Cerebral microembolization during atrial fibrillation ablation: comparison of different single-shot ablation techniques

Elsevier Editorial System(tm) for International Journal of Cardiology Manuscript Draft Manuscript Number: IJC-D-14-00422R1 Title: Cerebral microembolization during atrial fibrillation ablation:comparison of different single-shot ablation techniques Article Type: Original Article Keywords: atrial fibrillation, pulmonary vein isolation, transcranial Doppler, cerebral microemboli Corresponding Author: Dr. Alexandra Kiss, Corresponding Author's Institution: First Author: Alexandra Kiss Order of Authors: Alexandra Kiss; Edina Nagy-Balo, MD; Gábor Sándorfi, MD; István Édes, MD, PhD, Dsc; Zoltán Csanádi, MD, PhD Manuscript Region of Origin: HUNGARY Abstract: Background: Clinically silent cerebral ischemia (SCI) detected by diffusion-weighted MRI has been reported in 5-40% of patients undergoing pulmonary vein isolation (PVI). Although initial reports suggested a high rate of SCI with phased radiofrequency (RF) ablation on use of the pulmonary vein ablation catheter (PVAC), the incidence was subsequently markedly reduced in consequence of procedural modifications in recent studies. We analyzed cerebral microembolization as assessed with transcranial Doppler during phased RF ablation and with two other single-shot AF ablation technologies: the cryoballoon (CB) and the nMARQTM multipolar irrigated RF ablation system. Methods and results: A total of 89 patients (mean age: 57, SD: 12 years; 62 male) with paroxysmal or persistent AF, underwent PVI. Phased RF was used according to the initial protocol in 7 patients (PVAC Group I), with procedural modifications and a newer (14.4) version of the RF generator in 37 patients (PVAC Group II) and with the most recent (version 15.0) generator in 18 patients (PVAC Group III). Ablation was performed with the CB in 13 and with the nMARQ system in 14 patients. The number of microemboli (mean+(SD) detected in the middle cerebral arteries was 2703(918) in PVAC Group I, 1087(542) in PVAC Group II, 719(469) in PVAC Group III, 1057(784) with CB and 2166(1047) with nMARQ (p<0.01). Conclusion: Significant decreases in MES counts were observed thanks to the procedural modifications and newer RF generator with phased RF. High MES counts comparable to those with the initial phased RF resulted from the use of nMARQ. Suggested Reviewers: Ms. Ref. No.: IJC-D-14-00422 Title: Cerebral microembolization during atrial fibrillation ablation:comparison of different single-shot ablation techniques. International Journal of Cardiology Prof. Andrew J.S. Coats Editor in Chief, International Journal of Cardiology Dear Professor Coats, We are grateful to the Editors of International Journal of Cardiology and the reviewer for the evaluation of our manuscript ”Cerebral microembolization during atrial fibrillation ablation:comparison of different single-shot ablation techniques. (Ref. No.: IJC-D-14-00422) as well as for the opportunity to resend its revised version. Please find our responses and the revised paper attached. We did our best to respond to all questions and concerns of the reviewer and to modify the manuscript according to her/his suggestion. We really appreciate your consideration. Sincerely, Alexandra Kiss MD Zoltan Csanadi MD Cover Letter Comments from the editors and reviewers: Reviewer #1: The main objective of this clinical study is to assess and quantify the microemboli produced by different ablative catheters and methods in patients that underwent catheter ablation for atrial fibrillation. The objective is interesting in itself and furthermore because the selected methodology includes PVAC catheters and RF source. It is already known since a few years, how the original PVAC method produce cerebral mIcroemboli. So the authors using the same ablation protocol of pulmonary vein isolation in all the patients included, compare the incidence and quantify the microemboli and its material solid or aereal, produced with the old and the new technology of PVAC altogether with cryoablation and also with the new system of consecutive RF delivery applied through a new brand irrigated catheter by Biosense Webster. The epidemiological importance of atrial fibrillation makes of it an important issue, furthermore because many ablated patients today are young and without any other disease. Cerebral microinfarction is then a big issue to be studied. Concerning the methodology as the authors point out being a single centre study, the numbers of patients in each group are low, to obtain a heavy weight on statistical analysis. Besides it is not a randomized study. Another limitation is the method selected by the authors of doppler analysis during the procedure of the mdiddle cerebral arteries. Certainly this objective is weaker and should be supplemented by pre and post cerebral MR. In any case as each methodology could serve as control for the rest, I induce that the results are truly valid. It seems that most of the microemboli are gas and also that the PVAC I, and the new Biosense catheter produce more microemboli that the ammended PAVC II and III altogether with cryoblation. Concerning preablation anticoagulation the authors should state exactly the period it has been prescribed. We changed the text in the Methods / Patients section and included this information: ”1. Pre-ablation treatment with a vitamin K antagonist (VKA) for a minimum of 3 weeks and a therapeutic (above 2.0) international normalized ratio (INR) confirmed on the day of the procedure, and activated clotting time (ACT) levels above 300 s during ablations.” The manuscript has same items typed in black and this must be changed. We realized that some parts of the text appeared in bold and Italic in the PDF generated during online submisson, despite the Word file we submitted did not contain such sections. We kindly ask for your technical assistance to solve this problem in case it occurs again during this resubmission. Bibliography is correct and appropriate. The tables and figures are apropriate but need abreviatures, for any one used in them. Complete list of abreviations were included to all tables and figures in the revised manuscript. The figure 1 need a detailed text explaining each of the panels and what is seen in any of them, otherwise it cannot be understood. Figure 1 has been reconstructed with arrows and labels for clarification. In addition figure legend has been modified to facilitate interpretation. ”Bilateral Multifrequency Transcranial Doppler Monitoring of the Middle Cerebral Arteries (a) Demonstration of beam alignment of both right and left sided MCA and ACA. Continuous yellow line indicates the location of monitoring at 55 mm insonation depth (MCA). (b) MCA waveform. Arrows on right panel indicate the high intensity transient signals corresponding to cerebral microemboli during PV angiography. MCA, middle cerebral artery; ACA, anterior cerebral artery ” Author Agreement Form – International Journal of Cardiology Manuscript Title: Cerebral microembolization during atrial fibrillation ablation: comparison of different single-shot ablation techniques List of all Authors: Alexandra Kiss, Edina Nagy-Baló, Gábor Sándorfi, István Édes, Zoltán Csanádi Corresponding Author: Alexandra Kiss This statement is to certify that all authors have seen and approved the manuscript being submitted, have contributed significantly to the work, attest to the validity and legitimacy of the data and its interpretation, and agree to its submission to the International Journal of Cardiology. We attest that the article is the Authors' original work, has not received prior publication and is not under consideration for publication elsewhere. We adhere to the statement of ethical publishing as appears in IJC 2013 (Shewan LG et al 2013 in press). On behalf of all Co-Authors, the corresponding Author shall bear full responsibility for the submission. *Author Agreement Form Ms. Ref. No.: IJC-D-14-00422 Title: Cerebral microembolization during atrial fibrillation ablation:comparison of different single-shot ablation techniques. International Journal of Cardiology Responses for Reviewer #1 Comments from the editors and reviewers: Reviewer #1: The main objective of this clinical study is to assess and quantify the microemboli produced by different ablative catheters and methods in patients that underwent catheter ablation for atrial fibrillation. The objective is interesting in itself and furthermore because the selected methodology includes PVAC catheters and RF source. It is already known since a few years, how the original PVAC method produce cerebral mIcroemboli. So the authors using the same ablation protocol of pulmonary vein isolation in all the patients included, compare the incidence and quantify the microemboli and its material solid or aereal, produced with the old and the new technology of PVAC altogether with cryoablation and also with the new system of consecutive RF delivery applied through a new brand irrigated catheter by Biosense Webster. The epidemiological importance of atrial fibrillation makes of it an important issue, furthermore because many ablated patients today are young and without any other disease. Cerebral microinfarction is then a big issue to be studied. Concerning the methodology as the authors point out being a single centre study, the numbers of patients in each group are low, to obtain a heavy weight on statistical analysis. Besides it is not a randomized study. Another limitation is the method selected by the authors of doppler analysis during the procedure of the mdiddle cerebral arteries. Certainly this objective is weaker and should be supplemented by pre and post cerebral MR. In any case as each methodology could serve as control for the rest, I induce that the results are truly valid. It seems that most of the microemboli are gas and also that the PVAC I, and the new Biosense catheter produce more microemboli that the ammended PAVC II and III altogether with cryoblation. Concerning preablation anticoagulation the authors should state exactly the period it has been prescribed. We changed the text in the Methods / Patients section and included this information: *Detailed Response to Reviewers ”1. Pre-ablation treatment with a vitamin K antagonist (VKA) for a minimum of 3 weeks and a therapeutic (above 2.0) international normalized ratio (INR) confirmed on the day of the procedure, and activated clotting time (ACT) levels above 300 s during ablations.” The manuscript has same items typed in black and this must be changed. We realized that some parts of the text appeared in bold and Italic in the PDF generated during online submisson, despite the Word file we submitted did not contain such sections. We kindly ask for your technical assistance to solve this problem in case it occurs again during this resubmission. Bibliography is correct and appropriate. The tables and figures are apropriate but need abreviatures, for any one used in them. Complete list of abreviations were included to all tables and figures in the revised manuscript. The figure 1 need a detailed text explaining each of the panels and what is seen in any of them, otherwise it cannot be understood. Figure 1 has been reconstructed with arrows and labels for clarification. In addition figure legend has been modified to facilitate interpretation. ”Bilateral Multifrequency Transcranial Doppler Monitoring of the Middle Cerebral Arteries (a) Demonstration of beam alignment of both right and left sided MCA and ACA. Continuous yellow line indicates the location of monitoring at 55 mm insonation depth (MCA). (b) MCA waveform. Arrows on right panel indicate the high intensity transient signals corresponding to cerebral microemboli during PV angiography. MCA, middle cerebral artery; ACA, anterior cerebral artery ” Electrophysiology Inc., Lowell, MA, USA), which was positioned selectively in each PV. The electrical conduction properties of the PV were assessed on the basis of the signals recorded by the PVAC electrodes after placement inside the ostium. Before the first RF application at each PV, the positions of the electrodes relative to the PV ostium were always confirmed by means of contrast injection through the FlexCath sheath. Care was always taken to apply the RF outside the PV in the antral region, targeting potentials of high amplitude on as many electrodes as possible for each application. RF energy was applied for 60 s, usually 3-4 times per PV, until PVI was achieved. The target temperature was 60 °C, measured separately for all bipoles. Any electrode pair that failed to reach at least 50 °C during RF delivery was switched off to avoid ineffective ED due to improper contact at the electrode-tissue interface. Common ostia were isolated by inserting the guidewire into the different side branches and ablating subsequent segments of the targeted veins. The PV conduction was reassessed after each RF application, the electrodes being advanced inside the ostium. The endpoint of the procedure was the electrical isolation of all PVs, as confirmed by an entrance block. The GENius RF generator is capable of delivering RF in a duty-cycled mode with different bipolar/unipolar ratios to any or all of the electrodes on the PVAC. Three consecutive versions of the GENius RF generator (Medtronic Inc. , Minneapolis, MN, USA) were used in the course of recent years, also coupled with some procedural modifications as follows: 1. PVAC Group I. Initial series of ablations were performed with the use of software version 14.3 for the GENius generator. Bipolar/unipolar RF application was started at a ratio of 4:1 for each PV and changed to a bipolar/unipolar ratio of 2:1 for a deeper lesion when a sufficient reduction in local electrogram amplitude could not be achieved after multiple RF deliveries. No attempts were made to avoid the potential interaction between the first and the last electrode (E1-E10) in the PVAC. 2. PVAC Group II. Ablations were performed with software version 14.4 for the GENius generator. Modifications in the procedural technique were implemented in this group of patients as follows. Potential interaction between the most distal (E1) and the most proximal (E10) electrodes was considered and simultaneous EDs on these poles were attempted only after fluoroscopic assessment of the interelectrode distance, which was considered adequate if the space between E1 and E10 was at least double the fixed 3-mm interelectrode distance as assessed from multiple projections. Furthermore, ablations were started in the 2:1 mode and changed to 1:1 in those rare instances when adequate amplitude change and PVI could not be achieved after multiple RF applications. In addition, the distal circular segment of the PVAC catheter was submerged and captured by the introduction device in a saline bath prior to insertion into the FlexCath sheath. This maneuver was used to prevent air entrapment around the array and the introduction of air into the LA through the transseptal sheath. 3. PVAC Group III. Ablations were performed using the most recent software version (15.0) for the GENius generator. RF delivery to E10 is not supported by this software thereby excluding the possibility of E1-E10 interaction. No procedural modifications as compared to those in PVAC Group II. were implemented during these ablations. CB ablation The technology of CB ablation has been described in detail [17]. In brief, a 28-mm CB was used in all cases. The CB was introduced into the PV ostium over an inner lumen mapping catheter (Achieve, Medtronic Ablation Frontiers LCC, Carlsbad, CA, USA) which is capable of mapping PV potentials before, during and after cryo applications. The best possible occlusion of the PVs was facilitated by the steerable sheath and by positioning the guidewire in a PV branch to provide maximal support. Furthermore, all special maneuvers described previously, such as the “pull-down” or the “hockey stick” techniques, were used as needed [21]. PV occlusion was assessed by means of a hand-held injection of contrast medium (Optiray Covidien Deutschland GmbH, Neustadt/Donau, Germany) through the injection side-port of the Arctic Front catheter. A minimum of two 5-min freezing cycles were applied per PV. The balloon was repositioned for each application, preferably with the guidewire situated in a different branch of the PV in order to maximize the effect of freezing at different aspects of the ostium. Before the start of ablation of the septal veins, a quadripolar catheter was placed in the superior caval vein, where constant capture of the right phrenic nerve could be achieved. One stimulus at maximal output was delivered every 5 s, with manual assessment of the diaphragmatic movement. The freezing cycle was terminated immediately if loss or weakening of the diaphragm response occurred. PVI was assessed on the basis of the signals recorded by the Achieve wire. nMARQ ablation The nMARQ™ (Biosense Webster, Inc., Diamond Bar, CA, USA) is a multielectrode, irrigated RF ablation catheter with a uni-directional deflectable tip. The distal tip section is circular or semilunar and contains 10 platinum ring electrodes with irrigation holes at both ends for stimulation, recording and ablation. The diameter of the circular or semilunar loop is variable to accommodate the LA anatomy. The catheter is integrated with the CARTO 3 electroanatomical mapping system, which provides mapping and real-time navigation capabilities. For ablation, the catheter is used in conjunction with the nMARQ™ Multi-Channel RF Generator, which is able to deliver RF simultaneously to multiple electrodes in unipolar or bipolar mode. The circular-tip catheter was used exclusively in this study. The catheter was advanced to the LA through the FlexCath guiding sheath. The 3-dimensional map of the LA was constructed by using the CARTOTM electroanatomical mapping system (Biosense Webster, Inc., Diamond Bar, CA, USA) equipped with CartomergeTM software (Biosense Webster, Inc., Diamond Bar, CA, USA). The pre-ablation cardiac CT image of the LA with the proximal portions of the PVs was imported and registered for real-time mapping, focusing on the PVs and the PV antra of the LA. In addition, the positions of the electrodes relative to the PV ostium were always confirmed before the first RF application at each PV, by means of contrast injection through the FlexCath sheath. Care was taken to apply the RF outside the PV in the antral region, targeting potentials of high amplitude on as many electrodes as possible for each application. RF energy was applied for up to a maximum of 60 s at a maximum of 20 W/electrode in the unipolar mode, with the target temperature set at 43 °C. Electrodes not demonstrating the desired rise in temperature up to 40 °C during energy delivery were switched off. The irrigation flow rate between RF applications was 4 ml/min, which was increased to 60 ml/min, starting 5 s before the onset of RF application and maintained until 5 s after termination. The electrical conduction properties of the PVs were assessed via the recordings through the electrodes of the nMARQ catheter. The endpoint of the procedure was the electrical isolation of all PVs, as confirmed by an entrance block. TCD recording and evaluation of the MES count TCD recording was performed throughout the whole period of LA access (from the transseptal puncture to the removal of all catheters and sheaths from the LA). The transducer was held in place by a proprietary headpiece supplied with the system. The MCAs were bilaterally insonated from transtemporal windows by using a multifrequency Doppler (Multi Dop T digital, DWL, QL software 2.8) which insonates simultaneously with frequencies of 2 and 2.5 MHz. The system is capable of the automatic online identification of true MESs with a sensitivity of 100% and a specificity of 99.3% [22], and also of discrimination between gaseous and solid emboli with a specificity of 96.5%[23]. The identification of true MESs with parallel artefact rejection is possible by implementing an event detector system, using a previously published algorithm to detect high-intensity signals due to emboli[22]. This step is followed by a second algorithm using data from the dual-frequency insonation to determine whether the MESs are to be attributed to a solid or to a gaseous embolus. Differentiation is possible because the reflection of ultrasound power is dependent not only on the size of the embolus, but also on its composition and the insonating frequency used: solid emboli reflect more ultrasound at 2 MHz than at 2.5 MHz, whereas the opposite is true for gaseous emboli. TCD parameter settings as recommended by the consensus criteria [24] were kept constant during the procedures. The insonation depth was 45-55 mm, the sample volume was 8 mm, and the power was 60-100 mW. An example of a TCD record is given in Figure 1. MES counts were collected and evaluated separately during different stages of the procedure, as follows: 1. Transseptal puncture: the 30-s period after crossing the interatrial septum with the transseptal needle. 2. PV angiography: contrast injection through the injection port of the CryoCath catheter or the transseptal sheath during PVAC or nMARQ ablation. 3. Energy delivery: from the start until 15 s after the termination of ED 4. The remainder of the procedure: that part of the LA access period during which none of the aforementioned maneuvers were performed. As bilateral insonation of the MCA could not be achieved in all patients for technical reasons, the results were provided as MES count per MCA, i.e. either the mean of bilateral recordings or the number from the unilateral recording. Statistical analyses Statistical analysis was performed by using IBM SPSS 20. Data are reported as means and standard deviation (SD). In the case of Figure 1, data are shown as mean and 95% confidence intervals (95% CI). The normality of continuous variables was evaluated by means of the KolmogorovSmirnov test. Statistical differences between groups were determined by using analysis of variance when the data showed normal distribution and homoscedasticity (Levene’s statistic); otherwise, the Kruskal-Wallis test was performed. For comparison of the MES counts obtained during CB ablation versus those during the other 4 techniques, the Mann-Whitney test was used. In all statistical tests a p value below 0.05 was considered as significant. Results Patient characteristics A total of 89 patients were enrolled in the study. Demographic and clinical parameters on the patients in the 5 treatment groups are presented in Table 1. There were no significant intergroup differences in the baseline characteristics. Procedural data Procedural data are listed in Table 2. The total procedure, fluoroscopy, ED and LA access times demonstrated significant differences. The acute success rates were 100% in the 3 PVAC Groups, and 98% in both the CB and the nMARQ groups. The shortest LA access time was achieved in PVAC Group III, while the shortest ED time was obtained during ablation with the nMARQ. There were no significant differences between the intraprocedural ACT values. Symptomatic thromboembolic event did not occur in any patient. MES counts The MES count detected with the CB was used as a reference for comparison with the other technologies (Figure 2, left panel). No significant difference was found between the CB group, PVAC Group II (p=0.543) and PVAC Group III (p=0.317) in the total cerebral MES counts. However significantly higher MES counts were demonstrated in PVAC Group I (p=0.005) and with the nMARQ technique (p=0.007). The ratios of gaseous versus solid MESs detected in the 5 treatment groups did not differ significantly (p=0.688). (Figure 2, right panel) The distribution of the MES counts during different stages of the procedure is depicted in Figure 3. A relatively even distribution of embolus formation was observed across the whole LA access time in the CB group, and in PVAC Groups II and III, whereas, microemboli were detected mostly during ED in PVAC Group III and with nMARQ. Discussion Major differences have been reported in the incidence of SCI after AF ablation with various technologies and with the different methods and criteria applied to evaluate cerebral lesions. The diversity of the periprocedural anticoagulation routine in the various studies further hampers a direct comparison of the different AF ablation techniques. In the present study, we compared different single-shot ablation tools designed for PVI without additional LA ablation (eg. creating long linear lesions, or ablating complex fractionated electrograms) in patients with similar baseline characteristics. Further, periprocedural anticoagulation was homogeneous across all treatment groups with uninterrupted VKA administration and therapeutic INR level before the procedure and iv heparinization to a target ACT above 300 s in agreement with current recommendations [25]. Any differences demonstrated in the number of microemboli are therefore truly inherent to the ablation techniques compared. The rate of microembolization during phased RF ablation with the implementation of specific procedural modifications and the use of consecutive software versions of the GENius generator demonstrated a significant decrease in our study. The very same trend was observed in recent DW MRI studies on the rate of new SCI lesions after phased RF ablation. Importantly, no difference was detected in the level of microembolization between the procedure with CB ablation versus that with the PVAC after procedural and software changes had been implemented (PVAC Groups II and III). In contrast, significantly higher MES counts were recorded during phased RF ablation with the use of the old technique (PVAC Group I) and during ablation with nMARQ (Figure 2). The significant reduction in microembolization with phased RF was clearly related to the elimination of the MESs during the ED period of the procedure. Similarly to as observed in PVAC Group I, the majority of the microemboli were generated during ED with nMARQ, which also represents a multielectrode RF ablation technology (Figure 3). It is noteworthy that MESs were largely gaseous in nature in all treatment groups. Measures related to the reduction in cerebral embolization with phased RF ablation The significant reduction achieved in clinically silent microembolization, as demonstrated by DW MRI studies and our own results, were related to refinements in specific technical elements of the phased RF ablation, based on preclinical data [12,13].The observation of enhanced microembolization with blended unipolar:bipolar energy delivered through PVAC electrodes in close proximity to each other was of utmost importance. While this problem remained unknown, this was a likely common scenario, owing to the squeezed situation of the distal PVAC loop. It should be noted that actual physical contact between any two electrodes results in an electrical short circuit and immediate termination of the RF delivery. On the other hand, not contact, but a reduced interelectrode space (less than the fixed 3 mm between two neighboring electrodes mounted on the distal circular segment of the PVAC) may lead to blood and tissue overheating, due to a high current density. Simple measures to avoid this possibility include a careful fluoroscopic assessment of the electrode positions (as we did in PVAC Group II), exclusion of simultaneous RF ED to electrodes 1 and 10, as proposed by several authors [9-12] and a software modification implemented in the latest version of the GENius generator, which supports simultaneous RF delivery to a maximum of 9 electrodes (software version 15.0; PVAC Group III in our study). The earlier practice of starting ED in a 4:1 bipolar:unipolar mode at each PV was changed to start with a 2:1 ratio in PVAC Groups II and III. The rationale for this change was to avoid extensive bipolar ED and thereby reduce local heating between adjacent electrodes. Although animal data suggested a tendency for more microemboli with more bipolar RF delivery, the contribution of this change in the reduction of microemboli is uncertain. Nonetheless, starting with the 2:1 instead of the 4:1 ratio is the current practice at other centers [9-11,26]. As demonstrated in an animal model, a potential source of gaseous emboli was the introduction of air into the LA via the transseptal sheath. A significantly larger air volume was measured during the introduction of the PVAC, possibly owing to its more complex shape as compared with a conventional focal RF catheter. To prevent air entrapment around the array, the PVAC was submerged and captured by the introduction device in a saline bath prior to insertion into the FlexCath sheath. It is noteworthy that, in addition to the procedural changes as described above, the GENius RF generator has also been modified in recent years. An improved energy titration algorithm was implemented starting at version 14.4 (PVAC Group II), which regulates the power delivery to control the maximum, instead of the average temperature, with a target of 60 °C. Further, this software ensures a gradual and limited increase (4 W/s) during variable or intermittent electrode-tissue contact, to avoid high temperature peaks. The importance of the catheter-tissue contact has been highlighted since the introduction of contact force measurement for focal RF ablation catheters [27,28]. With multipolar ablation, this becomes even more critical, as the maintenance of good contact simultaneously on multiple electrodes 18. Boersma LV, Wijffels MC, Oral H, Wever EF, Morady F. Pulmonary vein isolation by duty-cycled bipolar and unipolar radiofrequency energy with a multielectrodeablation catheter. Heart Rhythm. 2008 Dec;5(12):1635-42. 19. Scharf C, Boersma L, Davies W, et al. Ablation of persistent atrial fibrillation using multielectrode catheters and duty-cycledradiofrequency energy. J Am Coll Cardiol. 2009 Oct 6;54(15):1450-6. 20. Boersma L, Duytschaever M, Geller JC, Scharf C. The PVAC Workbook Remedica, 2010 21. Chun KR, Schmidt B, Metzner A, et al. The 'single big cryoballoon' technique for acute pulmonary vein isolation in patients with paroxysmal atrial fibrillation: a prospective observational single centre study. Eur Heart J. 2009 Mar;30(6):699-709. 22. Russel D, Brucher R. Online automatic discrimination between solid and gaseous microemboli with the first multifrequency transcranial Doppler. Stroke. 2002 Aug; 33 (8):1975-80 23. Markus HS, Punter M. Can transcranial Doppler discriminate between solid and gaseous microemboli? Assessment of a dual-frequency transducer system. Stroke. 2005 Aug; 36(8):1731-4. 24. Ringelstein EB, Droste DW, Babikian VL, et al. Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection. Stroke. 1998; 29:725-729. 25. Calkins, H., Kuck, K. H., Cappato, R., et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Journal of Interventional Cardiac Electrophysiology, 33, 171–257. 26. Deneke T, Shin DI, Balta O, Postablation asymptomatic cerebral lesions: long-term follow-up using magnetic resonance imaging. Heart Rhythm. 2011 Nov;8(11):170511. 27. Neuzil P, Reddy VY, Kautzner J, et al.Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study.Circ Arrhythm Electrophysiol. 2013 Apr;6(2):327-33. 28. Kuck KH, Reddy VY, Schmidt B, et al. A novel radiofrequency ablation catheter using contact force sensing: Toccatastudy. Heart Rhythm. 2012 Jan;9(1):18-23. 29. Nagy-Balo E, Kiss A, Condie C, Stewart M, Edes I, Csanadi Z. Biophysical background of cerebral microembolization during phased radiofrequency ablation of atrial fibrillation: analysis of high resolution data from the ablation generator. European Heart Journal. 2013 34 ( Abstract Supplement ), 1096-1097 30. Khairy P, Chauvet P, Lehmann J, et al. Lower incidence of thrombus formation with cryoenergy versus radiofrequency catheter ablation. Circulation. 2003 Apr 22;107(15):2045-50. 31. Sauren LD, VAN Belle Y, DE Roy L, et al.Transcranial measurement of cerebral microembolic signals during endocardial pulmonary vein isolation: comparison of three different ablation techniques. J Cardiovasc Electrophysiol. 2009 Oct;20(10):1102-7. 32. Deneke T, Schade A, Müller P, et al. Acute Safety and Efficacy of a Novel Multipolar Irrigated Radiofrequency Ablation Catheter for Pulmonary Vein Isolation. J Cardiovasc Electrophysiol. 2013 Nov 14. doi: 10.1111/jce.12316. [Epub ahead of print] 33. Csanadi Z, Nagy-Baló E, Dank S, et al. Cerebrovascular Complications Related to Atrial Fibrillation Ablation and Strategies for Periprocedural Stroke Prevention. Cardiac Electrophysiol Clinics 2014; March (in press) DOI: 10.1016/j.ccep.2013.10.003 TABLE Table 1. Patient clinical characteristics Variable CB n=13 PVAC I. n=7 PVAC II. n=37 PVAC III. n=18 nMARQ n=14 p Age, years (SD) 57(15) 54(8) 60(10) 55(12) 53(12) 0.372 Male, n (%) 9 (69) 6(85) 25(67.5) 12(67) 10(71) Type of AF Paroxysmal AF, n (%) Persistent AF, n (%) 11(84) 2(16) 6(85) 1(15) 25(67.5) 12(32.5) 12(67) 6(33) 10(71) 4(29) Arterial hypertension, n (%) 7(53) 2(28) 28(75) 13(72) 8(57) Diabetes mellitus, n (%) 0(0) 2(28) 3(8) 1(5.5) 1(7) LA short diameter, mm (SD) 41(4) 40(4) 42(3.5) 43(6) 42(3.7) 0.825 LVEF, % (SD) 55(4) 52(8) 55(5) 54(10) 58(5) 0.325 Mean CHADS2 score 0.62 0.71 0.92 0.83 0.64 0.491 Mean CHA2DS2-VASc score 1.23 0.86 1.65 1.39 1.14 0.309 AF, atrial fibrillation; EF, ejection fraction; LA, left atrial; LV, left ventricular; CB, cryoballoon; PVAC, pulmonary vein ablation catheter; Table 2. Procedural parameters Procedural parameters CB n=13 PVAC I n=7 PVAC II n=37 PVAC III n=18 nMARQ n=14 p Total procedure time(min)(SD) 126 (24) 89 (23) 88 (16) 86(25) 108 (25) <0.001 Fluoroscopy time (min) (SD) 28.8 (8) 17.7 (8.4) 21.2 (8.8) 16.5 (5.3) 21.1(7.8) 0.002 Energy delivery time (min) (SD) 34.2 (18.8) 16 (4.5) 14.9 (4.1) 12(2.8) 7.7(3.4) <0.001 Left atrial access time (min) (SD) 80.8 (26) 70.4(22.7) 55.4 (15.1) 47.2(13.6) 75.9 (27.4) <0.001 Intraprocedural ACT (s) 340 380 358 328 317 0.148 Acute success rate (% of isolated PVs) 98 100 100 100 98 PV, pulmonary vein; other abreviations as above FIGURE LEGENDS Figure 1. Bilateral Multifrequency Transcranial Doppler Monitoring of the Middle Cerebral Arteries (a) Demonstration of beam alignment of both right and left sided MCA and ACA. Continuous yellow line indicates the location of monitoring at 55 mm insonation depth (MCA). (b) MCA waveform. Arrows on right panel indicate the high intensity transient signals corresponding to cerebral microemboli during PV angiography. MCA, middle cerebral artery; ACA, anterior cerebral artery Figure 2. Left panel: Total Microembolic Signal Count in the Five Treatment Groups. A plot of the mean number of microembolic signals (MESs) per middle cerebral artery in each treatment group, as compared with the CB group. Right panel: Ratio of Gaseous/Solid Emboli in the Five Treatment Groups. (Abrevations as in tables) Figure 3. Microembolic Signal Counts During Different Stages of the Procedure. (Abrevations as above) Figure 1 Click here to download high resolution image Figure 2 Click here to download high resolution image Figure 3 Click here to download high resolution image