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\begin{document}

\title{Taking the ``Pulse'' of Pulsed Field Ablation: Real-World Experience}



\author[1]{Tina Baykaner}%
\author[2]{Muhammad Fazal}%
\author[3]{Atul Verma}%
\affil[1]{Stanford Medicine}%
\affil[2]{Stanford University}%
\affil[3]{Southlake Regional Health Centre}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{Title:Taking the ``Pulse'' of Pulsed Field Ablation: Real-World
Experience}

\textbf{Authors:}

Tina Baykaner, MD, MPH\textsuperscript{1} ; Muhammad Fazal,
MD\textsuperscript{1} and Atul Verma, MD\textsuperscript{2}

\textsuperscript{1}Stanford University, Stanford, CA , USA

\textsuperscript{2}Southlake Regional Health Centre, University of
Toronto, Toronto, CA

\textbf{Correspondence:}

Tina Baykaner, MD MPH, 453 Quarry Road, 334C, Stanford CA 94304

Atul Verma, MD, 596 Davis Dr, Newmarket, ON L3Y 2P9, Canada

\textbf{Voice:} +1 650-7362563 \textbf{Fax:} +1
650-7246131;\textbf{Email:} tina4@stanford.edu\textbf{;}
atul.verma@utoronto.ca

\textbf{Word Count:} 1365 excluding title page and references

\textbf{Keywords:} Atrial Fibrillation, Catheter Ablation, Pulsed Field
Ablation

\textbf{Conflicts of Interest and Funding:} Dr. Baykaner reports grant
support from National Institutes of Health (HL145017) and serves in the
advisory boards of Medtronic, BIOTRONIK and PaceMate. Dr. Fazal reports
no disclosures. Dr. Verma reports grant support from Medtronic, Biosense
Webster, Abbott and Bayer and serves in the advisory boards of
Medtronic, Biosense Webster, Boston Scientific, Adagio, Ablacon, Kardium
and Galaxy Medical.

Atrial fibrillation (AF) ablation is the cornerstone of therapy for
symptomatic AF, with now increasing data on the safety and efficacy of
this approach over medical management in improving quality of life,
decreasing rates of stroke, cardiac hospitalizations and providing
mortality benefit in several populations {[}1{]}. Cardiac ablation using
pulsed field ablation (PFA) provides an exciting non-thermal approach,
enabling ablation lesions without causing thermal collateral injury to
structures such as the esophagus or phrenic nerve.

Multiple in-human studies since 2018 have shown feasibility and safety
of pulmonary vein isolation (PVI) with PFA in patients with paroxysmal
AF. Reddy et al. using a basket/flower over the wire ablation catheter,
a custom-built generator and monophasic bipolar PFA waveforms were able
to achieve 96\% durable PVI at 3-months with 1-year freedom from AF of
84.5\% {[}2{]}. Another circular catheter-based system delivering
bipolar, biphasic waveforms have also demonstrated excellent acute
procedural outcomes with no significant procedural complications
{[}3{]}. The only other PFA system tested in patients with published
acute outcomes involves 10 patients with paroxysmal and persistent AF,
showing the feasibility and safety of acute PVI.{[}4{]}

PFA may also be quite effective for lesions outside the pulmonary veins
(PVs). Reddy et al. demonstrated 100\% durability of both posterior wall
isolation and cavotricuspid isthmus (CTI) line at the time of 3-month
remapping in 25 patients with persistent AF {[}5{]}. Moreover, PFA with
a novel lattice tip catheter was able to achieve 100\% acute success in
achieving mitral (n=14), roof (n=34) and CTI lines (n=44) in a mixed
cohort of paroxysmal and persistent AF patients {[}6{]}. Verma et al.
also demonstrated acute posterior wall isolation in an extended pilot
study of a circular-based PFA system {[}3{]}. However, all of these
studies were performed by a limited number of investigators in a limited
number of patients. Now that PFA is approved in the European Union (EU),
publications of ``real-world'' experiences are needed.

In this issue of the \emph{Journal of Cardiovascular
Electrophysiology,}Gunawardene et al. studied PFA combined with
ultra-high-density mapping in 20 patients with paroxysmal or persistent
AF undergoing first time catheter ablation in a prospective, single arm,
observational study. All patients underwent PVI, and nine patients with
persistent AF also underwent additional ablation including left atrial
posterior wall isolation and mitral isthmus ablation using a multispline
PFA catheter (FARAWAVE, Boston Scientific, MA, USA). The authors also
utilized an electroanatomical mapping system
(Rhythmia\textsuperscript{TM}, Boston Scientific, MA, USA) to perform
voltage mapping and localize the PFA catheter. Using an initial
generator output of 1900 V, PVI was performed in all patients using at
least 8 applications (4 basket, 4 flower). If post-ablation voltage
mapping found conduction gaps or PV reconnections, additional ablations
were performed with 2000 V.

The authors confirmed several important assumptions about PFA. First,
they found a very high rate of acute PV and extra-PV isolation
(posterior wall, mitral isthmus) with rapid and significant abatement of
electrogram voltage over a large atrial surface area. The lesions also
seemed to have ``smooth'', well-demarcated borders as promised by the
preclinical studies {[}7{]}. PFA created wide antral circumferential
lesions with no complex fractionated electrograms (CFAE) along the PV
ostia in 85.2\% of patients and none on the LA posterior wall in 62.5\%
of patients. The authors also showed that PFA could be performed with
very few major complications. No esophageal lesions were seen on
endoscopy and no phrenic injury occurred.

Importantly, they also showed that PFA could be integrated with an
electroanatomical mapping system. Current electroanatomical mapping
systems use a combination of impedance based tracking through skin
surface patches and magnetic tracking using localization pads. Some even
run a small electrical current through the surface patches. These
systems were never designed to deal with delivery of large voltages to
the patient for ablation. These large voltages acutely change the
impedance of the catheter tip and possibly even the skin patches
(depending on whether energy delivery is bipolar or unipolar). This will
likely affect visualization of the catheter during PFA delivery and also
the stability of the map for the duration of the case. The authors, for
example, did not mention if the catheter disappeared from view during
delivery of the electrical fields and then re-appeared. The PFA catheter
was not visualized in a minority of patients (10\%), and the location of
the catheter did not match with the level of isolation in 12\% of
patients for right PVs. Map shift did occur in one patient (5\%). The
catheter also could not be visualized in its different shapes and a
work-around was created such that the catheter appeared as a circle.
These problems can be overcome with hardware and software adjustments
and manufacturers have already shown that successful integration can
occur {[}8,9{]}. This is critical since the reported left atrial dwell
time for the patients was less than one hour, but fluoroscopy time was
over 19 minutes. The full promise of PFA's efficiency will need to be
realized in conjunction with successful integration with electroanatomic
mapping.

Interestingly the authors found five early PV reconnections (5/80,
6.25\% acute reconnection rate) in post-ablation mapping. All the
connection gaps were located at the anterior superior aspect of the PV
ostium. Yet rapid and significant electrogram abatement was seen with
the initial delivery of PFA. This is one of the fundamental issues with
current PFA delivery systems. The pulses have been designed and
optimized to create ``transmural'' lesions in pre-clinical models and
confirmed with some early human remapping studies. However, PFA acutely
stuns the electrical activity of cardiac cells. Even a sub-therapeutic,
single delivery of PFA can cause electrograms to disappear. Furthermore,
data has shown that repetitive applications {[}10{]} are required to
``push'' the depth of the lesion to its maximum -- explaining the 8
pre-determined applications that were delivered per site in this
manuscript. But how does an operator assess when enough deliveries have
been placed? Do we need to have waiting periods of 20 minutes or longer?
Would this study have found higher rates of reconnection if this had
been done? Are there other electrogram or procedural components that
need to be monitored? This study importantly raises all of these
questions which will need to be answered.

The study also alludes to some other unknowns about PFA. They reported
one case of coronary artery spasm which fortunately resolved rapidly
with administration of nitroglycerin. Many studies have shown that PFA
preserves both microvasculature in the tissue and the integrity of
larger vessels {[}11,12{]}. It is therefore unlikely that permanent
coronary damage will occur. However, ablation in the mitral and
cavotricuspid isthmuses are close to coronary vessels and operators must
be conscious of the possibility of spasm. Pronounced vagal responses
have also been reported by several PFA systems {[}2,8{]}. This is likely
due to partial stimulation and/or ablation of the autonomic ganglionated
plexi. Unlike myelinated nerves which are insulated against PFA, the
cell bodies of plexi are prone to PFA ablation {[}8{]}. The authors have
shown nicely that pre-ablation atropine or pacing can easily resolve
this issue and it would be interesting to know whether additional
ablation of sites of ganglionated plexi will add to procedural success.

Finally, the biggest limitation of currently evaluated PFA systems is
tissue depth. Although there is excitement about the possibility of
greater transmurality with PFA, tissue depth of current PFA systems may
be limited to the standard 3-5 mm, also achievable by thermal ablation.
Hence, it is not surprising that acute reconnection was seen in this
study. The study also used PFA on the mitral isthmus which can be
relatively thick (0.6 -- 1.4 cm). Although they were able to achieve
acute block across the mitral isthmus, it is far from clear that this
block will be permanent. Adjustments are being made to achieve deeper
lesions with PFA, with the potential for creating adverse thermal
effects and skeletal muscle contraction{[}13,14{]}.

In summary, the authors should be congratulated on providing some of the
first ``real world'' evidence on PFA for AF ablation and integration
with mapping. It is reports like this that will help us to keep the
``pulse'' of PFA in the years to come.

\textbf{References:}

1. Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J,
et al. Cryoablation or Drug Therapy for Initial Treatment of Atrial
Fibrillation. N Engl J Med. 2021;384: 305--315.
doi:10.1056/NEJMoa2029980

2. Reddy VY, Dukkipati SR, Neuzil P, Anic A, Petru J, Funasako M, et al.
Pulsed Field Ablation of Paroxysmal Atrial Fibrillation: 1-Year Outcomes
of IMPULSE, PEFCAT, and PEFCAT II. JACC Clin Electrophysiol. 2021;7:
614--627. doi:10.1016/j.jacep.2021.02.014

3. Verma A, Boersma LV, Hummel JD, Calkins H, Sanders P, Haines DE, et
al. PULSED AF: first human experience and acute procedural outcomes
using a novel pulsed field ablation system. Heart Rhythm. 2020;8.

4. Loh P, van Es R, Groen MHA, Neven K, Kassenberg W, Wittkampf FHM, et
al. Pulmonary Vein Isolation With Single Pulse Irreversible
Electroporation: A First in Human Study in 10 Patients With Atrial
Fibrillation. Circ Arrhythm Electrophysiol. 2020;13: e008192.
doi:10.1161/CIRCEP.119.008192

5. Reddy VY, Anic A, Koruth J, Petru J, Funasako M, Minami K, et al.
Pulsed Field Ablation in Patients With Persistent Atrial Fibrillation. J
Am Coll Cardiol. 2020;76: 1068--1080. doi:10.1016/j.jacc.2020.07.007

6. Reddy VY, Anter E, Rackauskas G, Peichl P, Koruth JS, Petru J, et al.
Lattice-Tip Focal Ablation Catheter That Toggles Between Radiofrequency
and Pulsed Field Energy to Treat Atrial Fibrillation. Circulation:
Arrhythmia and Electrophysiology. 2020. doi:10.1161/circep.120.008718

7. Stewart MT, Haines DE, Verma A, Kirchhof N, Barka N, Grassl E, et al.
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

8. Verma A, Asivatham SJ, Deneke T, Castellvi Q, Neal RE. Primer on
Pulsed Electrical Field Ablation. Circ Arrhythm Electrophysiol. 2021;14:
e010086. doi:10.1161/CIRCEP.121.010086

9. Nakagawa H, Castellvi Q, Neal R, Girouard S, Kuroda S, Hussein AA, et
al. B-PO02-133 HISTOLOGICAL CHARACTERIZATION OF REVERSIBLE AND
IRREVERSIBLE VENTRICULAR LESION BOUNDARIES PRODUCED BY PULSED FIELD
ABLATION. Heart Rhythm. 2021;18: S151--S152.
doi:10.1016/j.hrthm.2021.06.386

10. Yavin HD, Higuchi K, Sroubek J, Younis A, Zilberman I, Anter E.
Pulsed-Field Ablation in Ventricular Myocardium Using a Focal Catheter.
Circ Arrhythm Electrophysiol. 2021;14: e010375.
doi:10.1161/CIRCEP.121.010375

11. van Driel VJHM, Neven KGEJ, van Wessel H, du Pr\selectlanguage{ngerman}é BC, Vink A,
Doevendans PAFM, et al. Pulmonary vein stenosis after catheter ablation:
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2014;7: 734--738. doi:10.1161/CIRCEP.113.001111

12. Stewart MT, Haines DE, Miklav\selectlanguage{polish}č\selectlanguage{english}i\selectlanguage{polish}č \selectlanguage{english}D, Kos B, Kirchhof N, Barka N, et
al. Safety and chronic lesion characterization of pulsed field ablation
in a Porcine model. J Cardiovasc Electrophysiol. 2021;32: 958--969.
doi:10.1111/jce.14980

13. van Zyl M, Ladas TP, Yasin OZ, Ladejobi AO, Tan NYL, Christopoulos
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14. Anter E, Yavin H, Biton D, Sroubek J, Higuchi K, Saliba WI.
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