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: Welcome to EP Edge Journal Watch. I'm Doctor. Sharma and I'm glad you are here for Issue 27, June 2026. This episode is about smarter targets, safer energy, and the new substrate conversation. We are not just asking: can we ablate better, pace better, image better, or monitor better?
We are asking something more mature: where is the true substrate, how much intervention is enough, and when does a signal that looks reassuring actually leave us with an incomplete answer, we will move through CT guided ventricular tachycardia ablation, posterior wall isolation, CTI functional substrate mapping, left bundle branch area pacing mechanics, PFA hemolysis and renal safety, postoperative AF phenotyping, inflammatory AF biology, vaping related ventricular ectopy, and alcohol as an AF risk factor. And I want to start by saying I appreciate the suggestions and feedback that helped shape this series. The written newsletter gives the full statistics, tables, references and graphics. In the podcast we are going to build the story, explain why each study was done, and talk about what it means in practice. Also, this continues the growing excitement around the EP Edge Journal Watch podcast with the Heart Rhythm Society.
The podcast format lets us take the same clinical questions from the newsletter and add nuance, interpretation, the practical EP perspective that often does not fit into a figure or abstract. Let us begin with procedural strategy and substrate targeting. Our first study is the In Your Heart trial, looking at CT guided ventricular tachycardia ablation. Here is why this trial matters. Ischemic VT ablation is one of the hardest procedures we do in EP.
These patients often arrive late. They have recurrent ICD therapies, electrical storm, scarred ventricles, worsening heart failure, and arrhythmias that may not tolerate activation mapping. So the operator spends a lot of the case trying to understand the battlefield. The idea behind In Your Heart is simple and powerful. What if the battlefield could be mapped before the patient enters the lab?
Post infarction VT circuits often travel through channels of relatively preserved myocardium within areas of thin scar. CT can show wall thickness, scar architecture, fat, calcification and anatomy. It does not show slow conduction directly, but it may tell us where slow conduction is likely to live. So the key question was not can CT replace electrograms? It was can CT move us into the right neighborhood faster, shorten the procedure and preserve clinical outcomes?
Methodologically, this was a multicenter, open label, randomized trial across 14 European centers. One hundred and thirteen patients with prior myocardial infarction and clinically significant VT were randomized to CT guided ablation or conventional ablation. In the CT guided arm, a pre procedural CT model identified wall thinning isthmases. Those targets were imported into the electroanatomic mapping system and ablation focused on those pre annotated channels. In the conventional arm, operators used their usual substrate and mapping workflow.
The primary endpoint was procedure duration, and that endpoint was positive. In the modified intention to treat analysis, procedure time fell from about one hundred and forty nine minutes with conventional ablation to about one hundred and twenty minutes with CT guidance. That was a 19% reduction with a p value of 0.0027. In the per protocol analysis, the reduction was even larger, down to about one hundred and seven minutes. That was a 28% reduction with a p value less than 0.0001.
What does that mean? It means the time saving was very unlikely to be a chance finding. And practically, nineteen-twenty eight percent less VT ablation time is not cosmetic. That may mean less anesthesia exposure, less hemodynamic stress, less lab occupancy, and potentially a workflow that more centers can adopt. But the one year VT free survival result was more cautious.
It was numerically better with CT guidance, seventy six point eight percent versus sixty seven point three percent, but the confidence interval crossed zero. So the trial did not prove superior rhythm outcomes. It showed faster procedures without an obvious safety penalty. The limitation is important. This was ischemic cardiomyopathy.
CT wall thinning is much more plausible in infarct scar than in non ischemic disease, and CT remains a structural surrogate. It does not directly measure conduction velocity, anisotropy, decrement, or functional block. The EP Edge take, CT may define the battlefield before the case begins. But anatomy is not destiny. Functional mapping still tells us what conducts.
The future is likely not CT versus E. It is CT first, E. L. Ablation third. For the full numbers and references, go to the written EP Edge Journal Watch newsletter.
Next, Posterior wall isolation in persistent AF using very high output pace capture testing. This is one of the most provocative papers in the issue because it challenges something that feels intuitive. Posterior wall isolation has always been attractive in persistent AF. The posterior wall shares embryologic continuity with the pulmonary veins. It has complex fiber orientation.
It sits near important trigger regions. It may help maintain fibrillatory conduction, but the clinical data have been inconsistent. So the field has asked a durability question. Maybe posterior wall isolation has not worked reliably because the lesion set does not stay isolated. This study asked a more aggressive version of that question.
If we test the posterior wall with very high output pacing and we ablate until even that capture disappears, will outcomes improve? The rationale was reasonable. Loss of pace capture can suggest more complete local lesion formation. The conventional output was 10 mA at two ms. This study escalated to 20 mA at 10 ms.
That is a much more demanding endpoint. Methodologically, this was a retrospective single center, single operator study of two thirty two patients undergoing radiofrequency ablation for persistent AF. Everyone had PVI, posterior wall isolation and CTI ablation. The investigators compared two sequential cohorts. The earlier group had posterior wall capture testing at ten:two.
The later group used the much stronger twenty:ten protocol. If the posterior wall still captured, more radiofrequency lesions were delivered. The primary clinical outcome was recurrent AF after a ninety day blanking period. The high output strategy did exactly what you would expect procedurally. It led to more posterior wall lesions, more ablation time, and more total energy.
But here is the twist: more ablation did not improve outcomes. The twenty by ten group had more recurrent AF or atrial tachycardia in time to event analysis, with a log rank p value of 0.01. At one year, recurrence was not significantly different, but between year one and year two, recurrence was higher in the very high output group. What do the statistics mean? The procedural p values show that the stricter endpoint changed operator behavior.
More lesions were delivered. The outcome curve tells us something more unsettling. The more aggressive strategy did not translate into better rhythm control, and may have been associated with worse late recurrence. This does not prove that high output testing caused harm. The study was retrospective and sequential, so time period effects and confounding are possible, but it does show that a more durable looking endpoint did not mean better clinical effectiveness.
The EP Edge take durability may not be the only problem. The future may not be more posterior wall. It may be better posterior wall selection. We need to know which patients actually have a posterior wall dependent substrate rather than applying empiric isolation to everyone with persistent AF. This study does not close the posterior wall debate.
It sharpens it. Now let us move from the left atrium to the right atrium with CTIDEP and atrial flutter in patients with AF. This study asks a practical EP question: During an AF ablation when the patient has no obvious flutter in front of you, how do you know whether the CTI is just an anatomic corridor or whether it is actually a vulnerable flutter substrate? DEEP stands for decrement evoked potential. I think of it as a stress test for local conduction.
You pace normally, then introduce a premature beat. If the local CTI electrogram suddenly widens or delays after that premature beat, the tissue is telling you something. At baseline, it may conduct, but under stress, it behaves like slow conducting substrate, and that is exactly what flutter needs. Typical flutter is an anatomic macro reentry around the tricuspid annulus, but anatomy alone does not make reentry. You need slow conduction, functional block, and a wavefront that can keep circulating.
Here is the setup: After cryoballoon PVI, the investigators tested the CTI. If atrial tachyarrhythmia persisted after PVI, they restored sinus rhythm with internal cardioversion before testing. They used three key catheter positions. A multipolar deflectable catheter was placed close to the tricuspid annulus, a coronary sinus catheter was positioned in the CS, and a high density multispline mapping catheter was placed at the CT eye to record local bipolar electrograms. Then they paced from two directions: first, from the lateral tricuspid annulus, representing the right atrial free wall side second, from the proximal coronary sinus, representing the septal side That is CS pacing.
The pacing protocol used a 600 ms drivetrain, then an extra stimulus S2, delivered 10 ms above the atrial effective refractory period. The measurement was simple but very EP. At the CT eye recording catheter, they found the electrode with the longest local atrial electrogram. They measured the electrogram duration during the regular beat s one. That was a.
Then they measured the electrogram duration during the premature beat S2. That was B. Deep = B A. If S2 prolonged the local electrogram by at least ten milliseconds compared with S1, that was D positive. They focused on sharp near field signals.
If a double potential appeared after S2, they counted only the first component, so they were not confusing separated far field activity with true local delay. So TA deep means the abnormal delay was provoked during lateral tricuspid annular pacing. CS deep means it was provoked during proximal coronary sinus pacing. The results were striking. Ninety one patients were included, twenty nine had documented atrial flutter and sixty two did not.
The structural measurements like CTI length, CTI depth, tricuspid annular perimeter, and tricuspid annular area did not separate the groups, but the functional test did. CTI deep was present in ninety three percent of flutter positive patients compared with thirty two percent of flutter negative patients with P less than 0.001. The most important signal was directional. TA Deep was present in sixty nine percent with flutter, but only eleven percent without flutter, again with P less than 0.001. The odds ratio was one point zero eight per millisecond for TA Deep.
In practical terms, each additional millisecond of delay raised the odds of flutter by about 8%. A ten millisecond increase more than doubles the odds in that model. A twelve millisecond cutoff gave about 96% sensitivity, 71% specificity, and an AUC of 0.82. So this was not perfect, but it was a strong functional discriminator. The limitations are important.
This was small, single center, and retrospective. Flutter was based on documented 12 lead ECG before or during ablation. A dedicated flutter induction protocol was not routinely performed, so D positive should not yet be treated as an automatic mandate to ablate the CTI. The EP Edge Take CTI flutter may be anatomically located but it is functionally expressed. The anatomy gives you the corridor.
DEEP may tell you whether that corridor has the conduction behavior needed for reentry. In practice, this could move us away from reflexive, empiric CT ablation and toward functional CTI stress testing. This makes CTI ablation feel less like a habit and more like a phenotype driven decision. And with that, let us shift from right atrial substrate to a very different procedural vulnerability. What happens during sheath withdrawal after left bundle branch area pacing?
Next, left bundle branch area pacing and a procedural moment many of us may underestimate: sheath withdrawal. Left bundle branch area pacing has moved quickly into clinical practice. The appeal is obvious: physiologic activation, narrower paced QRS, and less chronic right ventricular pacing dyssynchrony. But the technique has its own complications, including septal perforation. Traditionally, we focus on deployment: how deep is the lead?
What is the paced morphology? What is the impedance? What are the thresholds? Do we see capture transitions? This study asks us to look at what happens after the lead already looks successful.
The rationale came from an index case where septal perforation became apparent after sheath slitting, despite apparently stable lead position and electrical parameters after deployment. The authors asked whether sheath withdrawal itself can transmit axial force to the lead tip, especially in a constrained right atrium or with unfavorable sheath orientation. Methodologically, this was an exploratory mechanistic study. It combined a clinical observation with a benchtop model. In the model, the pacing lead tip was fixed into a silicone sheet on a digital scale.
The investigators then withdrew the sheath and measured the axial force transmitted to the lead fixation site. They tested two geometries: one was constrained, with five centimeters between entry point and fixation site. The other was less constrained, with 10 centimeters. They also tested three sheath orientations: neutral, clockwise, and counterclockwise. Each condition was repeated multiple times.
The result was mechanically intuitive but clinically important. Constrained geometry generated significantly higher peak axial forces. Counterclockwise orientation produced the highest force under constrained conditions. Peak force occurred early in sheath withdrawal, when the lead tip to sheath tip distance was around 3.5 to 4.5 centimeters. What do the statistics mean here?
This is not a mortality trial. The statistics are mechanical. A significant main effect of geometry means small atrial space truly change force transmission. A significant orientation effect means the rotational position of the sheath changed how force reached the lead tip, and the interaction means the two risks can amplify each other. The limitations are real.
This was one index case plus a simplified bench model. It cannot fully reproduce myocardial tissue, cardiac motion, breathing, or septal heterogeneity. But the practical message is immediate: the EP Edge take. The procedure is not mechanically over when the lead looks good. During early sheath withdrawal, watch the lead tip continuously.
Withdraw slowly, minimize unfavorable rotational bias, and pay particular attention in small right atria. The lead can be injured after it looks good. Now we move into PFA safety beyond acute success. The first paper in this group is the HemoPFA study, which compared hemolysis and myocardial injury markers across three different PFA systems. And this is a very important study because the PFA safety conversation has matured.
At first we were excited about what PFA seemed not to do: less esophageal injury, less pulmonary vein stenosis, less collateral thermal injury. But as the technology moves into broader practice, we have to ask a second order question: Do all PFA systems have the same biologic footprint? That is the setup for this study. PFA uses high voltage electrical fields. Those fields are intended to electroporate myocardium, but the energy is delivered inside the bloodstream.
Red blood cells are exposed too. So hemolysis is not a theoretical issue. It is a predictable biologic question. Most of the time this may only be a lab signal, but if the patient is older, has chronic kidney disease, receives a large number of applications, or undergoes extrapulmonary vein lesion sets, hemolysis could become clinically relevant. So the study asked a very practical question: When three different commercially available PFAS platforms are used in real world AF ablation, do they produce different degrees of hemolysis and myocardial injury?
Methodologically, this was a prospective single center study of 150 consecutive patients undergoing AF ablation. The investigators intentionally studied fifty patients with each of three PFA systems. Six patients were excluded from biomarker analysis because the blood sample itself showed sampling related hemolysis. That left one hundred and forty four patients for the final biomarker analysis. The three systems were different in design and workflow.
System A used a multi electrode catheter with two different deployment shapes. The standard protocol delivered four applications inside each pulmonary vein and four applications at the entrum for each vein. System B used a circular multi electrode approach. Its standard protocol also delivered four intra vein and four enteral applications per vein. System C used a mapping integrated variable loop multi electrode approach.
Its standard protocol used fewer applications: two intra vein and two enteral applications per vein. That matters because we are not just comparing abstract energy. We are comparing whole workflows: catheter design, electrode configuration, mapping integration, contact assessment, number of applications, and procedural time. All procedures were performed under deep sedation. The sedation regimen included dexmedetomidine, propofol, and pentazosin, with bispectral index monitoring maintained between forty and sixty.
Venous access was obtained through the right femoral vein. Transseptal puncture was performed to enter the left atrium. Heparin was used to maintain an activated clotting time of at least three fifty seconds. In all patients, pulmonary vein isolation was performed with PFA using a biphasic bipolar waveform with microsecond scale pulses. After the standard lesion protocol, the investigators performed three-dimensional mapping.
If residual pulmonary vein potentials remained, additional PFA applications were delivered. If tissue contact seemed insufficient, operators could add more applications at their discretion. Final three-dimensional mapping was then repeated to confirm complete electrical isolation of all pulmonary veins. Patients who had atrial flutter before or during the procedure could also receive additional linear ablation, such as CTI ablation, using radiofrequency energy. Importantly, those patients were still included in the analysis.
The blood sampling protocol was also important. The investigators collected venous blood at three time points: before the procedure, immediately after ablation, and at twenty four hours. They measured hemolysis markers (LDH, LD isoenzyme two), indirect bilirubin, and haptoglobin. They also measured myocardial injury markers CK, CKMB, and Troponin T, and they followed serum creatinine as the renal safety marker. So this was not just did the patient have a complication or not.
This was a biomarker study designed to compare the biologic signature of three PFA workflows. Now the procedural results already tell part of the story. The variable loop catheter had the shortest procedure time, about seventy six minutes compared with about ninety one minutes for the pentaspline catheter and ninety seven minutes for system B, the fixed loop catheter. Variable loop catheter also had the shortest left atrial dwell time, (about fifty two minutes compared with seventy one minutes for the pentaspline catheter) and seventy six minutes for the fixed loop catheter. Variable loop catheter also had the fewest applications (about 23 on average).
Pentaspline had about 40 applications, fixed loop catheter had the most (about 50. So before we even get to hemolysis, we have to recognize that the systems were not identical in workflow: One platform required fewer applications and less left atrial time, another used the highest application count, another had more frequent additional radiofrequency ablation. That is clinically relevant because hemolysis may reflect not only waveform but also how many times energy is delivered and how the catheter interacts with blood and tissue. Now to the hemolysis results. All three systems produce changes in hemolysis markers.
That is not surprising. But the magnitude differed. Pentaspline catheter had the largest rise in LDH (about 95 units per liter). Fixed loop was intermediate (about 63 units per liter). Variable loop had the lowest LDH rise (about 41 units per liter).
The p value was less than 0.001, meaning this difference across systems was very unlikely to be random. Haptoglobin told a related but slightly different story. Remember, haptoglobin binds free hemoglobin. When intravascular hemolysis increases, haptoglobin tends to fall. The largest haptoglobin drop was seen with pentaspline, about 57 mgdL.
Variable loop was intermediate, about 42 mgdL. Fixed loop had the smallest haptoglobin drop, about 28 mgdL. Again the p value was less than 0.001 mgdL. So if we simplify the hemolysis signal, system A, the pentasplined catheter, showed the strongest overall hemolysis signal. System B, the fixed circular catheter, had the smallest haptoglobin decline, though its LDH rise was intermediate.
System C, the variable loop, had the lowest LDH rise, but an intermediate HG drop. That is why this study is useful. It reminds us that hemolysis is not one lab value, it is a pattern. The myocardial injury markers also differed. Troponin T rose in all three systems, as we would expect after myocardial ablation, but the rise was lowest with system C.
The variable loop catheter around fifteen forty five picograms per milliliter. System B, the fixed circular catheter was higher, around 2,128. System A, the pentaspline was highest, around 2,392. The p value was 0.002. CK showed a similar pattern.
System C: The variable loop catheter had the lowest rise. Fixed circular catheter was intermediate. System A pentaspline was highest. The p value was less than 0.001. What does that mean practically?
The statistics tell us the biomarker profiles were different across the three workflows. But we have to be careful. This was not a randomized energy equivalence trial. It was a real world comparison of three systems, each used according to its own standard protocol, so we cannot say the waveform alone caused the difference. The difference may reflect waveform, electrode geometry, application number, tissue contact, mapping workflow, residual gap treatment, or additional radiofrequency ablation.
The clinical complications were few but worth noting. There were two acute kidney injury cases both in System A, the pentaspline catheter. Both occurred in patients with stage II to III chronic kidney disease, and both resolved with conservative management. There was one cardiac tamponade in system B requiring surgical repair. There were no strokes and no esophageal complications reported.
So how should we interpret the whole study? First, all three systems produced some measurable hemolysis and myocardial injury. That is expected after PFA. Second, the amount of biomarker change was not the same across systems. Third, application burden matters.
If one workflow uses more than twice as many applications as another, it should not surprise us that the biomarker footprint may differ. Fourth, patient reserve matters. A small hemolysis signal in a patient with normal renal function may be clinically irrelevant. The same signal in a patient with chronic kidney disease may matter. The limitations are important.
This was a single center study. The groups were not randomized, baseline patient characteristics were not perfectly balanced. Additional radiofrequency ablation was included. The study was not powered to compare rare clinical events like stroke, major kidney injury, or long term outcomes, and because each system was used according to its own real world protocol, this was a workflow comparison, not a pure waveform comparison. The EP Edge take is this: PFA is not one technology.
It is a family of technologies. When we talk about PFA safety, we should not speak as though every system, every waveform, every catheter design, and every application strategy has the same biologic effect. In practice, this means we should pay attention to baseline renal function, chronic kidney disease, lesion set size, application count, and hydration strategy. In patients with higher renal risk or larger lesion sets, it may be reasonable to monitor hemolysis or renal function more closely. This study does not say one system is good and another is bad.
It says the biologic footprint differs and that difference may become clinically important in the right patient. The future of PFA safety is not generic. It is patient specific, lesion set specific, and system specific. For the full details, tables, biomarker values, and reference details, go to the written EP Edge Journal Watch Newsletter. Staying with PFA safety, the next study asks whether twenty four hours is too early to stop looking at the kidney.
PFA related acute kidney injury is uncommon, but it has become an important safety signal. The presumed mechanism is hemoglobin mediated injury from intravascular hemolysis. The practical challenge is that many AF ablation patients go home quickly. If creatinine looks fine at twenty four hours, we may assume the kidney is fine, but what if the injury appears later? That is the rationale for this study.
The investigators wanted to look beyond a single twenty four hour creatinine and perform a more complete renal assessment. Methodologically, this was a prospective observational single center study of eighty eight patients undergoing PFA for AF. The median number of pulses was 63. Patients received mandatory periprocedural hydration with five hundred to one thousand milliliters of crystalloid and oral hydration afterward. Renal biomarkers included creatinine, urea, cystatin, CNGal, KIM1, urinalysis, and hemolysis indices.
Creatinine and urea were planned at baseline twenty four hours and forty eight hours. The average creatinine story looked reassuring. Median creatinine actually decreased at twenty four hours (from 86 to 82 micromoles per liter) with a p value less than 0.001. At forty eight hours, the group median was similar to baseline, but this is where statistics can mislead us if we only look at averages. Nine of eighty eight patients, or about ten percent, met acute kidney injury criteria.
All were stage one and transient, but six of the nine were detected only at forty eight hours. So the practical statistical lesson is this: a lower median creatinine at twenty four hours does not mean nobody had AKI. Hydration may improve the group average while individual patients still declare kidney injury later. NGAL increased at twenty four hours, suggesting tubular stress and age, plus the number of PFA pulses were the major predictors of AKI. Limitations matter.
Only sixty three percent had the forty eight hour blood draw. High risk CKD stage IV and V patients were excluded, and this was one PFA platform. Also, all kidney injuries were transient stage I events. The EP Edge take, a normal twenty four hour creatinine, should not always close the safety window. In older patients, CKD patients, and those receiving high pulse counts or extra PV lesion sets, consider a forty eight hour creatinine.
This is not a reason to avoid PFA. It is a reason to operationalize safety. No renal reserve, hydrate, track pulse burden, and monitor higher risk patients intelligently. Now let us shift to AF as a substrate disease, starting with postoperative AF after cardiac surgery. Postoperative AF has always lived in a gray zone.
Is it just a temporary response to surgery, inflammation, catecholamines and hemodynamic stress? Or is it the first visible sign of an atrium that was already vulnerable? That distinction matters. It affects anticoagulation, rhythm monitoring, long term follow-up, and patient counseling. The vision cardiac surgery cohort was done because our evidence base has been messy.
Retrospective studies, single center series, administrative data, and very different practice patterns. Methodologically, vision was a large prospective international cohort. The analysis included twelve thousand two hundred and thirty four cardiac surgery patients without preoperative AF. Postoperative AF was counted when it was clinically important, meaning it caused symptoms or required rate control, antiarrhythmic therapy, or cardioversion. The investigators then looked at outcomes from thirty days to one year after surgery.
The first result is that postoperative AF was common. About thirty two percent developed new onset postoperative AF within thirty days. Discharge treatment varied widely. Some received anticoagulation, some received antiplatelet therapy only, some received both, almost half received amiodarone. At one year, clinically detected AF occurred in six point nine percent of patients with postoperative AF compared with zero point six percent in those without.
The adjusted hazard ratio was 11.3. That number is important. It means patients with postoperative AF were more than 10 times as likely to have clinically detected AF later, but the absolute detected rate was still only six point nine percent, and that likely underestimates true recurrence because extended rhythm monitoring was not systematic. The primary composite of stroke or vascular death was numerically higher (2.3 percent versus one point five percent ) with an adjusted hazard ratio of 1.32, but the confidence interval included one, so this did not meet conventional statistical significance. All cause death was significantly higher, with an adjusted hazard ratio of 1.54.
What does this mean? Postoperative AF is not uniformly benign, but it is also not automatically equivalent to lifelong chronic AF in every patient. The main limitations are under detection of recurrence, non randomized management, no uniform long term monitoring, and no complete AF burden data. The EP Edge take: Postoperative AF is a clinical signal. It should trigger phenotyping, not reflexive, overtreatment or undertreatment.
Duration, burden, left atrial substrate, surgery type, stroke risk, bleeding risk, and early rhythm surveillance should drive the next step. Postoperative AF is not one disease. It is a spectrum. The next piece is not a randomized trial. It is a state of the art review of inflammatory pathways in AF, but it belongs here because it gives a framework for why so many AF strategies succeed in some patients and fail in others.
We often describe AF electrically: triggers, pulmonary veins, rotors, reentry, conduction, refractoriness, fibrosis. But the atrium is also a biologic organ. It responds to obesity, diabetes, sleep apnea, hypertension, heart failure, smoking, surgery, infection, and pericardial inflammation. The rationale of this review is that inflammation is not just associated with AF, it may actively remodel the atrium. Methodologically, the authors synthesized clinical and preclinical evidence on inflammation in AF.
They focused on cytokines, oxidative stress, autonomic imbalance, epicardial adipose tissue, immune activation, fibrosis, ion channels, connections, calcium handling, and potential therapeutic targets. The key message is that inflammation can remodel the atrium in two ways. First, structurally: cytokines such as IL-one beta, IL-six, and TNF alpha can stimulate fibroblast activation, myofibroblast differentiation, extracellular matrix deposition, and fibrosis. NLRP3 inflammasome activation, mitochondrial reactive oxygen species, RAAS signaling, TGF beta, and EPIC all converge on atrial fibrosis, second electrically. Inflammation can alter connexin 40 and connexin 43, sodium current, late sodium current, L type calcium current, ryanodine receptor behavior, calcium handling, and potassium currents.
That means conduction heterogeneity, calcium overload, triggered activity, and reentry. This is not a p value paper. The evidence is mechanistic and translational. But the practical interpretation is strong. Risk factor treatment is not cosmetic.
It is substrate therapy, weight loss, sleep apnea treatment, blood pressure control, glycemic control, exercise, smoking cessation, and heart failure optimization may change the biology that makes the atrium fibrillate. Limitations are also clear. Many markers are both cause and consequence. Much of the evidence is preclinical or observational. Targeted anti inflammatory therapy for AF remains incompletely proven.
The EP Edge take: Ablation remains important but it works inside a biologic environment. A good lesion set in a hostile atrium may fail. A modest lesion set in a healthier atrium may last. The future of AF care is not only PVI plus or minus substrate modification, it is electrophysiology plus metabolic, inflammatory, autonomic and fibrosis phenotyping. Now let us turn to modifiable exposures, starting with vaping coolants and ventricular arrhythmogenicity.
When we ask about vaping, we usually focus on nicotine. But modern e liquids are not just nicotine plus solvent, they include flavorants and additives. One major category is cooling agents. Menthol is familiar. WS3 and WS23 are synthetic cooling agents that create a menthol like sensation and are common in ice labeled products.
These compounds make vaping smoother and more appealing, especially for younger users. The EP question is direct: are these additives electrophysiologically neutral? The rationale of this study was to isolate the coolant effect. Commercial vaping products are mixtures, so it is hard to know what ingredient is doing what. The investigators tested menthol, WS3, and WS23 in controlled experimental models.
Methodologically, mice with telemetry were exposed to filtered air, nicotine containing e cig vehicle aerosol, or vehicle plus coolants at increasing concentrations. Investigators measured heart rate, heart rate variability, ECG morphology, QTC, and ventricular premature beats. They also measured nicotine and metabolites which was important. If coolants simply increased nicotine exposure, the arrhythmia story would be different. They also tested human induced pluripotent stem cell derived cardiomyocytes with and without norepinephrine stimulation.
The key result: coolants did not significantly change nicotine intake or metabolism, so the arrhythmia signal was not simply more nicotine. All coolants enhanced autonomic imbalance, but only the synthetic coolants (WS3 and WS23) potentiated ventricular arrhythmogenesis. Ventricular premature beats tracked with higher heart rate, lower heart rate variability, and QTc changes. The signal was strongest for WS23. What do the statistics mean in practical terms?
This was not a human risk trial. It does not tell us the absolute risk of sudden cardiac arrest in a teenager vaping an ice product, but it does show a coherent physiologic pattern: sympathetic dominant physiology, repolarization changes and more ventricular ectopy, especially with synthetic coolants. The limitation is translation. Mice are not humans. Only male mice were used.
Real world vaping involves chronic exposure, different products, stimulants, sleep deprivation, alcohol, dehydration, and individual arrhythmia susceptibility. The EP Edge take: Ask better vaping questions. Do not stop at Do you vape? Ask about ice products, cooling labels, nicotine concentration, frequency, palpitations, syncope, and co exposures. In a patient with unexplained ventricular ectopy, QT concerns, palpitations, syncope, or inherited arrhythmia risk, synthetic coolant vaping deserves attention.
The last study is the alcohol and AF meta analysis, and I want to be very clear at the start. This study does not show that alcohol prevents AF. What it does show is that the relationship between alcohol intake and incident AF may be more nonlinear than we sometimes teach. Traditionally, we talk about alcohol and AF in a very simple way: more alcohol, more AF, and clinically that makes sense. We have all seen holiday heart.
We have all seen patients whose AF episodes track closely with alcohol exposure, and we know heavy alcohol use can worsen blood pressure, sleep, weight, cardiomyopathy, and atrial substrate. But population studies have not always shown a perfectly straight line relationship. Some have suggested a threshold effect, some have suggested a J shaped curve, And that is why this meta analysis was done. The investigators wanted to ask a more quantitative question. Across different levels of alcohol intake, where does incident AF risk actually rise?
Methodologically, this was a systematic review, pairwise analysis and network meta analysis. It included 26 studies with nearly 15,000,000 participants. That sounds very powerful and in terms of sample size it is. But there is an important caveat. These were observational studies.
There were no randomized trials where people were assigned to drink or not drink and then followed for AF. The authors divided alcohol intake into categories: no alcohol, very low intake, up to about one standard drink per day Low intake, about one to two drinks per day. Moderate intake, about two to four drinks per day. High intake, about four to five drinks per day. And very high intake, more than five drinks per day.
A standard drink was defined as 12 grams of alcohol. The outcome was new, or incident The main clinically actionable result was at the high end. Very high alcohol intake (more than 60 grams per day) was associated with increased incident AF. The relative risk was one point seven five. In plain language, that means very high intake was associated with a seventy five percent higher relative risk of developing AF compared with no alcohol intake.
That is the result we can act on confidently. Heavy alcohol exposure remains a meaningful AF risk factor. Now here is the part that needs careful interpretation. In the pooled observational data, very low and low alcohol intake appeared to have lower incident AF risk compared with abstinence. For example, very low intake had a relative risk below one, and low intake also had a relative risk below one.
But a relative risk below one does not automatically mean alcohol is protective. That is the key statistical point. A relative risk below one means the group had fewer observed AF events than the comparison group. It does not tell us why. And in alcohol studies, the comparison group is complicated.
The abstinence group may include lifelong nondrinkers, but it may also include former drinkers who stopped because of illness, frailty, cardiovascular disease, medications, liver disease, prior alcohol problems, or symptoms. That is the classic sick quitter problem. Low level drinkers may also differ from abstainers in many other ways. They may have different diet, exercise patterns, social engagement, socioeconomic status, healthcare access, baseline health, or comorbidity burden. So the lower risk signal may tell us something about the people in that group, not necessarily something protective about alcohol itself.
There was also substantial heterogeneity across the included studies. That means the studies were not all estimating exactly the same thing. Alcohol intake was self reported. Drinking patterns can change over time. Binge drinking was not consistently captured.
Beverage type was not analyzed consistently. And AF burden was not the endpoint. So this study is useful, but it should not be over read. The right conclusion is not alcohol prevents AF. The right conclusion is that in observational population data, very high alcohol intake is clearly associated with higher incident AF risk, while low to moderate intake did not show the same excess risk signal compared with abstinence, but that low intake signal may reflect confounding abstainer bias and patient phenotype.
The EP Edge take: This study adds nuance, not permission. Do not prescribe alcohol for AF prevention. Do not tell patients alcohol is cardioprotective for AF based on this analysis. But do use the study to have a better conversation. Heavy drinking remains clinically important and should be addressed directly.
For patients with established AF, post ablation recurrence, hypertension, sleep apnea, obesity, cardiomyopathy, atrial enlargement, or frequent symptomatic episodes, alcohol reduction remains reasonable and often important. For the full dose categories, confidence intervals, and reference details, go to the written EP Edge Journal Watch newsletter. The message is individualized counseling, not alcohol as therapy. Let us close with the big synthesis. In Your Heart tells us that CT can shorten ischemic VT ablation by defining the battlefield before the case, but anatomy still needs electrophysiology.
The posterior wall isolation study reminds us that more lesions and stricter pace capture endpoints do not automatically mean better outcomes. CTI deep shows that functional conduction delay may identify who actually needs CTI ablation. The left bundle branch area pacing study warns us that the vulnerable moment may happen after a lead looks successful during early sheath withdrawal. The PFA safety studies show that hemolysis, renal timing, application count, and system specific workflows matter. PFA safety is not one dimensional.
Vision tells us postoperative AF is not uniformly benign. But it also should not automatically commit every patient to lifelong anticoagulation. The inflammatory AF review reframes AF as a biologic substrate disease, not just an electrical rhythm problem. The vaping study tells us non nicotine additives, especially synthetic coolants, may not be electrophysiologically neutral, and the alcohol meta analysis gives nuance. Very high intake is clearly risky, but low intake signals in observational data should not be interpreted as a reason to recommend alcohol.
The theme of this issue is substrate precision. The future of EP is not simply more ablation, more imaging, more devices, or more monitoring. It is better matching of mechanism to intervention. Thank you for listening to EP Edge Journal Watch. All references and graphics are available on the LinkedIn newsletter, EP Edge Journal Watch, as well as on Substack at epedge.substack.com.
Questions, suggestions, or concerns can be sent to epedge. Castgmail . com. Thank you again for listening. Take care and bye for now.