Circulation September 28, 2021 Issue

This week's episode features a panel discussion. Please join author Harmony Reynolds, editorialist David Newby, and Associate Editors Nicholas Mills and Sandeep Das as they discuss the articles "Natural History of Patients with Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study, "Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity," and editorial "Forget ischemia, it's all about the plaque."

Dr. Greg Hundley:

Welcome listeners to this week's, September 28th, issue of Circulation on the Run. And I'm Dr. Greg Hundley, Director of the Poly Heart Center at VCU Health in Richmond, Virginia, and associate editor at Circulation. And this week, listeners, we have an outstanding feature discussion. It's actually forum where we're going to discuss from Dr. Reynolds two papers pertaining to the ischemia trial. One looking really at the functional importance of stress testing, the other looking at the anatomical importance of cardiac CT scanning. We're going to have two of the associate editors along with Dr. Reynolds, each that handled the two papers and also a guest editorialist that will help put the entire paper together. Well, before we get to that, we're going to start and review some of the other papers in this issue. And let's grab a cup of coffee and get started.

Dr. Greg Hundley:

The first comes to us from Dr. Maliheh Nazari-Jahantigh from Ludwig Maximilian University in Munich, Germany, and it pertains to atherosclerotic plaque rupture. So the necrotic core of an atherosclerotic plaque is partly formed by ineffective efferocytosis, which increases the risk of an atherosclerotic plaque rupture. And in cell biology, efferocytosis comes from the Latin word effero, which means to take to the grave or to bury. And it's really the process by which apoptotic cells are removed by phagocytic cells. And so therefore, it can be regarded as the burying of "dead cells." Now MicroRNAs contribute to necrotic core formation by regulating efferocytosis as well as macrophage apoptosis. We also know that atherosclerotic plaque rupture occurs at an increased frequency in the early morning, indicating that diurnal changes occur in plaque vulnerability. Now all those circadian rhythms play a role in atherosclerosis, the molecular clock output pathways that control plaque composition and rupture susceptibility are unclear.

Dr. Greg Hundley:

And so these authors investigated this phenomenon. And what they found, interestingly, their results suggest that the molecular clock in atherosclerotic lesions induces a diurnal rhythm of apoptosis regulated by circadian Mer 21 expression in macrophages that is not matched by efferocytosis, and thereby increasing the size of the necrotic core of these plaques. So clinically, the implications are that a macrophage death clock controlled by mer 21 may enhance lesion growth and susceptibility to plaque rupture indicating that the molecular clock can have detrimental effects under pathologic conditions. And additionally, the molecular clock in lesional macrophages may contribute to the circadian pattern of myocardial infarction, which could be a target for preventive measures to limit the mismatch between apoptosis and efferocytosis and thus reduce plaque vulnerability in the early morning.

Dr. Greg Hundley:

Well, our second paper comes to us also from the world of preclinical science, and it's from Professor Thomas Braun from the Max Planck Institute for heart and lung research. And this particular paper pertains to pulmonary hypertension. And as we know, pulmonary hypertension and chronic obstructive pulmonary disease, or COPD, originate from a complex interplay of environmental factors in genetic predispositions and little is known about developmental abnormalities or epigenetic dysregulation that might predisposed individuals to develop pulmonary hypertension or COPD in adults. So these authors screen a cohort of human pulmonary hypertension in COPD patients for changes of histone modifications by immunofluorescent staining. And also, they developed knockout mouse lines targeting cardiopulmonary progenitor cells and different heart and lung cell types.

Dr. Greg Hundley:

Now molecular, cellular and biochemical techniques were applied to analyze the function of SUV420H1-dependent epigenetic processes in cardiopulmonary progenitor cells and their derivatives. Well, what did they find? So the investigators found that loss of SUV420H1 in cardiopulmonary progenitor cells caused a COPD-like pulmonary hypertension phenotype in mice, including formation of perivascular tertiary lymphoid tissue, and goblet cell hyperplasia, hyperproliferation of smooth muscle cells and myofibroblast, impaired alveolarization and maturation of defects of the microvasculature leading to massive ripe ventricular dilation and premature death.

Dr. Greg Hundley:

Now mechanistically SUV420H1 bound directly to the five prime upstream in regulatory element of Superoxide Dismutase 3 gene to repress its expression and increased levels of the extracellular Superoxide Dismutase 3 enzyme in SUV420H1 mutants increased hydrogen peroxide concentration causing vascular defects and impairing alveolarization. So what can we take away, listeners, from this clinically? Well, the author's findings reveal a pivotal role of histone modifier SUV420H1 in cardiopulmonary co-development and uncover developmental origins of cardiopulmonary diseases. And now these results suggest that this study will facilitate the understanding of pathogenic events causing pulmonary hypertension in COPD and aid the development of epigenetic drugs for treatment of other cardiopulmonary diseases.

Dr. Greg Hundley:

Well, listeners, what else is in, we call it, the mail bag, but some of the other articles in the issue? Well, doctors Varricchi and Wang exchanged letters regarding the prior article, the role of IgE FcεRI in pathological cardiac remodeling and dysfunction. And our own Sara O'Brien highlights articles from our circulation family of journals. Professor Ross has a Research Letter regarding the effects of walnut consumption for two years on lipoprotein subclasses among healthy elders findings from the WAHA randomized controlled trial. And then finally, Dr. Maurer has a really nice On My Mind piece that raises concerns pertaining to the use of cardiac scintigraphy and screening for transthyretin cardiac amyloidosis. And now listeners, we're going to turn to that forum discussion where we have an author, our associate editors and an editorialist discussing two really important papers from the ischemia trial.

Dr. Greg Hundley:

Well, listeners, we are very excited today to discuss in sort of the forum feature, two papers pertaining to the ischemia trial. And with us this day, we have Dr. Harmony Reynolds from New York University Grossman School of Medicine in New York city; two of our associate editors, Dr. Nick Mills from university of Edinburgh in Scotland; and Dr. Sandeep Das from UT Southwestern; and then also an editorialist, Dr. David Newby, who's also University of Edinburgh in Scotland. Welcome to everyone.

Dr. Greg Hundley:

Harmony, we're going to start with you. And in the first paper, the natural history of ischemia and no obstructive coronary artery disease, can you describe for us a little bit of the context of what shaped this question for you, what hypothesis did you want to test? And then describe for us a little bit your study population and your study design.

Dr. Harmony Reynolds:

Sure. Thanks so much for having me here to discuss these papers. I'm really appreciative of the attention from circulation, and I'm excited for this discussion today. So in this first natural history paper, we were looking at ischemia with non-obstructive corona arteries, INOCA, the kind of thing that used to be called cardiac syndrome X. And we know this is an extremely common problem. It's defined by having signs or symptoms of ischemia and no 50% or greater lesion on coronary imaging. And we also know from prior invasive studies that the mechanisms of this are overwhelmingly microvascular coronary disease and provokable coronary spasm. Some patients prove to be normal and invasive testing, but most will have some objective abnormality.

Dr. Harmony Reynolds:

We know this problem is associated with a higher risk of cardiovascular events and with high costs, but what we didn't know was whether the symptoms and ischemia on stress testing are tracking together in these patients. So if we're trying to treat these patients, should we be doing serial stress testing and targeting the medical therapy to ischemia abrogation or should we just be making their symptoms go away? And would this provide any long range insights for us into when we can figure out the symptom are truly ischemic in nature?

Dr. Harmony Reynolds:

So we decided to use the ischemia trial, and we had a fantastic platform for that in ischemia because, as you know, patients were screened in part for randomization using coronary CT angiography. And even though these patients had moderate or severe ischemia, some had no obstructive coronary disease on that CT coronary angiogram. And those are the patients that we enrolled in CIAO-ISCHEMIA. They had an assessment of angina at baseline, and they had to be symptomatic at some point. They didn't have to be symptomatic at the moment. They were enrolled in CIAO, but they had their stress test generally to evaluate ischemic symptoms. And they had their stress echocardiogram read by a core lab. Importantly, that core lab did not know the result of that CT scan. So they read them like all the other ischemia stress echoes. And then these patients had an angina and ischemia assessment with a repeat stress echo at one year.

Dr. Greg Hundley:

And what did you find?

Dr. Harmony Reynolds:

There were a number of interesting findings from this study. The first thing was that the severity of ischemia in the CIAO patients with INOCA was very similar to the ischemia patients who had obstructive coronary disease. So that tells us that the INOCA problem can happen with quite a lot of ischemia, and that had not been as well delineated before. Another finding expected, but we did find that is that there were many more women in the INOCA group, two thirds of our child population was female. And in ischemia, overall, it was closer to a quarter. We found that the symptoms and the ischemia were quite changeable. So at one year, the stress echocardiogram was normal in half of the child participant and only 23% still had moderate or severe ischemia. Angina had improved in 43%, and it worsened in 14%. There was an awful lot of change over one year, but the change in angina and the change in ischemia did not track together. And that was a bit of a surprise to me.

Dr. Greg Hundley:

Very nice. Well, Nick, I know serving it as an associate editor, you see many papers come across your desk. What attracted you to pushing this paper forward for publication?

Dr. Nicholas Mills:

Thanks, Greg, and congratulations. Harmony, we love the papers you've been sending from ischemia trial, which genuinely is changing clinical practice all over the world. And it's been great to see the secondary analysis and follow-up papers. So this paper attracted me because it addresses an area where I still don't fully understand in clinical practice, what recommendations to make for my patients and what tests to arrange. As you say, INOCA is more common in women. I think these patients have largely been understudied over many decades, and there remains a lot of uncertainty. I liked it because you had a core lab, blinded core lab analysis with systematic follow up and it was a really well-done study. It reassured me in many ways because it told me that actually a lot of these patients, their symptoms get better, sort of irrespective of what we do. The treatments didn't seem to track within improvements of symptom, nor did the severity of ischemia, and that I think provides a lot of reassurance to our patients who are in this situation.

Dr. Nicholas Mills:

Of course, there is a group there who continue to have moderate to severe ischemia a year later. And I think this trial helps us understand maybe how we should study this group more, understand the heterogeneity that you've observed in this population in order to really try and resolve that and resolve their ongoing symptoms. But for the majority, four in five patients, they're going to do well and they're going to get better over time. And I think that's an important message from this study.

Dr. Greg Hundley:

Thank you so much, Nick. Well, Harmony, we're going to come back to you. You have a second paper, the outcomes in the ischemia trial really based on coronary artery disease and ischemia severity. Can you describe for us, again, working us back through, what were some of the constructs that you really wanted to address here? What was your hypothesis? And again, how did this study population maybe differ a little bit in this second paper?

Dr. Harmony Reynolds:

Thanks so much. So this paper tracked outcomes based on the severity of ischemia and the severity of coronary artery disease on the CT coronary angiogram now in randomized patients in the ischemia trial. So all of these had obstructive coronary disease and they were selected for randomization. And the premise of the ischemia trial was partly that we would be able to select patients who might benefit from revascularization and from an invasive strategy really based on how much ischemia they had on the stress test. Moderate or severe ischemia was required for randomization and for entry into the trial, but a core lab read those stress tests independently and independently assessed ischemia. And in some cases, when the site thought there was moderate or severe ischemia, the core lab did not agree. And the core lab independently decided whether it was moderate or severe. So we wanted to understand whether the ischemia severity at the time of trial entry influenced outcomes and influenced the outcomes by randomization treatment assignment.

Dr. Harmony Reynolds:

Similarly, about half of the patient had a CT that was interpretable for the number of vessels disease. And we wanted to understand in the context of all those prior stable ischemic heart disease trials, showing a lot of heterogeneity by the amount of coronary disease, whether in ischemia as well, there would be heterogeneity of the treatment effect based on how much coronary disease you started with. So the ischemia population, and this is almost the entire randomized cohort, but it's important to recognize for the CT analysis that only about three quarters of the patients had CT. They didn't get a CT, if your GFR was too low or if you had known coronary anatomy. And among those Cts, not every CT is perfectly interpretable for the number of vessels disease. These are sicker patients. These are not the super stable patients who have a low prevalence of disease. These were pretty sick, multi-vessel coronary disease patients, and they couldn't always hold their breast all that well. There was a lot of calcification in these.

Dr. Harmony Reynolds:

So for example, if there was motion artifact in the right coronary artery, we wouldn't be able to quantify the number of vessels disease. And that left us with a cohort of about half of our ischemia population, but that's still a giant cohort of several thousand patients. So that's how our study.

Dr. Greg Hundley:

Very good. And what did you find here?

Dr. Harmony Reynolds:

Here, we found that more severe ischemia was not associated with outcomes. Now that does go along with the COURAGE study in which after you adjust for clinical characteristics, ischemia was not associated with outcomes. But still it came as something of a surprise that even severe ischemia was not associated with a higher risk of outcomes than moderate or mild ischemia. We also found that in the coronary disease group, no matter how you measure the severity of coronary disease, the Duke prognostic index, the number of vessels disease, the segment involvement score, the segment stenosis score, all of these measures were very strongly associated with our outcomes, whether it was all cause mortality MI or our composite.

Dr. Harmony Reynolds:

When it came to treatment effect, we found that the ischemia severity were no relationship to treatment effect. There was no ischemia subgroup in which there appeared to be an advantage with an invasive strategy. But in the coronary disease group, and again taking into account the caveats of not everybody had a CT interpretable for the number of vessels disease, in those with the most severe coronary disease, that's the Duke 6 subgroup. And they had multi-vessel severe disease, either two vessel including the proximal LAD at 70% or three vessels with 70% stenosis. There was no benefit on mortality. But if we looked at the composite endpoint of cardiovascular death or MI, there appeared to be some advantage to the invasive strategy.

Dr. Greg Hundley:

Very good. Well, Sandeep, similar to Nick, working as an associate editor and meeting weekly, what attracted you to this particular paper? And why did you want to really see it come forward to be published?

Dr. Sandeep Das:

So first of all, I want to echo Nick's comments that these are great papers, and thanks very much for sending those our way and letting us have sort of first crack at them before they're released to the world. And I also want to comment on the side that Harmony and her team were just absolutely fantastic to work with in this process. From having been on the other side when you get 300 different comments from the editors and reviewers and you respond to them thoroughly and with grace, that's a feat in and of itself. So I want to shout out Harmony and her team for just being fantastic partners, because really we see ourselves as sort of the author's partners in kind of making the paper as good as it can be as the best it can be.

Dr. Sandeep Das:

So I'll admit upfront, I think it's kind of fashionable for people to say, well, I knew that this was going to show this, I knew this all from COURAGE, and this is not surprising to me. But I'll admit that I was surprised. And so this has been practice-changing for me, so this whole evolution post ischemia. And I really feel like a little bit of an existential crisis because I'm not sure I understand what ischemia means anymore. You ask me five years ago, I would've been very confident that I knew the answer to that. So you know what, really, as soon as this paper crossed our desk, I thought, wow, this is something we want to keep, this is something that's going to be really important to practice of cardiology. It's going to be really important to our readers. It's a great paper from a great group. This is something we want. So really it was never a question of, well, am I interested or am I not? I was interested from reading the abstract.

Dr. Sandeep Das:

So the question then became what are the real important questions that we need to sort of tease out and help elucidate for the clinician for the reader? And really for me, the question has always been, is there a subset of people where... So in my heart of hearts, I always kind of thought that burden of ischemia, if there was enough burden of ischemia, that it probably did help to revascularize that, right? I definitely practiced that way, right? There was some sort of number where I would start to say, that's a lot of ischemic myocardium and maybe we need to do something about that. Even though I know my intellectual brain says, no, there's no data that supports this, I really kind of thought it was true. And so Harmony and her team put another nail in that coffin here because it doesn't seem to be true, which to me was interesting and different and practice-changing.

Dr. Sandeep Das:

So the real questions here were sort of to tease out the interaction between anatomic severity, and we've all known that sort of anatomic burden of disease is proportional to adverse outcomes. That's not surprising. But the question then is, can we tease out a group where there may be benefit to revascularization? So there's a real interesting sort of interplay here between degree of ischemia and anatomic burden of disease. And is there a subset with enough of an anatomic burden of disease where you really may be interested in going after that to improve heart outcomes? So that's what I thought this was really fascinating paper.

Dr. Greg Hundley:

Very good. Well, David, we're going to turn to you next as the editorialist and asking you to sort of put the results of each of these two studies together. One, kind of highlighting for us how functional imaging might be useful to identify whether ischemia is present or not. And then the second study, really defining for us an association between anatomy and outcomes. So putting these all together, could you share your thoughts with us regarding these two papers?

Dr. David Newby:

Yes. Thank you. So I think that the CIAO-ISCHEMIA is very interesting, isn't it? And those clinicians were often challenged with symptoms versus our objective tests and trying to work out exactly what's going on, and it is. And such an important group as Harmony says, I can't agree more. We have a lot of morbidity here. As Nick said, I think the short term, a lot of the patients do seem to get better with just conservative management is good, but there's a core group that clearly are a problem. And as Harmony highlighted, you've got people with terrible regional wall-motion abnormalities on stress echo and yet no angina, others with no angina with no apparent difficulty on repeat testing. And then you've got a core group that has both, and it is fascinating to try and unpick that. And clearly, the symptoms are not correlating with our tests, and that's not the patient's fault.

Dr. David Newby:

And very often, no, no, you're wrong, can we say that to the patient? No, no, the patient is right and our tests are wrong, and we've got to work out how best to manage them. And I have a bit of analogy with Takotsubo cardiomyopathy as well, I think is at play here. I mean, here, you've got people with stable pain. We're not coming in as an acute emergency, but they're having regional wall motion abnormalities at times. They're getting a lot of symptoms. And we see similar things with Takotsubo, which is, I suppose, a much more flurry thing. I know that's something close to Harmony's his heart too. Excuse the pun. But this ischemia relationship, these regional wall motion abnormalities with chest pain, particularly in women, is something we really need to get our heads around and understand what's going on. It just reflects our ignorance, I think, of knowing exactly how to manage these patients.

Dr. David Newby:

And so for me, ischemia testing is about symptoms. It's about working out what's going on with the patient. It doesn't always give us the answer, but I certainly think that the role of ischemia testing is more about the symptoms.

Dr. David Newby:

And then when it comes to the second paper and outcomes with the ischemia trial, I absolutely was delighted to see those findings. I have to say place to what my prejudice is, I suppose, as someone that's been working with CT. And I suppose the slightly obvious thing is that the more disease you have, the more you will benefit from an intervention. And plaque and the burden of plaque is critical to that because how do you have a heart attack? Well, you have to have plaque, right? And it has to rupture. So the more plaque you have, the more likely you are. And I think that the analysis is again reinforcing what we've learned from some of the imaging trials with PROMIS and SCOT-HEART. Actually, the more plaque you have, the worse you are.

Dr. David Newby:

And yes, ischemia predicts risk, but ischemia predicts risk through its association with plaque burden, not through ischemia itself. And what I think we're seeing very nicely being played out in ischemia trial is the risk is definitely much stronger for CT than it is for imaging. And that's very clear, and that's exactly what PROMIS found exactly what SCOT-HEART found as well, and it's a rise robust finding. The interaction with the treatment effect that I find also fascinating and again plays to some of the bypass surgery trials that we've seen, bypass surgery tends to prevent spontaneous MIs and, even in some cases, mortality. And we're seeing trends in ischemia for mortality, can't over call them. I'd love to see what happens in 10 years. But I think in terms of the prevention of MIs, I'm putting all my money in one basket, which is the bypass surgery, 25% of course of patients revascularized that way. I don't believe that PCI is going to prevent the myocardial infarction. So I think all my money is in that box.

Dr. David Newby:

But it's absolutely fascinating data. It is all about the plaque if you're talking about prevention of clinical events downstream. And I think that's where the dichotomy is, scheme is about symptoms and understanding the patient's problems in terms of symptomatic improvement. If you want to improve their long term outcome, it's all about the plaque, understanding the burden of plaque and what you can do to hopefully prevent downstream event.

Dr. Greg Hundley:

Great. Thank you so much. And so listeners, we're going to ask each of our speakers today in really 20 or 30 seconds to go through and identify what do they think is the next study really to be performed in this space? So Harmony, we're going to start with you and then Nick, Sandeep and then finish up with David. Harmony?

Dr. Harmony Reynolds:

Thanks. Well, when it comes to INOCA, I would like to see more studies in the vein of CorMicA. So I'd like to see routine invasive testing to define the underlying pathophysiology problem and then targeted medical therapy interventions, and I'd like to see outcome trials. There's one outcome trial going on. It's a challenge because the event rate, though very important and higher than in the general population for sure, is low enough that these trials have to be quite large, and we look at ischemia with a relatively high event rate. And even so it's a stable population and that had to be large, this would have to be even larger. So we're going to need more mechanistic studies in order to lead to the treatment trials that will really influence practice.

Dr. Harmony Reynolds:

And in terms of the severity of coronary disease, this is a tough one. We felt like ischemia was a lift, and I'm not sure that there will be another huge stable ischemic heart disease trial. But sure, I'd love to see in people selected by CT for their advanced severity of coronary disease, whether an invasive management strategy makes a difference compared to medical therapy. I don't know that we'll see that one come to pass, but you never know.

Dr. Greg Hundley:

Nick?

Dr. Nicholas Mills:

Yeah. I agree. We need more mechanistic research, but I'd like to see more non-invasive methods to understand the mechanistic basis of this condition because CorMicA has caught an invasive protocol for a condition, which we know is benign and who most patients get better without any treatment. I would also like to see randomized blinded studies of treatment effects and because there are too many observational on blinded studies here. And I think the outcome has to be patient-focused and symptoms.

Dr. Greg Hundley:

Sandeep?

Dr. Sandeep Das:

Yeah. So everything that's been raised so far are fantastic comments and really on point. For me, I think if we can tease out the population that may benefit to get back to Dave's earlier comment that there's possibly not going to be a little humble here, there's possibly a population that has extensive, extensive CVD that could benefit from bypass surgery. And I think that that hasn't really been firmly demonstrated yet, although it's been suggested strongly. So that I think is an interesting study, and I hope that that gets done as a trial, but I can understand that it'd be a giant undertaking. And then the other thing I think is just algorithmic approaches that are driven by anatomical studies like SCOT-HEART and things like that, where we really try to make decisions based on the anatomical approach and pretend like the last 15 years never happened and that we kind are starting fresh with our best approach to how to treat these patients.

Dr. Greg Hundley:

And finally, David.

Dr. David Newby:

Yeah. I'm actually going to agree with everybody there, and I'm rooting for this trial actually because that's the one I want to do is look at advanced coronary disease on noninvasive imaging, irrespective of symptoms. And that's the big call actually if you've got no symptoms to put yourself through a bypass, because it's bypass, it's not standing. Bypass, we need. I'd also love to see some substudy coming out of ischemia. I think you're doing them. I hope you are looking at plaque burden and plaque characteristics because I think that's another level of complexity. We're so obsessed with stenosis, actually. And again, even anatomical and ischemia testing plays to that, it's not just about stenosis, stenotic arteries have big plaque burdens, et cetera. And it's not bypassing them, it's bypassing all the nonobstructive plaque and the obstructive plaque that has given you the benefit of revascularization with surgery. So I think you need to think about a really nice cool trial where we can do that trial even in the presence of nonobstructive disease, but big plaque burden, adverse plaque characteristics, and think about bypass.

Dr. Greg Hundley:

Very nice. Well, listeners, we want to thank Dr. Harmony Reynolds for bringing us these two really informative studies from the ischemia trial, and also our associate editors, Dr. Nick Mills and Dr. Sandeep Das for providing their perspective and our editorialist, Dr. David Newby, who really helped us organize our thoughts and put both of these two studies into great perspective highlighting in the first that functional testing can really help us identify the presence or absence of ischemia. And then our second study highlighting the association between CT coronary angiography and the identification of the anatomic severity of disease with cardiac outcomes.

Dr. Greg Hundley:

Well, on behalf of Carolyn 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 2021. The opinions expressed by speaker in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.