Pulsed Field Ablation for the Treatment of Atrial Fibrillation: A Review and a Look into its Future
DOI:
https://doi.org/10.59958/hsf.7141Keywords:
arrhythmia, catheter ablation, atrial fibrillation, pulsed field ablation, nanosecond, electroporationAbstract
Pulsed field ablation (PFA) is a novel technology to treat atrial fibrillation (AF) utilizing electric fields to induce nonthermal irreversible electroporation of electrically active cardiac tissue to induce cardiac cell death. PFA offers improved safety benefits compared to traditional radiofrequency ablation (RFA) and cryoablation by specifically ablating only cardiac tissue. However, there are avenues for further optimization including neurological risk associated with microbubble formation and left atrial function post ablation. Various PFA devices with different electric pulse waveforms have been studied and tested in human trials, with the majority utilizing microsecond duration pulses. Shorter nanosecond duration pulses, or nanosecond PFA, is beginning to be studied for AF ablation. In this review we will delve into current waveforms used for PFA, areas for improvement, mechanisms behind nanosecond PFA, and its clinical impact for cardiac ablation.
References
Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. International Journal of Stroke: Official Journal of the International Stroke Society. 2021; 16: 217–221.
Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. The New England Journal of Medicine. 1998; 339: 659–666.
Verma A, Asivatham SJ, Deneke T, Castellvi Q, Neal RE, 2nd. Primer on Pulsed Electrical Field Ablation: Understanding the Benefits and Limitations. Circulation. Arrhythmia and Electrophysiology. 2021; 14: e010086.
Schaack D, Schmidt B, Tohoku S, Bordignon S, Urbanek L, Ebrahimi R, et al. Pulsed Field Ablation for Atrial Fibrillation. Arrhythmia & Electrophysiology Review. 2023; 12: e11.
Di Monaco A, Vitulano N, Troisi F, Quadrini F, Romanazzi I, Calvi V, et al. Pulsed Field Ablation to Treat Atrial Fibrillation: A Review of the Literature. Journal of Cardiovascular Development and Disease. 2022; 9: 94.
Stewart MT, Haines DE, Miklavčič D, Kos B, Kirchhof N, Barka N, et al. Safety and chronic lesion characterization of pulsed field ablation in a Porcine model. Journal of Cardiovascular Electrophysiology. 2021; 32: 958–969.
Reddy VY, Neuzil P, Koruth JS, Petru J, Funosako M, Cochet H, et al. Pulsed Field Ablation for Pulmonary Vein Isolation in Atrial Fibrillation. Journal of the American College of Cardiology. 2019; 74: 315–326.
Verma A, Haines DE, Boersma LV, Sood N, Natale A, Marchlinski FE, et al. Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial. Circulation. 2023; 147: 1422–1432.
Ye X, Liu S, Yin H, He Q, Xue Z, Lu C, et al. Study on Optimal Parameter and Target for Pulsed-Field Ablation of Atrial Fibrillation. Frontiers in Cardiovascular Medicine. 2021; 8: 690092.
García-Sánchez T, Amorós-Figueras G, Jorge E, Campos MC, Maor E, Guerra JM, et al. Parametric Study of Pulsed Field Ablation With Biphasic Waveforms in an In Vivo Heart Model: The Role of Frequency. Circulation. Arrhythmia and Electrophysiology. 2022; 15: e010992.
Meckes D, Emami M, Fong I, Lau DH, Sanders P. Pulsed-field ablation: Computational modeling of electric fields for lesion depth analysis. Heart Rhythm O2. 2022; 3: 433–440.
Howard B, Verma A, Tzou WS, Mattison L, Kos B, Miklavčič D, et al. Effects of Electrode-Tissue Proximity on Cardiac Lesion Formation Using Pulsed Field Ablation. Circulation. Arrhythmia and Electrophysiology. 2022; 15: e011110.
Duytschaever M, De Potter T, Grimaldi M, Anic A, Vijgen J, Neuzil P, et al. Paroxysmal Atrial Fibrillation Ablation Using a Novel Variable-Loop Biphasic Pulsed Field Ablation Catheter Integrated With a 3-Dimensional Mapping System: 1-Year Outcomes of the Multicenter inspIRE Study. Circulation. Arrhythmia and Electrophysiology. 2023; 16: e011780.
Reddy VY, Peichl P, Anter E, Rackauskas G, Petru J, Funasako M, et al. A Focal Ablation Catheter Toggling Between Radiofrequency and Pulsed Field Energy to Treat Atrial Fibrillation. JACC. Clinical Electrophysiology. 2023; 9: 1786–1801.
Anić A, Phlips T, Brešković T, Koopman P, Girouard S, Mediratta V, et al. Pulsed field ablation using focal contact force-sensing catheters for treatment of atrial fibrillation: acute and 90-day invasive remapping results. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2023; 25: euad147.
Turagam MK, Neuzil P, Petru J, Funasako M, Koruth JS, Reinders D, et al. PV Isolation Using a Spherical Array PFA Catheter: Application Repetition and Lesion Durability (PULSE-EU Study). JACC. Clinical Electrophysiology. 2023; 9: 638–648.
Reddy VY, Koruth J, Jais P, Petru J, Timko F, Skalsky I, et al. Ablation of Atrial Fibrillation With Pulsed Electric Fields: An Ultra-Rapid, Tissue-Selective Modality for Cardiac Ablation. JACC. Clinical Electrophysiology. 2018; 4: 987–995.
Reddy VY, Anic A, Koruth J, Petru J, Funasako M, Minami K, et al. Pulsed Field Ablation in Patients With Persistent Atrial Fibrillation. Journal of the American College of Cardiology. 2020; 76: 1068–1080.
Schmidt B, Bordignon S, Tohoku S, Chen S, Bologna F, Urbanek L, et al. 5S Study: Safe and Simple Single Shot Pulmonary Vein Isolation With Pulsed Field Ablation Using Sedation. Circulation. Arrhythmia and Electrophysiology. 2022; 15: e010817.
Koruth J, Kuroki K, Iwasawa J, Enomoto Y, Viswanathan R, Brose R, et al. Preclinical Evaluation of Pulsed Field Ablation: Electrophysiological and Histological Assessment of Thoracic Vein Isolation. Circulation. Arrhythmia and Electrophysiology. 2019; 12: e007781.
Ekanem E, Reddy VY, Schmidt B, Reichlin T, Neven K, Metzner A, et al. Multi-national survey on the methods, efficacy, and safety on the post-approval clinical use of pulsed field ablation (MANIFEST-PF). Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2022; 24: 1256–1266.
Deneke T, Shin DI, Balta O, Bünz K, Fassbender F, Mügge A, et al. Postablation asymptomatic cerebral lesions: long-term follow-up using magnetic resonance imaging. Heart Rhythm. 2011; 8: 1705–1711.
Deneke T, Jais P, Scaglione M, Schmitt R, DI Biase L, Christopoulos G, et al. Silent cerebral events/lesions related to atrial fibrillation ablation: a clinical review. Journal of Cardiovascular Electrophysiology. 2015; 26: 455–463.
Deneke T, Nentwich K, Krug J, Müller P, Grewe PH, Mügge A, et al. Silent Cerebral Events after Atrial Fibrillation Ablation - Overview and Current Data. Journal of Atrial Fibrillation. 2014; 6: 996.
Reddy VY, Dukkipati SR, Neuzil P, Anic A, Petru J, Funasako M, et al. Pulsed Field Ablation of Paroxysmal Atrial Fibrillation: 1-Year Outcomes of IMPULSE, PEFCAT, and PEFCAT II. JACC. Clinical Electrophysiology. 2021; 7: 614–627.
Schmidt B, Bordignon S, Neven K, Reichlin T, Blaauw Y, Hansen J, et al. EUropean real-world outcomes with Pulsed field ablatiOn in patients with symptomatic atRIAl fibrillation: lessons from the multi-centre EU-PORIA registry. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2023; 25: euad185.
Reddy VY, Gerstenfeld EP, Natale A, Whang W, Cuoco FA, Patel C, et al. Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation. The New England Journal of Medicine. 2023; 389: 1660–1671.
Mehrzad R, Rajab M, Spodick DH. The three integrated phases of left atrial macrophysiology and their interactions. International Journal of Molecular Sciences. 2014; 15: 15146–15160.
Packer M. Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation. European Heart Journal. 2019; 40: 1873–1879.
Gupta DK, Shah AM, Giugliano RP, Ruff CT, Antman EM, Grip LT, et al. Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. European Heart Journal. 2014; 35: 1457–1465.
Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovascular Research. 2002; 54: 230–246.
Habibi M, Lima JAC, Khurram IM, Zimmerman SL, Zipunnikov V, Fukumoto K, et al. Association of left atrial function and left atrial enhancement in patients with atrial fibrillation: cardiac magnetic resonance study. Circulation. Cardiovascular Imaging. 2015; 8: e002769.
Okada T, Yamada T, Murakami Y, Yoshida N, Ninomiya Y, Shimizu T, et al. Prevalence and severity of left atrial edema detected by electron beam tomography early after pulmonary vein ablation. Journal of the American College of Cardiology. 2007; 49: 1436–1442.
Reant P, Lafitte S, Jaïs P, Serri K, Weerasooriya R, Hocini M, et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation. 2005; 112: 2896–2903.
Lemola K, Desjardins B, Sneider M, Case I, Chugh A, Good E, et al. Effect of left atrial circumferential ablation for atrial fibrillation on left atrial transport function. Heart Rhythm. 2005; 2: 923–928.
Verma A, Kilicaslan F, Adams JR, Hao S, Beheiry S, Minor S, et al. Extensive ablation during pulmonary vein antrum isolation has no adverse impact on left atrial function: an echocardiography and cine computed tomography analysis. Journal of Cardiovascular Electrophysiology. 2006; 17: 741–746.
Wylie JV, Jr, Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm. 2008; 5: 656–662.
Xiong B, Li D, Wang J, Gyawali L, Jing J, Su L. The Effect of Catheter Ablation on Left Atrial Size and Function for Patients with Atrial Fibrillation: An Updated Meta-Analysis. PLoS ONE. 2015; 10: e0129274.
Gibson DN, Di Biase L, Mohanty P, Patel JD, Bai R, Sanchez J, et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart Rhythm. 2011; 8: 1364–1371.
Wen S, Indrabhinduwat M, Brady PA, Pislaru C, Miller FA, Ammash NM, et al. Post Procedural Peak Left Atrial Contraction Strain Predicts Recurrence of Arrhythmia after Catheter Ablation of Atrial Fibrillation. Cardiovascular Ultrasound. 2021; 19: 22.
Khan HR, Yakupoglu HY, Kralj-Hans I, Haldar S, Bahrami T, Clague J, et al. Left Atrial Function Predicts Atrial Arrhythmia Recurrence Following Ablation of Long-Standing Persistent Atrial Fibrillation. Circulation. Cardiovascular Imaging. 2023; 16: e015352.
Nakatani Y, Sridi-Cheniti S, Cheniti G, Ramirez FD, Goujeau C, André C, et al. Pulsed field ablation prevents chronic atrial fibrotic changes and restrictive mechanics after catheter ablation for atrial fibrillation. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology: Journal of the Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac Cellular Electrophysiology of the European Society of Cardiology. 2021; 23: 1767–1776.
Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation modality–clinical implications. Technology in Cancer Research & Treatment. 2007; 6: 37–48.
Lavee J, Onik G, Mikus P, Rubinsky B. A novel nonthermal energy source for surgical epicardial atrial ablation: irreversible electroporation. The Heart Surgery Forum. 2007; 10: E162–E167.
Davalos RV, Mir ILM, Rubinsky B. Tissue ablation with irreversible electroporation. Annals of Biomedical Engineering. 2005; 33: 223–231.
Kotnik T, Rems L, Tarek M, Miklavčič D. Membrane Electroporation and Electropermeabilization: Mechanisms and Models. Annual Review of Biophysics. 2019; 48: 63–91.
Kotnik T, Miklavcic D. Second-order model of membrane electric field induced by alternating external electric fields. IEEE Transactions on Bio-medical Engineering. 2000; 47: 1074–1081.
Semenov I, Zemlin C, Pakhomova ON, Xiao S, Pakhomov AG. Diffuse, non-polar electropermeabilization and reduced propidium uptake distinguish the effect of nanosecond electric pulses. Biochimica et Biophysica Acta. 2015; 1848: 2118–2125.
Tekle E, Astumian RD, Chock PB. Selective and asymmetric molecular transport across electroporated cell membranes. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 11512–11516.
Kotnik T, Pucihar G, Miklavcic D. Induced transmembrane voltage and its correlation with electroporation-mediated molecular transport. The Journal of Membrane Biology. 2010; 236: 3–13.
Beebe SJ, Fox PM, Rec LJ, Somers K, Stark RH, Schoenbach KH. Nanosecond pulsed electric field (nsPEF) effects on cells and tissues: apoptosis induction and tumor growth inhibition. IEEE Transactions on Plasma Science. 2002; 30: 286–292.
Beebe SJ, Fox PM, Rec LJ, Willis ELK, Schoenbach KH. Nanosecond, high-intensity pulsed electric fields induce apoptosis in human cells. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2003; 17: 1493–1495.
Stacey M, Stickley J, Fox P, Statler V, Schoenbach K, Beebe SJ, et al. Differential effects in cells exposed to ultra-short, high intensity electric fields: cell survival, DNA damage, and cell cycle analysis. Mutation Research. 2003; 542: 65–75.
Gowrishankar TR, Weaver JC. Electrical behavior and pore accumulation in a multicellular model for conventional and supra-electroporation. Biochemical and Biophysical Research Communications. 2006; 349: 643–653.
Schoenbachk KH, Joshi RP, Kolb JF, Chen N, Stacey M, Buescher ES, et al. Ultrashort electrical pulses open a new gateway into biological cells (pp. 205–209). In Conference Record of the Twenty-Sixth International Power Modulator Symposium. 2004 and 2004 High-Voltage Workshop. 2004.
Tekle E, Oubrahim H, Dzekunov SM, Kolb JF, Schoenbach KH, Chock PB. Selective field effects on intracellular vacuoles and vesicle membranes with nanosecond electric pulses. Biophysical Journal. 2005; 89: 274–284.
Ibey BL, Roth CC, Pakhomov AG, Bernhard JA, Wilmink GJ, Pakhomova ON. Dose-dependent thresholds of 10-ns electric pulse induced plasma membrane disruption and cytotoxicity in multiple cell lines. PLoS ONE. 2011; 6: e15642.
Ibey BL, Xiao S, Schoenbach KH, Murphy MR, Pakhomov AG. Plasma membrane permeabilization by 60- and 600-ns electric pulses is determined by the absorbed dose. Bioelectromagnetics. 2009; 30: 92–99.
Pakhomov AG, Kolb JF, White JA, Joshi RP, Xiao S, Schoenbach KH. Long-lasting plasma membrane permeabilization in mammalian cells by nanosecond pulsed electric field (nsPEF). Bioelectromagnetics. 2007; 28: 655–663.
Deng J, Schoenbach KH, Buescher ES, Hair PS, Fox PM, Beebe SJ. The effects of intense submicrosecond electrical pulses on cells. Biophysical Journal. 2003; 84: 2709–2714.
Pakhomov AG, Bowman AM, Ibey BL, Andre FM, Pakhomova ON, Schoenbach KH. Lipid nanopores can form a stable, ion channel-like conduction pathway in cell membrane. Biochemical and Biophysical Research Communications. 2009; 385: 181–186.
Son RS, Smith KC, Gowrishankar TR, Vernier PT, Weaver JC. Basic features of a cell electroporation model: illustrative behavior for two very different pulses. The Journal of Membrane Biology. 2014; 247: 1209–1228.
Vernier PT, Sun Y, Gundersen MA. Nanoelectropulse-driven membrane perturbation and small molecule permeabilization. BMC Cell Biology. 2006; 7: 37.
Ibey BL, Pakhomov AG, Gregory BW, Khorokhorina VA, Roth CC, Rassokhin MA, et al. Selective cytotoxicity of intense nanosecond-duration electric pulses in mammalian cells. Biochimica et Biophysica Acta. 2010; 1800: 1210–1219.
Cantu JC, Tarango M, Beier HT, Ibey BL. The biological response of cells to nanosecond pulsed electric fields is dependent on plasma membrane cholesterol. Biochimica et Biophysica Acta. 2016; 1858: 2636–2646.
Vernier PT, Levine ZA, Wu YH, Joubert V, Ziegler MJ, Mir LM, et al. Electroporating fields target oxidatively damaged areas in the cell membrane. PloS One. 2009; 4: e7966.
Wang S, Chen J, Chen MT, Vernier PT, Gundersen MA, Valderrábano M. Cardiac myocyte excitation by ultrashort high-field pulses. Biophysical Journal. 2009; 96: 1640–1648.
Semenov I, Grigoryev S, Neuber JU, Zemlin CW, Pakhomova ON, Casciola M, et al. Excitation and injury of adult ventricular cardiomyocytes by nano- to millisecond electric shocks. Scientific Reports. 2018; 8: 8233.
Dermol-Černe J, Batista Napotnik T, Reberšek M, Miklavčič D. Short microsecond pulses achieve homogeneous electroporation of elongated biological cells irrespective of their orientation in electric field. Scientific Reports. 2020; 10: 9149.
Pashakhanloo F, Herzka DA, Ashikaga H, Mori S, Gai N, Bluemke DA, et al. Myofiber Architecture of the Human Atria as Revealed by Submillimeter Diffusion Tensor Imaging. Circulation. Arrhythmia and Electrophysiology. 2016; 9: e004133.
Nuccitelli R. Application of Pulsed Electric Fields to Cancer Therapy. Bioelectricity. 2019; 1: 30–34.
Breton M, Mir LM. Microsecond and nanosecond electric pulses in cancer treatments. Bioelectromagnetics. 2012; 33: 106–123.
Campana LG, Daud A, Lancellotti F, Arroyo JP, Davalos RV, Di Prata C, et al. Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation. Cancers. 2023; 15: 3340.
Esser AT, Smith KC, Gowrishankar TR, Weaver JC. Towards solid tumor treatment by nanosecond pulsed electric fields. Technology in Cancer Research & Treatment. 2009; 8: 289–306.
Nuccitelli R, Wood R, Kreis M, Athos B, Huynh J, Lui K, et al. First-in-human trial of nanoelectroablation therapy for basal cell carcinoma: proof of method. Experimental Dermatology. 2014; 23: 135–137.
Hruza GJ, Zelickson BD, Selim MM, Rohrer TE, Newman J, Park H, et al. Safety and Efficacy of Nanosecond Pulsed Electric Field Treatment of Seborrheic Keratoses. Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]. 2020; 46: 1183–1189.
Munavalli GS, Zelickson BD, Selim MM, Kilmer SL, Rohrer TE, Newman J, et al. Safety and Efficacy of Nanosecond Pulsed Electric Field Treatment of Sebaceous Gland Hyperplasia. Dermatologic Surgery: Official Publication for American Society for Dermatologic Surgery [et Al.]. 2020; 46: 803–809.
Liu J, Fang C, Jin X, Tian G, Sun Z, Hong L, et al. Nanosecond pulsed electric field ablation-induced modulation of sphingolipid metabolism is associated with Ly6c2+ mononuclear phagocyte differentiation in liver cancer. Molecular Oncology. 2023; 17: 1093–1111.
Xu M, Xu D, Dong G, Ren Z, Zhang W, Aji T, et al. The Safety and Efficacy of Nanosecond Pulsed Electric Field in Patients With Hepatocellular Carcinoma: A Prospective Phase 1 Clinical Study Protocol. Frontiers in Oncology. 2022; 12: 869316.
Xie F, Varghese F, Pakhomov AG, Semenov I, Xiao S, Philpott J, et al. Ablation of Myocardial Tissue With Nanosecond Pulsed Electric Fields. PloS One. 2015; 10: e0144833.
Varghese F, Philpott JM, Neuber JU, Hargrave B, Zemlin CW. Surgical Ablation of Cardiac Tissue with Nanosecond Pulsed Electric Fields in Swine. Cardiovascular Engineering and Technology. 2023; 14: 52–59.
Koruth JS, Kawamura I, Maan A, Musikantow DR, Turagam MK, Miller MA, et al. PO-04-067 nanosecond pulsed field ablation: demonstration of halo-shaped lesions with a novel multielectrode system: initial preclinical experience. Heart Rhythm. 2023; 20: S516–S517.
Tan NY, Ladas TP, Christopoulos G, Sugrue AM, van Zyl M, Ladejobi AO, et al. Ventricular nanosecond pulsed electric field delivery using active fixation leads: a proof-of-concept preclinical study. Journal of Interventional Cardiac Electrophysiology: an International Journal of Arrhythmias and Pacing. 2022. (online ahead of print)
van Zyl M, Ladejobi AO, Tri JA, Yasin OZ, Connolly RJ, Danitz DJ, et al. Reversible Atrioventricular Conduction Impairment Following Bipolar Nanosecond Electroporation of the Interventricular Septum. JACC. Clinical Electrophysiology. 2021; 7: 255–257.
Sundararajan R. Nanosecond electroporation: another look. Molecular Biotechnology. 2009; 41: 69–82.
