Circulation January 27, 2026 Issue

Welcome listeners to Circulation on the Run. And I am one of your co-hosts, Dr. Greg Hunley, Associate Editor, Director of the Polly Heart Center at VCU Health in Richmond, Virginia. And I'm the other co-host, Dr. Peter Meyer, a professor at University of Oslo and social media editor in circulation. Petter, this week's feature discussion, very interesting, takes us to the world of transthyrocin amyloid cardiomy.

And as you know, the misfolding of that transthyroton form of amyloid and its accumulation in the heart muscle. Is an issue. And we certainly we have got many new agents under exploration that tried to address that misfolding in the liver, but don't necessarily extract. The amyloid protein from the myocardium? Well, this study will investigate caramata.

And it's an antibody strategy that actually removes some of that amyloid protein from the heart. But before we get to that phase two, randomized multi-cell. Double blind placebo controlled clinical trial and its discussion. Let's grab a cup of coffee and jump into some of the other articles in the issue. And this week, would you like to go first? I would love to and I can't wait to hear more about that new rug in amyloid. It's so much going on in that field and very exciting paper coming up.

But Greg, before we go there, we have another interesting paper, and it's also a clinical one, and it relates to the definition of myocardial infarction when it occurs in the setting of PCI, so that's percutaneous coronary intervention. And you know the d universal definition of PCI related MI has been substantially updated over the years, including an increase in the biomarker threat.

So used to be three times the upper reference limit, and then in the second version, and then up to five times the upper reference limit in the third and fourth version of the universal definition of Macaryl infarction. And also introduction of ancillary criteria such as ischemic symptoms, ECG and angiographic complications. Now the impact of these changes in acute coronary syndrome patient remains incompletely understood. And the objective of this stuff...

Which comes to us from the corresponding authors, Marco Vilgmigli from Lugano in Switzerland, was to compare the prognostic implications of evolving universal definitions of PCIMI in Large cohorts of acute coronary syndrome patients from the minimizing adverse hemorrhagic event by transragial exocite and systemic implementation of Angu X, the matrix trial.

Oh wow, Petter. So really an important topic, you know, both clinically and academically. So the definition of PCI-related myocardial infarction has been widely discussed. and often serves as an endpoint in many clinical trials. So what did they find in this particular Absolutely, Greg. So out of 6,724 patients who underwent PCI in this study, PCI-related myocardial infarction occurred in 9%.

When we applied the second universal definition, three percent when we applied the third universal definition, and also three percent with the fourth universal definition in the overall ACS population. Now, when only looking at N STEMA, so that's non-ST elevation markard infarctions, the corresponding figures were 15%, 5%, and 5%. And only PCI M I defined by the force. The most recent definition in patients with NSTEMI was associated with an increased risk of all cause mortality.

And that was significant with a has a ratio of two point zero eight and cardiovascular mortality and that was significant with a has a ratio of two point sixty two. While this was not the case when applying the second and third definition of universal definition So Greg, in patients with STEMI, so not N STEMI, but those with ST elevations, PCI related myocardial infarction was uncommon, only one to four percent depending on the working definition of PCI S.

And not associated with increased mortality in the absence of objective ancillary criteria. So that's ECG and angiographic complications. Isolated troponin elevations up to 20 times the upper reference limit were not associated with increased mortality risk. So quite interesting. Yeah, so Petter, a lot of data here for us to consider. So let's wrap this up. What's the take-home message?

Yeah, Greg, so to conclude this, so PCI related myocardial infarction defined according to the fourth, but not according to the second or third universal definition, was associated with an increased risk of one year mortality. And that was only in non-ST elevation acute coronary syndrome patients. And these data Greg support the evolution of the universal definition of PCI MI. So some clever people have done a good job in making this definition evolve. Very nice, Petter, beautifully described.

Well next with our listeners we're going to turn to the world of preclinical science and petter Emergency Myelopoesis by Bone Marrow Hematopoetic Stem Cell and Progenitor Cell. exacerbates disease pathology in a variety of chronic diseases, including, as you just mentioned, myocardial infarction, and then also in the progression of atherosclerosis. Yet, Peter, the mechanisms that trigger myeloplesis in the bone marrow after a distant organ injury, such as myocard infarction, they remain unknown.

Wow, what an interesting intersection with cardiology. But Greg, to be honest, I don't remember really what my lipuesis is. Can you perhaps remind me and the listeners to what you're referring to? Yeah, Bet Petter. So myloparesis is the process where the bone marrow produces myeloid cells. Okay, so that's like neutrophils, monocytes, macrophages, cells that can participate in the inflammatory process. and also are really crucial for the innate immune system.

And Petter, it's a vital part of blood cell development. And this whole myloparesis process, it's regulated by cytokines and transcription factors. You know, as an example, during psychosocial stress, Our brain delivers signals and myelopoesis is triggered in our bone marrow, and that prompts the release of cells that participate in systemic inflammation.

And so, Pedro, in this study, performed in association with corresponding author Dr. Partha Duta from the University of Pittsburgh or UPMC Heart and Vascular Institute, the team found that patients And my with myocardial infarction or mice with hind limb ischemia exhibited an increased number of circulating platelet derived extracellular vessels. and those which in turn augmented hematopoietic stem cell and progenitor cell numbers and their proliferation in the bone marrow.

leading to inflammatory myeloid cell generation and disease progression. And better both in vivo and in vitro inhibition. of platelet activation and exocytosis and bone marrow, hematopoietic stem cell, and progenitor cell endocytosis markedly lessen the production of platelet-derived extracellular vessels. Hamatopoietic stem and progenitor cell proliferation. and myeloid cell generation in emergency hematopoiesis. So very interesting. And so Petter.

What's the take-home message here? These discoveries in this preclinical science study uncover several therapeutic targets. within this hematopoietic stem cell progenitor cell component of the bone marrow that could reduce cardiac inflammation. and also cardiac remodeling after myocardial infarction through modification of this myelopoietic process. Very interesting. I agree, that is so interesting. And Greg, we also have some other interesting papers.

In this week's issue, and there is cardiovascular case series by Dr. Barry Borlog where he looks into rapidly progressive pulmonary hypertension. So kind of a malignant state of pulmonary hypertension and the importance of vascular disorder. Distribution. Then there is an exchange of letters. Revisiting lymphedema treatment, the promising role of UPARP modulation in restoring lymphatic.

By Dr. Zau and constructing Labyrinth Lymphatic Vessel, a novel strategy for reversing lymphedema by targeting Uparup by Dr. Ran. So two corresponding letters. Then there is an ECG challenge by doctor Xu entitled An Atypical Presentation of an Occlusion Myocardial Infarction Requiring Urgent Revascularization. And then Greg, there's an editors page by your own doctor Victoria Delgado, entitled Recognizing Outstanding Reviewers for Circulation in twenty twenty five.

You know, Petter, we certainly want to thank all of our reviewers. particularly those listening with us today, they participate just so important. in the uh review of manuscripts. And also even to some extent the editorial process by their constant interaction through the editorial team and with the authors of these outstanding publications. So thank you so much, Victoria, for recognizing them and thanks to all of those reviewers.

Well, Pedor, also in the mailbag. There's an in-depth piece from Professor Don entitled Current and Future Treatments for Takiasu's Auteritis Toward Cardiovascular Risk Modification. And then Petter two research letters. The first from Professor Martin entitled Prevalence of Apolipoprotein B and LDL cholesterol discordance.

Insights from the very large database of lipids and the National Health and Nutrition Examination Survey, or N. And then that other research letter from Professor Lemsey entitled Anticoagulation and Antiplatelet Therapy versus Anticoagulation Alone in Patients with Chronic Coronary Syndrome Receiving Long-Term Anticoagulation. A meta-analysis of randomized clinical trials.

Well Petter, what a great issue and how about now we get to that feature discussion and learn more about how we might remove that transthyroton misfolded protein and cardiac amyloid in I can't wait, Greg. Let's go.

Welcome listeners, as we now transition into our feature discussion today on this January 27th, and we're going to explore the world of transthyrocin cardiac amyloidosis with. a new therapy that will attempt to actually rid the left ventricular myocardium of the amyloid protein. And we have with us today Dr. Matt Maurer from New York Presbyterian Hospital and Columbia University Irving Medical Center in New York. City to discuss this wonderful paper.

Well, Matt, welcome. And maybe just to start off, could you describe for us some of the background information that went into the preparation of your study? And then what was the hypothesis that you wanted to address? Yeah, pleasure to be with you. I think everyone's aware transthyroid and cardiac amyloidosis was previously considered a pretty rare disease, but in all forms of cardiology.

in all clinical circumstances, individuals are identifying affected patients, thankfully at a sometimes earlier stage of disease. And we actually have for ATTRCM now three drugs approved on the market, and at least in the United States, to treat this condition. Unfortunately, there are still patients who present with late stage disease, and even patients who present with mild symptoms often have a very large cardiac amyloid burden.

And none of the approved therapies at this point remove amyloid from the myocardium, not just the left ventricle, but the right ventricle and the atrium as well, which are all affected. And so there's a great interest in the development of monoclonal antibodies that can target amyloid fibrils, in this case transthyrin being the precursor protein, in theory activate macrophages. And allow phagocytosis to remove amyloid fibrils from the myocardial.

And this is one of, if you will, three emerging strategies. We have stabilizers, typamidus and aciramidous. We have silencer based therapy with vitrouseran approved, and this is what people would call anti amyloid. antifibular or depleter based therapy. And so this is a study, phase two, looking at a a novel monoclonal antibody designed to try to remove amyloid from the myocardial.

And so just frame for us next, Matt, what question did you want to specifically answer related to this new therapy and who did you include in your study population and describe for us your study design. Yeah, so obviously this is a phase two study. The focus first and foremost was on safety. I wanted to make sure that administration of this agent, which is on a monthly basis, was safe and well tolerated.

And uh we sought to determine if there's uh some signal of efficacy over what would be considered, I think, for an amyloid trial, a relatively short time period, which is just twelve months or So this was a uh international randomized double blind multi-center trial in which uh patients with ATTRCM either diagnosed by invasive biopsy, but more typically by the non-biopsy approach.

who had significant elevations in their N T prob P, over six hundred if they were in sinus rhythm, or over a thousand if they were in atrial fibrillation, were randomly assigned to receive, um, in a blinded fashion, either a placebo uh ten milligrams of caramatug per kilo or sixty milligrams of caramatug per kilo. And I would note that this is uh a very typical population that most clinicians are seeing, well representative of the disease.

Average age of uh seventy, late seventies, predominantly males and predominantly wild. And importantly, 90% of these patients were already on one of the two classes of disease modifying therapies, either a a stabilizer or a silencer. So kind of a contemporaneous cohort of. How many subjects did you include in your multi-center trial? And then also maybe describe for us your study results.

Yeah, so um this was again a relatively small I'd say for amyloid trial of one hundred and four individuals who were randomly assigned to receive e little placebo and there were thirty five uh Karamitages. ten milligrams thirty four and thirty five individuals who received the sixty milligram dose at baseline. The drug up by the way was administered intravenously and it's administered every uh four weeks for the duration of the trial.

We had two pre-specified primary endpoints to look at, and that was the change from baseline in uh NT Pro B and P. think people are aware that naturic peptides are significantly elevated in patients with amyloid. And changes in NT pro B and P have been shown to be markers of disease progression, uh certainly with increases over time seen even unfortunately in people on disease modifying therapy. And the other co primary endpoint was the change in six minute hall walk from baseline to twelve.

So for those two primary endpoints, well starting with the six minute hallwalk, we did not see any statistically significant difference between the group. Uh, we can maybe come back to why that was the case. And we did see, however, a quite significant difference, particularly in the high dose caramatug group of sixty milligrams per kilo. with a uh forty eight percent reduction in the NT pro B and P compared to placebo from baseline to twelve months.

So pretty dramatic clinical or at least biochemical effect. I would note, obviously with regard to safety, the drug was very well tolerated. There were kind of minimal side effects. And most of the side effects that were described were very typical of patients with cardiac amyloidosis, not definitively attributable to drug therapy. And and notably the treatment emergent adverse events were actually numerically less.

in patients who receive drug therapy than placebo. Nothing we can conclude from that at this point, but certainly an interesting signal that it needs to be carried out and validated in a larger phase three trial. Very nice. And then often Matt in these patients we have imaging studies, either nuclear studies, sometimes Transthoracic echo and even cardiovascular MR. Were any imaging studies performed and did you notice any changes in the imaging markers?

Yeah, so great question. And yes, this study did leverage uh two imaging approaches, obviously transthoracic echocardiograms and cardiac MR. Both of which were obtained at the sites, but reviewed in a core lab. I would note that quite unfortunately uh cardiac MRIs were performed in a

minority of subjects. And so any signal that could emerge, particularly with regards to, for example, extracellular volume was highly underpowered and we didn't see any differences. So that was a a key secondary endpoint. Echocardiographically, there were several measures that were in I'd say exploratory phase of the study showed significant differences between caramatog at the sixty milligram per kilo Durse versus placebo.

And those included uh differences in the stroke volume in favor of therapy. RV systolic tissue velocity. left atrial and systolic volume, estimated pulmonary artery, systolic pressure, and uh EE prime. So effects on, if you will, L V systolic and diastolic function and left ventricular performance over a relative short time period, somewhat I think concordant and supportive of the uh findings uh related to naturic

So your results sound very encouraging. You really didn't have an adverse safety profile. Uh, you've got some favorable imaging parameter changes, and as you say, both on the systolic and diastolic function of the left ventricle, along with changes in NT pro B and P.

How do we put your results really now in the context of these other therapies that we have for cardiac amyloidosis? And where do you see this research moving forward? Yeah, it's a great question. So um there are other monoclonal antibodies that have been developed. that are currently being tested in phase three clinical trials. And Keramatug, the focus of uh this particular investigation, is just started a phase three uh clinical trial called Cleopatra, a study in ATTRCM patients.

who will be again randomly allocated to receive a caramatug or placebo on top of a standard medical therapy. And this is a large more than a thousand patient planned outcome trial that will be event driven. Actually the trial has initiated uh throughout the world. Our site actually started and screened our first subject yesterday.

And so a great deal of excitement about uh leveraging these impressive and important phase two data in what I think uh hopefully will be a successful uh phase three trial. Broadly I would say that many patients who come to clinic ask doctors uh important questions and we should always be attuned to what the patients are asking. The most common question is, you know, kinda how am I doing broadly or how much amyloid do I have in

Is it changing or not? And we have uh not really been able to address the amyloid load issue for individual patients. Which we think is tightly tied to their clinical outcomes. And so I have great hope for uh these type of therapies of being effective at ultimately reducing amyloid load, but more important, translating into improvements in

Ventricular function, atrial function, ultimately patients' functional capacity, and what patients really want from doctors, which is to feel better, function better, and live longer. But that we'll have to see in the context of appropriate science.

And I know you mentioned earlier, Matt, about the six-minute walk distance. And we wanted to make an additional comment in reference to that and the fact that maybe you didn't have quite enough patience to see a change, but perhaps follow up on what you wanted to share with us. Yeah, I mean, um obviously six minute hall walk is, you know, somewhat of a murky endpoint, easy to perform and does have a lot of functional relevance and prognostic relevance in all forms of cardiovascular disease.

Well the uh power calculation in this study wanted to look for a a forty five meter difference, which is quite large um over a relatively short time period. Uh these patients were pretty uh highly functional. They were on average NYJ class two and their baseline.

six minute hall walk was like in the three hundred and fifty meter range. Um all of those factors, uh plus the fact that patients are all being treated with disease modifying therapy probably I think significantly impaired our ability to meet uh any statistical significance on that secondary The other confounding factor I think is uh this is a population of extremely lovely but uh functionally impaired older adults that have multiple other comorbidities and there are lots of other things.

as you get older that can impair your six minute hall walk distance. And so we tend to rely on it, I think for a lot of logical reasons, but in many trials I think it fails to necessarily tell us exactly what's going on. So explanations for potentially why we did not achieve statistical significance on that particular uh.

Well, absolutely outstanding work, Matt. And we're so appreciative of your time today to discuss these very exciting results in this field where many new therapies are emerging. Well, certainly for our listeners wanna bring to the point that outstanding results from this phase two trial showing that Caramatug, an antibody targeting misfolded transthyrocin in ATTR cardialoid.

Was well tolerated and And at a dose of 60 milligrams per kilogram resulted in a statistically significant reduction in NT ProB, a validated marker of disease progression, and then also did not show any untoward safety effects. Well, on behalf of Petter and Sharin and myself, and also marked thanks to uh Dr. Matt Maurer today from New York Presbyterian Hospital and Columbia University Irving Medical Center in New York City.

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 other Please visit ajjournals.org.