Introduction

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia, affecting more than 33 million individuals worldwide. Catheter and surgical ablation are important treatment options for symptomatic patients. Although both approaches are efficacious, there is a substantial risk of AF recurrence, and the procedure can be both challenging and time-consuming. Consequently, there has been a constant evolution of novel tools and technologies for AF ablation. In particular, a continuously evolving area is the development and testing of novel energy sources for ablation. Today, radiofrequency energy represents the most common energy modality used for ablation followed by cryothermal. In addition to these two primary energy sources, microwave, high frequency ultrasound, and laser energy have been explored but are not currently available for percutaneous approaches or routine use in clinical practice. More recently, we have seen the emergence of pulsed electric fields (PEFs) as an ablation modality¹ with a recent first-in-human publication on its use for AF ablation.² In this expert review, we provide a primer for cardiologists on PEFs; examine current preclinical and clinical data, and close with a brief discussion on the future of PEFs as a cardiac ablation modality.

A Brief Primer on PEFs for the Cardiologist

PEF ablation (also referred to as electroporation or irreversible electroporation) refers to a process whereby short, high-voltage pulses (usually created with direct current) are applied to tissue/cells. When an electric field is applied across a cell, it leads to an induced voltage across the cellular membrane (induced transmembrane voltage), which is superimposed on the resting transmembrane voltage.³ When the transmembrane voltage (a sum of the induced and resting membrane potential) crosses a threshold or critical value, changes in membrane permeability are observed. It is assumed via theoretical models that the change in membrane permeability is either a consequence of or intrinsically related to the formation of hydrophilic pores in the lipid membrane (hence the term electro-POR-ation). This change in membrane permeability can be reversible or irreversible, contingent upon not only the parameters of the electric field delivered but also the size and shape of the cells in the tissue. Unlike radiofrequency or cryothermal, there are numerous PEF parameters (not to mention tissue and environmental factors) that play roles in the effect observed. These variables include the pulse amplitude (voltage), pulse duration (milliseconds, microseconds, or nanoseconds), number of pulses, and pulse frequency. Of the many PEF parameters, the magnitude of the electric field (pulse amplitude) and the duration of the delivered pulse have the most significant electroporation impact.

What makes PEFs such an attractive option over current available ablation modalities is that tissue destruction is largely non-thermal and tissue selective (e.g., application of a PEF to the myocardium will not necessarily have the same effect when delivered to a nerve), and energy can be delivered quickly in seconds or minutes compared with hours for radiofrequency. Further, in the arena of AF ablation, one particularly alluring preclinical finding is that the direct application of PEF to pulmonary veins (PVs) does not seem to result in PV stenosis.

Preclinical Studies

There have been numerous preclinical studies published on cardiac ablation with PEFs that are noteworthy; we will focus on the critical publications related to PEF AF ablation, particularly those that demonstrate a lack of PV stenosis and collateral damage. In 2011, Wittkampf et al.,⁴ after initially observing that internal cardioversion eliminated the left atrial electrograms recorded via a cardioversion catheter in the coronary sinus, applied electroporation (direct current delivered from a defibrillator) directly to PV ostia in 10 swine using a custom 7F decapolar 20 mm circular ablation catheter. In this study, they observed a decrease in PV ostial electrograms and an increase in stimulation threshold after a 3-week survival period. Remarkably, these results not only demonstrated safety but also showed a lack of chronic histological changes associated with PV stenosis that would be expected in radiofrequency ablation. These findings were further validated in a long-term study using radiofrequency energy as a comparator.⁵ DeSimone et al. also described a similar observation using a novel, balloon-based ablation catheter⁶ with the capability to sense, pace, and deliver ablation lesions. And more recently, Witt et al.⁷ demonstrated the same with an iterative balloon design, delivering PEFs to 5 canines (10 PVs) that survived for 27 days. This work demonstrated significant acute local electrogram diminution (mean amplitude decrease of 61.2 ± 19.8%) and a lack of PV stenosis by both computed tomography imaging and histological analysis.

Another important consideration with AF ablation is damage to collateral structures. In preclinical studies, PEF does not seem to cause injury to esophageal tissue,⁸ both directly when applied to the esophagus and indirectly through ablation in the left atrium. Further, data suggest there is no damage to the phrenic nerve.⁹

Clinical Studies

To date, there has been only one publication on the clinical (human) experience with PEF for AF ablation.² In this prospective, open-label, nonrandomized study, 22 patients underwent AF ablation with PEF using 2 different styles of devices; 15 patients underwent an endocardial approach using a custom endocardial catheter and 7 an epicardial approach with a linear catheter for encircling the PVs and posterior left atrium. The focus of the study was the acute procedural performance and safety of this ablative approach. To be included in this study, patients had to be between 18 and 70 years old and have paroxysmal AF refractory to or intolerant of at least 1 antiarrhythmic drug, with an anteroposterior left atrial diameter <5.5 cm and left ventricular ejection fraction ≥40%. For the epicardial approach, inclusion criteria were patients aged 18-70 years with a diagnosis of paroxysmal AF who were scheduled to undergo elective on-pump cardiac surgery (either mitral or aortic valve repair or replacement or coronary artery bypass grafting). Amongst those patients receiving an endocardial approach, each PV received at least 3 PEF applications (900 to 1,000 V), with the splines rotated between applications to ensure circumferential PV coverage. In the 15 patients who had an endocardial approach, PV isolation was successful in 57 PVs (100%) using a mean of 3.26 ± 0.5 lesions. The epicardial approach was successful in 6 of 7 patients (86%) using a mean of 2 lesions. There were no reported complications at 1-month follow-up. Although these data show excellent safety, the follow-up is relatively short, and we have no data on freedom from AF (recurrence).

The Future

With the current publication of preclinical and clinical data, PEF shows many unique features that suggest the potential for it to be advantageous over current thermal-based approaches. That noted, there are still many challenges and unanswered questions facing this novel technology. First, the need for long-term data on arrhythmogenic control and complications is critical. Second, a dedicated cardiac generator system for high-voltage pulses is required and should be widely available. Current cardiac PEF research involves a wide range of energy sources, from adapting Food and Drug Administration-approved technology (NanoKnife [AngioDynamics, Inc.; Queensbury, NY]) to using external defibrillators or customer-generator boxes (as in the latest human study).^10,11 Such a dedicated energy system should be able to deliver a wide range of electric field intensities and pulse width durations to allow for flexibility and dose titration. The third issue is pain and sedation. Published PEF protocols have shown a varying length of pulse delivery pulses, ranging from microseconds to milliseconds. Delivery of pulses at this length can cause pain and muscle stimulation; therefore, procedures generally require the administration of sedation along with muscle relaxants or neuromuscular blockade.¹² This can not only increase complications but also lead to an increase in procedure complexity. Ultimately, we feel that this issue will need to be overcome to enable broad adoption. Potential means to overcome this include high-frequency irreversible electroporation or nanosecond pulsing, though these protocols have not been specifically studied for cardiac ablation.

Conclusion

PEFs have emerged as a novel treatment approach for cardiac ablation and offer an attractive non-thermal ablation strategy. Current preclinical and clinical data show excellent safety, but further data on long-term arrhythmogenic and safety outcomes are required.

References

1. Sugrue A, Maor E, Ivorra A, et al. Irreversible electroporation for the treatment of cardiac arrhythmias. Expert Rev Cardiovasc Ther 2018;16:349-60.
2. Reddy VY, Koruth J, Jais P, et al. Ablation of Atrial Fibrillation With Pulsed Electric Fields: An Ultra-Rapid, Tissue-Selective Modality for Cardiac Ablation. JACC Clin Electrophysiol 2018;4:987-95.
3. Kotnik T, Pucihar G, Miklavcic D. Induced transmembrane voltage and its correlation with electroporation-mediated molecular transport. J Membr Biol 2010;236:3-13.
4. Wittkampf FH, van Driel VJ, van Wessel H, et al. Feasibility of electroporation for the creation of pulmonary vein ostial lesions. J Cardiovasc Electrophysiol 2011;22:302-9.
5. van Driel VJ, Neven KG, van Wessel H, et al. Pulmonary vein stenosis after catheter ablation: electroporation versus radiofrequency. Circ Arrhythm Electrophysiol 2014;7:734-8.
6. DeSimone CV, Ebrille E, Syed FF, et al. Novel balloon catheter device with pacing, ablating, electroporation, and drug-eluting capabilities for atrial fibrillation treatment--preliminary efficacy and safety studies in a canine model. Transl Res 2014;164:508-14.
7. Witt CM, Sugrue A, Padmanabhan D, et al. Intrapulmonary Vein Ablation Without Stenosis: A Novel Balloon-Based Direct Current Electroporation Approach. J Am Heart Assoc 2018;7:e009575.
8. Neven K, van Es R, van Driel V, et al. Acute and Long-Term Effects of Full-Power Electroporation Ablation Directly on the Porcine Esophagus. Circ Arrhythm Electrophysiol 2017;10:e004672.
9. van Driel VJ, Neven K, van Wessel H, Vink A, Doevendans PA, Wittkampf FH. Low vulnerability of the right phrenic nerve to electroporation ablation. Heart Rhythm 2015;12:1838-44.
10. van Driel VJ, Neven KG, van Wessel H, et al. Pulmonary vein stenosis after catheter ablation: electroporation versus radiofrequency. Circ Arrhythm Electrophysiol 2014;7:734-8.
11. Witt C, Padmanabhan D, Killu AM, et al. Successful Electroporation of the Pulmonary Veins in Canines Using a Balloon Catheter. Heart Rhythm 2017;14(C-PO06-49):S533.
12. Arena CB, Sano MB, Rossmeisl JH Jr, et al. High-frequency irreversible electroporation (H-FIRE) for non-thermal ablation without muscle contraction. Biomed Eng Online 2011;10:102.

Keywords: Atrial Fibrillation, Pulmonary Veins, Anti-Arrhythmia Agents, Electrophysiologic Techniques, Cardiac, Electric Countershock, Coronary Sinus, Phrenic Nerve, Membrane Potentials, United States Food and Drug Administration, Neuromuscular Blockade, Prospective Studies, Aortic Valve, Stroke Volume, Catheter Ablation, Heart Atria, Tachycardia, Defibrillators, Coronary Artery Bypass, Myocardium, Electroporation, Permeability, Tomography, Lipids

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