Disclaimer: This program is for educational purposes only and reflects independent editorial commentary. It is not medical advice and should not replace clinical judgment or review of primary sources and guidelines. The views expressed are those of the host and contributors.
Niraj Sharma: Hello everyone, this is Doctor. Sharma and welcome back to EP Edge Journal Watch Issue 26 for June 2026. I appreciate the suggestions, questions and critiques that many of you send in. They helped shape this series into a practical, clinically grounded and relevant review of the electrophysiology literature. This month is a strong issue.
We moved from pulsed field ablation and posterior wall isolation to left atrial appendage occlusion in higher risk patients to diagnostic testing after unexplained cardiac arrest, post myocarditis arrhythmic risk and then deep into the biology of sinus node dysfunction and nearly invisible Purkinje PVCs. I am also excited that EP Edge Journal Watch continues to expand as a podcast with Heart Rhythm Society. The newsletter gives you the figures, references and detailed appraisal. The podcast lets us build the story around why the trial was done, what question it was trying to answer and how the results should change the way we think. Let us start with the ablation frontier.
The first study is Persepolis, pulmonary using a circular multi electrode pulsed field ablation catheter. Here is why this matters. Has changed the AF ablation conversation because it gives us a near non thermal energy source with a more favorable collateral tissue profile, but once a platform can reliably isolate pulmonary veins, the next question is obvious, can we safely and efficiently extend beyond the veins? The posterior wall has always been attractive in persistent AF. It may contain non pulmonary vein triggers and may sustain fibrillatory conduction, but with thermal ablation the posterior wall raises concern about esophageal proximity, incomplete lesions, reconnection, and added time.
Persepolis asked a practical workflow question: Can PVI plus posterior wall isolation be done with PFA without excessive applications, excessive time, clinically important hemolysis, or unacceptable safety signals. This was a retrospective single center study of one hundred and seventy eight consecutive patients undergoing first time ablation for symptomatic paroxysmal or persistent AF. The workflow used fluoroscopy, intracardiac echo, and three-dimensional mapping. Posterior wall lesions were overlapped, isolation was confirmed with block, pacing, and voltage mapping, and radiofrequency ablation was reserved for residual gaps. The main outcome was feasibility.
Acute PVI was achieved in all patients and posterior wall isolation was completed in nearly all patients selected for it. Procedure time and fluoroscopy time were short for an expanded lesion set. The clinical signal comes later. At about one year, freedom from AF was strong in paroxysmal AF and reasonable in persistent AF, but among patients who returned for repeat procedures, pulmonary vein reconnection and posterior wall reconnection were common. So what do the statistics mean?
A one hundred percent acute success rate proves immediate electrical endpoints, not durable lesions. The higher repeat ablation rate in persistent AF had a p value of 0.04, which means the observed difference is unlikely to be random by conventional thresholds. Clinically, persistent AF remains a substrate disease, not simply a pulmonary vein trigger disease. Limitations include single center design, no randomization, operator selected posterior wall isolation, intermittent rhythm monitoring, and redo mapping only in a subset. What's the EP Edge take?
This study makes PVI plus posterior wall isolation look feasible and efficient with PFA. It does not make posterior wall isolation mandatory. The next frontier is durability, dosing strategy, contact confirmation, and patient selection. The next ablation paper shifts from where we ablate to how the pulse itself is designed. This nanosecond PFA study asked whether much shorter pulses can reduce neuromuscular stimulation.
Anyone who has watched PFA delivery knows this issue. The energy may be non thermal but skeletal muscle contraction can be dramatic. That affects anesthesia, patient movement, lab workflow and whether these procedures can be done with lighter sedation. The rationale is elegant. Nanosecond pulses may preserve myocardial electroporation while raising the stimulation threshold for skeletal muscle and nerves.
In plain language the goal is effective ablation with less movement. The investigators used a preclinical canine model. Six dogs underwent randomized pulmonary vein and atrial ablation with microsecond or nanosecond PFA at matched low energy and high energy settings. Neuromuscular stimulation was measured objectively with motion sensors on the thorax and abdomen. Lesion effectiveness was assessed by acute PVI and 14 histology.
The headline is straightforward. High dose nanosecond and microsecond protocols both achieved acute PVI and transmural lesions, but the contraction profile was very different. Microsecond PFA produced contractions in every application, low dose nanosecond PFA produced no detectable contractions, and high dose nanosecond PFA produced fewer and weaker contractions. Rather than listing every metric, here is the practical interpretation: at matched high dose microsecond pulses produced nearly double the peak mechanical acceleration and about twice as many contraction events. P values below 0.001 for the main motion measures make it very unlikely that these differences were random experimental noise.
The dose response is especially interesting. With microsecond PFA, increasing the dose caused a clear surge in contraction energy. With nanosecond PFA, contraction energy did not rise significantly despite higher energy delivery. That supports a wider therapeutic window, more ablation energy without a proportional increase in neuromuscular stimulation. Limitations are obvious.
This was a small animal study, and reduced movement in anesthetized animals is not the same as reduced pain in awake patients. EP Edge Take. This is not just a waveform paper, it is a sedation paper, a patient experience paper, and a lab efficiency paper. If confirmed in humans, nanosecond PFA could help decouple lesion formation from skeletal muscle activation. Now let us move to AFib plus heart failure with the CAMERA MRI two.
This trial asked a clinically useful question, if the ventricle has scar, should we still expect recovery after ablation? This is the patient we all know. AF and left ventricular systolic dysfunction coexist and we are trying to decide whether AF caused the cardiomyopathy, worsened it or is just present in an already diseased ventricle. Late gadolinium enhancement on cardiac MRI gives us a window into scar. For this prespecified sub analysis, eighty patients with AF and LV systolic dysfunction underwent catheter ablation, forty had LV scar burden at least 5%, and forty had scar burden below 5%.
All patients had optimization before baseline imaging. Ablation included pulmonary vein isolation with additional substrate work left to operator discretion. The main result is reassuring. Both scar positive and scar negative patients improved substantially. Mean ejection fraction increased by about 20 percentage points in both groups.
The between group p value was 0.578, meaning there was no statistically detectable difference in the amount of recovery. But scar still mattered. Patients with LV scar were less likely to normalize their ejection fraction. Normalization occurred in about half of the scar positive group versus more than eighty percent of the scar negative group, with a p value of 0.004, so scar did not prevent recovery but it lowered the ceiling. Scar burden gave the key nuance.
When LGE burden was above 20%, improvement in ejection fraction was much smaller. A p value below 0.001 suggests a robust relationship between extensive fibrosis and attenuated recovery. For AF recurrence, the hazard ratio confidence interval crossed one, so the study did not show a statistically significant difference in recurrence between scar positive and scar negative patients. Limitations include modest sample size, twelve month follow-up, non randomized comparison between scar positive and scar negative ablation cohorts, and limited power for mortality. The EP Edge Take.
Scar is not a stop sign. It is a calibration tool. In practice I would use LGE to counsel about probability of full recovery, not to deny rhythm control. The better question is not, is this tachycardia mediated cardiomyopathy? The better question is, how much of this cardiomyopathy is still reversible?
Next, let us shift to left atrial appendage occlusion in patients with reduced left ventricular function. This study matters because low ejection fraction patients are not easy left atrial appendage occlusion patients. They have high stroke risk, high bleeding risk, high procedural risk, and high competing mortality. They also may have embolic mechanisms that are not purely appendage based. The rationale was simple and important.
Pivotal appendage closure trials excluded many patients with severely reduced ejection fraction, yet in practice these patients are undergoing left atrial appendage occlusion. The investigators asked whether the procedure remains safe and whether low ejection fraction predicts worse stroke outcomes after closure. Using the National Left Atrial Appendage Occlusion Registry, the study included more than one hundred and eighty six thousand patients with documented ejection fraction. Patients were stratified by ejection fraction with preserved function as the reference group. Outcomes included procedural success, in hospital complications, stroke, systemic embolism, major bleeding, and one year mortality.
The procedural finding is reassuring. Procedural success was essentially the same in the severely reduced and preserved ejection fraction groups, around ninety eight percent. In hospital mortality was numerically higher in the lowest ejection fraction group, but after adjustment it was not statistically different. The stroke result is also important. At one year, stroke rates were similar.
The adjusted hazard ratio for any stroke in patients with ejection fraction below thirty percent was 1.1, with a confidence interval from 0.88 to 1.37. Because that interval crosses one, the study did not show a statistically significant excess stroke risk after left atrial appendage occlusion in this group. But mortality was the differentiator. One year mortality was much higher in the lowest ejection fraction group. The adjusted hazard ratio was one point nine three, meaning nearly double the adjusted hazard of death compared with preserved ejection fraction patients.
This is where statistics become clinical judgment. The procedure may work but the patient may not live long enough to fully realize the stroke prevention benefit. That is not a reason to avoid left atrial appendage occlusion automatically. It is a reason to discuss time to benefit, frailty, heart failure trajectory, bleeding history and goals of care. Limitations include observational registry design, missing ejection fraction data in many patients, incomplete follow-up imaging, only one year follow-up.
The EP Edge take: low ejection fraction is not a procedural contraindication by itself, but it should trigger a more serious net benefit conversation. The second left atrial appendage occlusion paper is about simplifying the procedure. The question here is whether selected patients can undergo appendage closure using local anesthesia and fluoroscopic guidance alone. Why does this matter? Standard left atrial appendage occlusion workflow often rely on transesophageal echo and general anesthesia.
That works well in many centers but it consumes resources and can be challenging in patients with respiratory disease, esophageal disease, frailty, or limited anesthesia access. The ROSEFLEX study was a prospective multicenter single arm registry of 400 high risk patients with non valvular AF. All procedures were performed under local anesthesia with exclusive fluoroscopic guidance. Patients still had pre procedure imaging with transesophageal echo or cardiac CT angiography to define anatomy and exclude thrombus. This was not casual fluoroscopy only closure.
Operators used standardized angiographic projections, device compression targets, a tug test, and the classic position, anchoring size and seal framework before release. Follow-up imaging was performed with or on-site practice. The main result was very high feasibility. Procedural success was one hundred percent, median procedure time was under an hour, fluoroscopy time was short, and major complications were uncommon. During follow-up, device related thrombus was rare, and among those with follow-up imaging, there was no significant leak of five millimeters or more.
The predictor statistics are useful, but should be interpreted carefully because event counts were low. Chronic obstructive pulmonary disease carried a hazard ratio of two point eight six for adverse events. Higher CHADS VASc score also predicted adverse events. In practical terms, even when the implant workflow is technically successful, patient comorbidity still drives outcomes. The limitations are major: single arm design, experienced centers, short follow-up, mixed imaging follow-up, and individualized antithrombotic therapy.
What's the EP Edge take? This is a proof of workflow study, not a license for casual fluoroscopy only left atrial appendage occlusion. Simplified can be safe when it is disciplined. For practice this pushes us to think less dogmatically about imaging modality and more rigorously about patient selection, operator experience and workflow quality. Now we move to inherited arrhythmia evaluation, epinephrine challenge after unexplained cardiac arrest and familial sudden death.
This is a test many clinicians have mixed feelings about. Epinephrine challenge has been used to evaluate long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. But a positive test can have huge consequences. Medications, exercise restriction, ICD decisions, family screening, genetic anxiety, and a diagnostic label that may follow a patient for years. The study was needed because the real question is not whether epinephrine changes the QT interval or provokes ectopy in the moment, the real question is whether that result predicts the final diagnosis after years of follow-up, repeat phenotyping, exercise testing, imaging, and genetic reassessment.
This registry sub study included three seventy six consecutive patients who underwent epinephrine challenge. Follow-up averaged more than eight years. The test was compared with final working diagnosis, and importantly the epinephrine result itself was excluded from the diagnostic gold standard. For long QT syndrome, sensitivity was about ninety percent and negative predictive value was about ninety nine percent, so a negative test can help reduce suspicion in the right population, but the positive predictive value was only twenty one percent. In plain language, most positive long QT epinephrine challenges did not end up being true long QT syndrome over long term follow-up.
For CPVT, specificity was higher and the positive likelihood ratio was better, but sensitivity was only about sixty two percent. So a negative test does not reliably exclude CPVT, especially when exercise testing or genotype later tells a different story. Another important finding: QT prolongation during epinephrine did not correlate meaningfully with recovery QTC on exercise testing. Pharmacologic adrenergic stimulation is not the same as physiologic exercise. Limitations include evolving diagnostic standards over two decades, possible follow-up bias, imperfect gold standards and difficulty measuring QT during adrenergic stimulation.
EP Edge take: Epinephrine challenge should not be treated as a diagnostic verdict. A negative test may lower suspicion for long QT syndrome in selected patients. A positive test should trigger more careful phenotyping, not diagnostic closure. For CPVT exercise testing and phenotype guided genetic evaluation remain central. The next paper is the Myocarditis Meta Analysis and this one is about what happens after discharge.
Myocarditis is often presented as an acute diagnosis. The patient comes in, gets worked up, improves and leaves. But for electrophysiologists the question is whether arrhythmic risk truly ends when the inflammation cools down. This meta analysis was needed because post myocarditis arrhythmic risk is still poorly defined, particularly in complicated myocarditis. Some patients have transient inflammation, others may have scar, and some may actually be presenting with the hot phase of an underlying genetic or arrhythmogenic cardiomyopathy.
The investigators analyzed 19 observational studies including nearly four thousand patients. The population was enriched for complicated myocarditis, meaning many had heart failure, high grade AV block, ventricular arrhythmias, cardiac arrest, or fulminant presentations. The primary outcome was major arrhythmic events after discharge, sudden cardiac death, ventricular fibrillation, aborted arrest, sustained VT, or appropriate therapy from an ICD or wearable defibrillator. The headline number was a pooled major arrhythmic event incidence of twenty eight percent at a median follow-up of about two years. Sustained VT and appropriate device therapy were common components.
Sudden cardiac death itself was low, around one percent, possibly reflecting device protection and selection. The statistics require caution. The confidence interval was wide and heterogeneity was very high, so the twenty eight percent estimate should not be applied to every myocarditis patient. This was a high risk selected population, not uncomplicated myocarditis in general. Predictors that tracked with higher risk were intuitive: high grade AV block at presentation, VT or VF at presentation, and fulminant myocarditis.
The sex signal was interesting but should be interpreted cautiously because observational meta regression can be confounded. Limitations include retrospective data, heterogeneous definitions, variable device use, limited genetic testing, and enrichment for higher risk cases. The EP Edge Take Discharge is not the end of the myocarditis story. For complicated myocarditis, the follow-up pathway should be deliberate: repeat imaging, rhythm monitoring, exercise restriction strategy, selected genetic evaluation, wearable defibrillator bridging, and individualized timing of permanent ICD decisions. Now let us go deeper into mechanism with a beautiful sinus node paper, Caviolar Compartmentalization of Pacemaker Signaling.
Sinus node dysfunction is one of the most common things we treat, but mechanistically it is often unsatisfying. We say bradycardia, pauses, chronotropic incompetence or tachy brady syndrome, but that is a phenotype, not a mechanism. The rationale comes from the coupled clock model. Pacemaker cells depend on coordination between membrane currents and intracellular calcium cycling, but sinoatrial node cells do not have a typical T tubule system, so how does local calcium release reliably talk to membrane proteins quickly enough to generate a stable action potential? The answer proposed here is caveolae, tiny membrane invaginations that act as pacemaker nanodomains.
The investigators used a multi scale strategy: in vivo ECG telemetry, ex vivo optical mapping, calcium imaging, electron microscopy, mouse and human sinoatrial node tissue, cardiac specific caveolin, three knockout mice, a heart failure model and computational modeling. The main finding was that caveolae organized key pacemaker proteins, including HCN4 channels, calcium channels and the sodium calcium exchanger, into local signalosomes near the sarcoplasmic reticulum. In normal cells this keeps calcium release close enough to activate the exchanger and help drive diastolic depolarization. When caveolae were disrupted, the distance between membrane and calcium release sites widened substantially. The calcium clock could still tick but it failed to reliably trigger global calcium transients and action potentials that produced bradycardia, pauses, rhythm lability, pacemaker shifts and tachy brady behavior.
The statistics here are not hazard ratios, they are spatial biology. A shift from roughly 18 nm to more than 40 nm sounds tiny but calcium signaling is a nanometer scale process. Small spatial changes can destabilize the rhythm. The knockout was cardiac specific, not sinoatrial node specific. The heart failure model is associative and restoration experiments are still needed.
The EP Edge take: Sinus node dysfunction may be a disease of nanoscale organization, not just channel expression or fibrosis. That is a major conceptual shift. Our final mechan mechanistic and procedural paper is about a PVC that is almost impossible to see, the His left bundle branched twig PVC. The clinical context is immediately recognizable. Some PVCs are obvious: wide QRS, clear axis, classic outflow or fascicular signature.
But some PVCs look almost identical to sinus rhythm. They can be easy to dismiss and dangerous to ablate because the origin may be near the conduction system. The rationale was to explain these near sinus PVCs and define a safer ablation strategy. The hypothesis was that they arise from a discrete proximal His Purkinje branch, not ordinary myocardium and not a major fascicle. Among more than 3,800 patients referred for PVC ablation, the investigators found twenty with PVCs whose QRS morphology was almost identical to sinus rhythm.
They mapped His and Purkinje potentials, measured activation intervals, and used a cautious strategy: Ablate from the adjacent right coronary cusp region first, then underneath that region if needed, and avoid ablation when the site was too close to the His bundle. The earliest activation site consistently showed a sharp Purkinje potential before the QRS. The anatomy pointed to a tiny branch anterosuperior to the His left bundle trunk and underneath the right coronary cusp region. Successful ablation was achieved in seventeen of twenty patients, without AV block or bundle branch block. Statistically, the study reported an eighty five percent success rate, but the denominator is only 20.
The lead II RS index had an area under the curve of 0.955 for predicting success from the cusp region, which looks excellent, but it needs external validation. The most important physiologic clue was the shorter HV interval during the PVC compared with sinus rhythm. That supports the idea that the impulse begins in a proximal Purkinje branch and rapidly recruits the conduction system. Limitations include single center design, small sample size, no direct anatomic proof of the twig, and visual rather than computational classification of near sinus morphology. EP Edge take: A PVC that looks like sinus rhythm is not necessarily benign.
It may be a Purkinje arrhythmia hiding in plain sight. Map carefully. Respect the His. And if the safety margin is inadequate, do not force ablation. So in one sweep this issue showed PFA moving beyond pulmonary vein isolation and towards smarter waveforms, cardiac MRI refining, AFib, cardiomyopathy counseling, left atrial appendage closure being tested in lower ejection fraction and simplified workflows, provocative testing and myocarditis data demanding better longitudinal phenotyping, and mechanistic studies reminding us that rhythm can fail at the level of nano domains and tiny Purkinje branches.
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Take care, and bye for now.