Niraj Sharma: Welcome to EP Edge Journal Watch issue five and welcome to 2026. I'm Doctor. Sharma and this is EP Edge Journal Watch where we break down the most important electrophysiology research and translate evidence into real world practice. This year is going to be defining for EP. Pulsed field ablation is moving beyond feasibility into durability and long term outcomes.
Device therapy is being reshaped by competing risk and patient selection. Atrial fibrillation ablation is increasingly shifting from one size fits all to substrate and patient specific approaches. We start with device therapy, because nothing forces clinical precision like long term mortality data. The extended follow-up of Danish is exactly that: a hard look at what ICDs do and what they do not do in non ischemic cardiomyopathy. This was the original randomized Danish cohort, eleven sixteen patients with non ischemic cardiomyopathy left ventricular ejection fraction 35 or less, NYHA class II to III, with class IV allowed if CRT was planned, and elevated NT proBNP.
Patients were randomized one to one to ICD plus optimal medical therapy versus optimal medical therapy alone. A key feature, cardiac resynchronization therapy, was used in about fifty eight percent in both arms, CRTD in the ICD group versus CRTP in the control group, so this is highly relevant to real contemporary practice. Follow-up was captured through Danish national registries with no loss to follow-up and the median follow-up was thirteen point two years. Here is the headline in numbers: All cause mortality was essentially identical: fifty two point nine percent in the ICD arm versus fifty three point four percent in the control arm, with a hazard ratio of 0.96 and a 95% confidence interval from 0.82 to 1.13, but sudden cardiovascular death was meaningfully reduced, hazard ratio 0.54, confidence interval 0.36 to 0.8. This is the central EP concept Danish keeps teaching us, and ICD is outstanding at preventing arrhythmic death, but it cannot override competing risks.
Progressive heart failure, comorbidity, and non cardiovascular mortality, especially as age increases, and that age signal is not subtle. In prespecified interaction testing, patients 70 or younger had a hazard ratio of 0.38, while those 70 had a hazard ratio of 1.27 with a p value for interaction of 0.01. So Danish long term follow-up doesn't say ICDs don't work, it says the mechanism works, but survival benefit depends on who you implant and when. Now, with that lens of precision, let's shift from defibrillators to pacing, where leadless systems are rapidly moving from novelty to scalable reality. Let's move into leadless pacing because the AVR data are starting to look less like a pilot experience and more like an ecosystem.
First, the AVR Doctor eye to eye dual chamber leadless pacemaker study. This was a prospective multi center non randomized investigational experience with four fifty two patients across 126 implanting physicians. Primary endpoints were implant success and thirty day safety. The procedural signal was strong, implant success was ninety nine percent, thirty day complications were eleven point one percent, and importantly the paper emphasized a learning curve effect. Procedure time and complications declined meaningfully with operator experience.
That matters for adoption. When a technology crosses from feasibility to scalability, outcomes become increasingly driven not by the device but by workflow training and patient selection. Now let's take a more nuanced physiologic question: What do you do when you see a high acute atrial capture threshold in an atrial leadless implant? Sohail and colleagues looked at 53 atrial AVR implants in a retrospective cohort, stratified by acute pacing threshold greater than or equal to three volts versus less than three volts. They track thresholds at tether mode after release at twenty four hours and at thirty days or longer using repeated measures analyses.
Here's the clinical punchline: High acute thresholds consistently declined over time. Mean chronic thresholds settled around 0.7 volts. And the predictor that mattered wasn't the acute voltage. What mattered was current of injury. Adequate current of injury predicted favorable remodeling and chronic performance.
This is classic EP thinking applied to Newtek. Acute numbers are not always biology. Sometimes they are contact, edema, microtrauma, or an early tissue response. So the practical takeaway is restraint. If your implant is stable and your current of injury is reassuring, don't chase a perfect acute threshold at the expense of unnecessary repositioning.
From here we pivot to the other side of device therapy, procedural infection risk, because the next trial is a reminder that small changes can deliver outsized outcomes. Let's talk about repeat CIED procedures and infection prevention, because this is where incremental technique can translate into real morbidity avoidance. Aiden and colleagues published a prospective, randomized, single blinded trial in four eighteen patients undergoing repeat cardiac implantable electronic device procedures. The primary endpoint was bacterial contamination, culture positivity. The secondary endpoint was one year device infection.
The intervention: iodine impregnated adhesive drapes. The result's pocket contamination was reduced by about fifty percent, and at one year the infection rate in the intervention group was zero percent. For EP labs doing high volumes of generator changes and revisions, that's a remarkably actionable finding because it's simple, scalable, and aligned with how infections actually happen: contamination at the time of reentry. Now let's shift to rhythm monitoring, not as diagnosis, but as management strategy. The Artesia AF progression analysis evaluated four thousand and twelve patients with device detected subclinical atrial fibrillation, followed for a median of four point one years.
They used time dependent Cox modeling and adjusted for factors like CHADS VASc, age, and heart failure status. The progression rate was nine point three percent per year, and progression was not benign. It was associated with increased all cause mortality, increased heart failure death, and increased stroke risk in patients on aspirin. So progression isn't just more AF, it's a biologic marker of worsening substrate and rising event risk, which means progression is not merely an observation, it's a trigger to reassess rhythm strategy, anticoagulation strategy, and overall risk trajectory. That idea is reinforced by the Monitor AF study, two thousand two hundred and ninety three patients in a retrospective multicenter comparison of implantable cardiac monitors versus conventional monitoring.
ICM monitoring wasn't just better detection, it changed management, more rhythm control attempts using antiarrhythmics and ablation. At twelve months, AF freedom was 86 with ICM guided care versus sixty one point eight percent with conventional monitoring. Stroke was lower, zero point three percent versus one point six percent. Major bleeding was lower, one point six percent versus two point nine percent. In other words, continuous data enables earlier intervention and smarter therapy decisions.
Now, let's bring that same insistence on measurable outcomes to the most disruptive technology in ablation today: pulsed field ablation and specifically the Vault program. Now we get to pulsed field ablation, where the field is moving from it works, to how durable, how efficient, and how safe. The Vault CE Mark program gives us one of the cleanest early chronic effectiveness signals for a first generation balloon in basket pulsed field platform. This was a prospective multi center pre market CE Mark investigation across 11 European and Australian sites. One hundred and fifty patients were enrolled and one hundred and forty six were treated.
Paroxysmal AF made up seventy point five percent (one hundred and three patients) and persistent AF was twenty nine point five percent (forty three patients). The lesion set was pulmonary vein isolation only, with a mandatory twenty minute waiting period and a ninety day blanking period. Monitoring was relatively stringent: ECG, bi weekly transtelephonic monitoring, and a twenty four hour Holter at six months. The primary safety endpoint was serious device or procedure related adverse events within seven days. The effectiveness endpoint combined acute PVI success and freedom from AF, atrial flutter, or atrial tachycardia longer than thirty seconds after blanking through six months.
Let's talk acute performance first because it was elite. Acute PVI success was ninety nine point one percent of pulmonary veins, five seventy three of five seventy eight veins. On a per patient level, acute success was ninety eight point six percent, one hundred and forty four of one hundred and forty six patients. First pass isolation was ninety seven point six percent of veins and ninety four point five percent of patients. Average pulse field applications were 17.6 per patient, plus or minus 5.7.
Total procedure time averaged one hundred point four minutes. Left atrial dwell time was thirty nine point four minutes. Fluoroscopy time was seventeen point three minutes. Now safety. The primary safety event rate was two point seven percent, four of one hundred and forty six, two were major vascular access or bleeding events, one tamponade, and one pneumonia.
There were no deaths, no atrioesophageal fistula, no phrenic nerve injury, and no clinically significant hemolysis. At six months, freedom from documented AF, flutter, or atrial tachycardia was eighty eight point two percent in paroxysmal AF and seventy six point seven percent in persistent AF. The primary composite effectiveness success was eighty six point two percent in paroxysmal AF and seventy two point one percent in persistent AF. Freedom from symptomatic recurrence was ninety point two percent in paroxysmal AF and seventy four point four percent in persistent AF. And there's an important subgroup signal among patients of class I or III antiarrhythmics after blanking, arrhythmia free rates were eighty nine point seven percent for paroxysmal AF and eighty four point four percent for persistent AF.
Durability is inferred from the redo subset. Seven patients (4.8 percent ) underwent repeat procedures. In that redo group, durably isolated veins were eighty two point six percent overall and ninety three point three percent post blanking. This is why the VOLT CE Mark dataset matters: high acute success, low early serious adverse events, strong six month effectiveness with stringent monitoring, and encouraging redo durability. The 12 CE mark outcomes presented at HRS twenty twenty five add longer horizon context still within a single arm PVI only framework.
The cohort remains one hundred and forty six total patients, one hundred and three paroxysmal, forty three persistent. At twelve months, freedom from documented AF, flutter or atrial tachycardia was eighty three point five percent in paroxysmal AF and fifty eight point one percent in persistent AF. Quality of life improved meaningfully. The AF EQT score increased by an average of 24 points from baseline, with a p value less than 0.0001. Reintervention signals were also strong.
Free from repeat procedure at twelve months was ninety four point five percent, one hundred and thirty eight of one hundred and forty six. And among those who returned for repeat procedures, durable isolation was seen in ninety percent of veins, twenty seven of thirty veins, though it's important to remember this reflects a redo selected sample, not mandated remapping. Now let's connect those chronic CE mark signals to the acute credibility established by the Global IDE dataset. Lo and colleagues reported the VOLT AF IDE trial as a prospective, single arm global IDE study across 38 international centers enrolling between April 2024. Three ninety two were enrolled, including fifty seven roll in cases.
The primary analysis cohort was three thirty five and three twenty patients ultimately underwent PVY with the VOLT system and formed the primary analysis population. AF type was nearly balanced: fifty one point nine percent paroxysmal and forty eight point one percent persistent. Mean age was 65 plus or minus eleven years. Sixty four point seven percent were male. Mean CHADS VASc was 2.3.
Mean ejection fraction was about 59%. So a relatively healthy LV population. The protocol was strict: PVI only, no adjunctive left atrial lesions, mandatory twenty minute waiting period, and confirmation of entrance block after waiting. Acute effectiveness was near universal. Per vein acute isolation was ninety nine point four percent in paroxysmal AF, six sixty six of six seventy veins, and ninety nine point eight percent in persistent AF, six thirty three of six thirty four veins.
Per patient, acute success was ninety eight point two percent, one hundred and sixty two of one hundred and sixty five in paroxysmal AF, and ninety nine point four percent, (one hundred and fifty four of one hundred and fifty five) in persistent AF. First pass isolation was ninety two point one percent in paroxysmal and eighty nine point seven percent in persistent AF. Energy delivery was efficient: 18.5 applications per patient, plus or minus 3.6, often fewer than other contemporary PFA systems. Workflow metrics: total procedure time was one hundred and five point nine minutes, ablation time thirty four point seven minutes, left atrial dwell time forty four point one minutes, and fluoroscopy fourteen point four minutes on average. Zero fluoro cases occurred in four point one percent, thirteen patients.
General anesthesia was used in eighty two point four percent. Safety, the primary serious adverse event rate within seven days was one point nine percent. Events included two tamponade or perforation events, one pericarditis, one ischemic stroke in a patient with CHADS VASc of five an anticoagulant dose was held, one vascular access complication, and one prolonged hospitalization. No deaths, no atrioesophageal fistula, no phrenic nerve injury, and no pulmonary vein stenosis were reported. Lab markers suggested myocardial injury rather than hemolysis, with stability in hemoglobin, haptoglobin, bilirubin, and creatinine.
So what does Volt give us right now? IDE establishes acute credibility and workflow. CE Mark provides early and intermediate chronic signals. What we still need is rigorous comparative durability, but the data already place Volt firmly among the leading PFA platforms. Next, let's move beyond technology and talk personalization, because some of the most important new AF data aren't about energy source, they're about strategy.
Before we close the discussion on pulsed field ablation, there is one study that must be addressed because it answers a question no randomized trial can. What happens when pulsed field ablation leaves the trial environment and is deployed at scale? That question is answered by MANIFEST US. This was a retrospective investigator initiated multicenter safety registry evaluating real world pulsed field ablation use in The United States. After FDA approval of the pentaspline PFA catheter, invitations were sent to four thirty five U.
S. Centers. 102 participated, contributing data on forty one thousand nine hundred and sixty eight consecutive patients treated between February 2024 and July 2025. This is now the largest safety dataset for pulsed field ablation ever reported. The patient population was unselected and real world.
Median age was 68 years, fifty six percent were male, seventy three percent were first time ablations. AF type included fifty four percent paroxysmal, thirty seven percent persistent, and nearly six percent long standing persistent atrial fibrillation. Pulmonary vein isolation was performed in over ninety two percent of cases, but importantly, more than half also underwent posterior wall ablation and nearly one third had cavotricuspid isthmus ablation, meaning this was not a PVI only population. Now the safety signal. The overall major complication rate was zero point six three percent.
Pericardial tamponade occurred in zero point one six percent. Stroke in zero point one percent. Vascular complications requiring intervention in zero point one eight percent. Thirty day mortality was rare, zero point zero four percent. Critically, there were zero cases of atrial esophageal fistula, zero cases of pulmonary vein stenosis, and zero cases of persistent phrenic nerve paralysis.
These are the complications that have historically defined the ceiling of thermal ablation risk. Manifest US also did what smaller data sets cannot: it surfaced rare events. Coronary artery spasm occurred in zero point one percent, most commonly during CTI or mitral isthmus ablation. Hemolysis related renal failure requiring dialysis occurred in zero point zero two percent, and there was a very low but non zero signal for unexplained sudden death or cardiac arrest (approximately zero point zero one nine percent ) occurring days after the procedure. This is exactly what real world registries are meant to do: not to declare perfection but to define the true safety envelope and identify where vigilance is required.
The take home message from Manifest US is not that pulsed field ablation is risk free. It is that when deployed across more than 40,000 patients, its safety profile remains consistent with myocardial selectivity and fundamentally different from thermal energy. When you place Manifest US next to controlled IDE and CE Mark trials like Vault, the picture becomes clearer. PFA is not just efficacious in trials, it appears scalable in practice. And that combination efficacy plus real world safety is what ultimately changes standards of care.
While large registries like Manifest US are essential for defining real world safety at scale, they also serve another purpose. They remind us that even exceptionally safe technologies can have rare complications that only emerge with widespread adoption. That brings us to an important and timely report from Gunnar Warden and colleagues published in early twenty twenty six in Circulation. This is not a trial and it is not a registry. It is a multinational case series designed to highlight rare but life threatening delayed ischemic and arrhythmic events occurring after pulsed field ablation for atrial fibrillation.
The investigators collected cases from seven high volume international centers between March 2023 and July 2025. Among 6,721 consecutive PFA procedures, eleven patients experienced severe delayed adverse events. That translates to an incidence of approximately zero point one six percent, or roughly one in six hundred procedures. The patient profile is worth noting. The mean age was 65 years, nearly three quarters had persistent atrial fibrillation, and almost half had known coronary artery disease.
Importantly, nine of the eleven patients underwent ablation beyond pulmonary vein isolation, most commonly involving the left atrial posterior wall or other non pulmonary vein targets. The clinical presentations were heterogeneous but alarming. Five patients developed delayed ST segment elevation, with a median onset of about twenty minutes after the final PFA delivery, though the range extended from minutes to more than twenty days. Several of these patients progressed to ventricular fibrillation. Two patients experienced malignant ventricular arrhythmias, including ventricular fibrillation occurring during or shortly after the procedure.
Two others developed profound bradyarrhythmias, including high grade atrioventricular block and prolonged junctional rhythms, and tragically, two patients suffered sudden cardiac death occurring three days and twenty two days after ablation. Autopsy findings available in two cases were particularly revealing. One patient demonstrated spontaneous ventricular fibrillation without evidence of myocardial infarction, tamponade, pulmonary embolism, or obstructive coronary disease. Another showed an acute inferior myocardial infarction in the absence of plaque rupture, thrombosis, or embolism, raising strong suspicion for delayed coronary vasospasm. Taken together, these observations suggest several plausible but not yet proven mechanisms.
These include delayed or generalized coronary vasospasm, electroporation related release of vasoactive mediators, ionic shifts affecting repolarization, autonomic imbalance with vagal or sympathetic perturbation, and interactions with underlying coronary or microvascular disease. Importantly, some events occurred despite prophylactic atropine or nitroglycerin administration, underscoring both the unpredictability of these rare events and the limitations of current preventive strategies. The authors are very clear about the limitations of this work. This is a small retrospective case series. It is hypothesis generating.
A causal relationship cannot be definitively established, and similar delayed catastrophic events have been reported, albeit rarely after thermal ablation as well. Still, the clinical message is important. Pulsed field ablation remains an exceptionally safe technology at scale as reinforced by Manifest US and other large data sets, but it is not risk free. The EP edge interpretation is this: rare does not mean irrelevant. These events appear more likely when ablation extends beyond pulmonary vein isolation, particularly in patients with persistent AF and underlying coronary disease.
In an era of same day discharge, delayed ischemic or malignant arrhythmic events demand heightened vigilance. For practicing electrophysiologists, this means maintaining a low threshold for telemetry, electrocardiography, and coronary evaluation when unexplained symptoms changes occur after PFA. It also reinforces the need for continued post market surveillance and transparent reporting as PFA adoption accelerates. When viewed together, Manifest US tells us what usually happens. This case series reminds us what can happen, very rarely, but with devastating consequences.
Responsible adoption requires understanding both. To close this issue, let's step back from individual devices and energy sources and focus on where atrial fibrillation ablation is clearly heading: personalization. One of the most compelling examples comes from the PAF by left atrial wall thickness trial, which asked whether lesion delivery should be tailored to left atrial wall thickness rather than using uniform ablation index targets. This was a prospective, multicenter, randomized, non inferiority trial enrolling one hundred and fifty six patients with persistent atrial fibrillation undergoing first time ablation. Patients were randomized one to one to a left atrial wall thickness, guided strategy versus a conventional closed protocol.
In the left atrial wall thickness guided arm, three-dimensional CT derived wall thickness maps were displayed to the operator and ablation index targets were adjusted accordingly. In the control arm, operators used standard posterior and anterior ablation index targets without wall thickness information. At twelve months, arrhythmia free survival was similar between groups, meeting non inferiority, but efficiency differed substantially. Total procedure time was reduced from eighty minutes to sixty point five minutes and radio frequency time was nearly halved, from twenty eight point six to fourteen point four minutes, without an increase in complications. This trial reinforces a core electrophysiology principle: when energy delivery is matched to atrial substrate, efficiency improves without sacrificing efficacy.
Personalization was also explored through a different lens in the TAILORED AF trial, particularly in the pre specified subgroup analysis of women. The parent study randomized three seventy patients to either pulmonary vein isolation alone or a tailored strategy combining PVI with AI assisted spatiotemporal dispersion guided ablation. Women comprised seventy seven patients, or about twenty one percent of the cohort, and had higher CHADS VASc scores and more persistent AF at baseline. In women, the tailored strategy produced a striking benefit: single procedure freedom from atrial fibrillation at twelve months was seventy six percent with tailored ablation compared with fifty percent with PVI alone, corresponding to a hazard ratio of zero point three one, While freedom from any atrial arrhythmias showed a favorable trend without reaching statistical significance, the signal suggests that PVI only strategies may underperform in certain substrates and that selective escalation may be more effective than empirical lesion sets for all patients. Another pragmatic personalization strategy comes from observational data examining patient height as a surrogate for atrial size and lesion requirement.
In two zero six patients undergoing paroxysmal AF ablation, first pass pulmonary vein isolation occurred in sixty eight percent of patients shorter than one hundred and seventy two centimeters but only forty seven percent of taller patients. When ablation index targets were increased in taller patients, specifically raising anterior targets from four fifty to five fifty, first pass isolation improved to sixty six percent and acute pulmonary vein reconnection fell from twenty two percent to two percent. Together, these studies highlight a central theme in modern personalization does not always require new technology. Often, requires smarter application of what we already have. When these personalization strategies are viewed alongside the pulsed field ablation data discussed earlier, particularly the VOLT trials and the 40,000 patient MANIFEST US registry, a broader narrative emerges.
Atrial fibrillation ablation is moving away from uniform protocols and towards strategies informed by substrate anatomy, continuous rhythm monitoring, and real world safety at scale. As we move deeper into 2026, the most important question will no longer be which catheter is newest or fastest. The question will be which approach delivers durable rhythm control with the lowest cumulative risk for each individual patient. For those who would like to explore all references, detailed tables, figures, and visual infographics supporting the studies discussed today, They are available in the EPEDGE Journal Watch Newsletter on LinkedIn. If you have comments, questions or suggestions for future issues, I genuinely welcome your input.
You can reach me directly at epedcastgmail dot com. Before we close, I want to say a personal thank you. I'm Doctor. Sharma, the author of EP Edge Journal Watch, and I'm deeply grateful to each of you who continue to read, listen, and engage with this series. Your thoughtful feedback, your discussions in the lab and clinic, and your commitment to evidence based electrophysiology are what make this work meaningful.
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