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Association of Plaque Location and Vessel Geometry With Future ACS–Causing Culprit Lesions


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INTRO: From the JAMA network. This is JAMA cardiology, author interviews, conversations with authors exploring the latest clinical research reviews and opinion featured in JAMA cardiology.

Dr Bonow: Welcome to this podcast from JAMA cardiology. I'm Dr. Robert Bonow editor in chief of JAMA cardiology, professor of cardiology at Northwestern University here in Chicago. And I'm delighted to be speaking with two established investigators at the Cedars-Sinai medical center in Los Angeles who are bringing forward a really novel manuscript hat we're publishing on the use of coronary computed tomography for the evaluation of patients at risk of acute coronary events. With me today is Dr.Daniel Berman, who is a professor of imaging and medicine, chief of cardiac imaging at the Smidt Heart Institute at Cedars-Sinai. Welcome Dr. Berman.


Dr Berman: It's a pleasure to be here and thank you for the invitation.

Dr Bonow: Also joining is the colleague of Dr. Berman, Dr. Donghee Han, who is a research scientist cardiologist also in the department of imaging and biomedical sciences at Cedar Sinai Smidt Heart Institute. Welcome Dr. Han.

Dr Han: Thank you for having us and for the opportunity to share our work.

Dr Bonow: This is really an important topic because the use of coronary CTA Computed Tomography Angiography is growing in our clinical armamentarium in patients with known or suspected coronary disease is now in our guidelines as well, or at least to consider using anatomic imaging as opposed to functional imaging. And so the data that we'll be discussing today is quite topical and quite pertinent. But before we begin, Dan, perhaps you should give us a little bit of a background about the large registry that this study is based upon: the CONFIRM registry that you and your colleagues have been so active in for over a decade. Perhaps just give us a background as to where we've been to date with CONFIRM and its database.


Dr Berman: I was very fortunate to be involved in the early development of the CONFIRM database, which it was, and is a registry of patients who have undergone clinical coronary CT angiograms. Participants included people from the United States and Canada, Asia, and Europe in this registry of 25,000 plus patients in CONFIRM. Approximately 15,000 of the patients were followed for MACE events. This allowed the identification of 234 patients who had an acute coronary syndrome following their coronary CTA. The images on these patients, as well as their clinical information regarding the ACS were then transferred for subsequent analysis of the coronary CTA studies, 234 patients develop the subsequent acute coronary syndrome. And these patients were then matched to 234 patients who did not develop acute coronary syndromes following their coronary CTA. And this population then made up the database, that formed, the ICONIC study, and the ICONIC study published a few years ago now established what were the characteristics of plaques that subsequently became the culprit plaques in the acute coronary syndrome.


Dr Berman: So, one of the very early things that we learned was how strong coronary CT angiography is for looking at stenosis and their prognostic value. But one of the questions that came up was can the coronary CTA predict lesions that are more likely than others to result in acute myocardial infarction down the line.We know that plaque characteristics add to precent stenosis in making this prediction, but there was a question about whether this could be extended even further.


Dr Bonow: Well, thanks. And that's a very good introduction to the topic. I think the other strengths of the CONFIRM registry is the fact that you have a central coordinating committee to adjudicate the clinical events that includes these major adverse coronary events or MACE events. Also, you have core laboratories as well to evaluate the invasive and noninvasive angiograms. So those are really important strengths of the CONFIRM Registry. So, this is a really rich database that, as you pointed out, has given us lots of information about not the plaque characteristics only, but also the patient characteristics likely to have subsequent coronary events.


Dr Bonow: I should point out that this registry that Dr. Han and Berman have been intricately involved in is international, involves multiple well-known people in the field of coronary CTA. And so it is coming to us from a group of really established international experts. In this study, you're taking it one step further, which we thought was quite interesting. So perhaps. Dr Han, the lead author of this investigation, can tell us exactly the nuances here, the novelty of this current investigation built upon the foundation of CONFIRM and ICONIC. So Dr. Han, maybe just tell us a little bit about how and why you developed this analysis and what it begins to tell us about the risk of future coronary events.


Dr Han: So when we use coronary CT angiography for this evaluation, we are really focused on the stenosis severity and more for what's called high-risk features, such as positive remodeling and low attenuation plaques, which have [00:06:00] been shown to be associated with adverse cardiovascular outcomes and future risk of acute coronary syndrome. But when we look at the plaque level, the risk of rupture, which is the leading cause, of the acute coronary syndrome is a function of both intrinsic plaque vulnerability, and extrinsic hemodynamic forces at the plaque surface. And there are previous studies from invasive, as well as non-invasive, imaging that showed that plaque location and vessel geometry are closely associated with altering coronary flow hemodynamics and biomechanical stress at plaque level.

And given the high spatial resolution and three-dimensional reconstruction from the imaging technique of CT angiography, we can accurately assess plaque distribution and vessel geometry in the entire chronic tree. So, the question that we wanted to [00:07:00] prove in this study is whether geometric features from coronary CT angiography data are independently associated with future risk of acute coronary syndrome beyond the current clinical CT angiography assessment.


Dr Bonow: And so this is built upon the prior work that you and your colleagues have done to date telling us that there are unique aspects of coronary CT angiography that allow us to look at plaque characteristics themselves. And as you point out, it's positive remodeling, spotty calcification, low attenuation identifying lesions that are probably fibro-fatty and have necrotic cores which can be done pretty routinely with coronary CTA. And the unique aspect of your current study is that you are now looking at the location of these high-risk plaques and the combination of plaque location, as well as plaque characteristics is giving us some new information. So how do you define, Dr. Han, the adverse plaque geometry?


DH: So the unstable adverse geometric characteristics is not entirely new, and there are a few previous invasive angiographic papers that show that certain plaque location and vessel geometry are associated with the risk of the acute coronary syndrome.So for the study hypothesis, in this study we assessed three additional plaque characteristics that are capturing clinically important plaque location and vessel geometry features. These are distance from the coronary ostium to lesion, plaque located at bifurcation and located at tortuous vessel segments. And we would like to define these features as adverse geometric characteristics in this study.


Dr Bonow: And when you did the analysis to look at the geometric features, this provided important statistically significant additive value to the plaque characteristics themselves.

DH: So when we look at the whole lesion basis, the risk within patients with acute coronary syndrome, the culprit lesion precursors had a shorter distance from the ostium and more frequently localized to bifurcations and had more tortuous vessel segments compared with non-culprit lesions. And these adverse geometry characteristics were independently associated with a higher risk of future culprit lesions after all adjustments for stenosis severity, morphology of the worst plaque characteristics, and even quantitative plaque characteristics, which include plaque volume and burden according to each subtypes.

And when we stratified the lesions by presence of morphologic and geometric adverse plaque characteristics, we found that lesions that have both morphologic and geometric adverse plaque characteristics have an increased probability of becoming culprit lesions compared to the lesions without these adverse plaque characteristics.

And finally the findings were consistent when we compared with the control patient, showing the patients with acute coronary syndrome have a higher frequency of lesions with adverse morphologic characteristics, adverse geometric characteristics, and both characteristics compared to propensity-matched controls.


Dr Bonow: I think that was one of the important strengths of your study.Other participants in the CONFIRM registry who did not have events, they were quite well matched for their clinical characteristics. And yet I take it they did not have most of or components of the high risk plaque features. Did they have similar plaque characteristics? But did not have the geometrical abnormalities, the anatomic abnormalities in terms of a plaque location, or did the control group also have fewer adverse plaque characteristics themselves?

Was it a combination of a better outcome if you have more benign plaque characteristics and more benign plaque locations? Is it one or the other or both that would lead to a lower risk strata versus a higher risk strata?


DH: Oh, yes, that's for both. So the control group of patients that were matched to age sex, critical risk factors and extent of coronary artery disease.

But when we compared the detailed plaque characteristics between case and control, the control patients had fewer of the worst morphologic plaque characteristics, such as the number of lesions with positive modeling or low attenuation plaque, as well as fewer lesions with adverse geometrical characteristics, as well as both.


Dr Bonow: So this does lead us to some new thoughts about how one might use coronary CTA in practice. Dan, you've been a leader in imaging for decades, provided so many new insights into our use of nuclear imaging and also computed tomography. How do you see this now fitting in? Is this something now that is available for clinicians who are sending patients for CTA or for imaging experts who are performing. The tests themselves. Is this now something that can be taken off the shelf and implemented right away, or is this take a lot of processing to derive the data, to give us the information regarding plaque characteristics, and also plaque location? How user-friendly will this be if we want to move this forward into real-time practice.


Dr Berman: Coronary CT angiography is really moving to the forefront as a diagnostic and prognostic tool in patients with chest pain, with a recent promotion to a class one by the ACC/AHA guidelines for managing patients with stable chest pain. When we interpret those studies, we routinely analyze percent stenosis and plaque characteristics.These things should be part of the standard reporting. As we’ve learned and teach our referring clinicians, the more high risk plaque features, the higher the risk in a given stenosis is. These are done as a routine at the time of visual interpretation in an interpretation session. Now they don't take a long time of course, unless the patient has very dense calcification. When interpretation of stenosis is more difficult. Adding the measurements that Donghee has put forth here is very simple. It's done without any specialized software. And just involves observation as to whether the plaques are at the bifurcation observation of the degree of tortuosity of the vessel proximal to the lesion and a simple measurement made on a computer workstation manually of the distance along the vessel to the point of the plaque. So it is something that is easily incorporated without additional time at the time of interpretation.


Dr Bonow: As Donghee mentioned, we've had prior studies using invasive angiography that have given us similar clues regarding plaque location and this geometrical position in the artery, bifurcation, lesions, torturous vessels, and so forth. But what you have now is a non-invasive way of providing this information combined with the information regarding high-risk plaque characteristics themselves. So we amongst the editors felt this was an important step forward in the use of coronary CTA. Donghee, what is our next step now? Do you have future directions using this as a foundation that would lead us to further insights? Does it matter whether we're talking about the proximal LAD or the proximal right coronary artery? Are there any other new avenues in which you wish to go to further explore the use of this technology?


DH: The current CT interpretation is mainly focused on the stenosis severity as well as a few others, including the adverse plaque characteristics and the thought for the plaque location.

We only implemented the information for the left main and the proximal LAD lesions. But our analysis indicated that the overall proximal LAD, circumflex and RCA lesions have a higher risk of future acute coronary syndrome, compared to the lesion located in mid to distal vessel, and also the lesion located at the bifurcation and tortuosity is also higher risk of the future acute coronary syndrome. So this information is a complimentary addition to the standard CT angiography assessment, which is mainly involving the stenosis severity. So we think these are features that will potentially improve the risk of stratification of patients with stable coronary artery disease at a high risk of future acute coronary syndrome.


Dr Berman: Bob, I might add to Donghee’s comments that I think in the future, we're going to see quantitative plaque analysis actually measuring the different plaque characteristics, such as the extent of noncalcified plaque, importantly the presence and extent of low attenuation plaque, which really represents the necrotic core, and is likely the most important predictive feature of these high risk features. With this quantitative assessment we’ll augment what we're able to state about prognosis. In terms of this, I believe that what we'll see is that there'll be an integration of quantitative analysis with these geometric characteristics, increasing the risk assessment from coronary CT.


Dr Bonow: Yeah, thanks Dan, and thanks Donghee. I think those last comments are quite helpful in determining where we'll be going in the future. One thing which has also been out there as a confounder in serial studies of patients is medication therapies, most notably statins, which can certainly change the plaque characteristics themselves. They are not going to change plaque location … but what's been your experience in patients receiving statins regarding the change in plaque characteristics and the perhaps greater degree of calcification? Is that going to make it difficult for us to use CT for serial studies? We identify a high-risk patient, we administer appropriate guidelines-directed medical therapy, including statins, and then does that make it difficult then to further study these patients in the future with CTA?


Dr Berman: I might comment about some work we've done in that regard a few years ago, Bilaji Tamarappoo reported on patients who had undergone clinical serial studies with coronary CTA. And, we separated the patients into those who by the time of their second study had had a greater than 10 mg/dL decrease in LDL cholesterol and those who didn't. And what we found was that there was a reduction in all of the noncalcified plaque components in the patients who had lowering of their LDL and this included the low attenuation plaque representing the necrotic core that I just referred to. And interestingly, the amount of calcified plaque increased. And we think that this increase in calcification is part of the healing of coronary plaques and making them more stable and less likely to rupture. That work has been now followed in our lab by a study that's currently underway in which we're looking at patients with evolocumab as the intervention. We took patients with high-risk coronary plaques, and then put them on evolocumab for 18 months, and then followed up there with an additional coronary CT angiogram. In this patient group, we also performed sodium fluoride PET scanning, which has been shown to be related to plaque inflammation, before and at the time of follow-up. And we are looking forward to the results of this study.


Dr Bonow: Well, that will be really interesting. I look forward to those results as well. I agree that your work to date, demonstrating the changes in plaque characteristics regarding the noncalcified plaque evolution, as well as the evolution of calcification with medical therapy, has been a really illuminating.

Well, I'd like to thank Drs. Han and Berman for bringing forward this interesting study. I wish you the best for your future work, Drs. Han and Berman. I’d like to thank our listeners for joining us today. This episode was produced by Shelly Steffens at the JAMA Network. The audio team here also includes Jesse McQuarters, Daniel Morrow, Lisa Harden, Audrey Forman, and Mary Lynn Ferkaluk. Dr. Robert Golub is the executive deputy editor. To follow this and other JAMA Network podcasts, please visit us online at jamanetworkaudio.com. Thank you very much for listing and thanks very much again to Drs. Berman and Han.


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