Introduction. CLINICAL RESEARCH Cardiac electrophysiology

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1 Europace (2016) 18, doi: /europace/euv249 CLINICAL RESEARCH Cardiac electrophysiology Real-time magnetic resonance-guided ablation of typical right atrial flutter using a combination of active catheter tracking and passive catheter visualization in man: initial results from a consecutive patient series Sebastian Hilbert 1 *, Philipp Sommer 1, Matthias Gutberlet 2, Thomas Gaspar 3, Borek Foldyna 2, Christopher Piorkowski 3, Steffen Weiss 4, Thomas Lloyd 5, Bernhard Schnackenburg 6, Sascha Krueger 4, Christian Fleiter 1, Ingo Paetsch 1, Cosima Jahnke 1, Gerhard Hindricks 1, and Matthias Grothoff 2 1 Department of Electrophysiology, University Leipzig Heart Center, Strümpellstr. 39, Leipzig 04289, Germany; 2 Diagnostic and Interventional Radiology, University Leipzig Heart Center, Leipzig, Germany; 3 Department of Electrophysiology, Heart Center Dresden, University of Dresden, Germany; 4 Innovative Technologies, Philips, Technology GmbH, Hamburg, Germany; 5 Imricor Medical Systems, Burnsville, MN, USA; and 6 Philips GmbH, Healthcare, Hamburg, Germany Received 7 March 2015; accepted after revision 15 June 2015; online publish-ahead-of-print 27 August 2015 Aims Recently cardiac magnetic resonance (CMR) imaging has been found feasible for the visualization of the underlying substrate for cardiac arrhythmias as well as for the visualization of cardiac catheters for diagnostic and ablation procedures. Real-time CMR-guided cavotricuspid isthmus ablation was performed in a series of six patients using a combination of active catheter tracking and catheter visualization using real-time MR imaging.... Methods Cardiac magnetic resonance utilizing a 1.5 T system was performed in patients under deep propofol sedation. A threedimensional-whole-heart sequence with navigator technique and a fast automated segmentation algorithm was used for and results online segmentation of all cardiac chambers, which were thereafter displayed on a dedicated image guidance platform. In three out of six patients complete isthmus block could be achieved in the MR scanner, two of these patients did not need any additional fluoroscopy. In the first patient technical issues called for a completion of the procedure in a conventional laboratory, in another two patients the isthmus was partially blocked by magnetic resonance imaging (MRI)-guided ablation. The mean procedural time for the MR procedure was min. The intubation of the CS was performed within a mean time of min. Total fluoroscopy time for completion of the isthmus block ranged from 0 to 7.5 min.... Conclusion The combination of active catheter tracking and passive real-time visualization in CMR-guided electrophysiologic (EP) studies using advanced interventional hardware and software was safe and enabled efficient navigation, mapping, and ablation. These cases demonstrate significant progress in the development of MR-guided EP procedures Keywords Real-time MRI Electrophysiological study Atrial flutter Ablation Active tracking Introduction For decades, fluoroscopy has been the standard technique for the visualization and appropriate placement of electrode catheters for diagnostic electrophysiologic (EP) studies and cardiac catheter ablation. Recently cardiac magnetic resonance (CMR) imaging has been found feasible for visualization of the substrate for cardiac arrhythmias, 1 real-time visualization and active tracking of cardiac catheters for diagnostic and ablation procedures, 2 8 and the visualization of ablation-induced cardiac lesions. This is the first report on * Corresponding author. Tel: ; fax: address: sebastian.hilbert@gmx.net These authors contributed equally. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Real-time magnetic resonance-guided ablation 573 What s new? This study describes the first series of patients undergoing a MRI-guided ablation of atrial flutter using active catheter tracking and catheter visualization using real-time MR. In each patient, two catheters were introduced with transfemoral access, advanced to the heart, and placed in the right atrium and coronary sinus, exclusively guided by MRI. All catheters were visualized, and ablation of the cavitricuspid isthmus was performed. No adverse events were observed. This is the first series of patients undergoing MRI-guided ablation of atrial flutter using catheter localization using active tracking and real-time MRI. An EP study was successfully performed in all patients. In half the patients a complete and in another third of the patients a partial cavotricuspid block could be achieved in the MR scanner. Ablation lesions annotated in the anatomical shell correspond well with post-ablation lesion location on MRI. In addition, fluoroscopy exposure to both patients and physicians could be dramatically reduced. a consecutive patient series in which ablation of the cavotricuspid isthmus (CTI) was performed with magnetic resonance imaging (MRI) guidance using a combination of real-time active catheter tracking and passive catheter imaging. Methods The study complies with the declaration of Helsinki and was approved by the local ethics committee, as well as the German Competent Authority (Bundesinstitut für Arzneimittel und Medizinprodukte). Table 1 Patient characteristics Patient population Six patients with an indication for a catheter ablation procedure for CTI-dependent atrial flutter provided informed consent and were included into the study. Detailed patient characteristics can be found in Table 1. Magnetic resonance catheters and electrophysiologic recording system Two MR conditional steerable diagnostic and ablation catheters (Vision-MR Ablation Catheter, Imricor Medical Systems, Burnsville, MN, USA) were inserted via femoral sheaths. The catheters have been described in detail previously. 2 In short, they are similar in appearance and function to conventional diagnostic and ablation catheters, but are specifically designed for use in the MR environment. The shaft of the catheter is 8.5 F, and it has a patient-insertable length of 115 cm. The deflection mechanism works in the opposite direction compared with most conventional ablation catheters. The catheter incorporates two gold electrodes at the distal tip for high-fidelity recording of electrograms (EGM) signals and pacing. Ablation energy is delivered through the distal 3.5 mm gold tip electrode, which includes six irrigation ports to cool the tip and allow more effective lesion creation. Two miniature MR receive coils are integrated into the tip section of each catheter. The MR signal received these coils allows the position and orientation of the catheter tip to be determined in the co-ordinate system of the MR scanner. A custom built MR-EP Recording System (Advantage-MR EP Recorder/Stimulator System, Imricor Medical Systems) was used. The EP recording system consists of three components: a digital amplifier stimulator (DAS), a tracking interface module, and a host computer (Figure 1). The DAS acts as the patient interface and provides connections for two Vision-MR catheters and a third-party surface electrocardiogram (ECG) (Philips Invivo, Gainesville, FL, USA). The DAS interfaces with a third-party ablation generator allowing for the delivery of radiofrequency energy during ablation. It also receives, filters, Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6... Gender Male Male Male Male Male Male Age in years Baseline rhythm Atrial flutter Atrial flutter Atrial flutter Sinus rhythm Sinus rhythm Sinus rhythm Rhythm at start of MR procedure Sinus rhythm Atrial flutter Sinus rhythm Basal escape rhythm Sinus rhythm Sinus rhythm Fluoroscopy for venous access No Yes No No No No Time from start of venous access to first catheter inserted in minutes Time from catheter insertion to CS cannulation in minutes Maximum ablation power in Watts Total RF time in seconds in MR Total MR time in minutes Rhythm at end of MR procedure Sinus rhythm Atrial flutter Sinus rhythm Atrial fibrillation Sinus rhythm Sinus rhythm Bidirectional isthmus block at end of No No Yes No Yes Yes MR procedure RF time in conventional lab in seconds Flouroscopy time in conventional lab 07:30 07:07 (06:05) 0 02:08 03:42 0 in m:s Total fluoroscopy dose in cgy cm (615.9) Total procedural time in minutes

3 574 S. Hilbert et al. Catheter 1 Catheter 2 Catheter filter Catheter filter Isolated channel 1 Isolated channel 2 Horizon patient interface module (PIM) Amplifier Stimulator Fiber optic ethernet cable Fiber optic temperature cable Slave display ECG (ECG) ABL (1,2) Cath 2 (1,2) Catheter cables Scanner room Control room Amp: 1,00mV PIM power supply Isolated DC voltages A1 Horizon catheter tip temperature processor 09:06:46 09:06:47 Figure 2 Bidirectional isthmus block as documented by pacing from the catheter in the coronary sinus (Cath2). Wide double potentials as well as a conduction delay (A1: 106 ms; A2: 260 ms) can be observed on the mapping catheter (ABL). Sweep speed was set to 100 mm/s. Voltage of the signal at A1 and A2 is 0.32 and 1.04 mv, respectively. A2 Horizon computer workstation DVI DVI Primary display Figure 1 Block diagram of catheters and catheter cables designed to be safe in magnetic resonance. Catheter filters reduce noise in the magnetic resonance image. Each catheter channel is isolated from all other catheter channels to eliminate gradient-induced currents, which can stimulate the heart. The patient interface module is a combined amplifier and stimulator. Patient isolation from mains is achieved in the patient interface module power supply. All signals in/out of the scanner room are fibre-optic for less interference and signal integrity. DVI, digital visual interface. and digitizes EGM and ECG signals (Figure 2), which are then sent to the host computer via a fibre-optic cable. The DAS also receives commands from the host computer and includes an integrated programmable stimulator. The tracking interface module acts as a preamplifier and MR interface for the tracking signals. The host computer is the interface between the electrophysiologist and the EP recording system. The host computer displays and records EGM and ECG waveforms, tip temperature data, and ablation generator status information. It also allows physicians to apply stimulation and monitor, record, evaluate, and take notes regarding patient events throughout the procedure. Magnetic resonance imaging and procedure guidance A three-dimensional (3D) dataset containing the heart and thoracic vessels was acquired in free-breathing on a 1.5 T MR-scanner using

4 Real-time magnetic resonance-guided ablation 575 A Figure 3 Three-dimensional reconstruction of the left (blue) and right atrium (yellow) in a left anterior oblique (LAO) view. The dataset containing the heart and thoracic vessels was acquired in free-breathing on a 1.5 T MR-scanner using a navigator and ECG-gated 3D-whole-heart balanced SSFP sequence. A reference catheter (green) has been placed in the coronary sinus and an ablation catheter (red) at the CTI in the right atrium (A). Slices of the MR dataset corresponding to the position of the actively tracked catheter (red) can be observed in (B D). Red dots correspond to the ablation line along the CTI. a navigator and ECG-gated 3D-whole-heart balanced steady-state free precession (SSFP) sequence (Figure 3B D). An advanced MR-EPplatform (Interventional MRI Suite, 7,8 Philips Research Hamburg) created auto-registered 3D models of all cardiac chambers (Figure 3A). The receive coils in the catheter are shown as a virtual catheter icon displayed in real-time in the auto-segmented/auto-registered 3D model 9 and in multiplanar reconstructed planes derived from the 3D dataset. The positions of the catheter tip were confirmed by passive imaging using a real-time balanced SSFP sequence. For visualization of postablational oedema, a navigator-gated black-blood T2-weighted shorttau inversion recovery (STIR) sequence in RAO orientation was used. Furthermore, T1-weighted navigator-gated 3D late gadolinium enhancement (LGE) images were acquired using an inversion recovery gradient echo sequence for visualization of post-ablational necrosis min after the intravenous administration of 0.15 mmol/kg of body weight of gadobutrol (Gadovist; Bayer Healthcare Pharmaceuticals, Leverkusen, Germany). Image parameters were identical for all used sequences in both patients with atrial flutter and patients in sinus rhythm. The 3D-whole-heart sequence was prospectively triggered and therefore robust against changes in the duration of the cardiac cycle. A sufficient image acquisition window in end-diastole was present in all patients. In all cases, auto-registration of 3D models was possible. The quality of active tracking is independent from heart rhythm as this technique measures catheter coordinates directly in the coordinate system of the MR scanner independent from surrounding structures. The image quality of passive catheter visualization using a real-time SSFP sequence is also independent from the underlying heart rhythm. Electrophysiologic study and ablation All procedures were performed under deep propofol sedation. 10 One arterial (4 F, invasive blood pressure monitoring) and two venous sheaths (14 and 12 F) were placed in the right and left groin, respectively. The CS was intubated with one catheter as a timing reference, and a B D C second catheter was positioned in the right atrium as an ablation catheter. The cavotricuspidal isthmus was identified considering both anatomical information and intracardial EGM. Ablation of the CTI was then performed by delivering radiofrequency energy (45 W, irrigation rate 17 ml/min, 60 s pulses). A decrease in voltage of the intracardiac EGM as well as an increase in catheter tip temperature was continuously assessed and used as a surrogate for ablation efficacy. Depending on signal attenuation energy was titrated up to 60 W. Completeness of the isthmus block was assessed under pacing from the reference catheter and measuring the delay between stimulus artefact of the reference catheter and atrial signal in the ablation catheter. Per study protocol maximum MR time was limited to 90 min. This included time for patient placement in the scanner, pre-ablation imaging, catheter placement, and the ablation itself. If complete isthmus block was not achieved within this time limit and if substantial parts of this time limit had been spent on tasks other than pre-ablation imaging and ablation, it was at the operator s discretion to extend the time allowed for ablation in the MR. In cases where complete isthmus block was not documented at the end of the MR procedure, the patient was transferred to the electrophysiology laboratory and the procedure was completed by fluoroscopy guidance using conventional reference and ablation catheters. Results The procedure was completed solely in the MR in two cases and in the conventional laboratory in four other cases. The mean procedural time for the MR procedure was min guiding the catheters by active tracking almost exclusively. Automatic segmentation of the cardiac chambers from the 3D balanced SSFP whole-heart scan 9 for isuite-based MR procedure guidance worked reliably in all patients (five patients in sinus rhythm and one patient in atrial flutter). The intubation of the CS was performed within a mean time of min by active tracking only with the catheter position verified by real-time MR imaging utilizing isuite for automated scanplane alignment with the catheter and fast scan protocol switching. In all patients, CTI ablation was attempted but complete isthmus block could only be demonstrated in the third, fifth, and sixth patient. In two other patients, a partial isthmus block could be demonstrated, and in one patient, technical reasons mandated a premature end of the MR procedure. In the first patient who was in sinus rhythm at the start of the procedure, complete isthmus block could not be achieved within the 90 min limit due to technical issues involving impaired real-time catheter tracking due to spurious electrical noise. The patient was moved to the conventional laboratory and complete isthmus block was achieved at the end of the procedure. Total fluoroscopy time amounted to 7.5 min. In the second patient who was in atrial flutter at the start of the procedure, application of s RF-energy pulses at 45 W led to conduction delay of 30 ms but no termination of the tachycardia. The patient was moved to the conventional laboratory and a single pulse of RF energy for the duration of 47 s terminated the tachycardia. Complete isthmus block was documented. Total fluoroscopy time amounted to 7.1 min (6.1 min for venous access). In the third patient who was in sinus rhythm at the start of the MR procedure, complete isthmus block was achieved within 91 min of MR time ( s RF-energy pulses with a maximum of 60 W). Bidirectional isthmus block could be demonstrated by pacing from

5 576 S. Hilbert et al. A B C Figure 4 Activation map of the right atrium in LAO from inferior. The isthmus line as depicted by the ablation tags (red dots) can be observed along with colour-coded activation timings (red: early activation; blue: late activation). Green dots depict sites of activation measurements on both sides of the ablation line. A reference catheter (green) is placed in the coronary sinus while the mapping catheter (red) is distal to the ablation line (A2 side). RV CS-catheter and ablation catheter (Figure 2). Confirmation of acute success was supported by activation mapping (Figure 4). No fluoroscopy was needed. In the fourth patient who was in sinus rhythm at the beginning of the procedure, ablation led to a conduction delay (20 ms) but complete isthmus block could not be achieved. After 85 min of MR time, the patient converted to atrial fibrillation which made further assessment of ablation-induced conduction block impossible. Because of the time limit, the patient was moved to the conventional laboratory and cardioverted. Two EGM-guided RF applications in a single spot amounting to 58 s led to complete isthmus block. In the fifth patient, imaging was unremarkable. Owing to intermittent difficulties with regard to patient sedation and catheter placement, the MR time was extended beyond the 90 min time limit. A complete isthmus block could be reached in the MR and was D RA IVC Figure 5 Late gadolinium enhancement image immediately after MRI-guided radiofrequency ablation of typical atrial flutter. The hyperintense areas (arrows) represent post-ablational linear necrosis of the cavorticuspid isthmus. Figure 6 Three-dimensional reconstruction of both atria in RAO from inferior. The isthmus line as depicted by the ablation tags (red dots) can be observed along with colour-coded activation timings (red: early activation; blue: late activation). The overlayed grey spots (arrows) indicate post-ablational oedema of the cavitricuspid isthmus depicted by T2-weighted imaging. A reference catheter positioned in the coronary sinus and the mapping catheter are shown in white and red, respectively. verified in the conventional laboratory. Retrospectively, an older thrombosis of the right femoral vein was diagnosed. Total procedural time was 228 min. In the sixth patient, complete isthmus block could be reached solely in the MR scanner (five 60-s RF-energy pulses, maximum of 50 W). Time from placement of the catheter in the CS to establishment of complete isthmus block was 11 min. The procedure was completed in 78 min. The position of the catheter tip as visualized by active tracking could reliably be confirmed with passive catheter tracking by using real-time MRI (balanced SSFP sequence). Visualization of the postablational oedema and necrosis was performed in the third and sixth patients and showed a high spatial correlation between ablation sites and the hyperintense signal in the T2-weighted STIR-sequence and LGE sequence, respectively (Figures 5 and 6). Oedema and necrosis imaging was not part of the clinical investigation protocol. Therefore, it has been restricted to two cases. In these patients, visualization of oedema and necrosis was performed immediately after completion of the ablation line. For this study, the focus was on timely completion of the procedure. Therefore when a complete isthmus block could not be achieved in the MR environment, patients were transferred to the fluoro-suite without delay from additional imaging. No intra-procedural complications and no device-related complications occurred during the 1-week follow-up. Discussion The current report on six consecutive patients having been treated by MRI-guided atrial flutter ablation using a combination of active

6 Real-time magnetic resonance-guided ablation 577 catheter tracking and real-time MR imaging illustrates recent advances associated with performing EP procedures in an MRI environment. Previous work done by our group has demonstrated feasibility and safety of catheter localization utilizing real-time MRI. 2,11 Active catheter tracking as evaluated in an animal model 8,12 and used in the current study enabled even more efficient catheter navigation as real-time MRI guidance provided enhanced tissue visualization as well as visualization of catheter location and orientation. These cases demonstrate significant headway in the development of MR-guided EP procedures, and as with any new interventional medical modality, several challenges still exist. Cardiac magnetic resonance-based EP procedures represent a change in the existing EP paradigm and require new workflows and operator training. While real-time visibility of the catheter has been greatly improved, including the shaft in the visible portion of the catheter would simplify more complex manoeuvres, such as looping the catheter to access the isthmus. As was found in the first patient, catheter tracking is sensitive to the introduction of external noise into the MR scanner room. This requires filtering conductors entering the room and use of fibre-optic communication where possible. In the cases discussed, the anatomical shells used for guidance are generated at the beginning of the procedure. Over time the position of the heart might change relative to the position of the reconstructed anatomical shell. Despite usage of repetitive real-time MRI confirmation scans for catheter and anatomy location, for long procedures this might call for an intra-procedural update of the MR reference series (3D-whole-heart dataset) or even a complete new acquisition including 3D reconstruction of the anatomical shell. 13 More research is needed to elucidate the true impact of this phenomenon. If the patient moves during the procedure, for example due to cardioversion to return the patient to sinus rhythm, intra-procedural update of the MR images and 3D reconstruction of the anatomical shell would be required. The use of deep sedation, worked fine in all patients but has inherent limitations. Although not used in this study, mechanical ventilation could potentially reduce the risk of patient movement and subsequent shift in heart position, thereby avoiding potentially time consuming re-acquisition of MR images. Another limitation is the comfort of the interventionalist. Design of a dedicated interventional MR suite should consider the position of the interventionalist relative to the tools and displays used and the point of patient access. Additionally, communication systems with active or passive acoustic cancelation should be considered. Imperative to the success of MR-guided EP procedures are wellestablished workflows for patient handling and the ablation procedure. To facilitate the development of efficient workflows, a series of five preclinical studies were performed prior to the current study. Because this is a new field and has a limited but growing toolset, it is important to be judicious during patient selection to ensure patient safety and procedural success. More research is needed to find solutions to overcome issues like unstable rhythms (e.g. PVC) during initial 3D-whole-heart image acquisition, for reliable and reproducible lesion visualization as well as to prevent intermittent EP signal degradation. Cardiac magnetic resonance has the potential to identify lesion transmurality and gaps. However, this was beyond the scope of the current study and not part of the clinical investigation protocol. The endpoint of the current study was complete isthmus block identified by conventional mapping. Future studies will have to be performed to elucidate feasibility and impact of lesion visualization with regard to procedural success. Conclusions The combination of active catheter tracking and MR image-based visualization in MR-guided EP studies using advanced interventional MR software (isuite) and hardware (Vision-MR Ablation Catheter and Advantage-MR EP Recorder/Stimulator System) was safe and enabled efficient navigation, mapping, and ablation. Performing cases in deep sedation instead of general anaesthesia are feasible and does not impair imaging. The learning curve can be shortened substantially by training all aspects of the setup (patient care, catheter handling, software package handling) in a series of animal cases. While further research is needed to address several procedural challenges, these cases demonstrate significant advances in the development of MR-guided EP procedures. Funding This study has been supported by an Imricor grant to the University of Leipzig, Germany. Catheter materials for this study were provided by Imricor. The Interventional MRI Suite (isuite) research prototype was provided by Philips. Conflict of interest: none declared. References 1. Nazarian S, Bluemke DA, Lardo AC, Zviman MM, Watkins SP, Dickfeld TL et al. Magnetic resonance assessment of the substrate for inducible ventricular tachycardia in nonischemic cardiomyopathy. Circulation 2005;112: Sommer P, Grothoff M, Eitel C, Gaspar T, Piorkowski C, Gutberlet M et al. 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