Europace Advance Access published online on November 13, 2008
Europace, doi:10.1093/europace/eun309
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CLINICAL RESEARCH
Pre-ablative predictors of atrial fibrillation recurrence following pulmonary vein isolation: the potential role of inflammation
Arrhythmia Service, Herz-Zentrum, Südring 15, 79189 Bad Krozingen, Germany
Manuscript submitted 21 August 2008. Accepted after revision 20 October 2008.
* Corresponding author. Fax: +49 76334022429, Email: k.letsas{at}mail.gr
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Abstract |
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Aims: An increasing body of evidence has demonstrated the essential role of inflammation in the genesis and maintenance of atrial fibrillation (AF). The aim of the present study was to investigate whether success or failure of electrical pulmonary vein isolation (PVI) in patients with AF is related with the presence of a pre-ablative inflammatory state as determined by known clinical parameters and conventional markers of inflammation including high-sensitivity C-reactive protein, white blood cell (WBC) count, and fibrinogen.
Methods and results: Seventy-two patients with paroxysmal (64%) or persistent AF (36%) underwent successful electrical PVI. The mean duration of arrhythmia was 5.5 ± 2.9 years. After a mean follow-up period of 12.5 ± 5.7 months, 44 patients (61%) were in sinus rhythm. In univariate Cox proportional hazard regression analysis, hypertension, body mass index (BMI), left ventricular ejection fraction, left ventricular end-diastolic diameter, left atrial diameter (LAD), WBC count, and high-sensitivity C-reactive protein were significantly associated with AF recurrence (P < 0.05). In multivariate Cox proportional hazard regression analysis, hypertension [hazard ratio (HR) 3.127; 95% confidence interval (CI) 1.269–7.706, P = 0.013], LAD (HR 1.077; 95% CI 1.014–1.144, P = 0.015), and WBC count (HR 1.423; 95% CI 1.067–1.897, P = 0.016) were independent pre-ablative predictors of AF recurrence following PVI.
Conclusion: Conventional markers of the inflammatory cascade such as WBC count and high-sensitivity C-reactive protein as well as elements of the metabolic syndrome such as hypertension and increased BMI were significantly associated with AF recurrence. The impact of a pre-ablative inflammatory state in the overall success rate of PVI needs further elucidation.
Key Words: Atrial fibrillation, Ablation, Recurrence, Inflammation, Obesity
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Introduction |
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An increasing body of evidence has demonstrated the essential role of inflammation in the genesis and maintenance of atrial fibrillation (AF).1
–3 Elevated levels of several markers of the inflammatory cascade including high-sensitivity C-reactive protein, interleukin-6, interleukin-8, and white blood cell (WBC) count have been reported in different AF populations.1–8 Atrial biopsies taken from AF patients have demonstrated evidence of inflammatory infiltrates compared with healthy individuals: a fact that strongly supports the hypothesis that ongoing inflammation may lead to structural remodelling of the atria and thus to promote the perpetuation of AF.9
Pulmonary vein isolation (PVI) has become an effective treatment for patients with symptomatic, drug-refractory AF.10 Despite the continuous improvement in outcomes with advances in ablation technique, recurrences of the arrhythmia remain a common clinical problem following PVI, occurring in 25–50% of the patients during follow-up.10,11 Several patients' selection criteria have been proposed in order to increase the success rate of PVI.10 To the best of our knowledge, the impact of inflammation on AF recurrence following PVI has never been tested before. In the present study, we hypothesized that the presence of a pre-ablative inflammatory state as determined by known clinical parameters and conventional markers of inflammation including high-sensitivity C-reactive protein, WBC count, and fibrinogen may be associated with AF recurrence following PVI.
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Methods |
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Patients
The study population comprised 72 consecutive patients with highly symptomatic, drug-refractory paroxysmal or persistent AF, who underwent electrical isolation of both ipsilateral pulmonary veins between January 2005 and March 2006. In patients with persistent AF, cardioversion was performed 6 weeks before the ablation procedure under a new anti-arrhythmic drug to maintain the patient in sinus rhythm. Exclusion criteria were left atrial diameter (LAD) >55 mm, intracardiac thrombi documented by transoesophageal echocardiography, myocardial infarction, or cardiac surgery in the previous 3 months, and previous ablation for AF. Furthermore, subjects with recent infection, malignancies, blood dyscrasias, autoimmune or inflammatory diseases, renal failure, or hepatic failure were excluded from the study. This clinical study is a retrospective analysis of prospectively collected AF ablation data. The institutional Ethics Committee approved the study protocol, and written informed consent was obtained from all patients.
Echocardiography
Comprehensive transthoracic M-mode, two-dimensional scans, and Doppler recordings were obtained in parasternal and apical views during sinus rhythm. Left ventricular ejection fraction (LVEF) was estimated using the Simpson's method (four-chamber apical view). Left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) diameters as well as end-systolic antero-posterior LAD were determined in parasternal long-axis view. Mitral valve flow velocities (E and A) were recorded with pulsed wave Doppler at the tip of the opened mitral leaflets in the four-chamber apical view and the E/A ratio was calculated. All measurements were averaged for three cardiac cycles.
Blood samples
Baseline blood samples were obtained the day prior to ablation after an overnight fast. The WBC count in the peripheral blood was determined by an automated cell counter (Sysmex NE 9000). Serum levels of C-reactive protein were measured using a high-sensitivity latex particle-enhanced immunoassay on a Hitachi 717 automated analyser (Tina-quant CRP detection, Roche Diagnostics, Mannheim, Germany). The precision of the assay calculated by the intra-assay and inter-assay coefficients of variation was <7%, the sensitivity of the method was 0.1 mg/dL, and the detection limit was 0.3 mg/dL. Plasma fibrinogen levels were determined by the modified Claus method using the Multifibren U reagent (BCS analyser; Dade-Behring, Marburg, Germany).
Electrophysiological study and ablation procedure
Oral anticoagulation was stopped 2 days before the intervention to achieve an international normalized ratio between 1.8 and 2.0. Anti-arrhythmic drug treatment was suspended for the day of the ablation procedure, restarted the following day, and stopped after 1 month. The ablation procedure has been described in detail elsewhere.12 For isolation of large areas around both ipsilateral pulmonary veins, the three-dimensional geometry of the left atrium was reconstructed with the EnSite NavX system (NavX; St Jude Medical, Inc., St Paul, MN, USA). Irrigated radio frequency energy was delivered with a target temperature of 50°C and a power between 25 and 35 W (Thermo-Cool, Biosense-Webster, Inc., Diamond Bar, CA, USA). Circumferential ablation was performed on the posterior wall >1 cm and on the anterior wall >5 mm away from the defined pulmonary vein ostia. The endpoint of ablation was the absence or dissociation of potentials in the isolated area, as documented with the circular mapping catheter (Optima, St Jude Medical, Inc.).
Post-ablation care and follow-up
After the procedure, warfarin was restarted, and intravenous heparin was administered until the international normalized ratio was >2. Warfarin was continued for at least 3 months. On the first post-procedural day, patients underwent surface ECG, transthoracic echocardiography, and 24 h Holter monitoring. Anti-arrhythmic drugs were stopped 1 month after the ablation procedure if there were no symptoms suggestive of arrhythmia recurrence; 1 and 3 months after the procedure, the patients were seen by the referring cardiologist for 24 h Holter monitoring. Six months following the ablation procedure, all patients were hospitalized to undergo echocardiographic study, 24 h Holter monitoring, and exercise test. Patients were additionally advised to report any symptoms of arrhythmia between scheduled visits. All patients with symptoms of AF, but no documentation on ECG or 24 h Holter monitoring, were provided with an event monitor for 8 weeks. A final re-evaluation of symptoms and 24 h Holter monitoring were performed 12.5 ± 5.7 months after the procedure. Symptomatic or asymptomatic AF episodes presenting after the first month were considered as a recurrence.
Statistical analysis
Continuous variables are presented as mean values ± SD, whereas categorical ones are presented as absolute and relative frequencies (percentages). The Shapiro–Wilk criterion was used for the assessment of normality. All variables, apart from high-sensitivity C-reactive protein, exhibited a normal distribution and therefore classic statistical tests were used. High-sensitivity C-reactive protein was log-transformed in order to obtain a normal distribution and to use it in a multivariate analysis. The mean differences between two groups (recurrence and no recurrence) were evaluated by calculating Student's t-test after controlling for equality of variances with the Levene's statistic. Mann–Whitney U-statistic was used for the comparison of high-sensitivity C-reactive protein distribution among the two study groups. Pearson's 
2 test was used in order to test for any associations between two categorical variables. Pearson's correlation coefficient was calculated for assessing any association between continuous variables. The recurrence was estimated using the Kaplan–Meier method, and the patients were censored at the date of recurrence of AF. The effect of the explanatory variables on AF recurrence was evaluated using univariate semi-parametric Cox proportional hazard regression models. Forward model-building procedure using likelihood ratio tests was followed in order to construct a multivariate Cox proportional hazard regression model having the highest possible predictive value. Interactions between explanatory variables were also tested. The proportionality assumption of the multivariate model was tested including interactions of the explanatory variables and both time and log (time) variables. The evaluation of goodness of fit of the model was performed using Cox–Snell residuals. Cut-off point analysis using the receiver operating characteristic (ROC) curves was applied to continuous explanatory variables that were significantly associated with AF recurrence in the multivariate model in order to evaluate the level at which we achieve the best predictive ability. Comparisons of the areas under the ROC curves (AUC) were performed using the Wilcoxon test. All reported P-values are based on two-sided tests and compared with a significance level of 0.05. Data were analysed using STATATM statistical software (Version 9.0, Stata Corporation, College Station, TX, USA).
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Results |
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Clinical, echocardiographic, and laboratory data of the patients are depicted in Table 1. The study population consisted of 72 patients (mean age 54.9 ± 8.8 years, 58 males), with either paroxysmal (n = 46) or persistent (n = 26) AF. The mean duration of AF was 5.5 ± 2.9 years. Hypertension, diabetes mellitus, and dyslipidaemia were present in 19, 22, and 52% of the patients, respectively. Structural heart disease including coronary artery disease (n = 2), valvular heart disease (n = 5), and cardiomyopathy (n = 3) was present in 14% of the patients. Regarding anti-arrhythmic medication after the ablation procedure, 21 were receiving a class I agent (quinidine, flecainide, or propafenone) and 35 a class III agent (amiodarone or sotalol). Of the 72 study patients, 12 were treated with a statin, 17 with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB), and six with spironolactone. Treatment started at least 2 months before ablation and was continued during follow-up. Regarding the complications following PVI, one patient developed asymptomatic ostial PV stenosis of 40% and two patients exhibited pulmonary oedema the day after the procedure. No thrombo-embolisms or fistulas between the left atrium and the oesophagus were observed in patients in the present study.
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After a mean follow-up period of 12.5 ± 5.7 months, 44 patients (61%) were in sinus rhythm without anti-arrhythmic drug treatment and 28 patients (39%) developed AF recurrence. The mean time to arrhythmia relapse was 9.8 ± 5.7 months. Atrial fibrillation recurrence occurred in 18 patients within the first 6 months after the procedure. As shown in Table 2, patients with AF recurrence exhibited a higher rate of hypertension, increased body mass index (BMI), less use of statins, reduced LVEF, increased LAD, increased LVEDD, increased WBC count, and high-sensitivity C-reactive protein levels compared with those who remained in sinus rhythm (P < 0.05).
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According to univariate Cox proportional hazard regression analysis, hypertension, BMI, LVEF, LVEDD, LAD, WBC count, and high-sensitivity C-reactive protein levels (after log-transformation) were significantly associated with AF recurrence (P < 0.05) (Table 3). All other variables studied including age, gender, AF type (paroxysmal or persistent), AF duration, structural heart disease, medications, and fibrinogen levels were not associated with AF relapse. Multivariate Cox proportional hazard regression analysis showed that hypertension [hazard ratio (HR) 3.127; 95% confidence interval (CI) 1.269–7.706, P = 0.013], LAD (HR 1.077; 95% CI 1.014–1.144, P = 0.015), and WBC count (HR 1.423; 95% CI 1.067–1.897, P = 0.016) were independent predictors of AF recurrence following PVI, after testing for the effect of all other explanatory variables (Table 3).
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Cut-off point analysis showed that a WBC count
6280 mm3 was the optimal point that discriminated those with AF recurrence from the rest of participants (sensitivity 70.4% and specificity 69.8%). Similarly, the optimal cut-off point for LAD was 43 mm (sensitivity 50.0% and specificity 79.6%). The AUC for WBC count and LAD were 72.6 and 67.3%, respectively (P = 0.597). |
Discussion |
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The main findings of the present study were the following: (i) hypertension, LAD, and WBC count were independent pre-ablative predictors of AF recurrence after successful PVI; (ii) well-known conventional inflammatory indices such as WBC count and high-sensitivity C-reactive protein were significantly associated with AF relapse; and (iii) hypertension and increased BMI, two major components of the metabolic syndrome that represent a pro-inflammatory state,13
,14 were significantly associated with AF recurrence.
The role of inflammation in the genesis and perpetuation of AF is still under investigation. Whether initiation of AF activates direct inflammatory effects or whether the presence of a pre-existing systemic inflammatory state promotes AF development remains unclear.1–3 Both mechanisms may interrelate, indicating that inflammation is not only a response to the underlying arrhythmic process but also an integral part of it.15 Abnormal atrial histology was uniformly found in multiple biopsy specimens in all patients with lone AF, with 66% of them showing evidence of occult myocarditis.9 Additionally, inflammatory markers, mainly high-sensitivity C-reactive protein, have been related to future AF development among patients in sinus rhythm.2 These findings favour the hypothesis that inflammation may act as an initiator, rather than as a consequence of AF. In contrast, rapid atrial activation has been shown to induce calcium accumulation within the atrial myocytes leading to overload and in some cases to apoptosis, which subsequently triggers a low-grade inflammatory response.15
Several inflammatory indices have been related to future AF development, AF persistence, and AF recurrence following electrical cardioversion.1–3 The WBC count is a readily available marker of systemic inflammation. Elevations in WBC count have been implicated in the pathogenesis of AF. A pronounced increase in post-operative WBC count independently predicted the development of post-operative AF.5,6 A significant decrease in WBC count has been additionally observed in patients with AF following successful electrical restoration of sinus rhythm.7 Neutrophil accumulation may participate in atrial remodelling by the release of activated substances, including oxygen-free radicals, proteases, and pro-inflammatory cytokines. We showed that pre-ablative WBC count is an independent predictor of AF recurrence following PVI after adjustment for confounding factors, including the use of statins, ACEIs/ARBs, and spironolactone. Cut-off point analysis showed that a WBC count 6280 mm3 predicted AF recurrence, with a sensitivity and specificity of 70.4 and 69.8%, respectively. C-reactive protein, a well-established marker of systemic inflammation, represents a robust and significant predictor of AF relapse following successful electrical cardioversion.1,3,4 Previous studies have shown that C-reactive protein levels are related to the left atrial size and AF duration before cardioversion, thus providing evidence of an association between inflammation and atrial structural remodelling.16,17 In the present study, high-sensitivity C-reactive protein levels were significantly associated with AF recurrence after PVI. However, in our population, high-sensitivity C-reactive protein was not an independent predictor of arrhythmia relapse.
Recent data have demonstrated a clear relationship between AF and obesity.18 A BMI >25 kg/m2 has been associated with AF development.19 Left atrial enlargement, a recognized risk factor of AF, has been correlated with increased BMI or adiposity.20 Furthermore, obesity, the most significant determinant of the metabolic syndrome, is characterized by a state of chronic low-grade inflammation.13,14 Mainigi et al.21 have reported that a baseline body weight of >200 lbs predicts very late AF recurrences following ablation. We showed that patients with arrhythmia recurrence exhibited increased BMI compared with those who maintained sinus rhythm. This correlation was further supported by the positive significant effect of BMI on AF recurrence in survival analysis. Moreover, an increased BMI was significantly correlated with increased LAD, elevated WBC count, and high-sensitivity C-reactive protein levels (data not shown), findings that strongly indicate the important role of obesity in left atrial remodelling, which in part may be attributed to chronic low-grade inflammation. In accordance with previous studies, we showed that hypertension is an independent predictor of AF recurrence following PVI.22,23
Clinical implications
The identification of reliable predictors of AF recurrence following PVI may assist a better patient selection strategy and therefore to improve the overall success rate of the method. We showed that simple markers of the inflammatory cascade such as WBC count and high-sensitivity C-reactive protein and major elements of the metabolic syndrome such as hypertension and increased BMI are significantly associated with AF recurrence. Inflammation-mediated left atrial structural remodelling has been implicated in the genesis and maintenance of AF1,3,15–17 and therefore may also play a key role in AF recurrence after PVI.
The presence of a pre-ablative inflammatory state is likely to represent a novel target for the prevention of AF recurrence following PVI. Treatment with glucocorticoids, statins, ACEIs, ARBs, and antioxidants has been reported to reduce the recurrence rate of AF following electrical cardioversion, possibly through an anti-inflammatory process.1,3,15 In this study, patients treated with statins exhibited fewer recurrences. However, this positive effect was not observed in the Cox proportional univariate and multivariate analysis. In accordance with these findings, recent studies evaluating the role of statins, ACEIs, or ARBs failed to demonstrate an improved outcome following AF ablation.24,25 In conclusion, the impact of a pre-ablative inflammatory state in the overall success rate of PVI needs further elucidation. The potential role of specific pharmacological agents that modulate the inflammatory pathways needs also to be investigated.
Study limitations
The study was a retrospective analysis of prospectively gathered data and hence is subject to the limitations inherent in any retrospective study. The number of patients included in the present study is relatively small. Despite regular screening of patients with outpatient visits, phone calls, and questioning of symptoms, the detection of all episodes of AF recurrence, particularly the asymptomatic ones, is very difficult to be established, and therefore, we may have underestimated the true incidence of AF relapse in our study. The limited accuracy of high-sensitivity C-reactive protein measurements due to the detection limit of 0.3 mg/dL may have influenced the results for this variable.
Conflict of interest: none declared.
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K.P.L. is supported by a Training Fellowship of the European Society of Cardiology.
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