Circulation January 20, 2026 Issue

Welcome listeners to now January 20th in this issue of circulation on the run. And I'm one of your co-hosts, Dr. Greg Hunley, Associate Editor, Director of the Pauli Hart Center at VCU Health in Richmond, Virginia. And I'm your other co-host, Dr. Sharinder, Associate Professor at the University of Arizona College of Medicine in Phoenix.

Well, Sharin, this week's feature discussion is gonna delve into the world of management of lipid therapy after acute coronary artery syndromes. And so the study is going to evaluate whether Triple versus dual lipid lowering therapy is more efficacious. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And perhaps this week you go first.

Absolutely, Greg. And this is a very interesting article and it actually combines a lot of my interests all in one. So Let's see how we do it. So our first study this week explores peroptosis and this is a type of iron dependent cell death. Driven by lipid damage. And this study examines how ferroptosis contributes to heart injury after a heart attack.

You know, Sharin, this spheroptosis is getting a lot of attention. So, who performed this study and how did they evaluate iron-dependent cell death? Greg, exactly. This study is led by Hu Yang Yin from the City University of Hong Kong and it's focused on a common genetic variant in the gene called ALDH2, which is found in about 40% of East Asians, and it affects the heart's ability to detoxify harmful lipid products.

And so these investigators studied patients with acute myocardial infarction and used mouse models to see how ALDH2 affects heart injury. Oh wow, beautifully described Sharin. And so what did they find? What were their results? Greg, they found that ALDH two variant carriers had worse than Heart failure after a heart attack and showed clear signs of feroptosis, that is, more toxic lipids and fewer antioxidants.

And Greg, in mice, blocking feroptosis or targeting a translation factor called EIF3E improved heart function. And mechanistically ALDH two, they found disrupts. normal control of protein translation, letting feroptosis promoting genes turn on. Oh wow, Sharin. So it sounds like a link between genetic Cell death and heart injury. Exactly, Greg.

So clinically, these findings suggest that ALDH2 variant carriers could be identified using plasma lipid markers and that Targeting feroptosis could become a new strategy to protect the heart after a heart attack. Oh wow, Sharin. So it sounds like you're describing precision medicine in action. Absolutely Greg. So understanding these pathways could help us personalize therapies and prevent worse outcomes in patients at genetic risk. Oh wow, beautifully described Sharin.

Well, listeners, our next paper comes to us from the world of clinical science and the field of electrophysiology. So, Sharin, this study really involves the diagnosis and management of patients with or suspected of. Having Bragata syndrome. And so Sharin, sodium channel blockade is routinely used for the diagnosis or exclusion of Brugata syndrome. in the absence of a spontaneous type 1 EKG pattern. Now, worldwide, different sodium channel blockers are used. And one such agent is prokanamide.

But to date, the safety, the yield, and the prognosis of a type 1 procanamide-induced brigata pattern are really incompletely understood, and they may differ from other sodium channel blockers with greater potencies. So Sharin, this team in association with corresponding author Dr. Benjamin Moore from the Division of Cardiology at St. Paul's Hospital and the University of British Columbia.

assess the safety of procanamide infusion and yield of a type one Brugata pattern According to study indication, in 947 consecutive patients from the Canadian Hearts and Rhythm Organization Register.

Enchin outcomes were evaluated in patients with standard. or high-lead procanamide-induced brogata pattern with prior cardiac arrest and compared to those with a spontaneous type 1 pattern. So Greg, a study that investigates both the safety and the prognostic importance of the emergence of a prokanamide induced progata pattern. In patients at concern for untoward arithmetic.

And what did they find? Right, Sharin. So the yield of a type one pattern was about 7.2% in 390 patients with unexplained cardiac arrest. And then twenty-two percent in a hundred and thirty-five patients with a family history of Burgata syndrome. And then lastly, 6.9% in 116 patients with a family history of unexplained cardiac arrest or sudden death. The test yield is was about forty seven percent in one hundred eighty nine patients with a nonspecific type two or type three Brugata pattern.

and then 92% in those with intermittent spontaneous type 1 pattern. That is, an implied sensitivity of 92%. Now Schirin, the estimated specificity was very high. In 137 procainamid induced type 1 Brugata pattern patients with no prior cardiac arrest. followed for a mean of almost six years. no patients met the primary composite arrhythmic endpoint, And in 105 spontaneous type 1 patients, only one patient met the primary endpoint after receiving appropriate shocks or ventricular fibrillation.

And then Sharin, thirteen percent had a primary prevention implantable cardiodefibrillator implanted at baseline with one appropriate shock, with an additional seven percent. undergoing ICD implantation during follow-up. predominantly for syncope with a suspected arrhythmic mechanism. And Sharin, no patient who underwent ICD implantation during follow-up subsequently received appropriate therapy. So Shirin,

What are the clinical implications of this very large collection of data pertaining to the results of this study? Well, what have we learned? That procanamide infusion is extremely safe for the diagnosis and exclusion of Brugata syndrome, with its yield dependent on the pretest probability and indication for testing. and estimated sensitivity and specificity appear to be very high.

And as an example, patients with asymptomatic procamide induced type 1 brugata pattern, well, they are at very low risk of malignant ventricular arrhythmia. Wow, thank you so much, Greg, for that beautiful description of the elegant studies, which sounds very helpful for clinical decision making, especially when considering who really needs an eye.

And our next study now moves from the rhythm lab to the vascular wall, exploring how changes inside vascular smooth muscle cells drive aortic aneurysm and dissection. Greg, this study, led by Professor Junbo Ge from Zongshan Hospital, Fudan University, looks at how epigenetic modification called

Histone lactylation affects vascular smooth muscle cell metabolism and contributes to aortic aneurysm and dissection. All right now, Sharin, you're throwing out a turn. This is like an old Carolyn's quiz. Uh histone lactylation? So now what exactly is that and what did these investigators do to describe it further? Exactly, Greg. So histone lactylation is a chemical modification where a lactate molecule attaches to a histone protein, which can then change how genes are turned on and off.

And so these investigators studied aortic tissue from patients and mice, and they looked at a 4K16 lactylation and Greg this is a specific type of histone lactylation where a lactate molecule attaches to the lysine 16 residue on histone H4. And so they looked at how this type of lactylation affects metabolism in vascular smooth muscle cells. And the investigators also tested CAT7, which is a histone lacteal transferase, and PDK1, which is a metabolic enzyme.

And they wanted to see how these pathways influence disease. Oh wow, Sharin. A lot of mechanistic study here and sounds just Super informative. So what did they find and how do their findings change how we think about aneurysm? Definitely Greg. So in aortic aneurysm and dissection, this type of lactylation, so H4K16 lactylation, was turned up. It was increased.

And that promoted an increase of this metabolic enzyme called PDK1 that I mentioned. And that rewired vascular smooth cell metabolism and fueled aneurysm growth. So this histone lactylation caused the aneurysm growth at the end. And then blocking PDK1 or Cat 7 eased aortic damage in mice. And Greg patients also showed this higher level of lactate too, which is part of this pathway, this lactylation PDK one metabolic rewiring.

And so this isn't just a lab finding, it's happening in people too. Oh wow, Sharin, that's just fascinating. So we're investigating a potential new treatment. series of targets here, perhaps involving PDK1 or CAT7 to slow aneurysm growth. Exactly, Greg. So PDK-1 inhibitors are already in trials for other diseases, and CAT7 could be a completely new approach.

And it's a prime example of how understanding these molecular pathways can open doors to future therapies for aortic aneurysm and dissection. Beautifully described, Sharin. You know, you really simplify, at least for me, some of the complexity of these very important.

uh preclinical science studies and just beautifully described Well, now perhaps before we get to that feature discussion, we jump into the mailbag this week, and there's a very nice on my mind piece from Professor Cohen entitled From Race-Based based to equity informed anti hypertensive medication selection, the rationale for the twenty twenty five AHA ACC guideline change. And then lastly, Sharin, there's a nice research letter from Professor Rodriguez entitled

Effects of real-time notification of AI-detected incidental coronary artery calcium on statin prescription. The Notify Picture Trial.

Well, just a wonderful issue this week, Sharin, and next perhaps we get on to that feature discussion and learn more about the comparison between two Types of lipid lowering strategies in patients that have sustained acute coronary syndromes. Very exciting. Let's do it.

Welcome listeners to the second half of January 20th issue of circulation on the run, and this feature discussion is super important as it relates to lipid lowering therapy and we all know how important that is after acute coronary syndrome. And in this randomized clinical trial, the investigators were really bold in testing a novel strategy of triple versus dual lipid lowering therapy upfront.

And to discuss this topic, I'm so pleased to have with me the last and corresponding author of this work. And that is Albert Arisa Soleil from Hospital Belvitque in Spain. And also with us today we have our associate editor, Parag Joshi, who handled this paper from UT Southwestern. Welcome both.

And Albert, perhaps you can give us a start to this by covering some of the background. What do we currently know about LDL cholesterol lowering after acute coronary syndrome? And what motivated you to do this?

Randomized trial. We know several things about this kind of patient. We know that ACS patients have a high risk of recurrent events, especially during the first weeks after the admission. And we also know that marked an early reduction of LDL cholesterol levels is associated with better outcomes, with a reduction in the risk of outcomes.

However, current guidelines still recommend a step-by-step uh strategy. It's a in hospital initiation of starting and perhaps in a second stage the addition of other drugs such as CMI or other important drugs. Perhaps because of this, uh recent registries continue to show uh a low rate of patients under good control.

Therefore, this was the main reason for that we performed this trial. We m our main hypothesis that an early initiation of a combination therapy with high potency lipid lorry therapy, a triple therapy. would uh might contribute to contribute to a better control and to improve outcomes in this context clinical setting.

Excellent. And I understand that you use this novel class of drugs, the Bempadoic Acid. And we're all very keen to hear how you design this. So triple therapy can be so much in this field. How did you identify the patients? What kind of uh treatment initiation did you give them? And also what outcomes were you particularly interested in? We tried to to design a a multicentre independent pragmatic and randomized step control trial. This is an open trial, blind at endpoint controlled.

which was conducted in in several Spanish centres, is an independent trial important and overseen by a steering committee and is uh promoted by the Spanish Society of Cardiology. We included patients with uh admitted with diagnosis of ACS with a significant coronary artery disease. uh which uh more than fifty percent stenosis of blame main of seventy percent in other arteries. And our thresholds of LDL cholesterol levels were different according to the baseline treatment.

Uh in static naive patients, we included patients with LDL cholesterol over one hundred and fifteen milligram deciliter. In patients under treatment with low potency statins or low dose of high potency statins, we included patients with L DL cholesterol over one hundred milligrams of deciliter. And in patients under high-dose, high-potency statins will include patients over 70 million per deciliter.

We obviously excluded patients with contraindication to photostatins, mimpedoic acid, or something like the other conditions such as treatment with cybrates, synchrogen, or PC9 inhibitors. gout, uh hyperhysemia, hyperglyceridemia, or renal kidney disease. These kind of patients, we randomized them during the first seventy-two hours of the admission in the coronary unit.

And they were uh randomized to triple therapy with uh including high dose high hypotensive statin plus acetyl mite plus benpedoic acid versus standard of care, which was consistent of high dose hypotency studies plus ST mite. Treatment began at the time of randomization and the rest of treatments were performed according to current recommendations and the criteria of the treatment physician.

And importantly, our main uh primary endpoint was the percentage of patients achieving an optimal LDL cholesterol control as defined by a lower than 55%. We did absorb the theater 8 weeks after the onset of Streamland.

As a secondary endpoint, we established the absolute change in LDL cholesterol levels at 8 weeks, the percentage of change in non-HDL cholesterol at 8 weeks, and the percentage change In HDL cholesterol and triglycerid levels at eight weeks, we also collected obviously cardiovascular veins at eight weeks, cardiovascular death, ACS, and plantary vascularization, ischemic stroke. and obviously a safety endpoint. Any event leading to discontinuation of tri uh therapy?

Allergic reaction, musculoskeletical pain, gout, hyperrissemia, abnormalities or liver function, choralithia, diabetes, doctrine, new set or cancer. This was in our main design. All right, what a nice summary of the methods. And just to summarize to the listeners, so patients with an ACS in the hospital randomized to getting triple lipid lowering therapy with high dose statins.

acetamide and bempadoic acid versus only hydrostatin and acetamide, and then the end point was changed in LDL or or proportion of patients achieving LDL cholesterol below fifty five. And that's equivalent to 1.4 millimole per liters, right? Exact. Perfect. So just quickly uh Albert, how many patients did you enroll and what kind of patient characteristics did they present with? Yeah, we finally included uh two hundred and six uh patients with this profile.

which were assignated uh randomized to triple therapy with one hundred and one and standard of care one hundred and five. Mean age was fifty nine point five years, uh twenty-one point four were female. Min LDL cholesterol levels at baseline were 173 mg per decilator. About two-thirds of our patients were statinase. and a lot of patients participated in cardiac rehabilitation programs after the initial admission.

Regarding comorbidities, uh about uh forty-five percent hip rotation, uh 15% diabetes. And a lot of patients were admitted because of ST-segment elevation myocardial infarction. LB function was good with a mean LB ejection fraction of 55. About 35% of patients had multi-vessel disease and complete reverse polarisation was achieved in about 80%.

And finally, regarding treatments after discharge, about almost all patients underwent double antiplanos therapy and uh treatment with beta block and cerebral and inhibitors and HLTO. was about uh the fifty, sixty percent. All right, so now let's move to the results. So did this triple upfront therapy reduce LDL or more specifically a high proportion reaching the target LDL cholesterol? Albert, please share with the listeners.

Yeah, first I have to say that we achieved data, available data about LDL cholesterol at eight weeks in 94% of our patients. and mainly the primary employing the LDL cholesterol levels at eight weeks. The proportion of patients achieving optimal control was not significantly different between both groups.

uh 59.4% in patients with the triple therapy as compared to 53.1 in the control group without significant differences. Likewise The percentage change in Lidocholester level at eight weeks was not significantly different between both groups: 57.5 in triple therapy versus 56.9 in the control group. And no significant differences were observed in the uh reduction of other anallipid particles such as non LDL choristol or trianguloselline between both groups.

And no differences were observed according to the tactiles of Big Line LDL cholesterol. Regarding safety, all both arms were safe. The proportion, the percentage of patients with immersive events was similar between both groups and was low. Only one patient had to discontinuate treatment because I'm episodes of doubt uh in the treat you know triple triple therapy.

And the most common event was uh asymptomatic hyperglycemia, uh which was uh about seven point three percent in the triple therapy group as compared to five point one percent in the control group without significant differences. No deaths were reported and the rate of cardiovascular image was also low without differences, uh four point two percent in the triple therapy group as compared to two percent in the control group.

All right. Congratulations, Albert, on these findings. And I must say a little bit surprising. So I'm so happy that we have with us today a specialist in this field. Parog who have handled this paper and Parag, I'm so curious to hear your thoughts around this. How do you interpret these findings and and how do you contextualize them with previous research? Yeah, this is as you said, very surprising findings header. Um

And Albert, thank you for submitting your work to circulation. We had a lot of spirited discussion around this and and it generated a lot of interest in the editorial board. You know, if we look at this space, there's a lot of interest in How do we achieve these lower LDL targets?

uh as soon as possible and and does that require combination therapy? And there are of course, you know, considerations in every uh region of the world in terms of, you know, the practicalities of that. But the clinical question of can you get to lower LDLs up front

which may have some benefit, has been looked at a couple of times and and this is the latest to look at this question, but with a a new agent. And, you know, we have to think about why this didn't achieve as low an LDL as you would have expected. From the uh combination therapy, the triple therapy compared with the dual therapy. The prior studies that have been in this space have looked at this.

Of course, improve it, which was uh statin plus azetamide. And then a few uh uh studies that have looked at the combination of statin plus PCSK9 inhibitors. really in the early post-ACS phase. And all of those have shown, you know, significantly lower LDL cholesterol achieved in the more aggressive therapy arm compared with the less aggressive therapy arm.

So this was indeed surprising that the addition of dempadoic acid, at least in this short eight week follow up time, did not achieve a significantly lower L DL or a significantly greater proportion of patients under fifty five. And we have to think about why that could be the case. You know, uh one of the things that stands out to me in this space, and I think we're learning more about this, is bempadoic acid and and statins converge on the same pathway of LDL lowering.

In this trial, the dual therapy treated group was on high intensity statin throughout the eight week follow up. There was uh essentially no non adherence to high intensity statin.

And we know in the real world that that's probably not something that can be uh duplicated uh certainly over a longer period of time. But in this short term follow up when you have uh high adherence to high intensity statin, that maybe bempadoic acid doesn't add as much LDL lowering because that pathway may be somewhat saturated. So I I wonder if this is, you know, speaks to that a little bit.

What was really striking though, Peter, I wanna highlight that uh more than fifty percent of this population achieved an LDL, less than fifty five. just on high intensity statin and azetamide. And uh there are considerations, bempadoic acid, at least in the US, has some cost considerations. Uh certainly PCS K nine inhibitors have had cost considerations.

Uh statins and the zetomib are generic here, and uh maybe this is a reasonable way to start out treatment at the ACS event, at the initial event. Uh so this really I think adds some credence to that approach. Fantastic. And uh I agree with you that there is so much more to learn from this trial besides That's the intervention here when you look at the the proportion achieving those goals. So that's perhaps also some of the key uh clinical take home messages from this study. But

Uh you see these patients and manage them daily. How do you think we should approach treating our patients with lipid lowering therapy following ACS based on what we know, including this trial? Yeah. So, you know, I think we've generally become a more aggressive or taking a more aggressive approach to our ACS patients up front and essentially doing what the control arm of this trial does it's

Many patients were trying to maximize their statin up front and adding azetomide at the beginning to try and achieve these really lower LDL levels. We know it's the first year where a lot of the recurrent risk is highest in this patient population. Whether that's mitigated by aggressive LDL lowering up front is still to to be determined in my opinion.

However, I do think that the risks of this approach are fairly modest at at most and and I think it's a safe approach to to start dual therapy up front after ACS. This trial, of course, doesn't speak to outcomes. Uh it's not uh certainly clinical outcomes. Uh it's it's not a long enough trial to really show that.

But I think as we move towards a more aggressive approach in this early phase, I I think this really supports the dual lipid lowering therapy for sure, with statin plus azetamide, which are generic and well tolerated. Perfect. And Albert, I'm kind of curious to also ask the same question to you. How do you interpret these findings? You must have been a little bit surprised yourselves, right?

Yeah, absolutely. Our main hypothesis is that we try will be positive with a further reduction in LDL with with the triple therapy, and we we did not see this effect uh after after uh assessing the data and the the paper and thinking about it during the in the last uh weeks or months, uh probably I I agree with uh Baraj. This that the convergence between uh Bempedoik and Stadins in the same uh pathway probably limits the the the effect and the the additional benefit for for this combination.

Probably is the worst scenario for bempedoic acid to show its potential benefits for for improving LDL cholesterol. An another important point for us as reprise is the high rate of control. in the control are more than fifty percent, which is significantly higher as compared to prior studies.

Our main conclusion is that probably, I said a few seconds ago, in high risk patients, uh probably a high dose, the high hypotency statins plus acetymite is a good treatment for achieving an optimal control. However, another important point is that we have reached a good control, but more than 40% despite our aggressive treatment.

still is uh with poor control and probably in high risk ACS patients we should early consider uh more potent uh parental drugs for uh achieving an optimal control and re reducing its rate of event. And um uh Albert, you already mentioned that this was an investigator initiated trial, which is fantastic, and also a pragmatic kind of trial. So I know th that has a lot of advantages. but also some challenges and limitations. So perhaps you want to share some of those with the listeners.

Yeah, absolutely, absolutely. This is a small trial conducted by investigators. And uh our sample size was moderate, was small, and conducted in only one country, European country, and probably uh our data, our our results are not should not stabulate to all kind of populations. For instance, rays and ethnicity were not uh properly collected in all patients, despite in Spain most people is you know it's wide, but probably did ha a limitation.

And another important point from the nature of our study is that we do not collect strictly adherence beyond patient self-reporting. And probably it is a significant limitation. However, we think that adorance was good because as said Parak before, this is a high risk style people are are afraid of their disease. And uh people they treat, they they take out medication, they they control their anti vascular dysfactor, but however uh our our adherence monitoring was uh improper.

Probably we need larger studies, long-term studies in order to collect those cardiovascular events and outcomes. because it would contribute to increase our knowledge about the role of PEMPATIC in this complex clinical setting. Great Albert, and that brings us to kind of our last wrap-up of this, and that is to look into the future a little bit. And I'm gonna start with you, Parag.

Where do you see this field heading and are there any more unanswered questions that we need to close the knowledge gap in uh lipid lowering therapy?

Yeah, things that are um you know, I think Albert uh mentioned this that we need outcome studies to look at this and see if there's actual change in clinical events. And I think that's a you know, certainly we would love to have outcome studies, but I wonder if that's practical or feasible to pull off There have been a couple of trials that have looked at PCSK nine plus statin and their impact on plaque.

um change in atheroma volume or, you know, change in um plaque composition. And those have shown favorable changes up to a year uh in L DL achieved of twenties and thirties compared with seventy or so. And so, you know, perhaps this is a good surrogate to follow for this field going forward as we have enough, I think, outcomes data for longer term with this combination therapy approach that lowers better.

But I I think that is a fair question is what is the right outcome to look at in this space? I think a real important question that comes from this or that I you know, at least I had is What is our role for bempadoic acid? And I I think this really confirms the role for me that it is in those who can't tolerate statins. And that's not an insignificant proportion of our patient population.

But it generally will emerge later after an event and months later potentially. And so I think we do still need to acknowledge that bempadoic acid can really play an important role in lipid lowering, but it may not be in this first couple of months where adherence may be very high because you've just had this scary event.

but where the sort of side effects or or adverse effects of statins may emerge over time. And that's why it's important to keep an eye on on our cholesterol levels and adherence to these regimens. And it's nice to have bempadoic acid as a tool for those folks as well. And then of course we'll have to understand cost effectiveness of all of these agents and how to best roll this out in the uh early phase after ACS, considering those costs.

That is such an important clarification that you know the the outcome studies that lay the ground for bempadoic acid most in patients that were intolerant to statins. So we have to keep that in mind. And uh Albert. Uh now it's your turn to look into the crystal ball. Where do you think we're going?

I don't know. What what I really know is that we have uh significant room for improvement and our patients that are sick, that can have readmissions and mortality and reinfaction need more treatments and more improvement. We are trying to plan uh all the studies in the same clinical setting, uh assessing other more potent parental lipid lowering drugs.

In addition, uh potentially other tools such as uh G L P one individuals, the role of weight loss and on lipid control in this setting might be very interesting. And on the other hand, as I said, the limitation of adurance, we're trying to explore potential telemedicine tools for assessing and improving adurance in this complex patient. Wow, what a fantastic discussion. And I want to thank you so much for taking the time to join us here today, Albert Arisa Sole and Parag Joshi.

It has been so interesting to learn about this new approach. And to summarize, Arisa Soleil and his team demonstrated that. High dose uh intensity statin acetamide and bempadoic acid did not improve the LDL cholesterol to a higher degree than only high dose intensity statin and acetamide. And listeners, you have probably enjoyed this as much as I have, and if you did, please tune in again next week for more of the latest of cardiovascular science.

On behalf of Greg Hendley, Shireen Duridgar, and myself, we thank you for listening. This program is copyright of the American Heart Association twenty twenty five. The opinions expressed by speakers in this podcast are their own and not necessarily those of the Of the American Heart Association. Is it H A Journal Stop?