Circulation January 6, 2026 Issue

Welcome listeners to the year of 2026. And here we are on January 6th for Circulation on the Run. And I'm one of your co-hosts, Dr. Greg Hunley. Associate Editor and Director of the Poly Heart Center at BCU Health in Richmond, Virginia. And I'm your other co-host, Dr. Sharinda Rudgar, Associate Professor at University of Arizona College of Medicine in Phoenix. Happy New Year, Greg, and our listeners.

Absolutely, Sharin. And this week's feature discussion, very interesting, it's into the world of the management of patients that have pretty severe pulmonary embolies. And this team is going to share the results of a randomized trial that compares mechanical thrombectomy with anticoagulation versus anticoagulation alone. So very exciting feature discussion on an important clinical topic. But Before we get to that feature discussion, how about we grab a cup of coffee or hot tea?

Still have this lingering cough and cold here. Hopefully it's not long COVID. But let's grab that cup of tea and get into some of the other articles in the issue. And Sharin, how about this week I go first? Yes, great. That would be great.

Right, so Sharin, cardiac allographed vasculopathy is an important cause of mortality after heart transplantation. And dyslipidemia is a major contributor to the development of cardiac allligraph vasculopathy. And the safety and effectiveness of the Of pro protein converte symbolic. Sublexin Kexin 9, or as we all know, PCS SK9 inhibition to lower cholesterol and prevent cardiac allograph vasculopathy early after heart transplantation is not well established.

And so Sharin, this team, led by corresponding author doctor William Firon from Stanford University School of Medicine. performed an investigator initiated prospective multi-centered double blind randomized trial in which participants were randomized early after heart transplantation to receive either alarucumab or placebo. In addition to all taking resuvacy.

So Sharin, now prior to randomization, and at one year all participants underwent invasive coronary assessments, including angiography, fractional flow reserve measurements, coronary flow reserve measurements, And indices of microcirculatory resistance, and then also intravascular ultrasound with near infrared spectroscopy. And Charin lipid values were assessed at baseline and at prespecified intervals.

And Sharin, the primary endpoint was the change in coronary artery plaque volume from baseline to one year post heart transplantation based on these serial intravascular ultrasound. Oh wow, Greg. So examining the potential benefit of a PCSK9 inhibitor on LDL lowering and coronary arterial anatomy after heart transfer. So what do they find?

Right, Sharin. So the team study included a total of 114 heart transplant recipients, with 57 assigned to Alareucamam and 57 assigned to placebo. Remember again, all taking resuvastec. And baseline characteristics were well matched between the two groups. Now

the low density lipoprotein cholesterol levels decreased significantly from baseline to one year in the Alarucomab arm, but they really didn't change with the placebo. But importantly, Alarukamab, in addition to that statin therapy, did not Okay, did not reduce coronary artery plaque progression or modify fractional flow reserve or coronary flow reserve after one year compared with Just the placebo arm who were taking resuvastatin alone in the patients with a low baseline LDLC.

And so, Sharin, this study highlights that while the introduction of a PCSK9 inhibitor to post-cardiac transplant patients lowers LDLC levels. This does not necessarily translate toward reduction of intracoronary arterial plaque progression or modify some of those common coronary physiology measures that we know so well, including coronary flow reserve or fractional flow reserve that we often assess in clinical practice. Interesting findings.

Very interesting. Thank you so much, Greg. So this study, the caviar trial, is an important study for the transplant community.

And that brings us to our next paper, which moves from lipid lowering to another cornerstone of cardiovascular health, cardiorespiratory fitness. This study, Greg, led by corresponding author, Dr. Jeremy Robbins from Beth Israel Deaconess Medical Center, tackles a question we all appreciate clinically. Why fitness is such a powerful predictor of survival? Right, Shrien. So fitness really is one of the strongest prognostic markers we have. So what did they do?

Exactly, Greg. So using metabolomics in participants undergoing cardiopulmonary exercise testing. The investigators identified a novel exercise responsive molecule called N-pulmatoyl glutamine that was strongly associated with higher VO2 mass. That is the maximal oxygen uptake, our gold standard measure of cardiorespiratory fitness. Importantly, this finding was validated in an independent cohort and levels of this metabolite increased with endurance training.

Even more compelling, Greg, higher levels were linked to lower all-cause mortality in large population studies. Oh wow, Sharin. Interesting finding. So what is our clinical takeaway? So great, great question. So for clinicians, this study reinforces that fitness isn't just a performance. it reflects underlying biology tied to survival. So while not ready for Clinical use, this opens the door to new biomarkers and potential targets that help explain the cardiovascular benefits of extracting.

Ah, a great example of science meeting clinical revelation. Absolutely, Greg. This is a powerful reminder that improving fitness remains one of the most effective interventions we have in cardiovascular care. Oh wow. You know, it brings back to the old days when uh we worked with Carolyn Lom and we had a lot of discussions about cardiovascular fitness. So uh super results there and beautifully described.

Well, Sharin, our next paper comes to us from the world of clinical studies. And Sharin, drug induced QT prolongation after successful inpatient loading of a class three anterior rhythmic may occur during routine outpatient care. Now Insertable Cardiac monitors offer continuous signals, but are limited by single-lead configuration. And so this team in association with corresponding author, Dr. Albert Rogers, again from Stanford University School of Medicine.

hypothesized that a spatially aware deep learning system could reconstruct spatial information from a single lead vector to quantify the QT or the QT corrected interval and identify high risk prolongation. So how'd they do this, Seren? Well they assembled a real world cohort of outpatients on defetilide or sodolol that were presenting to the hospital or the emergency room for any type reason, and then the rates of ventricular arrhythmias and QT prolongation were assessed.

And the device validation was tested in patients with insertible cardiac monitor recordings paired with information also obtained from a clinical 12 EDK. Well, so Greg interesting to now attempt to Harvest information from a single lead insertable cardiac monitor and identify from this the ability to quantify the QT interval and hence predict future cardiovascular events. Wow, what do they find? Right, Sharin, beautifully sometimes.

So they found that a single lead insertible cardiac monitor combined with an AI-based deep learning approach could achieve guideline level measurement accuracy. and then enable continuous QT corrected surveillance from non-standard ECG vectors and identify clinically meaningful outpatient QTC prolongation that in turn was associated with a fourfold increase in serious ventricular arrhythmia.

really interesting results you're in. And so This strategy, described here in this paper in circulation, may enhance safety monitoring after class three anterior rhythmic initiation and could even support further targeted intervention when that QTC interval becomes prolonged. It's really fascinating study. That's really great. All the ways that AI and machine learning can help us push medicine forward. Very exciting.

Yeah, super, super information. Well With our listeners now, let's jump into that mailbox. And again, Sharin, a research letter from Professor Tanaka entitled DAPA coflosin: Reduces Epicardial Adipose Tissue and Myocardial Fibrosis in Subclinical Heart Failure, the DAPA-Eat trial. We also have an exchange of letters by Drs. Wu and El Maria regarding the article entitled Electronic Provider Notification to Facilitate the Recognition and Management of Severe Aortic Stenosis.

A randomized clinical trial of And from our own Molly Robbins, we have highlights from the circulation family of subspecialty journals. In November, the journals cover a wide range of timely topics in cardiovascular medicine. Circulation heart failure examines the use of natrioretic peptides for risk assessment in patients with heart failure and recovered ejection fraction. Circulation Cardiovascular Quality and Outcomes reports on insurance coverage policies alongside recent guideline updates.

related to indications for coronary angiography and PCI. And in circulation cardiovascular imaging, a study introduces myocardial entropy, a novel CMR-based metric of tissue heterogeneity with potential implications for risk stratification in the Hypertrophic cardiomyopathy, circulation cardiovascular interventions highlight re-stenosis at the left circumflex osteum as a key limitation of PCI for left main.

Finally, Circulation Arrhythmia and Electrophysiology explores the use of semagluted after atrophibrillation ablation and its impact on arrhythmia recurrence. And finally, Greg, we have an important perspective piece by doctor Packer entitled Conceptual Models to Explain Heart Failure with a Preserved Ejection Fraction a tale of futility, frustration, and perhaps fruition.

Wow, Sharin, beautifully described. And that last title a tale of futility, frustration, and perhaps fruition. Oh my goodness. I hope that's not foreshadowing for twenty twenty six. No, we wanna start on the right foot here.

Well, thank you so much, Sharin. And now let's go ahead and jump into that feature discussion. And we're gonna learn more about the management of patients after they've sustained a pretty severe pulmonary embolus. Let's go. Well, welcome listeners as we transition now to our feature discussion on this January 6th, and explore the world of pulmonary embolism.

And we have a very interesting study today presented to us by Dr. Robert Lookstein from the Icon School of Medicine in Mount Sinai, New York. And also one of our associate editors, Dr. Josh Beckman from University of Texas Southwestern Medical Center in Dallas, Texas. Welcome to you both. Well Rob, could you start us off? Describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?

Uh thank you for that question. So by way of background, the first study the first prospector randomized trial evaluating endovascular therapy. versus anticoagulation alone for intermediate risk pulmonary embolism was the ultimatrial, which was completed and published now almost 12 years. And this study was also published in circulation, but it evaluated ultrasound accelerated thrombolysis versus antiquikes.

This trial was positive as it pertains to the primary endpoint, which was a reduction in the R V to L V ratio at 24 hours. using a transthoracic echocardiogram to determine that variable. Since then, there's been tremendous interest in activity regarding endovascular therapy for acute pulmonary embolism, especially as it pertains to intermediate risk patients. Uh there have been seven FDA approved products for clinical use in the United States.

Most conspicuously, there's been a significant activity with the approval of so called thrombectomy devices or thromboaspiration systems. There has unfortunately not been one subject. Mechanical thrombectomy plus anticoagulation versus anticoagulation alone. And so we set out as part of the Storm PE investigators to really answer that question. Of whether or not we can demonstrate efficacy of mechanical thrombectomy in this instance in the intermediate.

high risk population. So our trial design was randomizing a cohort. of intramadian high risk patients who would receive anticoagulation plus endovascular therapy. thromboaspiration system as compared to anticoagulation alone. We decided to use a CT pulmonary angiogram as our imaging endpoint. But the concept was similar. We chose to evaluate

changes in the R V to LV ratio at baseline and then compared to the 48-hour follow-up study between the two groups. And our hypothesis Was that we would be able to reduce the R V to LV ratio in a statistically superior way. with the endovascular cohort as compared to the medical cohort. And those are the results that we have shared with your audience in this initial manuscript in circulation.

Super, Rob, and beautiful description of the background and also your study design. We're hearing a randomized controlled trial. Rob, who did you include in this study population and how many subjects? The breakdown of men versus women? Again, a great question. So we looked at specifically the intermediate high-risk cohort. So these are patients that have imaging evidence. of right ventricular strain. In this particular study, it was a CT evidence of an elevated RV to LV ratio.

with a clinical history of acute symptoms less than fourteen days in duration. In addition to that, the patients would have elevated cardiac biomarkers, most conspicuously an elevated serum troponin or high sensitivity troponin, and/or elevated. pro BNP. Those patients Would most commonly again be presenting with acute symptoms. And those were the patients that were randomized as part of this trial. The trial enrolled patients over uh two years.

at 22 international sites, and we chose to randomize patients at the site level. So the randomization blocks occurred at the site level. We chose that scheme in order to match to the best of our abilities breakdown in gender, breakdown in race. And probably most importantly for this trial to randomize by the anticoagulation scheme. And we were very, very pleased that we had a very, very significantly matched rates of uh patients in both rooms as it pertains to race and gender.

And the anti-coagulation schemes for both groups were very, very well matched. And we chose that strategy in order to give us the best opportunity. to observe a treatment effect. for those patients treated with the endovascular therapy in addition to the anticoagulation alone.

Beautifully described. And so, Rob, as you describe your results, how many subjects did you include? And then again, what were the results of your study? So we had a hypothesis that we would observe reduction in the RV to LV ratio in the anticoagulation group or the controlled group. But we hypothesized that we would be superior in the endovascular group and uh further decrease the R V to L V ratio by 0.25.

Uh in a again in a superior reduction as compared to anticoagulation loan. Our statistical analysis, uh a 90% power level. uh informed us that we would need to randomize one hundred patients to reach statistical superiority of the endovascular arm. And that was the patient number that we chose. As part of the trial at the uh 22 sites, we actually screened over 760 patients in order to successfully randomize. And again it was one hundred patients that had acute symptoms.

that were clearly designated to be intermediate high risk, according to the European Society of guidelines and patients where they were comfortable with the equipoise of being randomized from anticoagulation to anticoagulation plus endovascular therapy. And what did you find? So we found that in fact endovascular therapy was superior to anticoagulation alone. Specifically the endovascular group. At 48-hour follow-up. And again, the baseline CAT scans and the 48-hour follow-up CAT scans.

were assessed by an independent blinded imaging core lab. But the endovascular arm was superior. The endovascular armory do. the R V to L V ratio by zero point five two, whereas The medical arm or the anticoagulation alone arm only reduced the R V to LV ratio by zero point two five. And so again, this was statistically superior, favoring the endovascular arm, plus anticoagulation versus anticoagulation alone. In addition to the reduction in the R V to LV ratio.

We saw significant changes on the follow-up CAT scan. favoring the endovascular group, specifically a statistically superior reduction in the refined modified Miller score. Which is a reflection of the thrombous burden seen on the CAT scans in the pulmonary arteries, as well as a more uniform stabilization of the vital cell. So the patients treated with endovascular therapy had normalization of their heart rate, again, favoring endovascular therapy.

normalization of their supplemental oxygen requirement with more patients in the endovascular group being able to be managed on solely room air and not requiring supplemental oxygen. And then lastly, we used a surrogate score, in this case, the news to score, which has been used in other cardiovascular trials and emergency medicine trials. to denote impending cardiovascular collapse as a measurement as part of this study. There was a dramatic reduction in the news two score.

suggesting cardiovascular stabilization, again favoring the endovascular as compared to the anticoagulation group. We were pleasantly surprised with these trial results. And we believe that this trial, again, the first of its kind. comparing mechanical thrombectomy plus anticoagulation versus anticoagulation alone. clearly suggests there is a role for endovascular therapy in the intermediate high risk group.

presenting to all of our practices as this clearly demonstrates a role at early cardiovascular stabilization and stabilization of right heart function.

Very nice. Well, listeners, we really appreciate Rob and presentation of those results. And now we're going to pivot to our own associate editor, Dr. Josh Beckman. And Josh, you have many papers come across your desk. What attracted you to this particular paper? And then how do we put Rob's description of his results really in the context of moving forward? with management of patients that present in this intermediate to high risk category with pulmonary embolas.

Well for me, the opportunity for us to consider this paper was a very obvious and clear one. First, if nothing else, they did a randomized controlled trial in a space that is a randomized controlled trial desert. Uh there's been nothing there for a long time. And so just the demonstration that a randomized controlled trial is possible in this space is an incredibly important demonstration.

That the field should not be beholden to single arm trials and observational trials. And so when we have the opportunity to publish an RCT in a space where there are none, that puts the weight of circulation behind this kind of research. Second, they went right at the population that everybody argues about all the time. Nobody really argues so much about aspirin and heart attacks, although I guess we're beginning to do that again.

Uh but people argue all the time about the value of an interventional therapy and pulmonary embolism outside of the massive or highest risk patients. Those with hemodynamic embarrassment. This is the group that everybody has wondered whether or not more intervention than anticoagulation alone would be beneficial. And they used the definitions that everybody in the community would use to define this. High intermediate risk. And so it was very much appreciated. I will also say that.

It was not difficult. to figure out if the patient in front of you would have qualified for this trial. You only had to look at the CT and a couple of blood tests. And then you were done and you knew whether or not they would be enrolled. So simple enrollment criteria, standard enrollment criteria, randomized controlled trial, and then probably the best established physiological outcome.

To understand whether or not the treatment would work. So again, they didn't create the new physiological outcome. They use what has been well established. And I think the combination of those things. an RCT, a h a population of incredible interest, the opportunity to publish something first. And then the demonstrated and verified physiological outcome.

Made it clear to me that this is something that was important and had to be brought forward. And then what we did at circulation was we tried to help the authors make it as sharp as possible so they can demonstrate the uh the quality of their work. And so that's why that's why it was so obvious.

Very nice. Well, Rob, coming back to you, what do you see as the next study to be performed in this sphere of research? Thank you for that question. So this trial evaluated one specific form of endovascular therapy, computer assisted vacuum thrombectomy. Which is a relatively novel technology, which is designed to simplify the endovascular procedure and improve its safety profile by minimizing blood.

And so that trial obviously has been completed. There are subsequent, currently either completed or nearly completed trials that will likely be presented over six to twenty four months. One trial is a a large randomized trial evaluating ultrasound assisted thrombolysis versus anti regulation alone, again in a intermediate high risk cohort.

Looking at the incidence of cardiovascular collapse among uh several other clinically uh hard endpoints. We're looking forward to that trial hopefully being presented in The other two trials that the cardiovascular community is also eagerly awaiting. Is the NHLBI-sponsored PE track trial? This is a large multi-center trial looking at all approved endovascular therapies.

versus anticoagulation alone, specifically with a physiological functional endpoint at 12 and then 24 month follow-up. And this will be very, very interesting to look at the of C TED or CTEF in patients subject to the U.S. to an acute pulmonary embolism presentation trying to determine the benefit hopefully of endovascular of preventing this devastating outcome. And then lastly, there's a large global trial looking at a large more aspiration.

System, the first system that was approved in the United States, versus anticoagulation alone. Again, for intermediate risk patients. This trial will be using a win ratio of cardiovascular adverse events, including cardiovascular deterioration requiring rescue therapy, EE related mortality. major bleeding as well as recurrent pulmonary embolism.

And so those trials uh again have uh either already completed enrollment or are very close to completing enrollment. And I think that the entire cardiovascular community is looking To hopefully glean insight. exact role is uh for endovascular therapy for intermediate and intermediate high risk patients. There are also at least two prospective randomized trials evaluating the role of endovascular therapy in high-risk patients.

defined role for that therapy for that specific population to echo Josh's point previously in an area that used to be a desert. For prospective randomized controlled trials, we appear to be living through an era of very, very significant activity. And I truly believe that these trials will inform the cardiovascular community at a global level.

And ideally live on to give us new guidelines and hopefully level one evidence to support our choices of which patients require and would benefit from endovascular rescue. Very nice. And Josh, anything to add in thirty seconds or so? No, I think Rob has really well surveyed the waterfront of what's happening, but I will just echo his sentiment that we are going to go from a land of scarcity to a land of plenty and have a much better understanding uh on a a much uh

Finer level, which patients benefit from which therapies at what time? And it's a really exciting time to be in the pulmonary embolism space. Very nice. Well, listeners, we want to thank Dr. Robert Lookstein from Mount Sinai in New York and our own associate editor, Dr. Josh Beckman from University of Texas Southwestern Medical Center in Dallas, Texas. For bringing us this very interesting study highlighting the computer assisted vacuum thrombectomy.

Was superior to anticoagulation alone in reducing the RV to LV ratio within 48 hours in those patients with intermediate to high risk pulmonary emblems. Well, on behalf of Petter, Sharin, and myself, we want to wish you a great week, and we will catch you next week on the run.

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 editors or of the American Heart Association. For more, please visit hajjournals.org.