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\begin{document}

\title{What is Different About Pulsed Field Ablation \ldots{} Everything?}



\author[1]{David Haines}%
\affil[1]{Beaumont Health System}%


\vspace{-1em}



  
  \date{June 06, 2024}


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\textbf{What is Different About Pulsed Field Ablation \ldots{}
Everything?}

David E. Haines, MD

Beaumont Health System, Oakland University William Beaumont School of
Medicine, Royal Oak, Michigan, USA

Funding: None

Disclosures: Dr. Haines is a consultant for Ablacon, Inc., Affera, Inc.,
Biosense Webster, Inc., Boston Scientific Corporation, Inc., Medtronic,
Inc., and Philips Healthcare, Inc. He has equity interest in Ablacon,
Inc. and Affera, Inc.

Corresponding author:

David E. Haines, MD Director, Heart Rhythm Center Professor,
Cardiovascular Medicine Oakland University William Beaumont School of
Medicine 3601 West 13 Mile Road Royal Oak, MI 48073 248-898-4176
dhaines@beaumont.edu

From the time of early preclinical reports of the efficacy, speed and
safety of pulsed field ablation (PFA), the interventional
electrophysiology community has been waiting in anxious anticipation for
its clinical approval and release. As most people actively engaged in
interventional electrophysiology know, PFA is the technology that
creates myocardial lesions with trains of very high voltage pulses that
are nanoseconds or microseconds in duration.\textsuperscript{1} This
form of ablation is nonthermal, and cell injury/death is created by
electroporation of the organelles and sarcolemmal membrane, with cell
death occurring via apoptosis as well as other
mechanisms.\textsuperscript{2} Because myocardial ablation is the result
of an electrical field effect, electrode-tissue proximity is important
but contact force is not. The physiological effect of acute PFA is
striking in that there is immediate loss of electrical signal so that
acute pulmonary vein isolation is achieved from a single shot catheter
in under one second (figure 1). Preclinical animal studies have
demonstrated effective chronic lesions that have been reliably
transmural for atrial ablations.\textsuperscript{3} But the most
compelling aspect of PFA is the apparent tissue selectivity of this
energy form. At doses sufficient to create reliable transmural lesions
in animals, there is little or no discernable injury to the esophagus,
phrenic nerves, coronary arteries or distal pulmonary veins, in contrast
to ablation with thermal techniques such as radiofrequency or
cryoballoon ablation, where thermal collateral injury to contiguous
structures can lead to substantial morbidity and
death.\textsuperscript{4,5}

So, what is the catch? Is there any downside to PFA compared to other
ablation technologies? The answer is that we do not know. Despite a
substantial body of preclinical experience published to date, clinical
outcomes with PFA are just starting to be reported. In this issue of
the\emph{Journal} , Neven et al describe the acute pathological effects
of PFA in a swine model over the first 60 minutes and compare them to
findings from chronic animals at 3 weeks and 3
months.\textsuperscript{6} For their study, they mostly employed a
suction electrode for epicardial delivery (some lesions created with a
circular catheter under blood) and delivered a single unipolar cathodal
pulse of mostly 200 J (some dose ranging performed with chronic lesions
between 30 -- 200 J) at various sites on the right and left ventricles.
Pathology on acute specimens was examined 0 to 60 minutes post ablation,
and chronic specimens were examined after 3 weeks and 3 months. They
reported that acute lesions showed contraction band necrosis and
interstitial edema, and at \textgreater{}/= 3 weeks, there was sharply
demarcated connective tissue that evolved into scar.

What new insights have we gained from the present study that we can now
apply to the burgeoning field of clinical PFA? Unfortunately, despite
considerable effort put forth by these investigators, their results are
not generalizable to the wider field of PFA. No study reporting outcomes
using one proprietary PFA system will be necessarily applicable to
results from a competing proprietary system. The field of catheter
ablation has become accustomed to interchangeability of one RF generator
or catheter for another. That is because the thermodynamics of
electrical resistive heating of tissue is predictable, and there are
limited operator parameters (power, time, contact force) and design
parameters (electrode size, convective cooling) that affect tissue
heating. The biological effects of hyperthermia are straightforward and
reproducible; thus, it is possible for scientists and clinicians to
compare experiences from one proprietary RFA system to another and draw
some generalizable conclusions. \textsuperscript{7} Not so with PFA. To
paraphrase an old saying, ``When you've seen one PFA system, you've
seen\emph{one} PFA system.'' The operator-controlled parameters are
familiar (energy level, catheter-tissue position), but the design
parameter variations are dizzying and most importantly \emph{unknown to
us} . A precedent was set early in the development of this field that
the PFA waveform was proprietary, and that the commercialized product
was a ``black box''. A few of the parameters that can be modulated by
the manufacturer include pulse amplitude, pulse duration,
unipolar/bipolar, monophasic/biphasic, interpulse delay, interphase
delay, pulse train number, pulse train duration and more. For example,
the waveform used by Neven et al. was a milliseconds duration,
monophasic damped sine wave generated by an external defibrillator
(Lifepak 9, Physio-Control, Inc; Redmond, WA) and delivered in a
unipolar cathodal fashion to an indifferent dispersive skin electrode.
In contrast, most PFA systems deliver pulses are nanoseconds to
microseconds in duration with a range of variation of the other
parameters listed above (figure 2). Thus, the outcomes from ablation
with a proprietary PFA system cannot and should not be extrapolated to
different proprietary systems that may have dramatically different
waveforms that result in different procedural outcomes.

One of the major unanswered questions in the field of PFA is what is the
time course of clinical effect after energy delivery? The hope and
anticipation has been that lesions created by PFA will be more durable
than those created with thermal ablation techniques (RFA or
cryoablation). A dramatic features of catheter ablation with PFA is that
disappearance of the local electrograms is seen immediately after pulse
delivery (figure 1). Unfortunately, this does not necessarily indicate
that a permanent lesion has been created. Beyond the border of
irreversible electroporation there is a penumbra of reversible
electroporation manifested by loss of the electrical signal but
maintenance of viability. In the heart, this has been described
pathologically as a rim of tissue with enhanced with hematoxylin and
eosin staining, and maintenance of mitochondrial activity as delineated
by cytochrome C oxidase staining.\textsuperscript{8} Thus, the acute end
point of conduction block and loss of local electrogram signal employed
in RF ablation does not indicate that a permanent lesion has been made
with PFA. With myocardial ablation, the extent of reversible
electroporation beyond the border of permanent injury has not been fully
characterized, nor has the time course of recovery of normal function.
There are many anecdotal reports of pulmonary vein reconnection after
acute PVI with PFA in patients with atrial fibrillation. Unfortunately,
the present study did not report mapping data and compare the extent of
acute physiological effect to the acute pathological lesions.

Therefore, a challenge for operators performing PFA is that acute
electrogram voltage mapping cannot be used as a metric to assess
therapeutic effect. The strategy adopted for PVI with PFA is to deliver
a very large ablation dose, since injury to collateral structures is
rare.\textsuperscript{9} The larger the energy delivery, the more likely
it will be that permanent block is achieved. One experienced operator
concluded ``Go big or go home''. Once again, the pulse wave morphology,
pulse width and pulse train number are proprietary features of the
system that are preselected. The operator can choose different pulse
amplitudes, but in almost all cases the maximum setting is selected. Is
there such a thing as too much energy delivery with PFA? In preclinical
studies, very high energy delivery has been associated with large volume
microbubble production and evidence of thermal effects (charring) at the
electrode-tissue interface. Creating a large uncontrolled lesion may be
appropriate for a narrowly defined anatomical target like the pulmonary
vein antrum but may not be appropriate for targeting other
arrhythmogenic substrates because of concern about excessive injury to
the surrounding myocardium. The consequences of very high PFA energy
delivery in the clinical setting are unknown but most experts believe
that there should be an upper safe limit established for each unique PFA
system. So, the manufacturers will decide the dosing that the clinician
will use. Will the recommended dose be safe and effective for all
patients going forward? Time will tell. Ideally, we should have a method
to assess myocardial viability after PFA prior to removing catheters
from the heart, so that touch up ablations with improved catheter-tissue
proximity can be performed. With RFA, promising technologies like real
time magnetic resonance imaging,\textsuperscript{10} near field
ultrasound imaging\textsuperscript{11} and NADH
fluorescence\textsuperscript{12} have been explored, but their utility
in assessing acute PFA lesions is unknown.

The era of PFA is exciting and full of promise, but there are many
unanswered questions that remain. As we gain more clinical experience
with PFA, the benefits and limitations of the various commercial systems
will become more obvious. Because of its speed and safety, PFA is likely
to become the dominant mode of ablation for PVI, but we need to move
forward in this field cautiously with recognition that all of the
consequences of this ablation mode are still unknown.

References:

\begin{enumerate}
\tightlist
\item
  Verma A, Asivatham SJ, Deneke T, Castellvi Q, Neal RE. Primer on
  pulsed electrical field ablation: understanding the benefits and
  limitations. Circulation Arrhythm Electrophysiol. 2021; 14: e010086.
  doi.org/10.1161/CIRCEP.121.010086.
\item
  Napotnik TB, Polajzer T, Miklavcic D. Cell death due to
  electroporation -- A review. Bioielectrochemistry. 2021; 141:107871.
\item
  Stewart MT, Haines DE, Verma A, Kirchhof N, Barka N, Grassl E, Howard
  B. Intracardiac pulsed field ablation: Proof of feasibility in a
  chronic porcine model. Heart Rhythm. 2019; 16:754-764. doi:
  10.1016/j.hrthm.2018.10.030.
\item
  Bradley CJ, Haines DE. Pulsed field ablation for pulmonary vein
  isolation in the treatment of atrial fibrillation. J Cardiovasc
  Electrophysiol. 2020 Aug;31(8):2136-2147. doi: 10.1111/jce.14414.
\item
  Koruth J.S., Kuroki K., Kawamura I., et. al.: Pulsed field ablation vs
  radiofrequency ablation: esophageal injury in a novel porcine model.
  Circ Arrhythm Electrophysiol 2020; 13:
\item
  Neven K, van Driel VJHM, Vink A, du Pre BC, van Wessel H, Futing A,
  Doevendans PA, Wittkampf FHM, van Es R. Characteristics and time
  course of acute and chronic myocardial lesion formation after
  electroporation ablation in the porcine model. J Cardiovasc
  Electrophysiol. 2022 (in press).
\item
  Haines DE. Biophysics and Pathophysiology of Radiofrequency Lesion
  Formation. In: Catheter Ablation of Cardiac Arrhythmias, 4th Edition.
  Huang SKS, Miller JM, editors. Philadelphia, PA: Elsevier Saunders
  Publishing, 2020.
\item
  Nakagawa H, Castellvi, Neal R, Girouard S, Kuroda S, Hussein AA,
  Saliba WI, Wazni OM. Histological characterization of reversible and
  irreversible ventricular lesion boundaries produced by pulsed field
  ablation. Heart Rhythm 2021; 18: S151-S152. doi:
  0.1016/j.hrthm.2021.06.386
\item
  Reddy VY, Neuzil P, Koruth JS, Petru J, Funosako M, Cochet H, Sediva
  L, Chovanec M, Dukkipati SR, Jais P. Pulsed field ablation for
  pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol
  2019; 74: pp. 315-326. doi: 10.1016/j.jacc.2019.04.021.
\item
  Mukherjee RK, Roujol S, Chubb H, Harrison J, Williams S, Whitaker J,
  O'Neill L, Silberbauer J, Neji R, Schneider R, Pohl T, Lloyd T,
  O'Neill M, Razavi R. Epicardial electroanatomical mapping,
  radiofrequency ablation, and lesion imaging in the porcine left
  ventricle under real-time magnetic resonance imaging guidance-an in
  vivo feasibility study. Europace. 2018 Sep 1;20(FI2):f254-f262. doi:
  10.1093/europace/eux341.
\item
  Haines DE, Wright M, Harks E, Deladi S, Fokkenrood S, Brink R, Belt H,
  Kolen AF, Mihajlovic N, Zuo F, Rankin D, Stoffregen W, Cockayne D,
  Cefalu J. Near-Field Ultrasound Imaging During Radiofrequency Catheter
  Ablation: Tissue Thickness and Epicardial Wall Visualization and
  Assessment of Radiofrequency Ablation Lesion Formation and Depth. Circ
  Arrhythm Electrophysiol. 2017 Dec;10(12):e005295. doi:
  10.1161/CIRCEP.117.005295.
\item
  Swift L, Gil DA, Jaimes R 3rd, Kay M, Mercader M, Sarvazyan N.
  Visualization of epicardial cryoablation lesions using endogenous
  tissue fluorescence. Circ Arrhythm Electrophysiol. 2014
  Oct;7(5):929-37. doi: 10.1161/CIRCEP.114.001750.
\end{enumerate}

Figures:

Figure 1 -- A circular ablation catheter is positioned in the right
superior pulmonary vein antrum (PV 1 thorugh 9) and high frequency near
field pulmonary vein potentials were recorded. Immediately after
delivery of a PFA pulse, the pulmonary vein potentials are eliminated.

Figure 2 -- A. Irreversible electroporation waveform similar to that
employed by Neven et al. from a Lifepak 9 defibrillator (Physio-control
Service Manual No. 803763-06, Physio-control, Redmond, WA). B.
Representative waveform from a pulsed field ablation generator using a
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