Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past?

Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past? | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Journal of Cardiovascular Electrophysiology This is a preprint and has not been peer reviewed. Data may be preliminary. 23 September 2024 V1 Latest version Share on Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past? Author : Dana Johnson 0000-0001-6995-2294 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.172708564.48241320/v1 Published Journal of Cardiovascular Electrophysiology Version of record Peer review timeline 309 views 170 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract This paper explores the innovative approach of cardiac calcium electroporation as a potential advancement in catheter ablation techniques, building upon the historical context of thermal ablation methods. While traditional radiofrequency and cryothermal ablation have significantly improved efficacy and safety, the risk of collateral damage persists. Pulsed-field ablation (PFA) has emerged as a promising non-thermal alternative designed to target cardiac myocytes while sparing adjacent tissues. However, concerns about unintended consequences remain. In this study by Toya et al., the efficacy of low-power PFA augmented with calcium chloride infusion resulted in enhanced lesion formation, with increased surface area, volume, and histological damage, suggesting a potential for improved targeted ablation. Despite these findings, the study acknowledges limitations, including a small sample size and the need for further investigation into calcium’s effects on lesion durability and safety. This exploration represents a nascent step toward redefining cardiac ablation practices, highlighting the possibility of enhanced therapeutic and safety outcomes through innovative strategies. As PFA continues to evolve, incorporating calcium electroporation may further separate the overlapping risks of effective tissue ablation from collateral damage, signaling a transformative shift in cardiac electrophysiology. Invited Editorial Commentary Local Calcium Chloride Infusion after Pulsed Field Ablation Enhances Acute Efficacy of Cardiac ElectroporationJournal: Journal of Cardiovascular Electrophysiology Manuscript ID JCE-24-0673.R1 Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past? Dana Johnson MD, MPH University of Illinois Chicago Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past? Dana Johnson MD, MPH University of Illinois Chicago Since the advent of catheter ablation with Scheinman’s seminal work, and later radiofrequency (RF) ablation by Frank Marcus and Borggrefe and Breithardt et al., there has been an indelible march to separate the overlapping bell curves of targeted tissue ablation and collateralized damage (1,2,3). Thermal ablation has undergone decades of refinement, becoming progressively safer and more effective at ablating clinical targets. RF catheter systems use force sensing, irrigation, and power modulation to provide preferentially resistive or conductive heating of tissues (4). Likewise, cryothermal ablation provides fairly predictable ablation of tissues with the ability to “cryomap” its ablative effect with limited and fairly predictable liability to local collateral tissue (5,6). While steady improvement in catheter design and thermal energy delivery schema have increased their clinical efficacy and reduced the risk of collateral damage, the overlapping risk remains. With the arrival of pulsed-field ablation (PFA), the promise of non-thermal ablative energy has been heralded as a therapeutic tool with near impunity from collateral damage, which invasive electrophysiology has sought since its inception. With its purported ability to preferentially induce irreversible electroporation in cardiac myocytes while preserving nearby nervous, vascular, and smooth muscle tissue, PFA presented as the archetype for safe ablation (7). While PFA has continued to build a growing body of literature supporting its promise, there remains a dearth of long-term experience with this energy source (8). While there does appear to be an increased safety profile, it is likely premature to declare a victory on unintended consequences. Where the cryoballoon was initially felt to be immune from atrioesophageal fistulas, even a “never event” becomes possible as the n increases (9). While collateral damage appears very rare for PFA, phrenic palsy, coronary spasm, and even esophageal heating and lesions remain a possibility (10,11,12). PFA systems rely on short, high-voltage bursts to induce reversible and irreversible electroporation in targeted tissues. The induced field strength and effect are variable dependent on the pulsed waveform, electrode orientation, and uni- or bi-polar delivery schema, with the fatal effect falling off at the margins of the field (7). With increasing voltage, pulse duration, or repetition, the field effect can be increased, and the balance of electroporation tips toward the irreversible. However, this can potentially extend a fatal lesion beyond its intended target. The field of oncology first utilized reversible electroporation and later irreversible electroporation to enhance the selective destruction of solid tumors while minimizing systemic impact. Electroporation allows subtherapeutic systemic chemotherapy to reach therapeutic levels in target tissues or increase impermeable tissues’ permeability to chemotherapeutics (13). Other studies have used calcium infusion to enhance irreversible electroporation in solid tumors, increasing the therapeutic margin over collateral damage (14,15). This concept of facilitated destruction of targeted tissues continues to provide avenues for increased separation of efficacy and safety in oncologic therapy. In their current paper, Toya et. Al. builds on the decades-long search for safe catheter ablation with their examination of calcium augmentation of low-power PFA to provide enhanced atrial lesion delivery. Using a dual-energy RF/PFA catheter (Dual Energy THERMOCOOL SMARTTOUCH™ SF Catheter, Biosense Webster Irvine, CA), the group administered 19 PFA lesions using 250 V with 20ns duration for a total of 50 pulses. Immediately following PFA on the experimental lesions, they administered 0.2 grams of calcium chloride while maintaining a stable catheter position at the lesion site. They analyzed tissue electrogram properties pre- and post-lesion delivery and subsequently examined acute pathologic lesion characteristics and lesion volume. They found that lesions that received calcium infusion had a significantly greater reduction in electrogram voltage, greater lesion surface area and volume, and more severe acute histologic damage supportive of both hemorrhagic and apoptotic processes. This study represents a very early exploration of the plausibility of calcium electroporation for cardiac ablation. The authors readily recognize and discuss the myriad shortcomings when the clinical question arises. This study examines only a small number of lesions in an acute setting, and while they point to studies supporting durable lesions with similar acute findings, this remains speculative. This study does not examine the effect of calcium titration on the lesion, nor does it explore the downstream implications of calcium augmentation on a larger scale. A similar use case in wide antral pulmonary vein isolation could result in 8-12 grams of calcium being infused over the course of 40-60 lesions, which could introduce its own secondary safety compromises. Their use of a dual-energy, irrigated point-by-point ablation catheter allowed local administration of calcium to the lesion site, but questions remain about how augmentation would look in other systems with single-shot or larger area pulsed field ablation catheters. Lastly, many may argue that this calcium electroporation could represent a solution in search of a problem. Two headline features of PFA are its collateral safety profile and its potential for fast, effective ablation. It may prove difficult to improve on PFAs baseline safety, and the potential for extending ablation time may prove a tough sell for many operators. While the prospect of cardiac calcium electroporation in a clinical setting remains a distant possibility on the horizon, this study points to a new and exciting era of cardiac ablation innovation. While thermal ablation has largely been iterative in its tools and techniques, PFA has opened a new path of unexplored potential. With the concept of facilitated electroporation, delivering more heating or cooling to the targeted tissues is not the only way to increase the efficacy of ablation. Just as PFA has allowed for novel catheter designs, it appears to have also opened the way for augmented ablation and new avenues for transforming our therapeutic approach. With these advances, we may see the bell curves of targeted ablation and collateral harm separated further than ever before. Gonzalez, R., Scheinman, M., Margaretten, W., & Rubinstein, M. (1981). Closed-chest electrode-catheter technique for His bundle ablation in dogs. The American Journal of Physiology , 241 (2), H283-287. https://doi.org/10.1152/ajpheart.1981.241.2.H283 Huang, S. K., Bharati, S., Graham, A. R., Lev, M., Marcus, F. I., & Odell, R. C. (1987a). Closed chest catheter desiccation of the atrioventricular junction using radiofrequency energy—A new method of catheter ablation. Journal of the American College of Cardiology , 9 (2), 349–358. https://doi.org/10.1016/s0735-1097(87)80388-1 Breithardt, G., & Borggrefe, M. (2021). The dawn of radiofrequency catheter ablation for cardiac arrhythmias. Heart Rhythm , 18 (3), 485–486. https://doi.org/10.1016/j.hrthm.2020.11.030 Loring, Z., Holmes, D. N., Matsouaka, R. A., Curtis, A. B., Day, J. D., Desai, N., Ellenbogen, K. A., Feld, G. K., Fonarow, G. C., Frankel, D. S., Hurwitz, J. L., Knight, B. P., Joglar, J. A., Russo, A. M., Sidhu, M. S., Turakhia, M. P., Lewis, W. R., & Piccini, J. P. (2020). Procedural Patterns and Safety of Atrial Fibrillation Ablation. Circulation: Arrhythmia and Electrophysiology , 13 (9), e007944. https://doi.org/10.1161/CIRCEP.119.007944 Andrade, J. G., Dubuc, M., Guerra, P. G., Macle, L., Mondésert, B., Rivard, L., Roy, D., Talajic, M., Thibault, B., & Khairy, P. (2012). The Biophysics and Biomechanics of Cryoballoon Ablation. Pacing and Clinical Electrophysiology , 35 (9), 1162–1168. https://doi.org/10.1111/j.1540-8159.2012.03436.x Wong, T., Markides, V., Peters, N. S., & Davies, D. W. (2004). Clinical usefulness of cryomapping for ablation of tachycardias involving perinodal tissue. Journal of Interventional Cardiac Electrophysiology: An International Journal of Arrhythmias and Pacing , 10 (2), 153–158. https://doi.org/10.1023/B:JICE.0000019269.96323.d0 Verma, A., Asivatham, S. J., Deneke, T., Castellvi, Q., & Neal, R. E. (2021). Primer on Pulsed Electrical Field Ablation: Understanding the Benefits and Limitations. Circulation: Arrhythmia and Electrophysiology , 14 (9). https://doi.org/10.1161/CIRCEP.121.010086 Reddy, V. Y., Gerstenfeld, E. P., Natale, A., Whang, W., Cuoco, F. A., Patel, C., Mountantonakis, S. E., Gibson, D. N., Harding, J. D., Ellis, C. R., Ellenbogen, K. A., DeLurgio, D. B., Osorio, J., Achyutha, A. B., Schneider, C. W., Mugglin, A. S., Albrecht, E. M., Stein, K. M., Lehmann, J. W., & Mansour, M. (2023). Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation. New England Journal of Medicine , 389 (18), 1660–1671. https://doi.org/10.1056/NEJMoa2307291 Stöckigt, F., Schrickel, J. W., Andrié, R., & Lickfett, L. (2012). Atrioesophageal Fistula After Cryoballoon Pulmonary Vein Isolation. Journal of Cardiovascular Electrophysiology , 23 (11), 1254–1257. https://doi.org/10.1111/j.1540-8167.2012.02324.x Pansera, F., Bordignon, S., Bologna, F., Tohoku, S., Chen, S., Urbanek, L., Schmidt, B., & Chun, K.-R. J. (2022). Catheter ablation induced phrenic nerve palsy by pulsed field ablation—completely impossible? A case series. European Heart Journal: Case Reports , 6 (9), ytac361. https://doi.org/10.1093/ehjcr/ytac361 Kirstein, B., Heeger, C.-H., Vogler, J., Eitel, C., Feher, M., Phan, H.-L., Mushfiq, I., Traub, A., Hatahet, S., Samara, O., Subin, B., Kuck, K.-H., & Tilz, R. R. (2024). Impact of pulsed field ablation on intraluminal esophageal temperature. Journal of Cardiovascular Electrophysiology , 35 (1), 78–85. https://doi.org/10.1111/jce.16096 Nies, M., Watanabe, K., Kawamura, I., & Koruth, J. S. (2024). Endocardial Pulsed Field Ablation and the Oesophagus: Are Atrio-oesophageal Fistulas Now History? Arrhythmia & Electrophysiology Review , 13 , e02. https://doi.org/10.15420/aer.2023.16 Larkin, J. O., Collins, C. G., Aarons, S., Tangney, M., Whelan, M., O\RL’Reily, S., Breathnach, O., Soden, D. M., & O\RL’Sullivan, G. C. (2007). Electrochemotherapy. Annals of Surgery , 245 (3), 469–479. https://doi.org/10.1097/01.sla.0000250419.36053.33 Frandsen, S. K., Gissel, H., Hojman, P., Tramm, T., Eriksen, J., & Gehl, J. (2012). Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis. Cancer Research , 72 (6), 1336–1341. https://doi.org/10.1158/0008-5472.CAN-11-3782 Wasson, E. M., Ivey, J. W., Verbridge, S. S., & Davalos, R. V. (2017). The Feasibility of Enhancing Susceptibility of Glioblastoma Cells to IRE Using a Calcium Adjuvant. Annals of Biomedical Engineering , 45 (11), 2535–2547. https://doi.org/10.1007/s10439-017-1905-6 Information & Authors Information Version history V1 Version 1 23 September 2024 Peer review timeline Published Journal of Cardiovascular Electrophysiology Version of Record 3 Oct 2024 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Journal of Cardiovascular Electrophysiology Keywords clinical: catheter ablation – atrial fibrillation clinical: catheter ablation – non-rf energy sources Authors Affiliations Dana Johnson 0000-0001-6995-2294 [email protected] University of Illinois Chicago View all articles by this author Metrics & Citations Metrics Article Usage 309 views 170 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Dana Johnson. Separating the Bell Curves: Will Cardiac Calcium Electroporation Push Collateral Damage Into the Past?. Authorea . 23 September 2024. 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