Studies Spotlight Safety Concerns With Pulsed-Field Ablation for AF

SAN DIEGO, CA—Emerging evidence is creating a fuller picture of the safety of pulsed-field ablation (PFA) for atrial fibrillation (AF), bringing into focus a risk profile that differs from other ablation modalities.

Studies presented recently here at Heart Rhythm 2025 highlighted increases in biomarkers suggestive of myocardial damage, hemolysis, and renal dysfunction as well as MRI evidence of asymptomatic cerebral emboli. Another showed potential risks of coronary stenosis.

PFA has been adopted rapidly by the electrophysiology (EP) community, with its mechanism of action—electroporation—believed to be more specific for myocardial tissue, a trait that limits complications of thermal ablation stemming from damage to nearby structures. Those include pulmonary vein (PV) stenosis, phrenic nerve palsy, and the dreaded atrioesophageal fistula.

As more and more patients have been treated with PFA, however, rare complications of the procedure have become apparent, and these new studies provide additional insights.

Dhanunjaya Lakkireddy, MD (Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, KS), abstract chair for the Heart Rhythm Society, presented results from the NEMESIS-PFA registry focusing on biomarker changes following PFA versus radiofrequency ablation. PFA was associated with significantly larger increases in cardiac troponin, lactate dehydrogenase (LDH), haptoglobin, and creatinine, as well as a larger drop in left atrial ejection fraction, compared with radiofrequency energy.

The study, published simultaneously online in JACC: Clinical Electrophysiology, “really reflects the things that we don’t understand that well from a PFA technology perspective,” Lakkireddy told TCTMD. “We, I believe, traded off one set of major problems, which is PV stenosis, esophageal injury, and phrenic nerve damage, for a set of maybe not as dire complications. But they’re still significant enough that we should be paying attention to them.”

Wilber Su, MD (Banner – University Medical Center Phoenix, AZ), said PFA is an exciting technology with a lot of upside from a safety perspective. “But it also has a side effect profile that we don’t fully understand,” he noted. The risks will be unique to each individual system, he said, adding that all PFA technologies need to be studied extensively to ensure that they are not only fast, but also safe and effective.

“Certainly, a lot of industry is pushing PFA as the next best thing, but I think over the years we have learned that . . . it’s not quite as perfect as they are selling it,” said Su.

Jonathan Piccini, MD (Duke University Medical Center, Durham, NC), told TCTMD that while there is a need to better understand the safety profile of PFA, “I think the net benefits to the patient are significant.”

PFA avoids catastrophic complications like atrioesophageal fistula, which carries a 50% mortality rate and a high rate of permanent disability, he said. It is also more efficient than other ablation modalities, he added. “If the procedure is quicker and you’re spending less time in the left atrium, then that also translates into benefit for the patient.”

There are also some indications that PFA may have somewhat better efficacy than other ablation types, Piccini said.

The EP field continues to tweak catheters that deliver PFA and there are even more on the way. “Everyone understands that the form factor [physical characteristics] of the catheter is really important and the form factor of the catheter that works best in a given type of case may be different as well,” said Piccini. “I think the field is doing all the right things we need to do to get this right.”

NEMESIS-PFA

In presenting the NEMESIS-PFA registry, Lakkireddy said: “The whole EP world has been consumed by the PFA mania. While we celebrate the success of this new energy form, there are a few things that I think we tend to conveniently ignore or forget or not have the desire to talk about.”

The NEMESIS-PFA registry included 871 patients (mean age 68.9 years; 70.8% men) who underwent AF ablation with either a commercially approved PFA catheter (88.7%) or radiofrequency catheter (11.3%). Most patients (59.4%) had paroxysmal AF.

Lakkireddy noted that the centers included in the study perform “pretty aggressive” ablation. The mean number of applications was higher with PFA versus radiofrequency ablation (75.3 vs 39.5; P < 0.001). “That’s actually a pretty large number compared to average applications that you see elsewhere,” he said.

The whole EP world has been consumed by the PFA mania. Dhanunjaya Lakkireddy

Biomarker changes were significantly larger with PFA than with radiofrequency ablation. After the procedure, PFA-treated patients had greater median changes in cardiac troponin (13,551 vs 128 ng/dL; P < 0.001), hemoglobin (-2.3 vs -1.2 g/dL; P < 0.001), LDH (107.5 vs 26.5; P < 0.001), haptoglobin (-102 vs -34 mg/dL; P < 0.001), and creatinine (1.0 vs 0.9 mg/dL; P = 0.007). In addition, mean plasma-free hemoglobin increased to a greater extent after PFA (61.2 vs 13.1 mg/dL; P < 0.001).

Differences in troponin, hemoglobin, and LDH were enhanced as the number of PFA applications increased, Lakkireddy noted.

Effects on left atrial function differed, as well, with a larger drop seen in left atrial ejection fraction in the PFA group than in the radiofrequency group (20% vs 5%; P < 0.001), “suggesting more profound atrial stunning or dysfunction following PFA,” according to researchers.

What these findings indicate, Lakkireddy said, is that “these large-profile, single-shot catheters, or large-profile, focal catheters, can actually cause a significant amount of hemolysis, increased risk of acute renal injury, and a significant amount of myocardial injury as it is reflected by a dramatic increase in the amount of high-sensitivity troponin levels, and also a drop in atrial function.”

These effects of PFA, he added, are dependent on a variety of factors that differ between catheters, including electrode geometry, electrode counts, spacing, contact, electric field size and strength, burst frequency, pulse duration, pulse count, pulse amplitude, polarity, target cell proximity, and others.

The key message as manufacturers continue to make new PFA catheters is to “be aware of these side effects and be watchful,” Lakkireddy said. “We don’t know what this myocardial injury means. There needs to be further study.”

Atul Verma, MD (McGill University Health Centre, Montreal, Canada), the discussant for the study, raised some issues to consider when interpreting the NEMESIS-PFA results, noting that PFA is expected to cause the release of more troponin from myocardial cells.

“There’s no doubt that if you use a large-form catheter and you’re applying all over the atrium versus drawing thin, narrow lines . . . there’s going to be a difference in the amount of cardiac tissue that is being killed,” he said. “However, you also have to understand that troponin can move through [electroporated] membranes. And so we know that in addition to the irreversibly electroporated cells, there are a lot of reversibly electroporated cells that are also leaking troponin, but those cells are not necessarily going to die, so we’re not necessarily killing the entire myocardium.”

He added, too, that LDH levels are not specific for hemolysis and that the atrial stunning seen shortly after PFA may be improved months later.

Asymptomatic Cerebral Emboli After PFA

Christopher Cheung, MD (Sunnybrook Health Sciences Centre, Toronto, Canada), in a separate presentation, shared data from a prospective evaluation of asymptomatic cerebral emboli (ACE) after PFA of atrial fibrillation, called PEACE-AF.

These emboli, detected on brain MRI, have been reported previously with all types of AF ablation, including PFA, although rates have varied widely.

The group evaluated consecutive patients undergoing AF ablation with a PFA catheter at a tertiary academic center in Canada between October 2024 and April 2025, excluding those with a history of cerebrovascular disease or stroke, a history of cardiac thrombus, and those expected to have a greater risk of periprocedural stroke. All patients underwent a neurological assessment at baseline and at 3 months, in addition to brain MRI within 72 hours after the procedure.

The PulseSelect PFA system (Medtronic) was used for all procedures, with operators using intracardiac echocardiography to rule out left atrial thrombus prior to the transseptal puncture; electroanatomical mapping was employed in all cases.

Cheung reported data from the first 35 patients (median age 63 years; 29% women) enrolled in the study. ACE was identified in 34% of those who underwent imaging. Both older age and persistent AF were associated with a greater likelihood of emboli in a multivariable analysis.

There were no clinical strokes or TIAs recorded during the study. Analyses of long-term neurological outcomes and quality of life are still ongoing.

“The etiology and ultimately the clinical significance of these ACE events still remain unclear,” said Cheung. “That being said, this does represent the largest prospective registry to date on ACE with pulsed-field ablation. And the combined events in this study outnumber the total events in the prior randomized and nonrandomized studies.”

Moving forward, he added, “I think these patients likely will require some form of long-term follow-up from a neurological perspective. And . . . in general, our future studies that are looking at A-fib ablations should have a systematic ascertainment for these types of cerebral embolism events.”

Coronary Narrowing

A third study, presented by Joseph Chan, MBBS (Prince of Wales Hospital, Hong Kong), and published simultaneously online in JACC: Clinical Electrophysiology, focused on the effects of PFA when applied close to the coronary arteries. Coronary spasm has been reported previously as a rare complication of PFA, but whether that translates into coronary stenosis over the longer term remains unclear.

Chan and his colleagues examined this question in 19 patients undergoing AF ablation combined with either cavotricuspid isthmus (CTI) or mitral isthmus ablation near the coronary arteries; intracoronary nitroglycerin was administered as a bolus at the beginning of the procedures and during ablation if needed. The investigators performed coronary angiograms and OCT scans before, during, and 3 months after the procedures in 20 vessels (one patient underwent both CTI and mitral isthmus ablation).

Despite a mean nitroglycerin dose of 800 μg, nine patients (47%) developed severe coronary spasm, defined as more than 70% narrowing of the coronary artery. Most patients with severe spasm (55%) didn’t have any associated ECG changes, Chan noted.

The 3-month OCT scans demonstrated that vascular wall area in the coronary arteries increased by a median of 17.1% from baseline, with a concomitant decrease in luminal area by a median of 10.1% (P < 0.01 for both changes), indicating “mild coronary artery stenosis,” Chan said.

Over longer follow-up (median about 16 months), none of these patients developed angina or acute coronary syndrome or required revascularization. Atrial arrhythmia recurred in 21%.

Importantly, it’s not known whether the effects observed in this study are catheter-specific, Chan said, pointing out that lesion sizes may vary across devices.

Jacob Koruth, MD (Icahn School of Medicine at Mount Sinai, New York, NY), the discussant for the study, said it’s reassuring there were no clinical coronary events detected. “It’s important to understand that the vast clinical experience is supportive of the fact that clinical, severe coronary events are not common,” he said, pointing out that thermal ablation technologies can cause coronary spasm as well.

Moving the Field Forward

Lakkireddy suggested that new catheters designed to deliver both PFA and radiofrequency energy could help mitigate some of the safety concerns with PFA by allowing the operator to choose which energy to deploy depending on what area they’re ablating. “There could be a potential pendulum swing going back to the single-tip, point-to-point catheters that are enabled with PFA and [radiofrequency],” he predicted.

He pointed to technologies like the Affera mapping and ablation system with Sphere-9 catheter (Medtronic), which was approved by the US Food and Drug Administration in 2024. “The ability to toggle between the two energies is actually a fantastic feature to have,” he said.

Taking a broad perspective, Lakkireddy said the EP field’s embrace of PFA has gotten ahead of the safety data “to some degree.” Some of these newly identified complications could be a significant problem in individual patients, he said.

“These are the potential pitfalls one has to keep in mind as the technology evolves,” Lakkireddy said.

All electrophysiologists should have a better understanding of what pulsed-field ablation really is and the concerns for this energy source. Wilber Su

Every PFA system has a different safety profile, and “there’s so many different factors that go into how to engineer a perfect PFA system that I’m not sure if anybody has the perfect solution just yet,” Su said.

Safety is always the top concern for AF ablation, he added, saying that “all electrophysiologists should have a better understanding of what pulsed-field ablation really is and the concerns for this energy source.”

Su said there will be a special edition of Pacing and Electrophysiology focusing on the fundamentals of PFA coming out in a few months to bring EPs up to speed. “I would say most electrophysiologists using PFA right now do not understand most of how PFA works and how each individual PFA system works,” he commented.