Prevention of Atrial Fibrillation Recurrence With Corticosteroids After Radiofrequency Catheter Ablation

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1 Journal of the American College of Cardiology Vol. 56,. 18, by the American College of Cardiology Foundation ISSN /$36. Published by Elsevier Inc. doi:1.116/j.jacc Heart Rhythm Disorders Prevention of Atrial Fibrillation Recurrence With Corticosteroids After Radiofrequency Catheter Ablation A Randomized Controlled Trial Takashi Koyama, MD, Hiroshi Tada, MD, Yukio Sekiguchi, MD, Takanori Arimoto, MD, Hiro Yamasaki, MD, Kenji Kuroki, MD, Takeshi Machino, MD, Kazuko Tajiri, MD, Xu Dong Zhu, MD, Miyako Kanemoto-Igarashi, MD, Aiko Sugiyasu, MD, Keisuke Kuga, MD, Yoshio Nakata, PHD, Kazutaka Aonuma, MD Tsukuba, Japan Objectives Background Methods Results Conclusions We sought to clarify the efficacy of corticosteroid therapy for preventing atrial fibrillation (AF) after pulmonary vein isolation (PVI). The inflammatory process may cause acute AF after PVI. However, no studies have examined the relationship between corticosteroid administration and AF after PVI. A total of 125 patients with paroxysmal AF were randomized to receive either corticosteroids (corticosteroid group) or a placebo (placebo group). In the corticosteroid group, intravenous hydrocortisone (2 mg/kg) was given the day of the procedure, and oral prednisolone (.5 mg/kg/day) was administered for 3 days after the PVI. The body temperature and high-sensitivity C-reactive protein level were measured before and on each of the first 3 days after ablation. The prevalence of immediate AF ( 3 days after the PVI) was significantly lower in the corticosteroid group (7%) than in the placebo group (31%). The maximum body temperature and C-reactive protein during the initial 3 days after ablation and the increase in the body temperature and C-reactive protein level from baseline were significantly lower in the corticosteroid group than in the placebo group. Corticosteroid treatment did not decrease AF s between 4 and 3 days after ablation. The AF-free rate at 14 months post-ablation was greater in the corticosteroid group (85%) than in the placebo group (71%, p.32 by the log-rank test). Transient use of small amounts of corticosteroids shortly after AF ablation may be effective and safe for preventing not only immediate AF s but also AF s during the mid-term follow-up period after PVI. (J Am Coll Cardiol 21;56: ) 21 by the American College of Cardiology Foundation Pulmonary vein isolation (PVI) is becoming an effective therapeutic option for drug-refractory, paroxysmal atrial fibrillation (AF). However, the rate of AF after successful PVI remains relatively high (1), and s commonly occur within the first several weeks after the PVI (2 4). There is much evidence of a mechanistic link between inflammatory processes and the development of AF (5,6). Electrical PVI by radiofrequency energy causes From the Cardiovascular Division, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan. The authors have reported that they have no relationships to disclose. Manuscript received October 2, 29; revised manuscript received March 1, 21, accepted April 13, 21. extensive myocardial damage, which may result in a systemic and local inflammatory response (7,8). Recent studies have found that inflammatory responses appeared shortly after PVI (7,8) and that those responses were closely associated with AF recurring within the initial 3 days after See page 1473 the procedure (7). Several studies have reported that corticosteroids reduce AF after cardiac surgery by preventing inflammatory reactions (9). Therefore, we hypothesized that corticosteroid therapy might negate AF s immediately after PVI by preventing post-ablation inflammatory responses. This study was designed and undertaken to clarify this point.

2 1464 Koyama et al. JACC Vol. 56,. 18, 21 Corticosteroids Suppress AF After Ablation October 26, 21: Abbreviations and Acronyms AAD antiarrhythmic drug AF atrial fibrillation APC atrial premature contraction BT body temperature CI confidence interval CRP C-reactive protein OR odds ratio PV pulmonary vein PVI pulmonary vein isolation Methods Patients. Between April 27 and March 28, 13 consecutive patients with drug-refractory AF were enrolled in this study (Table 1). All patients were newly enrolled in this study, and none had a history of ablation. All patients had symptomatic, paroxysmal AF, which was defined as AF episodes that spontaneously terminate and last for 3 s and 7 days during treatment with antiarrhythmic drugs (AADs) (7). All AADs were discontinued 5 half-lives before the ablation procedure with the exception of amiodarone, which was discontinued at least 6 weeks before and the other drugs were administered until the end of the study period. The study was approved by an institutional review committee, and all patients gave their written informed consent before participation. Study protocol. This study was designed as a prospective, randomized, double-blind study. All patients were randomized for treatment with corticosteroids (corticosteroid group) or a placebo (placebo group) on the first day of their hospitalization and were observed prospectively after a single PVI procedure (Fig. 1). In the corticosteroid group, 1 mg per 1 ml hydrocortisone sodium succinate (Solu-Cortef, Pfizer Manufacturing, Puurs, Belgium) in a.9% sodium chloride solution was administered intravenously (2-mg/kg dose) immediately after the procedure. Oral prednisolone (Takeda Pharmaceutical Co., Tokyo, Japan) was also administered (.5 mg/kg/ day) for 3 days after the PVI. A placebo solution (.9% sodium chloride, 1 ml/kg) and oral drug (lactose) were administered in a manner similar to that in the placebo group patients. Within each group, the patients were divided into 3 subgroups according to the results of the AF Baseline Table 1Patient Baseline Characteristics Patient Characteristics and Results and of Catheter ResultsAblation of Catheter Ablation All Patients (n 125) Placebo (n 65) Corticosteroid (n 6) p Value Age, yrs Male sex 1 (8.) 52 (8.) 48 (8.) 1. Duration of AF, yrs Underlying heart disease Hypertension 65 (52.) 29 (44.6) 36 (55.4).87 Coronary artery disease 1 (8.) 6 (9.2) 4 (6.7).6 Valvular heart disease 15 (12.) 9 (13.8) 6 (1.).51 structural heart disease 1 (8.) 5 (76.9) 5 (83.3).37 Antiarrhythmic drugs Class I 13 (82.4) 51 (78.5) 52 (86.7).59 Class Ia 23 (18.4) 11 (16.9) 12 (2.).66 Class Ib 13 (1.4) 6 (9.2) 7 (11.7).66 Class Ic 8 (64.) 39 (6.) 41 (68.3).21 Class III 56 (44.8) 33 (5.8) 23 (38.3).31 Class IV 18 (14.4) 6 (9.2) 12 (2.).8 Medication ACEIs or ARBs 62 (49.6) 29 (44.6) 33 (55.).93 Beta-blockers 56 (44.8) 24 (36.9) 32 (53.3).19 Statins 43 (34.4) 24 (36.9) 19 (31.7).54 Echocardiographic parameters LA diameter, mm LV end-diastolic dimension, mm LV ejection fraction, % Results of catheter ablation Total duration of procedure, min Total fluoroscopy time, min Duration of RF energy, min Total RF energy delivered ( 1 3 J) Additional ablation procedures LA roof line 1 (8) 4 (6.1) 6 (1).43 SVC isolation 7 (5.6) 3 (4.6) 4 (6.6).62 Values are reported as mean SD or n (%). ACEI angiotensin-converting enzyme inhibitor; AF atrial fibrillation; ARB angiotensin receptor blocker; LA left atrial; LV left ventricular; RF radiofrequency; SVC superior vena cava.

3 JACC Vol. 56,. 18, 21 October 26, 21: Koyama et al. Corticosteroids Suppress AF After Ablation 1465 Registration Catheter ablation After ablation 1 month AF 2 (31%) 6 14 Placebo group AF 32 (49%) AF 12 (18%) 8 4 AF 33 (51%) 5 28 Corticosteroid group AF 16 (27%) AF 4 (7%) AF 12 (2%) 6 6 Exclusion: 5 patients 2: n-pv foci 3: Refuse AF 44 (73%) months 19 (29%) AF 46 (71%) AF 9 (15%) AF 51 (85%) AF Figure 1 Flow Diagram and Results of the Present Study AF atrial fibrillation; PV pulmonary vein. during the initial 1 month after ablation (7): immediate AF group, early AF group, and non-af group. and early AF s were defined as AF episodes that occurred within 3 days and between 4 and 3 days after the PVI, respectively. n-af was defined as no AF after the PVI. The primary end point of the study was the proportion of patients free of recurrent AF, and the secondary end point was recurrent AF and any serious complications caused by catheter ablation or treatment with corticosteroid. Catheter ablation. Extensive PVI was performed using the double Lasso technique (7) without a 3-dimensional mapping system. A 7-F deflectable catheter with an 8-mm distal electrode (Ablaze, Japan Lifeline Co., Tokyo, Japan) was used for ablation in the temperature control mode at a target temperature of 52 C and maximum power output of 3 to 35 W. Two fluoroscopic angles were used for confirming the catheter position. The end point of the PVI was the creation of a bidirectional conduction block from the atrium to the PVs and vice versa (7). After the PVI, if AF was sustained or induced with coronary sinus burst pacing at a cycle length down to 18 ms during the administration of intravenous isoproterenol (1. to 3. g/min) and lasted more than 3 min (7,1), additional ablation, consisting of linear ablation of the left atrial roof and/or superior vena cava isolation, was performed. If the AF did not terminate or was inducible after these procedures, sinus rhythm was restored by transthoracic cardioversion (1). A cavotricuspid isthmus block line was created in all patients with confirmation of bidirectional block. Follow-up. Patients remained hospitalized under continuous rhythm monitoring (CNS-97, Nihon Kohden, Tokyo, Japan) for at least 1 week after the procedure and were followed for 14 months after the PVI procedure. After discharge, all patients underwent follow-up at 2 weeks post-procedure and then every month thereafter. At each hospital visit, the patients underwent 12-lead electrocardiography and intensive questioning regarding any arrhythmiarelated symptoms. Holter monitoring for 24 h was performed at 2 weeks and 1, 3, 6, and 14 months after the PVI. Portable electrocardiographic monitoring (HCG-91, OMRON, Kyoto, Japan) was also performed for 3 min twice daily (morning and night for a total 6 min/day) on 3 consecutive days at 2 weeks and 1, 3, 6, and 14 months after the PVI. Twelve-lead electrocardiography, 24-h Holter electrocardiography, and portable electrocardiographic monitoring were also used any time that the patients reported palpitations. If the electrocardiogram showed any AF episodes during follow-up, patients received a diagnosis of clinical of AF, irrespective of the presence of symptoms (7). Patients with AF were treated temporarily with Class I, II, III, and/or IV AADs, and the AADs were discontinued if stable sinus rhythm could be maintained. Discontinuation of the AADs was then attempted in those patients in whom the recurrent AF disappeared after temporary treatment; if sinus rhythm could be maintained, the drugs were stopped permanently. Repeat ablation was not performed in any of the patients during the study period. Other definitions and data analysis. The patients body temperature (BT) was measured on the morning of the

4 1466 Koyama et al. JACC Vol. 56,. 18, 21 Corticosteroids Suppress AF After Ablation October 26, 21: ablation and every 6 h during the first 3 consecutive days after the PVI; the highest BT and maximum difference in the BT ( BT), defined as the difference between the highest BT during the first 3 days post-procedure and the BT measured before the ablation, were obtained. The BT was measured by an electrical axillary thermometer (C22, TERUMO, Tokyo, Japan) placed in the axilla of the arm not receiving a fluid infusion. After the patient rested in bed for 2 min, the patient s axilla was wiped free of sweat, and the BT was measured 3 times and averaged. The highly sensitive C-reactive protein (CRP) level was also measured before and for 3 consecutive days after the PVI procedure; the maximum CRP level and rise in the CRP ( CRP), defined as the difference between the maximum CRP and CRP before the ablation, were obtained (7). During the first 3 days after ablation, all patients were examined for the presence of frequent atrial premature contractions (APCs), defined as 1 APCs within 1 min, and nonsustained AF lasting for 3s(7). The of AF within the first month only was considered transient (3,11). This first 1-month period was applied as a blanking period and was used to classify the patients into the 3 AF subgroups and to account for the fact that AF s early after the PVI may be transient and may not necessarily imply a failed ablation. Only the prevalence of AF s during the period from 31 days to 14 months after the ablation was examined. Statistical analysis. From the results of a single procedure outcome of PVI for paroxysmal AF (12,13) and a relative decrease in AF occurrences after cardiac surgery (9), we assumed that sinus rhythm would be present at 14 months after ablation in 8% of patients who received corticosteroid therapy after the ablation and in 5% of patients who did not. We estimated that a minimum of 52 patients were required in each group to give the study a statistical power of 9% with a 2-tailed alpha value of.5. Continuous variables are expressed as the mean SD. A Student t test or analysis of variance with a Tukey analysis was used to analyze the differences between groups, as appropriate. For non-normally distributed data, a Kruskal-Wallis test was used when comparing more than 3 groups, and the Mann- Whitney U test was used when comparing 2 groups. A B C Body temperature ( C) p<.5 CRP (mg/dl) p<.1 APCs (%) p= / /65 Placebo Corticosteroid Placebo Corticosteroid Placebo Corticosteroid 3 p<.1 1. p<.1 1 p=.3 Δ Body temperature ( C) 2 1 Δ CRP (mg/dl) 5. n-sustained AF (%) /65 1/6. Placebo Corticosteroid Placebo Corticosteroid Placebo Corticosteroid Figure 2 Differences in Clinical Parameters Between the Placebo and Corticosteroid Groups During the Initial 3 Days After a Pulmonary Vein Isolation Procedure (A) Body temperature and the difference between the highest body temperature (top) for the 3 days and the body temperature measured before the ablation ( BT, bottom). (B) Maximum level of C-reactive protein (CRP) (top) and the difference between the maximum CRP and CRP before ablation ( CRP, bottom). Data are shown as the distribution (left) and mean SD (right) for each group. (C) Prevalence of frequent atrial premature contractions (APCs, top) and nonsustained atrial fibrillation (AF) (bottom).

5 JACC Vol. 56,. 18, 21 October 26, 21: Koyama et al. Corticosteroids Suppress AF After Ablation 1467 Categorical variables were compared by a chi-square analysis and Yates correction, if necessary. A univariate and multivariate logistic regression analysis was used to identify predictors of immediate and early AF s. A Cox regression analysis was also used to identify predictors of AF s during the 14-month follow-up period. All parameters with a significance.1 in the univariate analysis were entered into the multivariate model. A receiver-operator characteristic curve analysis was used to determine the ability of the BT or CRP level to predict AF s. The time to AF s was estimated by the Kaplan-Meier method, with comparisons made using the log-rank test. A p value.5 was considered significant. Results Study design and participants. In the corticosteroid group, 5 patients were excluded from this study: 3 refused to participate, and 2 patients with non-pulmonary vein (PV) foci from the superior vena cava that triggered AF before the transseptal puncture, did not undergo PVI. patients in the placebo group were excluded from this study. As a result, 125 patients were enrolled and randomized under this protocol: corticosteroid group (n 6) and placebo group (n 65) (Fig. 1). Baseline characteristics and acute results of catheter ablation. Although the duration of an AF history was longer in the corticosteroid group than placebo group (p.1), no significant differences were found in terms of the other variables between the 2 groups (Table 1). Extensive PVI and cavotricuspid isthmus ablation were successfully performed in all patients, and bidirectional conduction block was created at all 4 PVs and the cavo-tricuspid isthmus. Linear ablation of the left atrial roof and/or superior vena cava isolation were performed in 1 patients with sustained AF (n 3) or induced AF lasting more than 3 min (n 7) A Placebo p <.1 B Steroid therapy p =.17 Body temperature ( C) p <.1 p =.35 Body temperature ( C) p =.28 p =.97 p <.1 p =.11 Δ Body temperature ( C) p <.1 p =.69 Δ Body temperature ( C) p =.18 p =.97 Figure 3 Relationship Between the Atrial Fibrillation Recurrence Patterns and Body Temperature and Change in Body Temperature (A) Placebo group. (B) Corticosteroid group. Data are shown as the distribution (left) and mean SD (right) for each group.

6 1468 Koyama et al. JACC Vol. 56,. 18, 21 Corticosteroids Suppress AF After Ablation October 26, 21: (Table 1). A mitral isthmus line was not created in any of the patients. Catheter ablation parameters and prevalence of additional ablation were comparable between the 2 groups (Table 1). AF during the initial 1-month follow-up period after ablation. During the initial 1 month after ablation, AF s were observed less frequently in the corticosteroid group (16 patients, 27%) than in the placebo group (32 patients, 49%; p.1) (Fig. 1). A subgroup analysis of the patients in the 2 groups showed the prevalence of early AF s in the corticosteroid group (2%) was comparable to that (18%) in the placebo group (p.9). However, the prevalence of immediate AF s in the corticosteroid group (7%) was less than that in the placebo group (31%; p.1) (Fig. 1). Inflammatory responses, pericarditis, and atrial arrhythmias during the initial 3 days after ablation. During the initial 3 days after the PVI, the highest BT (p.5) and BT (p.1) were both lower in the corticosteroid group (Fig. 2A). The maximum CRP and CRP in the corticosteroid group were also lower than those in the placebo group (both, p.1) (Fig. 2B). Only 1 placebo group patient reported slight chest pain transiently with deep breaths, but no pericardial effusion or electrocardiographic changes suggestive of pericarditis were found. The prevalence of frequent APCs and nonsustained AF did not differ between the 2 groups (Fig. 2C). Subgroup analysis of inflammatory responses. In the placebo group, both the highest BT and BT during the initial 3 days after the PVI were greater in the immediate AF group than the other 2 subgroups (both p.1) (Fig. 3A); however, in the corticosteroid group, these variables were comparable among the 3 subgroups (Fig. 3B). In the placebo group, both the maximum CRP and CRP in the immediate AF group were the highest among the 3 subgroups (maximum CRP; p.1, CRP; p.1) (Fig. 4A). However, in the corticosteroid group, there was no significant difference in these variables among the 3 subgroups (Fig. 4B). The leukocyte count was comparable among the 3 subgroups of both groups (data not shown). A Placebo p =.1 B Steroid therapy p = p =.2 p = p =.27 p =.98 CRP (mg/dl) 5. CRP (mg/dl) 5... p <.1 p = p =.2 p = p =.18 p =.97 Δ CRP (mg/dl) 5. Δ CRP (mg/dl) 5... Figure 4 Relationship Between the AF Recurrence Patterns and CRP Levels (A) Placebo group. (B) Corticosteroid group. Data are shown as the distribution (left) and mean SD (right) for each group. Abbreviations as in Figure 2.

7 JACC Vol. 56,. 18, 21 October 26, 21: Koyama et al. Corticosteroids Suppress AF After Ablation 1469 In the placebo and corticosteroid groups, frequent APCs and nonsustained AF were observed more often in the early AF group than in the immediate AF and no AF groups, and the differences among the 3 subgroups were statistically significant in both groups (Figs. 5A and 5B). significant differences were found for these variables among the subgroups of the placebo and corticosteroid groups. Post-ablation course and resolution of AF s. During the ablation procedure and 14-month follow-up, no major complications occurred in any patients. Groin hemorrhages occurred in 2 patients but resolved with manual and bandage compression. In the placebo group, recurrent AF attacks disappeared in 14 (7%) of 2 patients with immediate AF s and in 4 (33%) of 12 with early AF s between 31 days and 14 months after the PVI (Fig. 1). However, in the corticosteroid group, recurrent AF attacks disappeared in all 4 (1%) patients with immediate AF s and in 6 (5%) of 12 with early AF s during that period. Thus, the prevalence of no AF s without any antiarrhythmic drugs at 14 months post-ablation was greater in the corticosteroid group (85%) than in the placebo group (71%; p.5) (Fig. 1). sustained atrial tachycardia was observed in any patients in either group during this period. The prevalence of an AF-free rate at 14 months postablation in the subgroup analysis of the patients with immediate AF s was higher in the corticosteroid group than in the placebo group (4 of 4 [1%] vs. 14 of 2 [7%]; p.5) (Fig. 1). However, it was comparable in the patients with early AF s (corticosteroid group, 6 of 12 [5%] vs. placebo group, 14 of 2 [33%], p.43) (Fig. 1). A Kaplan-Meier survival analysis showed that the AFfree rate without any antiarrhythmic drugs at 14 months post-ablation was greater in the corticosteroid group than in the placebo group (p.32 by the log-rank test) (Fig. 6). A Placebo p =.53 B Steroid therapy p =.62 APCs (%) 1 5 p <.5 7/12 p <.1 APCs (%) 1 5 p <.1 11/12 p < /2 2/33 25 /4 8/44 p <.5 p =.92 1 p <.5 p <.1 1 p <.1 p <.1 n-sustained AF (%) /2 8/12 2/33 n-sustained AF (%) 5 25 /4 8/12 2/44 Figure 5 Relationship Between the AF Recurrence Patterns and Prevalence of APCs and nsustained AF (A) Placebo group. (B) Corticosteroid group. Abbreviations as in Figure 2.

8 147 Koyama et al. JACC Vol. 56,. 18, 21 Corticosteroids Suppress AF After Ablation October 26, 21: Freedom from AF Blanking period Corticosteroid-group Placebo-group Log-rank test: p= Months of Follow up Univariate AF Recurrences and Univariate Multivariate After and Multivariate Catheter Analyses Ablation of Analyses of Table 3 AF Recurrences After Catheter Ablation Univariate analysis p Value Odds Ratio 95% Confidence Interval Frequent APCs nsustained AF Highest body temperature, C Body temperature, C Highest CRP, mg/dl CRP, mg/dl Corticosteroid treatment Multivariate analysis Frequent APCs nsustained AF Corticosteroid treatment Figure 6 Kaplan-Meier Curve of the Freedom From AF Kaplan-Meier plot of the effect of the corticosteroid treatment on the incidence of recurrent atrial fibrillation (AF) after pulmonary vein isolation. Predictors of AF after ablation. A logistic regression analysis revealed that the BT (odds ratio [OR]: 32.33; 95% confidence interval [CI]: 7.76 to 147.7; p.1) and CRP (OR: 1.739; 95% CI: 1.7 to 3.5; p.47) were associated with immediate AF s (Table 2). APCs (OR: 15.96; 95% CI: 4. to 63.66; p.1), and nonsustained AF during the initial 3 days after ablation (OR: 7; 95% CI: to 81.62; p.1) were associated with early AF s (Table 3). In the Cox regression analysis including the highest BT, maximum CRP, frequent APCs, nonsustained AF, and corticosteroid treatment, APCs (hazard ratio: 3.56; 95% CI: 1.89 to 7.7; p.1), and nonsustained AF (hazard ratio: 3.526, 95% CI: to 6.697; p.1) were associated with AF s during the follow-up period (Table 4). Corticosteroid treatment decreased AF Univariate and AF Univariate Recurrences Multivariate and Multivariate After Analyses Catheter of Analyses Ablationof Table 2 AF Recurrences After Catheter Ablation Univariate analysis p Value Odds Ratio 95% Confidence Interval Frequent APCs nsustained AF Highest body temperature, C Body temperature, C Highest CRP, mg/dl CRP, mg/dl Corticosteroid treatment Multivariate analysis Highest body temperature, C Highest CRP, mg/dl Corticosteroid treatment AF atrial fibrillation; APC atrial premature contraction; CRP C-reactive protein. Abbreviations as in Table 2. s during the follow-up period (hazard ratio:.458; 95% CI:.226 to.929; p.31). By a receiveroperator characteristic analysis, a post-crp level of 1.21 mg/dl was the threshold value for AF s with 91.7% sensitivity and 97.2% specificity (area under the curve:.871, p.1) and a BT of 37.6 C with 79.2% sensitivity and 95.% specificity could distinguish patients with AF s (area under the curve:.95, p.1). Discussion Major findings. The present study showed the following: 1) acute inflammatory responses occurring during the initial 3 days after PVI were greater in patients with immediate AF s than in those with early AF s; 2) corticosteroid treatment inhibited inflammatory responses and decreased immediate AF s; 3) corticosteroid treatment was associated with fewer AF s at 1 month after PVI and during the 14 months after the initial 1-month follow-up; and 4) corticosteroid treatment did not reduce early AF s or affect the AF-free rate at 14 months in patients with early AF s or no AF s within 1 month after PVI. Inflammation and AF s after ablation. The CRP levels were more than 2-fold higher in patients with AF than in control patients, and the persistent AF patients had higher CRP levels than those with paroxysmal AF (14). Cox AfterRegression Catheter Cox Ablation Analysis Regression of AF Analysis Recurrences of AF Recurrences Table 4 After Catheter Ablation Variables p Value Hazard Ratio 95% Confidence Interval Highest body temperature, C Highest CRP levels, mg/dl Frequent APCs ( 1 APCs within 1 min) nsustained AF Corticosteroid treatment Abbreviations as in Table 2.

9 JACC Vol. 56,. 18, 21 October 26, 21: Koyama et al. Corticosteroids Suppress AF After Ablation 1471 A recent study demonstrated that the leukocyte count was an independent pre-ablative predictor of AF s after PVI (5). These findings suggest that non- or preoperative inflammation may play a prominent role in the etiology, initiation, and maintenance of AF (5,6,15). It is well-known that AF often occurs several days after cardiac surgery (9) as well as after successful electrical cardioversion (6,16). The serum CRP and cytokine levels correspond to AF rates after cardiac surgery (17), and CRP levels can be elevated within the first 24 h after AF initiation after successful electrical cardioversion (6). In the PVI procedure, extensive radiofrequency energy delivered throughout the left atrium may result in significant and extensive histopathologic tissue damage (18). Therefore, we think that in the genesis of AF shortly after a successful AF ablation, the inflammation surge caused by the procedure is important, and the transient use of very low-dose corticosteroids is effective for inhibiting immediate AF s after PVI. In the present study, early AF s occurring within 4 days to 1 month after ablation were not associated with an inflammatory response, which is the same result obtained in a previous study (7). Furthermore, in patients with early AF s, the prevalence of an AF-free rate at 14 months did not differ between the 2 groups. Recovered conduction between the left atrium and PVs and the appearance of non-pv foci triggering AF might be responsible for the early AF s (19). Effect of corticosteroids on late s of AF after PVI. We found that corticosteroid treatment decreased the overall prevalence of AF at 14 months postablation by preventing immediate AF s caused by inflammatory responses. Because the biological half-life of prednisolone is 12 to 36 h and because it was used only for the initial 3 days after ablation in the present study, the effects of prednisolone, including suppression of the inflammatory response, could last for more than these first 3 days. However, it seems fairly implausible that corticosteroid use shortly after PVI could prevent reconduction between the left atrium and PVs over the long term. Structural and electrical remodeling commences within a few hours of the onset of AF, whereas reverse remodeling after restoration of sinus rhythm occurs much more slowly (2). This longer AF-free period after ablation in patients with corticosteroids might have enabled the atria to halt any electrical or functional remodeling and allowed reverse remodeling to progress, resulting in a greater AF-free rate at 14 months post-ablation. Atrial tachyarrhythmias also cause inflammation (21), and such induced inflammation might cause AF. Corticosteroid treatment administered shortly after PVI might halt the relationship between inflammation and rapid atrial arrhythmia formation, which may represent a vicious cycle. Utility and significance of early reablation procedures. The efficacy of an early repeat ablation after the initial ablation procedure has been reported (22). However, several studies (2 4,7) and our present results show that a delayed cure for AF despite early after PVI is found in a considerable number of patients, and the prevalence in patients with AF recurring within a few days to 1 month after PVI is reported to be as high as 76% (7) and 57% (2), respectively. Therefore, in patients with early and especially with AF within a few days after the ablation, relatively quick resolution of the AF episodes can be expected, and an early reablation procedure may not be indicated in most of these patients. Study limitations. First, this study included a relatively small number of patients and a short follow-up period, and some patients with asymptomatic AF might have been missed. Second, the effect and risk of various doses of corticosteroids on AF s after PVI were not examined or determined. Third, our findings were not confirmed by a protocol using different ablation methods, ablation catheters, or energy settings. Fourth, the serum CRP and BT are nonspecific markers of inflammation, especially in the acute phase, and the origin of those inflammatory responses after the ablation has not been clarified. Finally, the precise mechanism of corticosteroid use shortly after PVI for preventing AF in the long term could not be clarified. Conclusions Transient use of small amounts of corticosteroids shortly after AF ablation may be effective and safe for preventing not only immediate AF s but also AF s during the mid-term follow-up period after PVI. Reprint requests and correspondence: Dr. Takashi Koyama, Cardiovascular Division, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba 35-85, Ibaraki, Japan. tkoyama-tym@umin.ac.jp. REFERENCES 1. Shah AN, Mittal S, Sichrovsky TC, et al. Long-term outcome following successful pulmonary vein isolation: pattern and prediction of very late. J Cardiovasc Electrophysiol 28;19: Lee SH, Tai CT, Hsieh MH, et al. Predictors of early and late of atrial fibrillation after catheter ablation of paroxysmal atrial fibrillation. J Interv Card Electrophysiol 24;1: Oral H, Knight BP, Ozaydin M, et al. Clinical significance of early of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol 22;4: Richter B, Gwechenberger M, Socas A, et al. Frequency of of atrial fibrillation within 48 hours after ablation and its impact on long-term outcome. Am J Cardiol 28;11: Issac TT, Dokainish H, Lakkis NM. 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