculated using Kaplan-Meier analysis. The log-rank test was used to compare survival distributions across groups.

Further analyses were conducted to compare the magnitude of the association of MS, the composite predictor, with outcome in contrast to its individual components. Separate multivariate Cox models were fitted with MS and the component predictors (keeping other baseline covariate unchanged). The maximum likelihood estimates with associated p values from the models were used for the comparison. All tests were 2 sided, and p values <0.05 were considered statistically significant. Analyses were performed using SAS (SAS Institute Inc., Cary, North Carolina).

As expected, dyslipidemia, diabetes, hypertension, and higher BMI were more frequently reported in group 1. Besides that, coronary artery disease, congestive heart failure, and larger left atria were more prevalent in this group. Baseline CRP (median 5.18 mg/dl [interquartile range: 0.39 to 8.43 mg/dl] vs. 3.24 mg/dl [interquartile range: 0.31 to 6.82 mg/dl], p = 0.017] and total WBC (6,880 ± 1,030 vs. 6,572 ± 1,007 per mm³, p = 0.034) were significantly higher in group 1. No difference in type of AF was noted. Clinical characteristics of the 2 groups are presented in (Table 1).

During the procedure, non-PV triggers were more frequently observed in the NPAF population of group 1 compared with the NPAF patients in group 2 (270 [82%] vs. 379 [52%], p < 0.001). At end of the procedure, persistence of arrhythmia was observed in 70 patients in group 1 (14.4%) and 122 in group 2 (12.1%) (p = 0.201). Sinus rhythm was achieved in these patients by cardioversion. The mean fluoroscopic, RF, and procedural times were not different between the groups (Table 1). Compared to patients with NPAF, those with PAF had significantly shorter RF times (60 ± 30 min vs. 81 ± 36 min, p < .001) and fluoroscopic times (49 ± 20 min vs. 59 ± 24 min, p < .001).

After 21 ± 7 months of follow-up, 189 patients in group 1 (39%) and 319 in group 2 (32%) had arrhythmia recurrence (p = 0.005). When stratified by AF type, patients with NPAF in group 1 had significantly higher failure compared with those in group 2 (150 [46%] and 257 [35%], p = 0.002) (Figure 1), whereas no difference existed in the PAF subgroup (39 [25%] in group 1 vs. 62 [22%] in group 2, p = 0.295) (Figure 2). Among patients with recurrence, the distribution of arrhythmia type was similar across both groups (AF 41%, AFL 38%, AT 15%, and AF or AFL 6% in patients with MS vs. AF 36%, AFL 43%, AT 13%, and AF or AFL 8% in those without MS, p > 0.05). Kaplan-Meier survival curves showing each group's cumulative probability of AF-free survival are presented in (Figures 1, 2).

Compared with group 2, group 1 had significantly lower baseline scores on all SF-36 Health Survey subscales (Table 2). At 1-year follow-up, both MCS (Δ5.7 ± 2.5, p < 0.001), and PCS (Δ9.1 ± 3.7, p < 0.001) scores showed improvement in patients in group 1, whereas only MCS scores (Δ4.6 ± 2.8, p = 0.036) were improved in group 2.

For patients with successful ablation, 1-year PCS and MCS scores demonstrated substantial improvement in both groups (MS and no MS). No statistically significant change was noted among those in whom ablation failed (Table 3).

Multivariate analysis for recurrence-free survival was performed using Cox proportional hazards modeling. The covariates in the model are described in the section on statistical analysis. After adjusting for important confounders, presence of MS (HR: 1.28; 95% CI: 1.04 to 1.57; p = 0.021), sex (female) (HR: 1.39; 95% CI: 1.13 to 1.71; p = 0.002), and NPAF (HR: 1.51; 95% CI: 1.24 to 1.59; p < 0.001) demonstrated significant association with arrhythmia recurrence.

Subanalysis assessing possible predictors of recurrence in the PAF and NPAF populations revealed that MS (HR: 1.42; 95% CI: 1.04 to 1.67; p = 0.022), sex (HR: 1.28; 95% CI: 1.02 to 2.17; p = 0.033), CRP ≥0.9 mg/dl (HR: 1.87; 95% CI: 1.34 to 3.71; p = 0.002), and WBC count (HR: 1.22; 95% CI: 1.01 to 1.86; p = 0.016) were independent predictors of AF or AT recurrence in patients with NPAF.

However, in patients with PAF, presence of MS (HR: 1.08; 95% CI: 0.71 to 1.63; p = 0.731), CRP ≥0.9 mg/dl (HR: 1.11; 95% CI: 0.38 to 2.06; p = 0.436), and WBC (HR: 1.03; 95% CI: 0.78 to 2.09; p = 0.204) failed to predict recurrence.

Further analyses were performed to compare the predictive performance of the composite measure (MS) with its individual components. (Table 4) shows the adjusted HR and maximum likelihood estimate for each of the covariates. In our series, the model with MS exhibited significant association with arrhythmia recurrence, while the alternative model with individual components showed relatively smaller regression coefficients and no significant association.

During ablation, 4 (0.82%) and 7 (0.69%) pericardial effusions were reported in groups 1 and 2, respectively (p = 0.779). Additionally, 1 groin hematoma in group 1 and 1 pseudoaneurysm each in groups 1 and 2 were seen.

In the present study, we aimed to examine the impact of MS on long-term ablation outcomes in patients with AF. As a secondary analysis, we included measurements of CRP and total WBC count in the study and assessed their influence on ablation outcomes as well. Inflammation being a close associate of both MS and AF, this step was justified.

Our main observations were as follows. First, in the overall population, MS was associated with significantly higher AF recurrence. Second, when stratified by AF type, in the NPAF cohort, patients with MS had a higher recurrence rate compared with those without MS. This association was not observed in the PAF subgroup. Third, multivariate analysis demonstrated AF type, presence of MS, and female sex to be independently associated with failure. Fourth, more impairment in baseline QoL and larger improvements in follow-up assessments were observed in patients presenting with MS. Last, in the NPAF subgroup, baseline CRP, WBC count, and presence of MS were independent predictors of AF recurrence. This was not observed in patients with PAF.

The pathogenesis of AF is known to be an interplay of 2 factors: initiating triggers from ectopic foci and an abnormal arrhythmogenic substrate that mostly arises from structural remodeling of heart (10). As is well evident by now, 2 types of atrial remodeling take place in AF, leading to maintenance and perpetuation of the arrhythmia: electrical and structural remodeling. Electrical remodeling includes shortening of the atrial refractory period, the loss of rate adaptation, prolongation of atrial conductivity, and accumulation of calcium within atrial myocytes, which result in the promotion and continuance of multiple wavelet re-entry circuits (11).

Structural remodeling runs in parallel with electrical remodeling and includes left atrial dilation and increased atrial fibrosis (11). Fibrosis leads to the separation of myocytes from one another, which significantly impairs the transmission of electrical signals at the cellular level and results in chaotic atrial conduction (12).

Inflammation, fibrosis, and oxidative stress seem to play a crucial interactive role in remodeling-induced abnormalities that result in the perpetuation of arrhythmia, giving rise to persistent AF or long-standing persistent AF (10,13). Because all components of MS are closely associated with inflammation, MS logically seems to be related to atrial remodeling. In fact, several earlier studies have demonstrated left atrial diameters to be significantly larger in patients with AF with MS than in those without it (14- 15). We also observed a similar trend in the present study. Metabolic and hemodynamic variations associated with MS are known to lead to enlargement of the left atrium (16). Wang et al. (17) suggested that left atrial diameter constitutes an intermediate phenotype that favors AF in the MS population. An earlier study by Bhargava et al. (18) indicated that MS may have a more pertinent role in the pathogenesis of persistent or long-standing persistent AF, possibly resulting in a higher recurrence rate after catheter ablation in those AF subtypes than in PAF. The exact mechanism by which MS influences the perpetuation of AF resulting in higher arrhythmia recurrence, is still not very clear. Possibly, it has some direct or indirect influence on atrial electrophysiology. Kipshidze et al. (19) proposed that the dispersion of refractoriness between the right and left atria, caused by MS, directly triggers the development of AF. Furthermore, Oliveira et al. (20) postulated that the dispersion of refractoriness may be one of the mechanisms that lead to the maintenance of AF, depending on the degree of electrical homogeneity of the atrial tissue and the number of re-entry wavelets.

Elevated risk for recurrence and a higher frequency of non-PV triggers have been reported to be associated with NPAF (18). We observed more non-PV triggers and higher recurrence in the NPAF cohort of group 1 compared with that of group 2. Obesity, a prominent component of MS, has been demonstrated to be prevalently associated with non-PV triggers (21). Because non-PV triggers are more challenging to eliminate, this could have contributed to the observed higher recurrence rate in the NPAF subgroup of group 1.

In a multivariate analysis, we found MS, as a composite measure, but not its individual components, to be associated with AF recurrence. An earlier study demonstrated MS to be an independent predictor, whereas no association was reported between components of MS and AF recurrence, except BMI ≥25 kg/m² (22). In a separate study, Tang et al. (23) reported BMI ≥25 kg/m² to be a univariate but not independent predictor AF recurrence, whereas MS as a group was.

Our study demonstrated inflammatory markers such as CRP and WBC count, along with MS, to be independent predictors of failure in patients with NPAF only. In a meta-analysis of 16 trials, Boos et al. (11) suggested an intricate and close association of inflammation with persistent and long-standing persistent AF (24). Previous studies have also shown that CRP levels are related to left atrial size and AF duration before cardioversion (25- 26). Longer AF duration results in more atrial structural remodeling (25), which serves as an arrhythmogenic substrate leading to the perpetuation of AF. Our findings corroborate these observations. Therefore, it is reasonable to state with prudence that the mechanism linking MS to a higher recurrence rate in NPAF is mediated via inflammation. Why inflammatory markers failed to predict outcomes in patients with PAF is not known. But it can be speculated that differential expression of biomarkers due to a lower frequency of associated comorbidities could have resulted in such failure.

Several independent studies have reported associations of poor QoL with either MS or AF (6,27) separately. This is the first study to examine the impact of MS on QoL in patients with AF. Lower baseline scores and higher post-ablation improvement of QoL were seen in the MS group in our study. Inflammatory markers, enhanced hypothalamus-pituitary-adrenal axis activity, as well as simply being labeled with an additional disease (components of MS) are reported to account for the association between MS and lower QoL (6,28).

A lower baseline score has been reported to be associated with more robust improvement in QoL (29- 30). In this study, we observed a similar trend; patients with MS had lower baseline QoL scores, and they demonstrated significant improvement on follow-up. With AF and components of MS intruding daily life by imposing physical, mental, and social limitations, the lower pre-intervention QoL scores were well anticipated in group 1. After catheter ablation, these patients perceived a greater improvement in QoL, as they experienced huge changes in their capabilities to overcome hardships in daily life because of the elimination of AF symptoms and the frequent use of health care resources. In group 2, patients experienced improvements in only the mental score components of the SF-36 Health Survey; physical components did not exhibit any noticeable changes. It is known that diabetes and obesity affect the physical domains of functioning most profoundly (6,30). Therefore, it can be cautiously speculated that because a significantly lower proportion of patients in group 2 had these comorbidities, the baseline score for physical functioning was much higher and thus the post-ablation improvement was not perceived as something as dramatic, as it was in group 1.

This study was limited in several respects. First, a single generic questionnaire was used to assess QoL. Disease-specific instruments would have contributed complementarily toward capturing subtle differences in different patient groups with 1 or more components of MS. Second, patients were not followed for any status changes in their MS components, and thus any influence of changes on ablation outcomes cannot be ruled out. Last, we did not obtain waist circumference measurement data, which would have illustrated the abdominal obesity status of the patients, which is considered by some as a better tool to assess obesity.

This study demonstrated a strong association between AF recurrence and components of MS, as well as conventional inflammatory markers such as CRP and WBC count, in patients with NPAF undergoing catheter ablation. No such association was observed in patients with PAF. Additionally, the presence of MS was associated with lower baseline QoL, which improved substantially after ablative treatment for AF.