University of Illinois Chicago
In this edition of JCE two papers focus on the thermal (1) and pathological changes associated with the use of the Farapulse PFA ablation system to isolate the PVs. The first study Bettina et al (1). recorded the esophageal temperature changes using the Circa Scientific temperature probe while Meininghaus (2) used endoscopy, endoscopic ultrasound, and electrogastrography before and after PVI to define periesophageal injury (mucosal lesions, food retention, periesophageal edema, or vagal nerve injury). Meininghaus et al. compared the esophageal injury post PFA in 20 post PVI patients to previously collected data from 24 radiofrequency (RF) and 33 cryoballoon (CB) PVI.
In both studies, “PVI was performed with a 31 mm pentaspline FARAWAVE-catheter (Farapulse, Boston Scientific, Marlborough, MA, USA). For each vein, a minimum of eight pulsed field cycles (four in ‘flower’- and four in ‘basket’-configuration of the catheter, respectively) were applied in a train of five consecutive impulses for a total of 2.5 seconds and an energy of 2.0 kV If needed, additional cycles were applied to fully isolate the veins.”
Luminal esophageal temperature (LET) was monitored using Circa Scientific, LLC, Englewood, CO, USA. However, Meininghaus et al. recorded the temperature in only four PFA-cases, and LET monitoring was not done in the remaining procedures after documentation of the “absence” of any LET rise.
While the first study investigated the impact of PFA on the esophageal temperature and potential pathology the second study compared the esophageal pathology to previous investigations using the same examination of the esophagus post RFA and Cryo PVIs. The patients underwent endoscopic evaluation within one week before and within two working days after the PVI procedure.
Bettina et al. demonstrated a statistically significant increase in luminal esophageal temperature of 0.8±0.6 ℃, p <0.001. The temperature increase was ≥1 ℃ in 10/43 (23%) patients, and the maximum was 40.3 ℃. Meininghaus et al. reported that PFA was not associated with any mucosal esophageal lesions or signs of vagal nerve injury. Whereas esophageal or peri esophageal injury was observed in 33/57 patients post thermal ablation (58%) (CB: 21/33 [64%] and RF: 12/24 [50%]) In 30/57 patients (CB: 20/33, RF: 10/24) had endoscopically detected pathology (ELs, edema, food retention). Mucosal lesions were more common with RF, peri-esophageal edema was more frequently observed with CB, and food retention was significantly more common following CB-PVI. Signs of vagal nerve injury based on EGG were observed in 17/57 patients following thermal ablation (30% [RF: 21%, CB: 36%]).
An unresolved observation in all of these ablation modalities is the finding of periesophageal edema (RF: 30%; CB: 45% and in 25% with PFA following ablation). The origin and pathophysiologic relevance of periesophageal edema is unknown and the authors of the second paper observe that so far it has not been shown to be associated with the risk of progression to Atrio-esophageal fistula (AEF) and minimize this finding to be a none specific response of the surrounding tissue. The authors suggest that this observation may be due to preexisting inflammation of esophageal tissue (i.e., chronic esophagitis or reflux) and not due to the ablation itself. This explanation is not supported by the fact that such edema was not reported to be present pre-ablation. Furthermore, the authors minimize any possible adverse findings post PFA PVI and have not reported any long-term complications associated with RF or Cryo PVI.
It is concluded that “esophageal safety of PFA-PVI eliminates the key safety obstacle to early interventional treatment of AF (2).”
While both studies provide a great deal of reassurance as to the remarkable safety of using PFA regarding phrenic and esophageal integrity at this time the findings are applicable only to Farawave catheter and the pulse configuration used in both studies. Furthermore, so far, the clinical efficacy of PFA has been found to be comparable to RFA and Cryo (3).
Is PFA hot or cold
Fundamental to the dissipation of electrical energy across resistive conductors is the induction of heat. In fact, as has been shown high power and short duration of RF create effective lesions.
Given that the pulse configuration of high voltage short duration of the electrical energy the temperature measurement requires temperature sensors with a very high response time and sampling rate that is twice the maximal rate of change of the temperature. In both studies, the Circa temperature probe was used to assess the luminal temperature. The Circa temperature probe delivers 240 data points per second; 12 thermocouple temperature sensors update 20 times per second. While these specifications are appropriate for RF they will unlikely to record the rapid rise of the temperature generated by PFA.
The Farapulse system delivers a minimum of eight 2.0 kV cycles in a train of five consecutive impulses for a total of 2.5 seconds. The electrical energy is delivered in a bipolar configuration to the Farawave catheter electrodes spaced 2.5 mm, the electrode length is 2.5 mm, and the electrode diameter is 2.33 mm. The short-spacing small ring electrodes the electrical energy dissipation remains in close proximity to the two ring electrodes limiting the current density and the electrical field to close proximity to the energy source. Furthermore, the short application time minimizes the conductive heating. In contrast, RF ablation electrical power is delivered to an irrigated 3.5-4mm long 2.66 mm diameter unipolar electrode with the reference electrode being a large conductive patch placed on the patient’s skin. High current density is near the ablation electrode the maximal heating vector is radially and into the depth of the tissues. Furthermore, application time may typically range from 4 sec (in the case of high-power short duration application) to as long as 1 minute or more which allows for conductive heating deep into tissues and thus the potential of impacting the extracardiac tissues such as the esophagus.
In contrast to the thermal ablation modalities of RF and Cryo, PFA primary ablative mechanism is irreversible electroporation. The exposure of polypeptide polar membrane to a high electric field results in the temporary appearance of pores within the cell lipid bilayer that resolve. As the voltage amplitude increases as well as the pulse duration, frequency, and the increasing number of delivered pulses the membrane disruption becomes permanent leading to irreversible electroporation and cell death (4 ).
As noted by Bettina et al. The detection of temperature rise using the Circa esophageal temperature probe clearly suggests that Farapulse recipe of high voltage short duration electrical sequential pulses causes a temperature rise in the esophagus which is likely under-estimated. Human cell proteins are generally the most sensitive to temperature rise and start to denature at relatively small temperature increases at ∼43–45 C (4).
Presently, the only means to assess lesion integrity is the elimination of PV electrical activity and documentation of PVI. Furthermore, tissue stunning has been reported (5).
In case of lack of isolation, PFA energy applications are repeated. LA tissue thickness can vary from 2mm to 6mm and the only means to increase the PFA lesion depth is to increase the pulse amplitude, pulse width, number of pulses, and pulse cycle length (6). In such circumstances, the likelihood of thermal injury would increase.
It can be concluded that:
  1. Using the Farapulse pulse configuration and ablation procedure results in a significant esophageal temperature increase that is underestimated using the Circa probe and it is likely significantly higher temperature can be recorded at close proximity to the ablation electrodes.
  2. A near-field tissue ablation is a mix of irreversible electroporation and thermal injury.
  3. The bipolar energy delivery using the Farawave-catheter limits the field and thermal ablation to close proximity to the bipolar ablation electrodes limiting the impact on extracardiac tissues.
  4. In the two published papers accompanying this editorial, the Farapulse PFA technology is shown to have no short or long-term adverse effect on the esophagus. However, reported phrenic nerve conduction stunning may occur (7,8). It is also noted that while Meininghaus et al. reported significant esophageal acute injuries using RF and Cryo no long-term data is provided that these findings resulted in long-term disabilities.
  5. PFA is hampered by the inability to adequately assess irreversible lesion formation in real-time.
  6. The advantage provided by using PFA ablation technology is added safety and faster procedure time. These conclusions need further affirmation when the technology is widely used.
References:
  1. Bettina et al. JCE-23-0416
  2. Meininghaus et al. JCE-23-0756
  3. Europace (2023) 25 , 1–11 https://doi.org/10.1093/europace/euad185 EUropean real-world outcomes with Pulsed field ablatiOn in patients with symptomatic atRIAl fibrillation: lessons from the multi-centre EU-PORIA registry. Boris Schmidt 1,2*, Stefano Bordignon 1, Kars Neven 3,4 et al. ).
  4. Yarmush ML, Golberg A, Sersa G, Kotnik T, Miklavcic D. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng. 2014;16:295-320.
  5. Pulsed-field ablation combined with ultrahigh-density mapping in patients undergoing catheter ablation for atrial fibrillation: Practical and electrophysiological considerations. Gunawardene MA, Schaeffer BN, Jularic M,  Eickholt C, Maurer T,Anwar O, Pape UF. Maasberg S,  Gessler N, Hartmann J, Willems S. JCE 2022;33(2),Pages 345-356,
  6. Sugrue A, Vaidya V, Witt C, DeSimone CV, Yasin O, Maor E, et al. Irreversible electroporation for catheter-based cardiac ablation: a systematic review of the preclinical experience. J Interv Cardiac Electrophysiol. 2019;55(3):251-65
  7. 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(8):1838-44.
  8. Schoellnast H, Monette S, Ezell PC, Deodhar A, Maybody M, Erinjeri JP, et al. Acute and subacute effects of irreversible electroporation on nerves: experimental study in a pig model. Radiology. 2011;260(2):421-7.