Circulation December 16, 2025 Issue

Welcome, listeners. We are here at Circulation on the Run, and it is December 16th, and I'm one of your co-hosts, Dr. Greg Hunley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

And I'm the other co-host, Dr. Petter Meiery from University of Oslo in Norway. And Greg, this feature paper is so exciting because we're going to look at first in human trial assessing pulse field ablation. Not to treat atrial fibrillation, but now to treat scar-related ventricular tachycardia. Super exciting. But before we go there, what about taking a look in the mailbag to see what else is there? And perhaps you want to go first this week.

You bet, Petter. So our first study is a clinical study. And Petter, as an introduction for this study, let's remember that the clinical benefit of PCSK9 inhibitors on major adverse cardiovascular events is modified by... baseline lipoprotein levels, such that an elevated LP is associated with both greater relative and absolute benefit of treatment.

Now, Petter, recent studies indicate that an equimolar concentrations of LpA particles are approximately six times more atherogenic than LDL particles, indicating that elevated... LP little a imparts a substantial contribution to cardiovascular risk. So Petter, this suggests that apolipoprotein B100, which is common to both LDL and LP little a, may not drive this additional increased atherogenicity of LpA. Now, among the lipoproteins, LpA is the predominant carrier of

oxidized phospholipids in plasma. Now, Petter, multiple studies have shown that a major contributor of LP little a mediated cardiovascular disease risk. is its content of these pro-inflammatory oxidized phospholipids on apolipoprotein B100. And these reflect these pro-inflammatory properties of LpA. Now, Petter, the effect of these oxidized phospholipids, ApoB100,

on major cardiovascular events in patients with acute coronary syndromes is really not known. So this team, in association with corresponding author Dr. Sotiros SIMICOS from the University of California, San Diego, measured these oxidized phospholipid ApoB levels and lipoprotein little a in 11,630 participants prior to and then 5,185 participants four months after randomization to alirucumab or placebo in the Odyssey outcomes trial. Now, Petter, let's go back.

As you may recall, the Odyssey Outcomes Trial, what was that? Well, that included 18,924 patients with recent acute coronary syndrome, so myocardial infarction or unstable angina, at 1,315 sites in 57 countries who were followed for a median of 2.9 years. And all were treated with either 40 to 80 milligrams of atorvastatin or 20 to 40 milligrams of rosuvastatin. And then between one and 12 months after their index ACS, they were randomized in a one-to-one ratio.

to receive aliricumab or a matching placebo subcutaneously every two weeks. So better coming back to this study. So in this study, proportional hazards models were adjusted for baseline covariates and evaluated associations between the oxidized phospholipid ApoB and lipoprotein delay in those that experience MACE. The results, again, were followed for 2.9 years. The average age of these participants was 58 years, and about 24% were women.

All right, Greg, so a deep dive into oxidized phospholipids on the APOB, so those hyper-atherogenic particles, and now assessing that association. with accelerated atherosclerosis related to lipoprotein little a. So what did they find? Right, Petr. So in patients with recent ACS, receiving optimized statin treatment. elevated oxidized phospholipid ApoB levels predicted MACE, a relationship that was attenuated by alirucumab. The interaction of this oxidized phospholipid ApoB

and LP little a in the placebo group indicates that the oxidized phospholipid ApoB independently predicted MACE when the LP little a levels were relatively low. So, Petter. In conclusion here, perhaps a new marker for accelerated atherosclerosis-associated events in those with LP a, an interesting mechanism.

All right, Greg, that's truly interesting. And now, Greg, we are going to shift gears a little bit and look into the world of atrial fibrillation. and genetic factors that are associated with this common arrhythmia. Because prevention and control of AFib and its sequela remains difficult, particularly due to heterogeneous causal mechanisms.

And both common and rare genetic factors have been previously described to have large influences on the development of cardiac arrhythmias. And when it comes to AFib, it has been shown to be highly polygenic. And ion channels play a large role in this development of cardiac arrhythmias, especially atrial fibrillation, because they're essential for cardiac signaling. And there's one gene, Greg, called SCN5A.

which encodes the pore-forming subunit of the cardiac sodium channel responsible for the initiation and propagation of cardiac action potentials. So a super important channel. Thus, Genetic variants within this SCN5A can increase the risk for certain cardiac arrhythmias and arrhythmia syndromes. And the most well-known is, of course, the Brugada syndrome, which we're all familiar with.

But now we're going to see if there's also an association with AFib and this gene variant. So Greg, these investigators led by... Co-corresponding authors Dr. Hain and Dr. Wanner from Hasso Plattner Institute for Digital Engineering in Germany studied the impact of SCN5A missense variant on cardiac arrhythmias. associated mortality, and ECG phenotypes in more than 1 million individuals across three cohorts. So that's FinGen, UK Biobank, and Health2000.

Okay, so it sounds like this team will investigate the role of genetic variants in sodium channels on the risk of the most common arrhythmia, atrial fibrillation. So, what did they find? Yeah, Greg. So let's jump straight to it. So this team actually identified a rare genetic variant entitled T220I. So T220I in the SCN5A gene.

that emulates a lifelong cardiac sodium channel blocker, as evidenced by its specific electrophysiological and clinical phenotype. So, in the general population, T220i was associated with a reduced risk of tachyarrhythmias such as atrial fibrillation, so lower risk of atrial fibrillation, but also a reduced risk of heart failure and an increased risk of Brady arrhythmias.

but overall a reduced risk of mortality from cardiac arrhythmias. Moreover, T220i seem to lower the lifetime risk of atrial fibrillation in individuals with a high genetic liability.

to risk comparable to the general population. So the highest risk individuals had most benefit from this mutation. Now, Greg, the most interesting part. In sharp contrast to these beneficial effects seen in the general population, When looking at individuals with a recent myocardial infarction, the T220i gene was associated with an increase in mortality in the first five years after myocardial infarction.

And this, Greg, may even explain some of the adverse outcomes seen in the sodium channel blocker flecainide post-MI, which we all learned about some years ago from the famous CAS trial. Isn't that interesting? Wow, Petter, that's really interesting. And it sounds like this data might indicate a balanced risk-benefit profile in long-term sodium channel blockade in the general population, but with harm.

from sodium channel blockade after a recent myocardial infarction. Well, Petter, again, our next paper goes back to the world of preclinical science. And Petter, hypertrophic cardiomyopathy is a prevalent inherited cardiac disorder. marked by LVH and hypercontractility. Now this excessive mechanical workload creates an energetic mismatch where consumption exceeds production.

leading to myocardial energy depletion. Now, Petter, while creatine kinase plays a key role in cardiac energy homeostasis, its involvement in hypertrophic cardiomyopathy remains unclear. So this study, in association with corresponding author Dr. Vasco Sequeira from University of Clinic in Würzburg, investigated how hypercontractility-driven mitochondrial stress and the resulting increase in mitochondrial... hydrogen peroxide disrupt creatine kinase function in hypertrophic cardiomyopathy.

And to achieve this, the team analyzed creatine kinase function using myocardial left ventricular tissue from 92 patients with hypertrophic cardiomyopathy with and without pathogenic sarcomere variants and... 30 non-failing human controls. Oh, what a timely topic, Greg. You know, with all these new treatments for HCM, with the myosin inhibitors, etc. So what did they find, Greg? Well, Petter...

The results revealed a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and creatine kinase dysfunction in hypertrophic cardiomyopathy. perpetuating a cycle of energetic dysfunction. And so Petter targeting hypercontractility and oxidative stress through myosin inhibition. Well, that can now offer a strategy to restore energy balance and reduce the arrhythmogenic risk in patients with hypertrophic cardiomyopathy, another really interesting application.

of myosin inhibition. I agree, Greg. This is so interesting. Thanks and congratulations to the investigators. Now, Greg, there is more in this paper. Perhaps you remember we had Dr. Glagard from Denmark here to talk about the TAP-IT trial, the randomized controlled trial of thoracic synthesis in acute heart failure. Now, this trial has generated a lot of interest, so there's no less than three letters to the TAPI trial, one from Wang et al., one from Boca Tonda et al., and one from Harris et al.

And then, of course, also a response from Dr. Glagord et al. to these three papers. And then, Greg, there is an ECG challenge by Dr. Lu et al. entitled A Storm of Tachycardia Following Stroke. What is the mechanism? Very nice, Petter. And also in the mailbag, there's a perspective piece from Professor Witt Futh entitled Troponin Autoantibodies, Macrotroponin and Assay Interference. And then finally, Petter, there's a research letter from Professor Tello.

entitled Acute Hemodynamic Effects of Soteracetept. All right, now let's talk about PFA to treat ventricular tachycardia, Greg. Are you ready? Yep, let's go.

Welcome, listeners, to the second half of the podcast of December 16, 2025. And this feature discussion coming up is super interesting and novel. because we're going to look into a new technique for ablating ventricular tachycardia. You've all heard about PFA for atrial fibrillation, but guess what? It now has come to VT ablation. And to discuss this...

I'm so fortunate to have with me the first and corresponding author, Dr. Vivek Reddy from Mount Sinai Fuster Heart Hospital, and also our own senior associate editor, Sana Al-Khatib from Duke University Hospital. Thank you so much both for joining us today. And to begin, Vivek, perhaps you could set the stage by giving us a background to this field.

As I said, we all know about PFA and AFib, but what about treating this in patients with ventricular tachycardia? Where do we stand before this study? Yeah, no, thanks first of all for having me, Peter, and thanks to Circulation for accepting our article.

You know, it's a good point. Pulse field ablation for atrial fibrillation is now well appreciated, I think, by the cardiology community. And the major advantages there are because of the safety profile and to some extent, the workflow, the fact that the procedures are very quick.

VT is a different story. When you're thinking about scar-related ventricle attack cardia, what's really interesting is, on the one hand, in many ways, we understand the physiology of scar-related VT quite well. It's been worked out very well over the past couple of decades between... surgical studies, and then in vivo clinical studies, as well as preclinical studies. But at the same time, our ability to eliminate these tachycardia circuits, well, has been, let's say, modest at best.

okay and it's a problem because um well i mean vt is a it's a life-threatening condition patients yes we do have defibrillators but defibrillators are there basically to shock patients nobody likes having icd shots So we need a way to control the VT. Why have we been sort of limited in our ability to ablate VT? It's largely because of our inability to make deep enough ablation lesions.

You know, most ablation catheters, arguably all ablation catheters, were developed really for targeting atrial fibrillation. At least that's how the development has been, and certainly the clinical development. And so most catheters... We're developed for AFib, and we're sort of using the moth label for VT. That's been our whole sort of field for the past, whatever, 30 years or whatever it's been. So in that context, these catheters, while they can make lesions...

they oftentimes are not deep enough to ablate the target tissue. Now, in the context of that, pulse width ablation has obviously been tested. And coincident with all of the clinical work in the atrium, there has been preclinical work using

sort of, let's say, conventional pulse-field ablation catheters or focal pulse-field ablation catheters. And there are a couple of observations that have been found in the preclinical work. The first is that when you make these lesions, whether or not they're scar tissue or not,

the pulse field lesions go right through that. And that's, by the way, different than our conventional radiofrequency ablation. So the scar tissue does not seem to be an impediment to lesion formation. So that's point number one. And that probably is the most exciting point because this made us more interested. Oh, you know what? We could actually potentially make deeper ablation lesions with Paul's field.

There are some safety advantages. There's less chance of clot formation and things like that. But really, it's about the potential improvement efficacy. And then on top of that, the particular catheter that we're studying here, a pulse field ablation catheter, is...

It's a catheter that's not FDA approved for anything at this point. It was actually developed specifically for VT ablation, and it uses very high energy. I mean, just to give you some general idea, most pulse field ablation catheters are being used for AFib.

are around two kilovolts this one is around 10 kilovolts so it's about five times the amount of energy now it's also for very short duration literally it's less than a second it's about 200 milliseconds long so it's a very short amount of pulsing But that energy is able to make very deep ablation lesions. So that's really sort of the background for both the field and the pulsoid ablation catheters.

That is so interesting. And it's so good for us here in circulation and the listeners that we now have the results of this, I think, first in human study of PFA, this new PFA catheter. to ablate scar-related VT. But Vivek, what kind of patients did you enroll to find these scar-related VT patients? And also, what kind of methods did you use when you designed this study with respect to...

exposure and also the outcomes. Sure, absolutely. So indeed, so the study called VCAS was the first in human evaluation of this catheter. The kind of patients that we enrolled were scar-related VT, and specifically the vast majority were post-MI VT patients. So history of myocardial infarction sometime in the distant past, they all had defibrillators as expected, and they had recurrent VT.

The patients, there were a total of 26 patients. It was not a huge study. Again, it's a first-year human study, so this really is an observational study perspective, of course. And these 26 patients were enrolled in two centers. The patients, as you'd expect, had mean ejection fraction that was reduced around 30%. And many of these patients had previous ablation procedures. So about 40% of the patients had a previous ablation using a conventional approach.

usually radiofrequency energy. And about 40% also had what we'll call VT storm or ICD storm. So at least three ICD events in a 24-hour period. So these are patients who we would say are let's say, a relatively high-risk population and a population that, well, many had already received a treatment and failed. In terms of the methodology, again, there's an observational study. And so we...

You know, we looked at the outcomes before. We looked at, obviously, our procedural outcomes, and we looked at the outcomes in six months following the period, following the ablation period. But there's one other interesting thing that we did, which I was very happy about. I think it's actually the first time it's been done in a clinical study like this, which is one of the exciting aspects of this particular technology.

and we saw this in some preclinical work, which is also in the manuscript, was that it appeared that we could make transmural ablation lesions. So from the endocardium deliver lesions that can ablate tissue all the way to the epicardium. Now, that's very nice in preclinical studies, but how do you prove that in patients? And so what we did is in a subset of these patients, about 40% again, they had not had previous cardiac surgery. And so we were able to gain pericardial access.

There's a technique to go pericardial, which the field is very aware of. So what we did was, our strategy was, let's get pericardial access, map the endocardium and the epicardium of the scar tissue. then deliver lesions endocardially and see what happens in terms of, did we really get transreality? Were we able to eliminate those potentials on the epicardial surface that adjust from endocardial ablation?

So that was sort of in a subset of patients. And the idea was if we weren't, then we could also deliver epicardial lesions at that point to eliminate the substrate. So that was the sort of a sub-study of the major study, which I thought was very important. I won't say novel is probably too strong a word, but certainly an interesting way of trying to assess transmirality in vivo. Great. Sounds like a very well-designed study, I must say, Vivek. Congratulations on that.

And now let's move to the results. So first, what was the baseline characteristic briefly for these patients? You mentioned VT storm and prior VT ablation. What's the proportion for that? And then to the main findings, did you see any procedural success from this strategy? Yeah, no, absolutely. So how do we assess success? Well, certainly we look at things like acute inducibility and...

before the ablation and after the ablation. So there are a couple things that we observed. Number one, the procedure ended up being very efficient. Now, what do I mean by that? Look, this is a clinical study. We're doing lots of mapping, more mapping than we otherwise would. Okay. So overall procedure times were around two and a half or just over two and a half hours. So that's reasonable, but that's not terribly interesting. What was interesting is...

the transpired ablation time, meaning the time from the beginning of the first lesion to the end of the last lesion, was only about 30 minutes. And that's very important because that's actually where all the work is being done. So the fact that it didn't require a lot of time to ablate the tissue. And by the way, that's not surprising. Each ablation lesion was basically delivered over five heartbeats. So it was a very quick delivery of the energy.

And especially when you consider this our first in human sort of experience, you can imagine this is a very efficient. So I guess maybe the numbers belie the true sort of experience, which is hard to otherwise quantify. The second thing, if we look at the, let's say the procedural success, so 88% of the patients had inducible VT at the beginning of the procedure, and it was down to 6% by the end of the procedure.

So that's actually very good. And so we're very happy about that using the stimulation protocol. Now, again, that's not perfect. What you care about is what happens over the long term. So we'll talk about that also. get such good procedural success, we're very, very happy about. And then the third point is our sub-study. So we had a subset of patients, as we said, 40% of the patients, where we did endocardial ablation to look at epicardial effect.

And in those patients where we delivered endocardial ablation, we were able to eliminate the potentials epicardially in all those patients. In fact, we didn't have to deliver epicardial lesions in any of those patients.

Now, there was one patient, interestingly, who had more epicardial scar and had a diminutive endocardial scar. So in that patient, we actually delivered the lesions epicardially because we didn't want to ablate through a bunch of normal tissue to get to the epicardial. That makes no sense. No clinical sense, that is. So I was very, very happy about that. That probably is, that was an aspect of the procedure that made us the most excited. The first time that we could actually.

deliver the size of lesions that we wanted to, if we wanted to. So, yeah, so that was basically the procedural experience. And yeah, it went very well, I think. Thank you so much, Vivek. And congratulations again. These are truly remarkable findings.

Now, listeners, it is such a pleasure to introduce our senior associate editor, Sana Al-Khatib, who handled this paper and is an expert in the field. So, Sanna, we're all curious to hear what attracted you and the other editors to this paper. Why is it important?

Well, you know, thank you very much, Peter. I first want to congratulate you, Vivek, on completing this important study. And I really want to wholeheartedly thank you for submitting this to circulation. It was a pleasure to handle this paper. Certainly, this is very important, as Vivek explained, in terms of what the potential clinical relevance of these findings is.

Of course, I've had so many patients over the years, I still do, who have VT or PVCs that unfortunately did not respond well to catheter ablation because of how deep. the circuit is, because of how deep the substrate is. And so it's really wonderful to kind of see this as a potential to overcome this major issue here. I do have a couple of questions for you, Vivek. So the first question that I want to ask you is, what do you see as the next steps in terms of with this catheter?

And especially in relation to patients, for example, with non-ischemic cardiomyopathy, who are more likely to have... epicaudial VT. In your study, only two patients, I think, had non-ischemic cardiomyopathy. So could you tell us a little bit about what the next steps will be? Yeah, no, absolutely. Thank you, Sana. So a couple of things. First,

You know, as I said, we had good results here. 82% of the patients had no VT or ICD events after the procedure. If you look at the burden of ventricular rhythmic events before ablation. The six months before versus the six months after, it was like a 98% reduction. So it was a tremendous improvement. But it's a single arm study. It was conducted at two centers, basically three operators.

I think in this context, what we need now is to see this in a large multicenter study. And this is, by the way, the plan. The plan is, I know that there's a plan to do a large multicenter study in the United States. It'll be an IDE and probably a pivotal IDE.

And it would involve, obviously, probably 20 plus centers and several hundred patients. So I think that's the next step from both from a... proving out from our first in human paper that this is actually applicable and also frankly giving us a product that we can use to treat our patients day to day.

But look, your point is very important, which is what about, I mean, we look largely at postimide patients, as you correctly pointed out. The non-ischemic patients in many ways are even more difficult.

they have more epicardial circuits but also they have more deep septal circuits particularly in the perivalvular region that's one thing i think we've all noticed and they can be very difficult to treat i mean the the size of the scar is not that big but for whatever reason they have very high number of ventricular rhythmic events so that is a population we really want to study in the pivotal id and again this is still being negotiated with the fda but

In the pivotal IDE, we will have a sort of a second arm looking at the non-escaping patients. And I should also say, as you can imagine, we and actually several other centers in the United States. have actually treated patients on a compassionate use basis in the U.S. It's not a large number of patients, but total maybe about 10 to 15 patients.

most of, well, I shouldn't say most, many of which have non-ischemic myopathy. So we feel optimistic that this technology and other technologies like this using Pulsefield will be able to address non-ischemic patients. So, yeah, I think that's good. The other interesting aspect, and I think this is really an important one, is that we have a technology now that, at least in theory, based on our experience, we could...

homogenized scar very efficiently, very safely, okay? And you could easily imagine a situation where in patients who are post-MI, who either for secondary prevention or high-risk primary prevention patients, we may consider... doing this as at the same time of ICD implantation. So we published SmashVT about two decades ago, but using that kind of approach, but basically saying, you know what, here's your defibrillator because you need it, but we really don't want it to go off.

and let's homogenize the substrate in an efficient way. That could be a very efficient procedure that really could improve the quality of life of these patients. So anyway, these are the different things we're talking about. That last thing, obviously we'd need a randomized trial, a prospective large randomized trial.

try to prove everything. No, that sounds amazing. Two quick questions before I turn it over to Peter. Can you comment on the durability of these results? Because you looked at these patients at six months, obviously, what about like a year? What about two years? So that's one thing. And then in your mind, how do you compare this system with the other PFA systems that are available now that are largely being used for AFib? So, yeah, if you think about durability, look.

I would love to restudy these patients. That's hard to do in a clinical trial and in a clinical practice. But I take solace in the fact that, you know, when you look at the KM curves, you see the dip initially, and then it's flat. OK, suggesting that, yes, there's some patients where we failed for various reasons.

but then it's flat suggesting the durability we're not going to see a continuous drop-off in effect if we follow 12 months or 24 months or whatever obviously we're going to continue to follow these patients but the fact is That is, I think, very comforting. As you know, in most VT ablation studies, it's usually a six-month follow-up because that's when all the recurrences tend to happen. But again, your point is well taken. We've got to study these patients longer.

And then with regard to other technologies, you know, there are some focal PFA technologies that we have available in the United States and in the world for treating AFib. and those are also starting to be tested for vt by the way that you know because they're available and that's what we have they're pretty good they don't make deep enough ablation lesions they don't go transmural yet but um fortunately i know that that

they're also being tested to use higher energy waveforms to give you trans morality. So this is work that's in progress.

i think the technology that we studied here with this this high voltage pfa is a little bit further along but look ultimately we need more than one solution and i think we will have it so i think that in many ways It's interesting, when I talk to my colleagues, the experience from the VCAT study has sort of showed what is possible and people are very excited about trying to apply that with this catheter and with other potential catheters.

Thank you, Sana, for asking these very relevant and insightful questions. And I actually have a question for you now, Sana, as well, because this study is kind of a pivotal study in the field. Seeing these patients on everyday practice, Sanna, where do you see this field moving forward? And how does this fit in with the previous literature that we already had?

Yeah, no, thank you, Peter. I am, I'm actually pretty excited about the potential of PFA for ventricular arrhythmias for sure. Like, and as was very articulately stated by Vivek. We see these patients not infrequently where their circuit is deep, where the focus is deep and being able to apply PFA that can go deeply will hopefully ensure success of a lot of these ablation procedures. So no, I'm like...

excited about that. From my perspective, I absolutely would want to see more data on safety as well, Peter. The safety data in Vivek's study were pretty promising. But like, especially when it comes to like the ventricles and we know that with PFA for AFib, like for the, for atrial flutter, for sure, that you may cause coronary spasm. Like if you're doing ventricular ablation with PFA.

What would the effect on the coronary arteries be? So like I would be very much looking forward to seeing what the safety data will look like as well as we expand and do this in more patients. But I think this is very promising.

Fantastic. And Vivek, we're getting close to an end there. Do you have any final comments or thoughts around the future of this field? No, I mean, I think I addressed most of it. I think, I have to say, my final comment is, you know, I've been working in VT ablation for, whatever, 20 plus years.

And I've been waiting for this. I've been waiting for a catheter that's been designed for VT ablation that can achieve the kind of lesions we want. I'm very excited for our field and our patients with regard to this. Thank you so much, Vivek Reddy and Sana Al-Khatib for taking the time to discuss this with us today.

And thank you listeners for joining us to learn about this new pulse field ablation technique to treat scar-related ventricular tachycardia. Such an interesting field and more to come as you can hear.

Everyone, thank you for joining and please tune in again next week. On behalf of Greg Hundley, Shirin Durugar and myself, we thank you for joining the Circulation on the Run podcast. This program is copyright of the American Heart Association 2025. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ajjournals.org.