Dr. Thomas Nero speaks with Dr. Mathew Budoff about Coronary Calcium Scoring, CT Coronary Angiography and cardiovascular outcomes. The discussion goes beyond basic risk factor enhancement, highlighting its role to help evaluate disease progression, power future clinical trials and determine efficacy of therapy. Along the way, they discuss coronary inflammation, perivascular adipose tissue imaging and fat attenuation index (FAI) as well as diving into the plaque stabilizing effects of EPA.
Dr. Thomas Nero speaks with Dr. Mathew Budoff about Coronary Calcium Scoring, CT Coronary Angiography and cardiovascular outcomes. The discussion goes beyond basic risk factor enhancement, highlighting its role to help evaluate disease progression, power future clinical trials and determine efficacy of therapy. Along the way, they discuss coronary inflammation, perivascular adipose tissue imaging and fat attenuation index (FAI) as well as diving into the plaque stabilizing effects of EPA.
CAC and CTA with Dr Mathew Budoff
D Nero: Hello, and welcome to Future Pulse. Today is November 30th, 2023, and I'm Dr. Thomas Nero. I have the pleasure of speaking with Dr. Matthew Budoff. Dr. Budoff is Professor of Medicine at the David Geffen School of Medicine at UCLA and the Program Director and Director of Cardiac CT at the Division of Cardiology at the Harbour UCLA Medical Center.
Dr. Budoff has been a national leader in primary prevention and lipid lowering trials, but today we're going to focus on his work in cardiovascular imaging and diagnostics. Dr. Budoff, you've been a prolific cardiovascular researcher , , analyzing coronary artery calcium scores.
And established it as a way to improve risk stratification over traditional risk factors.
Dr Budoff: Thank you for having me on. , , , calcium scoring has come a long way when I, when I was an intern,, my boss, Bruce Brundage, who is the chief of cardiology said, , this is going to be the mammogram of the heart that everyone's going to get a calcium score.
And we're going to know if they have heart disease or not, just like a mammogram. We're going to know how bad it is and we're gonna be able to act on it. And it sounded like a great idea. I, I bought in, I've been pursuing that. And now 30 years later, almost it is coming to fruition. , we are seeing it as a way of identifying who has early atherosclerosis and we can act on that early atherosclerosis.
And remarkably, I see some patients who are 80, 90 years old who have no plaque at all. Cause not everybody dies of heart disease. So it is an excellent yes, no. But it's also gives us more information than whether or not you just have the disease. It tells us how much, and then it gives us an opportunity to intervene.
Dr Nero: So, We tend to do , not as many coronary calcium scores and not as many CT angiograms as they do in Europe. Why do you think that we're behind the Europeans on utilizing these,
Dr Budoff: ,
Unfortunately, I think it's largely economic. I think we are incentivized in the U. S. to do nuclear testing. It pays a lot more than a calcium score or a CT angiogram. And I think, unfortunately, that's why a lot of doctors have stayed with that practice because it pays the bills. And at one point nuclear imaging accounted for 40 percent of cardiologists revenue in their practice.
So taking that away and saying, you're going to make less or taking that away and say, we're going to ship that out to a radiologist is a big bite. , they don't have those economics in Europe and they've adopted CT and calcium scoring much more widely.
Dr Nero: , they're utilizing it early, they're utilizing it, , more frequently in the emergency room. , and we've seen it also in a lot of our, , research studies. Looking at some of the newer trials that have been coming out, especially ischemia Will it change the way that we're utilizing this technology.
Dr Budoff: I really do. I think being able to do a non invasive angiogram, lower risk for the patient, lower cost, easier access, opens the door for a lot of, a lot more patients to be studied. You know, the old days we did these intravascular ultrasound studies where you had to be in the hospital, usually with an acute coronary syndrome, getting an angiogram to be enrolled in the trial.
So we can only study a small portion of the population. Now we're doing 10, 10 large scale pharma trials. I don't know a large pharma that's not doing a CT angio trial, looking at plaquette baseline, putting them on drug X or drug Y versus placebo, and then following them up with another CT angio. Cause we could study asymptomatic.
people. We can study people with high cholesterol. We can study people on the keto diet. We can study people with diabetes without them being in the cath lab and without that risk or cost.
Dr Nero: It will be very interesting to see , , we've been hung up on the coronary calcium partially because of all of what you've done with coronary calcium in the past. And it's really not the calcium, it's the atheroma and it's the lipid rich atheroma that's really going to be important there.
Have you seen utilization of plaque volumes to determine whether you're effective with your therapy?
Dr Budoff: Absolutely. There's a new company that I've worked with a little bit called CLEARLY they do AI quantification of soft plaque and I think that's very, very helpful. Um, but you know, calcium is the tip of the iceberg. So if we see calcification, we know you have more. We don't know how much more, and now we can quantify that with CT angiography.
So we are seeing a shift, but I would still argue that from a population based standpoint in any country, rich or not rich, the calcium score would be better for asymptomatic people. Do you have disease? Yes. No. Do you have a lot of disease? And then, if the answer is the latter, that you have a lot of disease, then we can do the CTA angio and define it better.
Do you have left main? Do you have three vessel disease? Or is it all non obstructive, and we can just treat it medically.
Dr Nero: And are you also using it in patients who have, have very high risk but have very low coronary calcium scores also to look for that missing group?
Dr Budoff: Yeah, absolutely. And it's remarkable. Sometimes you take patients with diabetes, high blood pressure, cholesterol, they're obese, you put them on the scanner thinking you're going to find this disaster and their coronaries are clean. So we can't guess. We're very bad at cardiology, at looking at a person and guessing.
I mean, if you think about it, Winston Churchill, big old fat guy, never exercised, never, no picture ever taken without a cigar in his mouth. Lived to 92. Then Jim Fixx, this thin runner. Ran marathons, dies at 52, right? So like you, you just can't know what's happening in the coronaries just by looking at a person.
And that's why we have to look inside the heart and it's easy. It's widely available. And I think it's going to become very standard of practice over or every year it's going up significantly.
Dr Nero: I think that it's certainly as far as primary prevention, , it has not yet hit its stride. ,
Dr Budoff: And you know, LP little a , , I believe both current drugs that are being investigated will have CT angiotrials accompanying the outcome studies to see, does lowering LP little a reduce atherosclerosis, or is it working through another mechanism? , and that helps also the mechanistic side of things is also, I think, very informative.
But, you know, we've had this LP little a registry. Yeah. And not everybody with sky high LP little a has atheroma or has any significant amount of atherosclerosis. And I think that's very informative for who we might want to treat ,
Thomas Nov 30: yeah, it would be nice to have a more granular approach to how we're going to look at our risk factors, , and our risk assessments. And yes, I have one patient we looked at. She's 80 and has a family that had elevated LPA. And so we looked at her and her LPA was 380. And we did a, CTA on her and it was completely normal. Uh, and I would love to study her and find out why it was completely normal, but that's a, you know, that's a, another topic for another time. Do you think that there's an, any other technologies that are going to become add ons to CT angiography.
We can see the plaque, but it would be nice to know whether the plaque is metabolically active or not, where we are with it. Uh, there was some interesting information from the ORFAN trial that came out at the AHA, uh, that I was sort of excited about. , have you looked into fat attenuation indexing and where that may be as an add on to CT angiography?
Dr Budoff: Yeah. So, you know, I think fat attenuation index is very exciting. There's very little data to be honest. Over the years, it's been hit with a big splash in 2018 with an article in Lancet. And since that time, it's been quiet and , just recently, they had one, , paper, but, , I think that it's a great opportunity to look at the metabolic activity of the plaque itself and, and There's obviously that tie in with inflammation and atherosclerosis is so strong, um, that we now need to understand who's metabolically active and that probably will change our algorithms of care.
We have Colchicine, we have new drugs that are being studied, IL 6 blockers, IL 1 inhibitors. That may actually help us manage these inflammatory type patients
Thomas Nov 30: Yeah, . We're really looking at this sort of triangle of lipids and plaque inflammation as being that metabolically active piece and then thrombosis and , all of these three things are going to be tied together and we have to try to figure out how we can identify things earlier rather than later.
Regarding your discussion about, the metabolically active portion of the plaque. Are there other technologies that are looking at ways that we can image the metabolically active plaque and how we may utilize those , clinically?
Dr Budoff: There's a lot of work done with now that's being done with different companies that are looking at plaque vulnerability, , thin fibro cap atheroma. , plaque volumes, , low attenuation plaque, the necrotic core, , dense calcification may be safer. Maybe it's been there longer and it's more stable.
So there's a lot of different approaches that are being taken. And also don't forget the flow studies that we can add to these to find out about physiology. By using FFR CT to identify whether or not those plaques are actually causing physiological obstruction.
So there's a lot being added to a CT that really enhances the value of a CT angiogram well beyond just do I have a blockage or
There was actually a randomized trial that starting with the NIH. , it's going to use CT Angio to direct care. So they're going to get a CT Angio and then you're going to get randomized to either no intervention stent or bypass based on the on the CT angiographic data. So we are moving that way and hopefully that trial will be positive and that'll move us one step further towards that algorithm of care where less invasive.
less radiation and a lot safer for patients, , to do a CT angio than an invasive angio. And then you do the selective invasive angio when you need to put in that stent, which is obviously the only way we're going to be able to deliver , that life saving care.
Dr Nero: So there are certain subpopulations that, uh, are concerning, that may be missed with CT angiography and , specifically, , SCAD can be missed on an initial CTA. Um, MINOCA may have a role with CTA
But, specifically with SCAD and some other subpopulations. , how do you see that we can move forward where we're not going to sort of throw the baby out with the bath water?
Dr Budoff: Yeah. So, and I totally agree. SCAD right now is a concern. I think, Based on the acute clinical setting, I think cath labs still the right way to go when you have a high risk person with acute chest pain, especially if they have , , other risk factors or other, other things going on. We use CTA NGO a lot for acute chest pain in the lower risk patients, where I think SCAD is going to be much less likely and probable, but, but there is still issues.
Now we are moving towards what's called photon counting, which is a better scanner with. better resolution and that will probably at least partially answer the SCAD issue, , of being able to get better looks at the coronaries and see that fine membrane that represents a spontaneous coronary artery dissection.
Dr Nero: Well, that'd be really exciting. Certainly the resolution question , there's been some theoretical limits to what we can see, but that will, , certainly help that out. , that's extremely exciting. When we're looking at other pieces of the coronary anatomy, the perivascular adipose tissue and trying to image those things,
you have to get down to these very fine resolutions and being able to tell the difference between the tissue characteristics. Do you guys do a lot of, um, adipose tissue imaging and, , looking at the differences in the various kinds of perivascular adipose tissue, , periarterial, , pericardial , and throughout the rest of the body.
Dr Budoff: , we do in research trials, we do a lot of that. We look at, at all of those different fat beds, even hepatic, even the liver fat in an attenuation of the liver fat. , but epicardial fat fat around the artery, think of the heart, think of that as visceral fat.
This is the same. We can see the heart, and if it's encased in fat, that's not good. And then if the fat is metabolically active, that's worse. So we are looking into that. It's not yet a clinical tool, I don't think anywhere, but, down the road, as we continue to validate it, I think we can simply add that metric to a simple calcium score , or to a CT angio and , get additional information for the clinician.
Dr Nero: , it's quite intriguing that we already have the data there, right? It's already on the scan. So this is, a lot of this is going to be post processing where you will be able to look back at it and say, okay, there it was, or, , this is another piece of information that we can get out of these scans that we already have.
So you had brought up, , a issue about the metabolically active. fat versus non metabolically active fat. And I'm gonna, I'm gonna ask you to weigh in on a controversy when we're talking about perivascular adipose tissue and that, , there's the question of inside out versus outside in signaling.
, where do you stand? Is it an inside out signaling where the , metabolically active plaque is signaling to the fat and the fat is changing? Or is it because of the metabolically active portions of the fat that are then changing signaling within the artery?
Dr Budoff: I am very much an outside in person. I totally disagree , with the papers that have been put forth with the people who invented PFAI and, uh, they believe it's inside out that the, that the plaque itself somehow signals to the fat and makes the fat more metabolically active. I, believe that the cytokines come from fat cells. To think , that you're triggering that from the artery is, , a little bit hard for me to, to believe. So I, , I'm very much a believer that the fat is metabolically active. , it activates the plaque, , through local cytokines.
Uh, IL one, IL six CRP. And that triggers more atherosclerosis. I think inflammation stirs the pot , of athero , and that's where you end up getting the vulnerable plaques , and the plaque rupture.
Thomas Nov 30: certainly , there's a lot of research that would support. What you're saying. I've been involved with some of the folks over , in Oxford who've been doing the, uh, FAI studies and, it , will inform the way that we're going to look at this technology , because if you believe that it is inside out and that it changes the fat and causes,
adipocyte apoptosis. Well, that will then essentially tattoo that adipocyte and that, or that, that fat, and it shouldn't improve. , and you won't be able to necessarily use FAI into the future to see whether you've had improvement given your therapies, which would be quite different to how you're looking at, , the lipid content within the cell to see improvement.
Um, so it will be interesting to see , whether or not we can utilize those to determine who will benefit from the intervention. , that would be really nice to be able tell, right, especially as we're using these very expensive drugs, as you said.
Dr Budoff: I can give you, , though an observation that , I believe will, will prove it one way or the other. So, , there is no atherosclerosis in vessels or arteries that are not surrounded by fat. , the mammary arteries. Never calcify or get plaque. No fat. Arteries that go into the myocardium, whether it's a bridged or intramyocardial segment of the LAD, or whether it's septal perforators, once they get into the myocardium, , don't develop atherosclerosis.
And I'm talking about now at least my own personal observations in over a hundred I've never seen a bridge segment or a septal perforator once it enters the myocardium with any type of atherosclerosis. And the reason is there's no fat there. And the minute that artery pops out of the myocardium, like the distal LAD, atherosclerosis starts to form again and you'll see calcification and soft plaque.
So without the fat cells there is no atherosclerosis. So I believe it has to be outside in because if it was inside out then you would still get athero from the artery, it just wouldn't affect the local fat, but without fat. There is no athero. , so , I'm a very strong believer.
We'll need to continue to look at it, but I think the evidence strongly weighs towards fat cells are the problem and active fat cells are the real problem and they influence the vessel next door to
Thomas Nov 30: And certainly, it really does argue, um, for, as you said, this more systemic approach to lipid lowering and, , risk stratification,
Dr Budoff: Even weight loss, right? We're seeing now with, , simagultide. the select trial, you treat obese patients and they have less cardiovascular events. Um, so it might be just getting rid of some of those, , adipocytes or getting them
Dr Nero: Yeah, I, I tend to believe that there's more, that there's more going on to than just the weight reduction. Um, I'm sort of hoping so, so that, you know, those patients of ours who have type 2 diabetes who are not overweight, so they can be treated as well. And we're going to have to figure out how to address that but yeah, it's going to be a very exciting time . .
Dr Budoff: Unfortunately, most of the new trials, both with terzapatide and with the new triple inhibitors, um, and semaglutide all have a minimum , a BMI of 27. So we won't be well informed on the thin. diabetic. I don't think, um, overall, but hopefully we'll get some data from these trials that will help us understand whether or not they benefit as much as the person who has obesity as a comorbid
Thomas Nov 30: Yeah, well, I'm sure there'll be some types of, , post hoc analysis that'll look at, , percentage weight reduction, initial weight versus, , obtained body weight and all those kinds of pieces. The same thing that we've done in the past with lipid trials .
Okay.
You've done a lot of trials what's your favorite trial . , if you went back and you look at, , yeah, this is my baby.
I'm really proud of this one. What would that be?
Dr Budoff: I think actually the most recent study that I published, , is hopefully going to be the most informative, , and that's that, , calcium score above 300 is equivalent to secondary risk , and deserves secondary prevention, that you're just as high a risk if you're an asymptomatic person walking around with a score above 300 as a post M.
I. survivor. And that's what we were able to show from the CONFIRM registry, , and it was published in JACC, , , this past July, and I think that's going to be hopefully something that's really going to change , our approach to prevention and our approach to how low should you go for LDL.
When do you start adding on things like GLP 1s or icosapent ethyl or bempedoic acid or inclisiran or, you know, PCSK 9s? When do you go to the next level with some of these asymptomatic patients who don't have a diagnosis of ASCVD yet?
Thomas Nov 30: Yes, sir. And I've loved your papers that go over the same data with the utilization of aspirin. , aspirin is probably being underutilized in some of these otherwise high risk patients just because they have not yet had a stent placed, or They have not yet had an M.I. an mi , We have to realize that coronary artery disease isn't the presence of an obstructive plaque.
Uh, it really starts as soon as you have atheroma , as soon as you have calcium , and that we should really be moving the clock back and starting to treat this earlier.
Dr Budoff: Yeah, I add aspirin, low dose aspirin to anybody with a calcium score above 100 unless they have a contraindication to aspirin. , I believe firmly that they are at increased risk and they would be the high risk asymptomatic people who would actually benefit . And there's some good observational data out of multi ethnic study of atherosclerosis and other cohorts to show that, that is correct.
Dr Nero: . Which trial were you so impressed with recently that you wished you had performed?
Dr Budoff: , I'm very enthusiastic about some of these CT angiotrials. I'm actually involved in the CT angiotrial you mentioned earlier with Zeus. And I think that's going to be a very interesting and informative trial. I'm looking at the plaque changes in concordance. Embedded in a trial that's looking at outcomes, right?
Because I think that's going to be where we're going to get the most information about plaque changes. And we have a trial that we did recently that they haven't looked at the PFAI yet, but it would be a great opportunity. It's called REPRIEVE. It was an NIH trial looking at a patavistatin, , in patients with HIV, half the patients got patavistatin, half did not.
And we have CT angiographic plaque in 800 patients, serial studies. So. Great opportunity to look at the effects of, , patavistatin on the plaque and the pericardinary fat attenuation index, and then subsequent events, right? So I think we have some good opportunities coming up with Zeus and, and with the patavistatin trial to, to answer some of these questions and tie in this pericardinary fat.
Is it modifiable? And if you modify it, is that good?
Dr Nero: , the number of ways that we can look at , that this data is going to be, , staggering. And now I can understand how you have so many papers under your auspices. Because every time there's one trial brings up more questions for you that you're going to answer in different ways and, and give us more information.
Dr Budoff: Even my small evaporate trial, which got a lot of press, , just 80 patients randomized to icosapent ethyl versus placebo followed for a year and a half. I had five late breakers out of that one small trial. I was on, on stage or one of my colleagues was on stage at ESC, AHA, or ACC five different times breaking down that data, um, and publishing multiple papers out of that.
So you're right. It doesn't take a large cohort to get some really good science out of it.
Dr Nero: The data that you were providing for EPA was some of the strongest data we had. , there was enough controversy about the trial and about the, the placebo comparator to make people, scratch their heads a little bit., but you really showed that it's more than just the triglyceride lowering that it's also LDL lowering.
And really it's . Plaque stabilizing, .
Dr Budoff: I think raising the EPA is very plaque stabilizing. And I think that that's something we'd be able to show with FFRCT and with advanced plaque metrics from a different core lab. that it stabilizes the plaque and therefore is doing something more than just, as you said, lowering triglycerides.
Dr Nero: Very, very exciting stuff. Well, I want to be, , cognizant of your time. Thank you so much, uh, for spending the time with us today. I really do appreciate it. And, , before we go, are there any shout outs to any other people doing research or you say, Oh yeah, take a look at what they're doing because this is the next exciting new thing.
Dr Budoff: Well, I think in the world of coronary calcium, you can't look beyond uh, Roger Blumenthal and Mike Blaha's work out of Hopkins and, and, and really answer a lot of great questions on how to best use this test, not only for risk stratification and for patients, but also to power trials. , the Jupiter trial had We believe approximately 50 percent of patients who had clean coronaries and no chance of having an event.
And you could have reduced that sample size by at least 50%. If you just used a simple calcium score and said, if they don't have a score, that's positive or above 100, let's not randomize them because they're. You know, if you have clean coronaries, you might believe some people can have an event, but the event rates are going to be really, really low.
So I think powering trials on calcium scores is going to be a huge way to move forward and lower the price point of these giant phase three, 500 million trials, um, and allow us to do more studies and more drugs, allowing smaller pharma companies to also get in the game and do phase three trials as well, without having a billion dollar.
Fundraising
Dr Nero: Yeah, that , I've had that conversation with a number of the pharmaceutical companies , over the past few years saying that, yes, you should be doing that. And also secondarily having an early, , test to see plaque stabilization or decrease inflammation , as an interim analysis, because if you can see that things aren't going in the direction that you want to go, or that, that, that the much more positive, decreasing the overall cost. Because, , at this point, since a drug costs about a billion to a billion and a half dollars to get to market, you know, we're going to have to do something that's a little bit smarter,
Dr Budoff: Yeah. And, and hopefully that'll lead to decreased prices of drugs once they hit the market because the investment by the pharma company isn't so dramatic that they have that extra 1 to 2 billion to recap before they even break even on the drug.
Dr Nero: here, a billionaire at some point you're talking real money. All right. All right. Well, Dr. Budoff, thank you again. I really appreciate you spending your time today and I look forward to hopefully speaking with you again at some point soon.
Dr Budoff: No, it's been a pleasure. Thanks for having me on.