Author + information
- Edward P. Gerstenfeld, MD∗ ()
- Section of Cardiac Electrophysiology, Division of Cardiology, University of California-San Francisco, San Francisco, California
- ↵∗Address for correspondence:
Dr. Edward P. Gerstenfeld, Section of Cardiac Electrophysiology, Division of Cardiology, University of California-San Francisco, MU-East 4th Floor, 500 Parnassus Avenue, San Francisco, California 94143.
In 1982, Scheinman et al. (1) first described use of high-energy direct-current (DC) shock via a transvenous catheter for performing closed-chest atrioventricular (AV) node ablation in humans. By current standards, this was a crude method for ablating cardiac tissue, but it transformed the field of cardiac electrophysiology to one that could provide curative therapy for most cardiac arrhythmias using a closed-chest, catheter-based nonsurgical approach. The subsequent development of radiofrequency (RF) energy greatly improved the efficacy and precision of catheter ablation, and further modifications, including irrigated ablation and contact force sensing, have further enhanced the approach.
RF energy creates ablative lesions via 2 mechanisms: resistive heating, which largely destroys the myocardial cells directly under the catheter tip; and conductive heating, which radiates from the core lesion to irreversibly damage cells that are heated to a temperature of >50°C. Because resistive heating falls off rapidly with distance, the majority of the RF lesion is formed by conductive heating to the surrounding tissue. This process requires time to reach maximal lesion size. Typically, RF energy is delivered for 20 to 60 s/lesion; however, some have advocated use of high-power, short-duration lesions to minimize procedure time and conductive heating at depth. However, even with this approach, delivering multiple ablation lesions over a wide area can be time- consuming.
Early ablation strategy therapies that target focal arrhythmias have now expanded to complex lesions designed to isolate anatomic structures, such as the pulmonary veins (PVs) and the posterior left atrial wall to treat atrial fibrillation (AF). Despite all the advances in catheter-based technology, it has been apparent that use of a focal catheter for such broad circumferential ablative approaches can be painstakingly tedious and has significant limitations, including: 1) procedure time needed to perform wide area ablation [>2 h (2)]; 2) gaps in circumferential ablation patterns, some of which cannot be completely closed acutely due to edema from the surrounding lesions; 3) char and/or thrombus formation during ablation that leads to symptomatic and asymptomatic thromboemboli; and 4) likelihood of damage to collateral structures, such as the phrenic nerve, esophagus, and PVs. Despite many attempts to develop energy sources capable of circumferential ablation (ultrasound, laser, cryoablation), focal RF catheter ablation has withstood the test of time because of its adaptability to varied anatomy and its ability to titrate power differentially based on tissue thickness and the presence of collateral structures. The cryoballoon was the first competing technology designed specifically for PV isolation, and has had growing adoption throughout the world, largely due to ease of use and the shorter procedure time compared with RF. Laser ablation is now another competing modality, yet the longer procedure time has not yet led to wide adoption. Most centers worldwide (68% in the RE-CIRCUIT trial [Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy] ) continue to use RF ablation as the primary modality for AF ablation.
In this issue of JACC: Clinical Electrophysiology, Reddy et al. (4) present the first-in-human experience using high-energy pulsed electric fields (PEF), otherwise known as electroporation, for PV isolation. Electroporation is a technique for increasing cell permeability using high-energy, short-duration electric field pulses. Reversible electroporation was first used to increase cell permeability to allow chemicals, drugs, or DNA into cells. Later, irreversible electroporation (IRE) was described by Rubinski et al. (5) as a method of damaging cancer cells by applying higher strength electric fields that created micropores in the cell membrane, which led to cell death. IRE had the unique characteristic of damaging cancer cells while leaving vascular and connective tissue intact. This specificity makes the approach attractive for human ablation. Use of IRE to destroy healthy myocardial cells was first described in large animal models by Wittkampf et al. (6). IRE allows delivery of destructive lesions to a broad area of myocardium, essentially instantaneously, without the attendant char and thrombus formation that occurs with conductive heating, and with apparent specificity toward myocardial cells.
The investigators tested 2 novel, custom-manufactured catheters to perform PV isolation: 1) a flower-shaped catheter designed for endocardial PV ablation; and 2) a linear epicardial catheter designed to isolate the PVs and posterior left atrial wall during cardiac surgery. Endocardial procedures were performed in 15 patients with paroxysmal AF, and epicardial procedures were performed in 7 patients who underwent AF ablation concomitantly with valve or bypass surgery. Both catheters were connected to a generator capable of delivering the pulsed waveform to electrodes on the catheter, with pulses of 900 to 1,000 V for the endocardial ablations and 2,100 to 2,400 V for the epicardial ablations. Focusing on the endocardial procedures, the investigators achieved 100% acute PV isolation with a median of only 3 energy applications per PV. This led to a total duration from first to last ablation for all PVs of 19 ± 2.5 min, with an astoundingly short total energy delivery time of <60 s/patient. PV isolation was confirmed using standard approaches, and post-ablation voltage maps revealed reasonably antral wide area ablation lesions. General anesthesia and paralysis were required during ablation to avoid skeletal muscle stimulation with the high-energy pulses. However, detailed testing of the phrenic nerve before and after ablation yielded no phrenic nerve injury. Although esophageal temperature monitoring was not performed uniformly due to the presumed tissue selectivity of electroporation, 2 patients underwent endoscopy shortly after ablation with no erythema or esophageal lesions noted. Surgical ablations were equally efficacious with posterior wall and PV isolation after 2 delivered lesions in all patients who underwent PEF therapy.
The major limitations of this study were the lack of any clinical outcomes after ablation or documentation of PV isolation persistence after ablation. The investigators reported no procedural complications and no adverse events after 1-month follow-up in most patients. However, more typical clinical endpoints, such as freedom from atrial tachyarrhythmias or symptoms, were not included in this initial report. In addition, despite the described tissue sensitivity of electroporation, I would have liked to see this confirmed with a lack of any increases in esophageal temperature, which was notably missing. The PEF approach, because it did not create char and/or thrombus, would also be presumed to have a low incidence of thromboembolic events, particularly cerebral events, which were documented in many previous studies of new ablation technologies. However, air bubbles created with electroporation or thrombus from catheters and/or sheaths might still occur. The investigators did not perform brain imaging before and after ablation due to limited resources; this should be done in future studies. The investigators also performed 3-month remapping studies in several previous early studies of new technologies for PV isolation (7). Although the investigators realized the large hurdles involved in performing these studies, such information would be valuable in understanding any advances and limitations of this new technology. Follow-up imaging to exclude PV stenosis, because portions of the catheter may enter or overlap with PV tissue, would be important to document. Finally, the current catheter maximal diameter of 30 mm and small patient numbers also raises the question of whether the approach would be suitable for patients with unusual PV anatomy. Although there was no particular effort made to screen out complex PV anatomy in this study, patients with large atria, large common PVs, or middle and/or roof PVs could be anticipated to pose a challenge. The ability to have larger or multiple flower catheter dimensions are certainly modifications that seem straightforward for future catheter iterations, and integration of electrodes for mapping should also be feasible.
Could electroporation be the tool we have all been waiting for, allowing antral PV isolation with extremely low risk in <1 min? The current paper is certainly enticing; however, more information is clearly needed. Lack of phrenic nerve injury during direct PEF application in a pre-clinical report (8) and the current clinical report is reassuring. Although pre-clinical work also suggests a low risk of esophageal injury (9), more safety data are needed. For example, despite the described preferential myocardial sensitivity, direct PEF application to the esophageal adventitia led to inflammation of the outer muscular layer. The mechanism of left atrium−esophageal fistula is still poorly understood, including whether this is due to direct esophageal injury, an inflammatory reaction, and/or injury to the surrounding vasculature (which appears minimal during PEF). Certainly a study that includes endoscopy in all patients after PEF therapy that shows no esophageal erythema would be reassuring. Given the low incidence of this devastating complication, we should remain vigilant about minimizing esophageal injury with any new technology. Finally, clinical outcome persistence of PV isolation and freedom from AF after 1 year are certainly needed.
Those of us who have been performing AF ablation for the past 2 decades have certainly learned not to be Pollyannaish about any new approach that seems to offer the “holy grail” of PV ablation therapy. However, I am encouraged that PEF holds promise for PV isolation and other arrhythmias that require broad tissue ablation, such as scar-based ventricular tachycardia. Perhaps one day we can all lament about the days “when we were fellows” and spent hours standing and ablating the left atrium with RF. The ability to achieve rapid, safe, persistent PV isolation would move the next horizon to the challenge of mapping and targeting AF triggers and/or drivers outside of the PVs in more persistent forms of AF.
It is appropriately ironic that the DC shock therapy pioneered by Scheinman et al. (1) has come back in a more targeted form to perhaps give us the tool for which we have been waiting. I anxiously await further reports of this early approach to rapid PV isolation using IRE and/or PEF. The investigators should be congratulated for an important contribution to the clinical application of a novel approach to AF ablation, as well as Drs. Rubinski and Wittkampf for their work moving this approach from the bench to the clinical arena.
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Gerstenfeld has reported that he has no relationships relevant to the contents of this paper to disclose.
The author attests he is in compliance with human studies committees and animal welfare regulations of the author’s institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2018 American College of Cardiology Foundation
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