Reduction of myocardial necrosis using “CLOSE” protocol during pulmonary vein isolation—Preliminary results from ACTIVE‐AF trial

Abstract Background New protocols of pulmonary veins isolation (PVI) result in easier and more efficient procedure performance. Ablation index (AI) is the novel tool which helps to achieve transmural lesions during catheter ablation. However, benefit of this protocol in the reduction of myocardial injury is still not known. Purpose The aim of the study was to compare myocardial injury during catheter ablation using standard and AI protocol. Methods To the analysis we included 24 patients with paroxysmal atrial fibrillation, who underwent radiofrequency catheter PVI using CARTO system (Biosense Webster, Inc). In all patients cardiac troponin I (cTnI) levels were assessed before and 24 hours after the procedure. In 12 patients PVI was performed using continuous applications (dragging technique) and in 12 patients during PVI ablation AI protocol was implemented. To unify analyzed groups, we excluded patients with additional ablation lines (including line separating ipsilateral pulmonary veins). Results In analyzed group mean age was 59.3 ± 7.7 years and 18 (75%) patients were male. There were no differences in the clinical characteristic between both subgroups. Trend in shorter total x‐ray time was observed in AI group compared with dragging group (8.6 ± 5.4 vs. 5.3 ± 3.2 min.; P = .093) with no differences in total procedure time (146.3 ± 28.9 vs. 153.2 ± 37.1 min.; P = .616). Twenty‐four hours after the PVI procedure cTnI levels were significantly lower in AI group than in dragging group (1.984 ± 0.644 vs. 3.369 ± 1.818 ng/mL; P = .026), with no difference in mean baseline cTnI levels (0.004 ± 0.006 vs. 0.015 ± 0.032 ng/mL; P = .304). Conclusion Presented study revealed that compared with standard, continuous applications, AI protocol implementation results in reduction of myocardial injury during catheter PVI in patients with paroxysmal atrial fibrillation.


| INTRODUC TI ON
According to current guidelines, pulmonary vein isolation (PVI) should be performed in symptomatic patients in whom we use a rhythm control strategy, especially in the absence of antiarrhythmic drug efficacy. 1 Despite of the lack of mortality reduction with PVI compared to antiarrhythmic drugs, invasive treatment significantly reduces the incidence of arrhythmias. 2 In recent years we have observed the development of invasive techniques. However, the frequency of atrial fibrillation (AF) recurrence after PVI treatment is still relatively high, which is a significant limitation of this method. Previous studies have indicated that 40%-80% of patients with paroxysmal AF experience a 1-year period free of recurrent arrhythmias. [3][4][5][6][7] The effectiveness of the 12-month AF-free period was significantly improved when using the CLOSE protocol, where it was 94% compared to 80% in patients using conventional contact force guided PVI. 8 The CLOSE protocol considers the Ablation Index (AI) parameter, which is a function that takes into account the radiofrequency (RF) application power, contact force, and duration of the application. AI can only be used when using the point-by-point method. Some operators, however, apply a dragging technique involving continuous application and gradual shifting of the catheter to achieve an ablative line. Although both methods allow PVI to be obtained, looking at the results of recent studies, it seems that the point-by-point method-especially with the use of AI-allows more permanent changes to be made which results in a reduction in the frequency of AF recurrences.
RF ablation is associated with intentional damage to the myocardium to achieve PVI. 9 It seems that the size of the damage to the muscular tissue of the heart affects the magnitude of the inflammatory response, which may affect the rate of recurrence of arrhythmias. 10 In addition, numerous applications, especially those that do not cause transmural damage to the myocardium, may increase the risk of atrial flutter-an arrhythmia observed in some patients after

PVI. 11
The aim of the presented study is to compare the amount of damaged myocardial tissue, assessed by the serum level cardiac troponin I (cTnI), among patients after PVI performed point-by-point (CLOSE protocol) and dragging technique.

| ME THODS
The current study is the subanalysis of the ACTIVE-AF (Inflammatory

Response as a Prognostic Factor of Recurrence of Atrial Fibrillation
After Ablation) trial (NCT02844959). The ACTIVE-AF study was designed to evaluate inflammatory response as a prognostic factor of AF recurrence after ablation. Patients ≥ 18 years old with paroxysmal AF qualified for radiofrequency PVI procedure were included in the study. Exclusion criteria were as follows: previous PVI procedure, planned ablation other than PVI during the procedure, AF at the beginning of ablation procedure, direct current cardioversion during the procedure or in 24 hours after the procedure, usage of "single shot" devices. All patients underwent 7-day Holter monitoring directly after the PVI was performed. Blood samples were collected twice: right before the ablation-taken from the vascular sheath in the femoral vein and 24 hours after the end of the PVI procedure. Study was registered on clinicaltrials.gov (NCT02844959). All patients signed informed consent for participation in the trial. The study protocol was approved by the local Ethics Board (number KB/143/2016).

| Follow-up
In every patient after PVI procedure four 24-hours Holter ECG tests at 3-months intervals were recommended to perform. Patients' follow-up was conducted based on Holter ECG test results and a telephone conversation. Arrhythmia recurrence diagnosis was based on a minimum 30-seconds episode of AF, atrial flutter or atrial tachycardia recorded by Holter ECG or one of these arrhythmias recorded by 12-lead ECG.

| Laboratory assessment
All laboratory assessments were performed from venous blood samples. Troponin I level was assessed directly before the procedure and 24 hours after the end of procedure. All other parameters including compete blood count, ions, creatinine, and liver enzymes were assessed from blood samples collected in the 24 hours before the procedure. In the following analysis, there was lack of baseline cTnI assessment in one patient in dragging group and in two patients in AI group. These patients were excluded from the analysis assessing cTnI changes. All laboratory assessments were performed directly after the blood sample collection. To assess cTnI level Siemens Dimension EXL automatic chemiluminescence immunoassay analyzer was used.
According to the reagent manufacturer's documentation, normal values of cTnI were considered as 0.00-0.056 ng/mL.

| RE SULTS
Of the 29 patients screened for the presented study, 24 were included for the final analysis, 18 (75%) male and 6 (25%) female. The mean age of patients was 59.3 ± 7.7 years. There were no differences in the clinical characteristics between both groups. A lower contact force during RF applications (11.5 ± 1.7 vs. 13.3 ± 2.1; P = .04) and trend in shorter total x-ray time (8.6 ± 5.4 vs. 5.3 ± 3.2 min.; P = .093) was observed in the AI group compared with the standard group with no differences in total procedure time (146.3 ± 28.9 vs.
CTnI levels 24 hours after PVI procedure positively correlated with total RF application time in the dragging group (r = .76; P = .005). While, this relationship was not observed in the AI group (r = .06; P = .81) (Figure 4). Similarly, a trend was observed in the dragging group between cTnI levels 24 hours after PVI and age (r = .54; P = .07) without correlation between these two variables in the AI group (r = −.41; P = .18) ( Figure 5).

| D ISCUSS I ON
The presented study showed that PVI with CLOSE protocol using AI results in a reduction of myocardial necrosis assessed with serum cTnI level compared to the dragging technique. A positive correlation between total RF time and serum cTnI level was revealed only in the dragging group.
The increase in the concentration of markers of myocardial necrosis after RF ablation was confirmed in previously published studies. Haegeli et al showed that 4 hours from the end of ablation, cTnT was elevated and its value exceeded the cut-off point for the diagnosis of acute myocardial infarction (AMI). 13 Interesting results were also obtained in the study evaluating the stability of biomarkers of myocardial necrosis and comparing the concentrations of these biomarkers between patients who underwent PVI with RF and who underwent PVI with balloon cryoablation. 14 The first important finding in this study was the high stability of cTnI molecule at both low and high temperatures. This means that the high temperature reached during RF application should not have a significant effect on the obtained results of cTnI level. Secondly, this study showed that an increase in cTnI concentration above the cut-off level for AMI had already occurred in the first hour after the end of the procedure. It is worth bearing in mind, however, that the start time of an RF application is on average >1 hour before the end of the procedure.
It has been shown that in case of acute AMI, the peak cTnI concentration is reached after 18-24 hours of symptoms onset and an increase above the upper limit of the norm may persist for up to 14 days. 15 Results of studies describing the effect of troponin on the size of the myocardial necrosis are not conclusive. 16 A study by Chia et al analyzing serial cTnI serum concentration assessments in patients after AMI treated with primary coronary angioplasty, showed the best correlation between cTnI concentration and the size of cardiac necrosis for blood samples collected ≥24 hours after onset of ischemia. 17 Bearing in mind the variable total time of RF applications in the analyzed patients, it seems that blood samples collected 24 hours after the end of the procedure allow determination of the study showed a strong correlation between the total RF application time and the cTnI serum levels evaluated 6 hours after the end of the procedure. 19 An analogous relationship was demonstrated in the presented analysis only in the dragging group. The lack of such correlation in the AI groups may again indicate more targeted changes and greater stability of the ablation catheter position.
Outcome of the patients after the PVI differed between the groups, however, it did not reach statistical significance. Small number of patients in both groups seems to be an important limitation in comparison of the procedure effectiveness. In presented study, in the AI group effectiveness of single PVI procedure was lower than described in Phlips et al publication. 8

| CON CLUS IONS
The presented study revealed that compared with standard, continuous applications (dragging technique), CLOSE protocol implementation results in a reduction of myocardial injury during catheter PVI in patients with paroxysmal AF. Moreover, when using CLOSE protocol, myocardial injury is independent of RF application time.