The Promise of Pulsed Field Ablation

Introduction

A variety of techniques, catheter designs, and energy sources have been investigated for pulmonary vein isolation in the treatment of atrial fibrillation. The most common approaches are point-by-point ablation with radiofrequency (RF) energy, or circumferential balloon ablation with cryothermic energy. Pulmonary vein isolations with all approved technologies can be incomplete with resultant pulmonary vein reconnection and AF recurrence. At the same time, inadvertent ablation beyond the targeted tissue can result in significant injury to collateral structures such as the esophagus and phrenic nerve.

Pulsed field ablation (PFA) employs trains of high voltage in very short duration electrical pulses to injure tissue by the mechanism of irreversible electroporation. This approach is nonthermal, and myocardium is highly susceptible to this type of injury, whereas collateral structures seem to be relatively resistant to injury. Thus, PFA offers the promise of achieving durable pulmonary vein ablation with very low risk. In addition, using a circular multipolar catheter, pulmonary vein isolation can be achieved very rapidly (within one minute). Accordingly, PFA may dramatically shorten the procedure time.

Biophysics and Pathophysiology of Pulsed Field Ablation

Pulsed field ablation employs a high voltage pulse delivery in a unipolar or bipolar fashion in close proximity to the target tissue. The electrical field applied to the myocyte causes dielectric breakdown of the sarcolemmal membrane with resultant pore formation. The pores allow macromolecules and ions to freely enter and exit the cell. If a lower PFA field strength is used, the pores may close in time for the cells to re-establish normal homeostasis and maintain viability (reversible electroporation). If the field strength is greater, then larger, more persistent pores form. The nonspecific entry and exit of macromolecules and ions can result in inactivation of intracellular and membrane proteins triggering cellular apoptosis, and calcium entry can overwhelm the intracellular calcium buffering systems leading to tetany and cell death (irreversible electroporation).^1,2 Even though high voltage and current amplitudes are employed with PFA, the very short pulse durations cause little ohmic heating. This coupled with convective cooling from circulating blood flow results in no appreciable temperature rise within the tissue. However, if very high voltages are employed, the current density generated may be high enough to cause resistive heating at the electrode-tissue interface, which is undesirable since hyperthermic effects are what we hope to avoid with this new ablation technology.

Modulation of PFA

There are many parameters that can be modulated to create the final waveform including bipolar or unipolar delivery, biphasic or monophasic pulses, voltage amplitude (hundreds to thousands of volts), pulse duration (nanoseconds to milliseconds), interphase interval, interpulse interval, number of pulses in the train (single pulse to hundreds), and number of trains delivered. The characteristics of each pulse that can vary include pulse rise time, pulse fall time, voltage overshoot and ringing, and waveform tilt (Figure 1). A critical difference between the waveform of modern PFA compared to that employed with DC shock ablation during the early days of catheter ablation is that the pulse duration is short enough that there is minimal vapor formation, no vapor globe expansion, and no arcing during energy delivery.³ Therefore, the risk associated with DC shock ablation from barotrauma and arcing are not observed with PFA.

An important point that differentiates RFA from PFA is that the waveform of the former is generic. RF energy is typically delivered at frequencies of 500 or 750 kHz, but there is no measurable difference in the mechanism or magnitude of heating over frequency ranges of 300 kHz to 10 MHz. In all cases, myocardial heating is proportional to the power density squared (or current density to the fourth power). Thus, the manner and magnitude of tissue heating is very similar among all commercial RF ablation systems. In practice, RF generators from one manufacturer are often coupled with ablation catheters from competing manufacturers with no adverse consequences. In contrast, the ablation waveform generated by the PFA generator is highly proprietary. Also, the PFA field distribution and resultant clinical effects are unique to each delivery catheter design. Thus, PFA results cannot be predictable unless the proprietary ablation catheter is coupled with the proprietary generator. In addition, clinical results observed with one ablation system cannot be generalized to ablation with other generators or catheters.

Currently, the only commercially available generator for PFA is the NanoKnife System (AngioDynamics, Inc.), although several investigational systems are in varying stages of clinical testing for ablation of atrial fibrillation. Since much of the preclinical research regarding waveform optimization for PFA in the heart has been performed by companies seeking to commercialize their product, the influence of changing various modulating factors of the waveform on efficacy and safety of these systems is not in the public domain. However, a large pool of data regarding the use of PFA for tumor ablation in oncology exists, and there is significant heterogeneity regarding what levels of electric field need be applied for the desired effect.⁴ Parameter ranges reported are typically 500-3000 V/cm voltage delivered, 1-100 pulses delivered, over a wavelength of microseconds, with a frequency range of 1-5 Hz. Delivery pulses may be delivered in a monophasic or biphasic format, and the waveforms can be altered to allow for voltage decay. It has been reported that biphasic waveforms, when delivered in an asymmetric fashion, may increase lesion depth. Upward titration of the delivered voltage, pulse duration, and pulse number have largely resulted in greater electric field and more tissue destruction.⁵

Thermal ablation techniques require several seconds to achieve measurable effects and minutes to achieve steady-state temperature gradients. The effects of PFA, in contrast, are almost instantaneous. A single PFA delivery is accomplished within one heartbeat, and typically a lesion is created with 3-5 PFA deliveries. Therefore, pulmonary vein isolation can be achieved with a circumferential electrode catheter within 4 heartbeats.

Contact Dependence

Achieving tissue-catheter contact is critical to produce adequate lesion size and intended effect with thermal ablation modalities. In contrast, pulsed field ablation effects rely upon tissue proximity and are not contact dependent, because they are a result of the electric field created (Figure 2). This effect is termed electric field strength dependence. The effects are a result of the voltage delivered, and the distance over which the voltage is applied. An increase in the voltage applied will result in an increased effect upon the tissue. The creation of an electric field, rather than contact-dependent lesions, is an attractive alternative for ablation of pulmonary veins.⁶

Electrode Design

Tissue injury is a function of voltage field strength within the tissue. This, in turn, is a function of field shape which is determined by electrode configuration and proximity to the electrodes. Commercially available electrodes employed in oncology are needle electrodes. Electrode catheters being tested for pulmonary vein isolation have multiple electrodes and are either circular, linear, or basket shape in design. In the future, electrode balloon or expandable lattice catheters may be employed for PFA delivery. The geometry of delivered pulsed field energy can be calculated if tissue geometry and impedance are known. The electric field can be generated in a unipolar fashion, with an active electrode coupled with a dispersive electrode placed on the skin. Unfortunately, this results in significant skeletal muscle stimulation and pain, requiring the use of general anesthesia. Instead, bipolar energy delivered between local electrodes may confine the electric field, resulting in effective local tissue ablation without significant muscle stimulation.⁶

Cardiac PFA in Preclinical Studies: Effects on Myocardial Tissue

Early testing of PFA demonstrated full thickness lesions without a measured temperature rise. Preclinical studies have achieved reliable cardiac ablation without development of vapor globes, arcing, or pressure waves. Energy deliveries have been reliably titratable. Electroporation acutely reduces pulmonary vein electrogram potentials, as well as offers effective ganglionic plexus destruction after epicardial electroporation. Local electrogram voltages are acutely reduced, and there is acute loss of pacing capture.^6-8

Pathological examination of pulsed field ablation lesions reveals a sharp demarcation between ablated and normal tissue. Histologic examination of myocardial tissue shows elimination of cardiomyocytes, sparing of the structural extracellular matrix, and the presence of remnant fibrosis or fibroblasts (Figure 3).^8,9 Unlike RFA lesions, PFA lesions do not show coagulation necrosis, but have myofiber disruption and inflammation¹⁰, as well as have more homogenous fibrotic remodeling of the cardiac wall. Sequestered viable myocytes are common after RFA, but are rarely seen in PFA lesions. Chronically, lesions produced with PFA showed homogeneous fibrosis without endocardial disruption, few lingering sequestered myocytes, and minimal arterial remodeling.

Tissue Specificity

One of the most appealing aspects of PFA is the high sensitivity that myocardium has to injury with this energy modality compared to the relative resistance to effects of PFA in surrounding tissues. The exact mechanism for why cardiac tissue is more sensitive to lower electric fields is not completely understood, but may relate to cell size, orientation, membrane characteristics, and sensitivity to nonspecific cation entry. This differential sensitivity to PFA results in a wide therapeutic margin in ablation with this modality.

Esophageal effects. Esophageal thermal injury during posterior left atrial ablation with formation of an atrioesophageal fistula is the most feared complication of PVI. Hyperthermic ablation can extend beyond the 2-3 mm thick posterior LA wall and cause direct injury to the anterior esophagus. In dramatic contrast, PFA applied directly to the esophagus typically produces no visible lesions. When injury is observed, it has been characterized as damage limited to the muscular layer, sparing the epithelial and lamina muscularis mucosa (Figure 4).¹⁰ Linear suction ablation with electroporation directly onto porcine esophageal tissue showed no histologic changes two months after ablation.¹¹

Pulmonary vein effects. In the early era of pulmonary vein isolation for the treatment of atrial fibrillation, a prevalent complication was pulmonary vein stenosis caused by the propensity of hyperthermia to induce contraction of the vein wall. Subsequently, the field has migrated toward a wide area circumferential ablation (WACA) approach to incorporate more antral tissue within the isolated segment and to lessen the risk of PV stenosis. Despite this transition, patients still present (infrequently) with symptomatic PV stenosis requiring PV stenting. Aggressive ablation in the pulmonary veins with unipolar electroporation or bipolar biphasic PFA failed to induce any PV stenosis, whereas similar ablation with RFA showed a 45% decreased PV luminal diameter compared to baseline on serial CT scans (Figure 5).¹²

Coronary arteries. The risk of coronary artery injury from RF ablation is low due to convective cooling by the arterial blood flow, with the adverse consequence of sparing of the tissue surrounding the vessel. However, RF delivery in very close proximity to a coronary artery can cause thrombosis, stenosis, and occlusion. In contrast, PFA ablates the myocardium surrounding intramural arteries because the mechanism of injury is not thermal, and the arteries themselves are entirely spared, with no luminal narrowing acutely or chronically (Figure 6).⁹ This characteristic makes PFA a promising modality for ablation in proximity to coronary arteries, such as epicardial ablation of septal summit PVCs and ventricular tachycardia.

Phrenic nerve. The phrenic nerves are in close proximity to the superior vena cava, right pulmonary veins, and left atrial appendage. Phrenic nerve palsy has been a well-known complication of pulmonary vein isolation procedures with RF and cryothermy. Preclinical studies report minimal effects of PFA on nervous structures, and if nerve palsy is induced, the effects are usually temporary.¹³

Preliminary Clinical Experience

At this time, only limited human experience with PFA has been presented. The largest published series to date reported on four sequential pilot series at two European centers with an iterative approach to selection of ablation parameters.¹⁴ Although the investigators reported 100% acute pulmonary vein isolation with PFA, only 18% of patients who underwent remapping at 3 months after PFA using a monophasic waveform had durable isolation of all pulmonary veins. With change to a biphasic waveform and further “waveform refinement,” the authors reported progressive improvement of durable vein isolation to 43%, 56%, and finally 100% of patients. The details of waveform modification were not reported, but it does appear that the “box” configuration of the ablation catheter was more effective than the “flower” configuration, emphasizing the importance of electrode geometry and the resultant ablative PFA field. A very low complication rate was reported (1 patient out of 81 with pericardial tamponade). Other pilot studies with different waveforms and different delivery catheter designs are presently underway. As clinical experience grows, we will learn more about the nuances of catheter ablation with this technology, and the difference in performance among various proprietary systems.

Possible Risks Associated With PFA

Preclinical testing has strongly indicated that PFA will ultimately be a safer technology for pulmonary vein isolation than RFA. However, some possible pitfalls lie ahead. Delivery of direct electrical current into the blood pool results in microbubble production. With RFA, we know that microbubbles are associated with asymptomatic cerebral emboli. However, the mechanisms of microbubble formation are different (electrolytic versus hyperthermic), and it is anticipated that PFA microbubbles will not result in adverse outcomes. But clinical trials will be required to confirm that hypothesis. Cardiac arrhythmias can be induced with long monophasic pulses timed during the T-wave vulnerable period. Arrhythmias have been reported after irreversible electroporation of liver tumors, but causality in these cases has not been established.¹⁵ Current systems deliver R-wave synchronized PFA pulses, but there is a theoretical concern that asynchronous PFA could induce arrhythmia.

Conclusion

Pulsed field ablation is a very promising new technology for the treatment of cardiac arrhythmias. The mechanism of ablation is nonthermal, and its effects show a high degree of tissue selectivity. It is anticipated that durable pulmonary vein isolation will be rapidly achievable with very low risk of collateral injury. We all await the results of clinical trials to further elucidate the characteristics of this new modality. 

Acknowledgements. All images were provided with the permission of Medtronic.

Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Dr. Haines reports grants and personal fees from Medtronic, and personal fees from FARAPULSE.

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