Integrated RFA/PSOCT catheter for real-time guidance of cardiac radio-frequency ablation

: Radiofrequency ablation (RFA) is an important standard therapy for cardiac arrhythmias, but direct monitoring of tissue treatment is currently lacking. We demonstrate an RFA catheter integrated with polarization sensitive optical coherence tomography (PSOCT) for directly monitoring the RFA process in real time. The integrated RFA/OCT catheter was modified from a standard clinical RFA catheter and includes a miniature forward-viewing cone-scanning OCT probe. The PSOCT system was validated with a quarter-wave plate while the RFA function of the integrated catheter was validated by comparing lesion sizes with those made with an unmodified RFA catheter. Additionally, the integrated catheter guided catheter-tissue apposition and monitored RFA lesion formation in cardiac tissue in real time. The results show that catheter-tissue contact can be characterized by observing the features of the blood and tissue in the acquired OCT images and that RFA lesion formation can be confirmed by monitoring the change in phase retardance in the acquired PSOCT images. This system demonstrates the feasibility of an integrated RFA/OCT catheter to deliver RF energy and image the cardiac wall simultaneously and justifies further research into


Introduction
In the past two decades, cardiac arrhythmias have become one of the direst public health issues and a major cause of health care expenditure in western countries [1]. They affect millions of people in the United States and are a significant cause of morbidity and mortality, leading to more than 400,000 sudden cardiac deaths annually [1]. Additionally, cardiac arrhythmias are a major risk factor for stroke and heart failure and have even been linked to the development of Alzheimer's disease [2]. Arrhythmias are also a major economic burden, costing the US healthcare system more than $67 billion annually [3]. Since its initial description in 1982, catheter-based radiofrequency ablation (RFA) through percutaneous access has been commonly practiced in interventional electrophysiology (EP) to treat cardiac arrhythmias. During the RFA procedure, a small catheter is guided into the heart to heat and destroy the culprit tissue that was causing abnormal electrical conduction with radiofrequency energy. This has become the standard of care for cardiac arrhythmias as it is often curative, eliminating the need for medications that potentially last a lifetime [4,5]. Complication rates from the procedure are also low, with 0.8%-6% of patients experiencing a major complication depending primarily on the type of ablation and the patient's severity of illness [6].
Despite the success of RFA in treating many cardiac arrhythmias, challenges still remain. Currently, RFA lesion formation is monitored through indirect methods, such as temperature, impedance, electrograms, and contact force. Fluoroscopy and 3D catheter tracking provide gross guidance. This creates several challenges, including verifying catheter-tissue contact [7], monitoring and confirming lesion completion [8], detecting complication precursors, and visualizing tissue structures to target and avoid. These challenges result in long procedure times (2 to 8 hours depending on the type of the arrhythmia), higher recurrence rate, and compromised patient safety. Atrial fibrillation (AF), which is the most prevalent sustained arrhythmia in the western world, is especially difficult to treat, with a single procedure success rate as low as 17% after 5 years. Even with multiple procedures, 2.1 on average, the success rate is approximately 65% after 5 years [9][10][11]. One important reason for the high recurrence is insufficient direct, real-time guidance of the ablation which leads to incomplete (i.e., non-transmural) lesions or gaps in continuous lines of lesions [9,12]. Direct feedback may also enable detection of complication precursors, identification of tissue structures, and confirmation of the quality of catheter-tissue apposition, which would result in faster, more accurate, and safer procedures.
To address some of these issues, multiple solutions have been proposed. Recently, force sensitive catheters have been rapidly adopted by EP practitioners to confirm catheter-tissue contact force and angle. Since poor contact force and improper contact angles have been shown to directly correlate with increased recurrence due to poor lesion quality, these catheters give the provider feedback on lesion quality in real time [13]. Unfortunately, this information is only an estimate extrapolated from research data and not a direct measurement of the quality of an individual lesion. Therefore, it does not completely meet the clinical need. Magnetic resonance imaging (MRI) has been used to monitor the formation of RFA lesions [14,15]. However, the low resolution and expensive specialized equipment limits the use of MRI-based RFA procedures. An ultrasound integrated RFA electrode probe for RFA procedure guidance has been reported [16,17], but the image resolution and contrast is low. An M-scan ultrasound integrated RFA catheter has been proposed to assess the lesion formation and prevent complications from steam pops in real time [18,19]. However, it cannot provide catheter-tissue contact and tissue substrate information, which is very important for procedure guidance. Others have reported direct monitoring of RFA lesion formation with photoacoustic technology [8,20], but these systems have not been tested in vivo and currently suffer from a very low frame rate and low imaging resolution. Additionally, the diameter of the photoacoustic probe is greater than 10 mm, which limits its usage, especially in pediatric arrhythmia treatment. Near-infrared spectroscopy (NIRS) has also been reported to monitor lesion formation by sensing tissue endogenous metmyoglobin content changes caused by ablation [35,36], but it has not been shown to provide enough information to identify tissue structure.
Previously, we proposed that an RFA catheter with integrated optical coherence tomography (OCT) imaging can address many of the current challenges with RFA. OCT imaging provides real-time, in-depth imaging of biological tissues with high spatial resolution (on the order of ten micrometers). We have previously demonstrated (both in vitro [21][22][23]26] and in vivo [24,25]) that direct imaging feedback from catheter-based OCT can confirm catheter contact and angle [24,25], identify tissue structures [21,25], confirm ablation lesion formation [21][22][23][24]26], and may detect precursors of complication, like gas formation ahead of steam pops [22,24,25]. We have also shown that the loss of birefringence in cardiac tissue, which can be easily detected by PSOCT, is a strong marker of thermal ablation and has the potential to provide feedback during lesion formation [22,26,27]. Herranz et al. have described an RFA catheter integrated with optical coherence reflectometry (M-mode OCT, not imaging) to monitor the RF ablation process in real time based on the loss of birefringence [27,28,31]. However, like NIRS, it has not been shown to identify tissue substrates.
Taken together, these encouraging previous studies have demonstrated that integrating PSOCT imaging into the RFA catheter may be able to address all of the unmet clinical needs outlined above, and therefore has the potential to reduce procedure time, recurrence, and improve safety. USA) with 20 mW average output power was used as the light source. A fiber Bragg grating (FBG) was used to generate a stable line trigger signal for data collection synchronization. Two fiber-based polarizing beam splitters (FPBS) and 2 balanced detectors (Det 1, 2) are used to collect the image data from two polarization channels. The intensity and retardance images are calculated from the 2 images obtained from these two channels with orthogonal polarizations [29]. To validate the retardance measurement accuracy, a zero-order quarterwave plate was imaged in various fast-axis orientations, both with a fixed beam (M-mode) and rotating wave plate, and with a scanning beam and a fixed wave plate. In addition, a highbirefringence plastic phantom was imaged to validate the retardance contrast of the system.

Sample preparation and experimental validation
Freshly excised swine hearts and freshly drained heparinized swine blood (from intravascular OCT catheter training swine, approved by the Institutional Animal Care and Use Committee of Case Western Reserve University) were used to test the RFA/OCT system. To keep the tissue fresh, it was kept in ice-cold phosphate-buffered saline (PBS) before imaging. The right ventricular (RV) free wall was carefully dissected for the study.
In order to test the impact of the glass window in the RFA electrode on lesion creation, two groups of RFA lesions were created in fresh RV samples using the integrated RFA/PSOCT catheter and an intact, unmodified commercial RFA catheter of the same model, respectively. A Maestro 3000 RFA generator (Boston Scientific) was used to generate two groups of lesions under the same ablation parameter setting (temperature control mode: 70°C, maximum delivery power: 50W, and ablation time: 20 seconds). As mentioned in 2.1, the thermocouple was removed during integration to make room for the OCT probe. For this experiment, to enable both catheters to operate in temperature control mode (more commonly used in clinical procedures compared to power control mode) for optimal comparison of lesion formation, the thermocouple of the integrated catheter was soldered to the external surface of the distal tip electrode to provide temperature sensing capabilities. (The thermocouple was not used for subsequent experiments described below.) Staining with 2,3,5triphenyl-tetrazolium chloride (TTC) was used to validate lesion formation and quantify lesion size [23,30]. TTC is a vital stain which has been widely used to differentiate necrotic from viable tissue in the acute setting [18]. By TTC staining, healthy tissue will present dark red color, while ablated tissue will be white. To compare the two groups of lesions, the lesions were imaged with a 10X microscope with a calibration marker to measure the size of the lesions at the tissue surface. Then, the lesions were sliced perpendicular to the tissue surface acros phosphate buf imaged by the To test the tissue was sub lesion monito temperature ( generator in p images were r   Fig. 3(a). Th sample, and 8 application co riation in the p caused by cath y referring to d to image a hig he integrated ca ing the data a -shaped display ng" the 3-D co ntensity image aped phase reta the PSOCT se banded stru . The results of ages as well as he integrated c o 10 lesions c The same RFA hown in Table  tween Fig. 5. Fig  Fig. 5 biased results, but no evidence from the experiment indicated that this was the case. Future prototype catheters will incorporate temperature sensing in the electrode (which will obviate this concern) and will be tested using this same approach.

Results
A potential benefit of this technology is direct feedback of catheter-tissue contact and apposition. This contact information would be useful for EP practitioners because it impacts lesion formation and allows EP practitioners to produce high quality lesions in multiple different scenarios. For example, when creating a point lesion, the optimum orientation is for the catheter to be perpendicular to the tissue; when dragging the catheter to create a line lesion, the catheter needs to be oriented at an angle and maintain contact. Having direct feedback of the catheter-tissue contact and angle allows the EP practitioners to verify apposition in real time. As demonstrated above in Fig. 5, non-contact, tilted contact, and complete perpendicular contact can be readily differentiated by observing the features of the blood and tissue in the acquired OCT images. Additionally, the images allow EP practitioners to understand the approach angle before the tissue is even contacted. The recent, rapid adoption of force-sensing catheters is evidence of the significant value of real-time cathetertip apposition feedback. In addition to quality and angle of contact, contact force has been shown to impact lesion quality, size, and rate of arrhythmia recurrence and is an important piece of information for physicians [32]. Images may provide valuable complementary information to force feedback. In addition, we have previously shown that endoscopic OCT images of gastrointestinal mucosa clearly depict tissue structural deformation in response to catheter pressure [34]. In the future, we will investigate the relationship between observed tissue deformation and lesion quality, and the potential of predicting and confirming lesion quality directly from OCT images.
To validate the lesion monitoring functionality of the integrated catheter, PSOCT images were obtained throughout the ablation process. As noted above, Fig. 6 shows that during ablation, the tissue becomes more reflective in the OCT intensity images, while the birefringence signal disappears in the PSOCT images, providing much stronger contrast. The disappearance of the birefringence signal indicates that the proteins composing the oriented fiber structure have been thermally denatured by the RF energy [33]. This result is consistent with our previous report and has also been reported in the literature as a reliable marker for irreversible muscle injury in the myocardium [22,37]. Due to the depth limitation of PSOCT imaging, the denaturing process can only be monitored to around 1 mm in depth. However, the depth of an optimal lesion in the ventricle is usually deeper than 2 mm, so the full extent of the lesion will not always be directly visible with PSOCT imaging. Therefore, more experiments are warranted to correlate loss of birefringence (including the dynamics of the process) with lesion depth, and to investigate monitoring of lesion placement in the atrium, which has thinner walls but more complicated tissue structures. Though additional investigation is required, the current results indicate that the RFA/OCT integrated catheter can be used to confirm and monitor lesion formation, and that the retardance signal from PSOCT provides clear, strong contrast during lesion formation.

Conclusion
In conclusion, we prototyped and demonstrated a 2.3 mm (7 Fr) diameter, flexible, integrated, RFA/OCT catheter, which can be used to monitor RFA lesion formation with PSOCT imaging in real time. The integration of the OCT probe into a commercial RFA catheter did not affect lesion formation. With this integrated catheter, catheter-tissue contact was readily characterized by observing the features of the blood and tissue in the acquired OCT images. RFA lesions can also be confirmed by the loss of birefringence in the heart tissue.
Direct imaging by OCT has the potential to improve guidance during RFA procedures ensuring catheter-tissue contact and providing real-time monitoring and confirmation of lesion formation. Importantly, this may decrease procedure time and fluoroscopy imaging time, therefore reduce radiation exposure to the patient and physician. Furthermore, real-time feedback from OCT during RFA therapy may potentially decrease recurrence rates and procedural complications by allowing real-time confirmation of lesion quality and detecting potential complications early. In the future, the objective is to improve the integrated catheter for real-time monitoring of the RFA procedure in vivo.