This transcript has been edited for clarity.
Robert A. Harrington, MD: Hi. I’m Bob Harrington from Weill Cornell Medicine. I’m here at the ESC (European Society of Cardiology) in Madrid, Spain, really having an opportunity to see the latest clinical trials in cardiovascular medicine, but maybe more importantly, having the chance to catch up with friends and colleagues from around the globe to talk about the latest issues in cardiovascular medicine, science, and research.
What I want to talk about today is something that I know has been of keen interest to people in the Medscape Cardiology audience, and that is cardiac prevention. This is really a big change. Over the years, the focus has largely been on how to treat the consequences of cardiovascular disease, but I would say in the last several years, there’s been a major shift toward trying to understand who is at risk and how we prevent them from having cardiac events.
I’m really fortunate to be joined today by two good friends and colleagues to have this conversation. Certainly, they bring much more expertise to the stage than I do.
First, Dr Fatima Rodriguez. Fatima is an associate professor of medicine in the Division of Cardiovascular Medicine at Stanford University, where she’s also the section chief of preventive cardiology. Thanks for joining us.
Fatima Rodriguez, MD, MPH: Thanks, Bob.
Harrington: Next is Paul Ridker from Boston. Dr Paul Ridker is the Eugene Braunwald Professor of Medicine at Harvard Medical School. He’s also the leader of preventive medicine and cardiovascular medicine. Paul, thanks for joining. Paul and I also have a large amount of experience in working on trials together, as his regular DSMB (Data and Safety Monitoring Board) chair.
Paul M. Ridker, MD, MPH: Thanks, Bob. You help us out in many different ways.
Population Level Risk Scores vs Individual Risk
Harrington: Let’s start, Fatima, with you. As we think about prevention, let’s do assessing risk. How do we decide who might be eligible for treatments? Let’s talk about some of the new data. Then let’s move to a discussion about things like advanced imaging, whether that’s CAC (coronary artery calcium) or whether that’s CT angio, and particularly now, as we combine anatomic information with physiologic information non-invasively, how do we think about that? Let’s talk about biomarkers. I know, Paul, that’s certainly one of your areas of expertise. Then let’s talk about treatment. Sound good?
Rodriguez: Sounds like a great plan.
Harrington: We’re going to do all that in 20 minutes. Let’s start with you, Fatima, and let’s talk about traditional risk assessment. You’re a preventive cardiologist. How do we do this?
Rodriguez: Well, first of all, I’ll start by saying that it’s a great time to be a preventive cardiologist. We see that our trainees are excited about it. There are new therapies that we’ll talk about, and I’ll make a note that I was Bob Harrington’s fellow in clinic, and he calls himself a reformed interventional cardiologist because, again, my focus has been largely on prevention.
The way we do traditional risk assessment is to focus on modifiable cardiovascular risk factors that we think about. For example, hypertension, high cholesterol, blood glucose, obesity, inactivity, and smoking.
Harrington: This is the Essential 8 that the AHA talks about.
Rodriguez: Sometimes called SMuRFs, so standard modifiable risk factors that we’ll hear more about. These are really factors that, at a population, can cause a lot of the attributable risk, particularly for atherosclerotic heart disease.
We have several risk calculators that are constantly being updated. Framingham was one of them. Again, some limitations that these are population-based equations. The American Heart Association has released many equations. ESC has different equations. We now have a new equation of the PREVENT equation from the American Heart Association.
Again, all of these risk equations are considered traditional risk factors. Now, with the new PREVENT equations, we have the addition of creatinine, renal function, and obesity, but they really work very well at a population level.
Harrington: Meaning that, at the individual level, information may be lacking,
Rodriguez: It may be lacking. Something that we see in clinic often, especially in my clinic as a preventive cardiologist, is that many of our patients may lack traditional risk factors but still carry cardiovascular risk.
Harrington: When you’re seeing a patient for the first time in clinic, do you routinely get what I’ll call a gestalt oh, this person is a bit overweight, they’ve got some hypertension and some lipid abnormalities. Or do you go through the process of using the scores that are built into the electronic medical record to actually calculate and facilitate a conversation?
Rodriguez: I think they’re both very helpful. How we communicate risk and prevention has to be very individualized. However, if I just told the patient, your risk is estimated at 25% based on this calculator, some patients thought that was great. That means that they’re otherwise 75% — they’re okay. I think conveying risk with risk calculators is actually very challenging. Whereas, conveying risk visualizing plaque, something like a coronary calcium scan, is very, very helpful.
Harrington: Paul, it has to be the best headline that I’ll see this week: SMuRF-less. Congratulations, first off, on your nice paper that came out in European Heart Journal. Tell us about what is SMuRF-less and what did you present today at the ESC?
Ridker: Sure. Like Fatima says, we have risk scores that generally are trying to predict, on a population level, are you higher or lower risk? They’re okay. They’re not bad, but they’re not great. For individual patients, they can be quite misleading, as we’re all learning, meaning that they overestimate or underestimate risk, or both?
Harrington: They do both.
SMuRF-Less and Inflamed
Ridker: That’s part of the problem. You won’t know for an individual patient. Also, I think that they’re really kind of stuck in a 1970s biology. They haven’t really incorporated new things that really matter. Lp(a) is not incorporated. Inflammation is not incorporated. These things really matter for patient care.
A Smurf is a little blue, cute character, which is easy to remember, but a SMuRF is a standard modifiable risk factor, as Fatima said. SMuRF-less are people who have none of those. You’d be surprised SMuRF-less people who have a myocardial infarction. Gemma Figtree has been at the forefront of this, really, and has shown that these patients are frequent, very often women, and their mortality is almost twice as high as people with traditional risk factors. Now, some of that is probably because we don’t recognize them, we don’t treat them very seriously, and also because it’s different biology in primary prevention.
What we’ve discovered recently is that these traditional risk factors pick up about somewhere between 50% and 60% of most patients. That’s a big gap that’s missing.
SMuRF-less, but inflamed, is the new thing that we’ve presented today. We went back to our Women’s Health Study. We had 12,530 initially healthy American women who literally 30 years ago, we started tracking. We simply measured their hsCRPs (high sensitivity C-reactive protein), and we said, are they low, middle, or high?
Harrington: You measured that at baseline.
Ridker: We measured it 30 years ago. On a random blood draw, by the way. It wasn’t even a fasting blood draw. It turns out that if your hsCRP is above 3 mg/L, which is the threshold for higher risk, these women are at a 77% higher risk on a lifetime basis of having coronary heart disease, about a 35% increased risk of stroke compared to the low CRPs.
Harrington: The SMuRF-less people with a low CRP vs the SMuRF-less with the high CRP.
Ridker: That’s right. This is what SMuRF-less but inflamed is talking about. Now, what we presented today, though, was a second piece. I think we’ve learned over the years, it’s one thing to say someone’s at risk and another thing to say, “What will we do about it?”
We all are preventive cardiologists, and so we’ll say, “Well, look, I’d rather tell a woman when she’s 35 or 40 that she should stop smoking, exercise, eat well, and do the right things.” But we also might want to think about a statin in these people who don’t even have hyperlipidemia.
Both of you will remember, we did this clinical trial called JUPITER a long time ago. Bob, you were involved again. We showed that if your LDL-C was actually low, but your CRP was high, you benefited enormously from being on a statin. Well, we went back and looked at the SMuRF-less but inflamed people in that trial. We had 8800 of them.
Harrington: Now you retrospectively applied the label to the people who were entered back then?
Ridker: Right. By definition, their LDL-C was already low. Now, we took out anyone who had hypertension, we took out the smokers, and we took out people with obesity. We had 8000 people left. They got the exact same result, about a 40% reduction in heart attacks and strokes, and a 65% reduction in MI.
I’m not suggesting that SMuRF-less but inflamed people should automatically get a statin. What they should get, though, is a conversation with their physician, which they’re really not having. I think the challenge for the preventive cardiology community is to say, look, yes, our general guidelines work, but many of our patients are having events that fall outside that — completely outside it.
These SMuRF-less but inflamed people will be completely missed. Their PREVENT scores are almost 0, but they’re having events. I think we have to recognize that, and we have to start incorporating this.
Rodriguez: I want to make a comment about the risk score. The risk scores are very, very heavily driven by age and gender as well, right? If you’re a young woman, your risk score by definition will be low. Many of those conversations about starting therapies may be just delayed, unfortunately. Again, in preventive cardiology clinics, we have other tools to assess risk.
You asked this question, Bob: When you see a patient, is it just based on a risk calculator? The reality is by the time they come see me, there’s usually something else going on. A family history or they have incidental atherosclerosis, so something else is going on.
Harrington: Before we get to how to take the next step in assessment, let me ask you both: Why is SMuRF-less more likely to be women? Do we know?
Rodriguez: I think these are the people who may be missed. We know there’s a long history of women being delayed in diagnosis when they present to the hospital for myocardial infarctions. For most of them, their first symptom of heart disease is an MI.
Ridker: Look, I think we can face the reality that women still, despite everything that WHI (Women’s Health Initiative) tried to do at the NIH 30 years ago, are underdiagnosed and undertreated. Now, it turns out that SMuRF-less men also exist. There are actually quite a few of them. They also have the same issues.
Harrington: The same increased risk and same benefits from statin?
Ridker: Exactly. I think what’s really going on here is that men tend to have more traditional risk factors because they just have them. We’re missing many men as well.
The Role of CAC and CT Angiography
Harrington: Let’s make sure that we’re looking at our entire patient population. You’ve both brought it up, other methods of assessment. One of the things that excites me, as you say, as a former interventional cardiologist, is the improvements in imaging through CT. We’ve had CAC for a long time. More recently, we’ve had CT angio with now the ability to combine physiologic measurement non-invasively with the anatomic measurement.
Let’s talk about patient care. Who are you sending for CAC? Who are you sending for CTA? I’ll ask you both the same question.
Rodriguez: I think, again, as a preventive cardiologist, my practice has changed in the past few years with technology and the focus on imaging. I’ll say, particularly before we get to what it does, it really helps have that conversation with the patient in a much better way than a risk score can do.
For most of my patients, particularly those patients over age 40, when they’re intermediate risk — their risk scores seem low but there’s something about them that seems high risk, particularly those that are maybe reluctant to take therapies — a coronary calcium scan is usually the start. This is a gated CT scan, without contrast, that will tell you very accurately the amount of calcified plaque in Agatston units. That number really has a graded relationship with cardiovascular risk. Again, this is calcified plaque.
Harrington: Where’s risk start?
Rodriguez: Risk starts really at any calcium score above 0, and again, depends on your age. I often will see a young patient with a calcium score of 10, which is not normal, right? It should be 0. There is a threshold, but we know that calcium scores above 300 are really equivalent risk to coronary artery disease, and I tell the patients they have coronary disease. A calcium score above 1000 Agatston units, same thing. Very, very high risk.
Harrington: You’re getting CAC on virtually everybody?
Rodriguez: I would say in individuals, again, who are unwilling to get treated, to motivate them or patients who are low risk by traditional risk factors. The primary care community now is ordering more of these tests and they are referring them to my clinic.
Harrington: Based on the CAC score.
Rodriguez: Based on the CAC score. They’ll send them to me. Before, they used to actually be referred directly to our interventional cardiology colleagues for cath. They said, your calcium score is high.
Now we know with the disease physiology, that that’s not what needs to be done. We don’t do that, right, as an interventional cardiologist, but can we use now their biological numbers, their LDL-C, to treat.
Harrington: Now, talk about who do you send for CT angio?
Rodriguez: For CT angio in primary prevention, there is no indication right now. It is currently not covered by insurance. Do I get CT scans on most patients with indeterminate chest pain? It’s very useful for the symptomatic patient. I do have some patients where I practice who will pay out of pocket for these primary prevention CT scans. They are extremely valuable because, in addition to telling you how much calcified plaque you have, they also tell you how much noncalcified plaque you have. Now there are AI quantification methods that can help you track the progression.
Harrington: You and I have talked about this in other settings.
Rodriguez: Yes. Very, very helpful, again, for a specific type of patient. I will say that I’m part of a study called the Transform study that’s sponsored by Cleerly. We’re testing the hypothesis that using this type of…
Harrington: I’m the DSMB chair.
Rodriguez: Which again, is an important question to answer. Does this actually change outcomes in our patients beyond coronary calcium scores?
Harrington: Paul, that’s what’s being done in Palo Alto. What’s being done in Boston?
Ridker: I think in Boston we’re probably a little more conservative, but we are shifting in the same direction. It’s really a question of what our primary care doctors are doing. I think most of them are probably saying, I understand the data. There’s no doubt about it that a picture of the disease is going to be better than a risk factor. You have it or you don’t have it.
Many of our folks are going to scan the chart for CT scans and other evidence of calcification say, “Oh, it’s there. I don’t need to know the Agatston score. I just want to know it’s there.” We’re slowly shifting toward more people getting CACs. It’s inexpensive. The radiation is very low.
Where I’m coming into this, though, is with a slightly different twist, which is that I like the imaging as a way of saying who has the disease in primary prevention. Remember, the image tells me nothing about what the biologic driver of that individual person’s disease is. We’ve been trying to get a marriage between the modifiable biomarkers and the imaging.
What we’ve been talking about is get the imaging test to say that this person is primary prevention, but they have the disease. I need to intervene. I still need the LDL-C. I think I need an Lp(a). I think I need a CRP to say, is my intervention going to be anti-inflammatories or simple lipid lowering. If the trials work out, might it be Lp(a) lowering.
Imaging is going to tell us who has disease, but it tells us nothing about the biologic reason this particular person has the problem. I think we’re at a point where, if we can marry the biomarkers and the imaging, I think that’s the future.
Harrington: That allows you to do more personalized treatment for that particular patient.
Ridker: Right. We’ve got to get past this idea that everyone’s atherosclerosis is the same, right? We lived in that world for 30 years because we really just had statins, but now we have many other ways of getting there and new biology coming online. We have to get to personalized prevention.
What Biomarkers Do You Measure?
Harrington: Tell our audience, what’s the panel of biomarkers specifically that you order? What do you find most helpful in a preventive cardiology practice?
Ridker: I’m a pretty simple guy, Bob. We just published this paper in the New England Journal of Medicine in December where we had three things. We just had the LDL-C, the hsCRP, and the Lp(a). All three predicted 30-year outcomes. All three were completely independent of each other, and these are three things I can actually modify.
Harrington: They all contribute information to the risk.
Ridker: Some people had one, some people had two, and some people had three. What was really interesting is the patients who had all three elevated, their risk was actually much higher than what the PREVENT scores were selling us anyway, and vice versa.
Not only was I getting a sense of what their risk was, but now I could say to them, “Yes, I need you to stop smoking. I need you to go to the gym. I need you to do X, Y, and Z.” I also need you to think about getting your cholesterol down for this patient. I need to target your inflammation for that patient. This one, I need weight reduction in a very serious way. If the Lp(a) trials work out, I think we’ll have another access to this.
It’s trying to figure out not just what’s your risk, but what I can do about it.
Harrington: Do you check HDL-C?
Ridker: I do because my patients want it. It’s like triglycerides, right? I mean, if the triglycerides are extremely high, that’s a different issue. We’ve had guidelines asking us to measure triglycerides and HDL-C for 40 years and I don’t really act on them.
Harrington: Because we don’t know what to do.
Ridker: Right.
Harrington: What about hemoglobin A1C? Do you routinely get that?
Ridker: It’s a routine part of what we do for other reasons in the metabolic sense of things. What’s interesting is I started to get GFRs when the new data came out, and they’re all normal. I was like, “Oh, I already know who has kidney disease.” I actually must say on that piece, I’m sort of like, hmm, but that’s all right.
Harrington: What are you doing, Fatima?
Rodriguez: Again, my clinic is so preventive that many of the patients will show up with a set of all the Boston lab panels. Most of the time, I’ll tell you that I don’t use any of the information, but it is helpful to track. For many patients, ApoB is the most useful. HDL-C and triglycerides are important markers, right? I think especially the triglycerides for insulin resistance.
For HDL-C, unfortunately, people are like, oh, my ratio is good. I actually saw that in a physician’s note the other day. LDL-C is high, but HDL-C is also high, so they’re all good and we need to obviously move away from that.
Harrington: It’s called a teachable moment.
Rodriguez: Exactly. We wrote a nice letter to the referring clinician. We have to have something to target. I’ll give you a very specific example. I had a patient with a very low LDL-C (60 mg/dL), she was on many therapies, primary prevention. She had a CCTA that was done for other reasons, and we did a plaque analysis on it. She had a large amount of noncalcified plaque.
I said, “For you, let’s consider what else is going on. Let’s intensify your antithrombotic therapy. Let’s think of anti-inflammatory therapies. Let’s get that LDL-C much lower because for you, this is obviously not enough.”
Harrington: Are either of you using colchicine in the primary prevention population? Most of the data are in secondary prevention.
Ridker: I have to be very careful here. In secondary prevention, chronic stable angina, I have many patients who are candidates for colchicine. I think it’s a remarkably underutilized drug.
Harrington: I was using it for secondary prevention.
Ridker: It’s incredibly inexpensive and it seems to work very well. For primary prevention, I’ve been holding off. There are some patients who have very high scores with the imaging, who I almost treat like secondary prevention. Jean-Claude Tardif is doing a trial in very-high-risk primary prevention. There are so many patients who should be on the drug in secondary prevention. I think if we start there, it would be a good thing.
Harrington: We should focus there. What are you doing?
Rodriguez: Completely agree.
Harrington: What about LDL-C in primary prevention? Are you trying to go as low as you can go? We now have many tools in the toolbox, right? We’ve got statins, we’ve got PCSK9 inhibitors, we’ve got ezetimibe, we’ve got bempedoic acid. We have many ways to lower it.
Rodriguez: Let me take a step back and say that what we’ve realized with imaging is there’s really not these clear-cut differentiations between primary and secondary prevention. It’s really a continuum of risk.
Harrington: I used to call it prevention 1.5.
Rodriguez: That’s right. We used to call it that in clinic. Once they have atherosclerosis, they have the disease.
Harrington: Are they primary or secondary?
Rodriguez: At that point, I don’t want to wait for them to be high-risk secondary prevention to have an event. I don’t treat those patients as primary prevention and those lipid targets. I’m not targeting LDL-Cs of under 100 mg/dL, which for primary prevention, may be appropriate, I go much lower.
Harrington: What’s much lower?
Rodriguez: Under 70 mg/dL, I think, when there’s some atherosclerosis, ideally, as low as you can go. I think all of us in the preventive field don’t see a downside to going as low as you can go.
Harrington: It’s interesting. You are the Eugene Braunwald professor, he says that you can’t have too low an LDL-C.
Ridker: It’s almost true that we almost always agree. I think it is true that you can’t be too low. It’s not dangerous. We all understand that. I think the question is the financial incremental cost to get your LDL-C from 70 mg/dL, which most people on a high-intensity statin can get close to, down to 40 mg/dL, it starts to become exponentially expensive for a pretty small absolute risk reduction.
Our trials are pretty much based on relative risk reductions, but the absolute risks are getting very small. What I’m concerned about, and we’ve published now large amounts of data, that in secondary prevention on a statin, it’s the CRP that’s telling us about your likelihood of dying and having a recurrent event, not the LDL-C.
The LDL-C is pretty well taken care of with a high-intensity statin alone. That doesn’t mean I don’t use ezetimibe, of course I do. I use bempedoic acid. I add drugs on. I have patients on PCSK9 inhibitors, but most of my patients, once they’re on a high-intensity statin, I’m more concerned probably about their CRP and I’m going to start thinking about colchicine. I’m going to start thinking about other ways of getting them to do things, such as weight reduction. That is, to me, the untapped potential here. …
Harrington: Tamp down the inflammation at some point.
Rodriguez: I agree. Just to build on what you said, one of the values of imaging is to show who should have these more expensive therapies, right? I think there are many great therapies out there. The SGLT2 inhibitors, I say they’re like the new statins, right? GLP-1s are really game changers for prevention.
Does everyone need every drug? Probably not, especially when we think about the cost of these drugs and the population benefits. Imaging is extremely helpful to help guide that.
Future Therapies
Harrington: One last question. I’m going to ask the same question to both of you. I’ll start with you, Paul. What are you most excited about that’s coming down the pike?
Ridker: I have to tell you, I think cardiology is an explosive area. I walk through these meetings. I learned so many things I didn’t know about. I think we all get focused on our area, and to see things happening in heart failure that are mind blowing compared to where we were just a few years ago. The whole ATTR (transthyretin amyloid cardiomyopathy) situation, a disease that most of us didn’t even know existed, suddenly has four incredibly effective therapies. That excites me because that means science and biology are coming into our field yet again. That’s great.
You’ve already mentioned one of the downsides. It’s getting kind of expensive and we’re going to have to figure out, as a society, who does need these various things. From a scientific point of view, I think about the stuff going on at Verve. Think about the things going on in terms of genetics. It’s a pretty exciting time.
Harrington: It’s interesting the way you said it, because for a while I think many of us were a little depressed that every drug we had was generic, which meant that there was nothing new. There were beta-blockers and statins and ACE inhibitors, and like, well, where’s the new stuff? Now, as you say, there’s been an explosion. And it’s driven by science and it’s driven by discovery science and figuring out new mechanisms of disease. I agree with you. That’s exciting.
Rodriguez: This is the hardest question because there’s so many exciting things in prevention. I would say the first is that there are things now that are outside of our lane of atherosclerosis, the cardio-kidney metabolic syndrome, and all the therapeutic areas. Why cardiologists need to know about the liver and the kidneys. It’s so exciting to keep learning this and to help our patients because our patients are really one patient being taken care of by many specialists, so how do we bring that care together?
The second thing is this new excitement around the science on treating residual risk, which is, I think much of what you’re talking about. Some of it is inflammation, some of it we just don’t know yet. Is it the lipoprotein(a)? So just the data that will come out on that in the next few years.
Harrington: To try to understand where we might go.
Rodriguez: It may be different for each patient.
Harrington: Well, this has been really fantastic. I want to thank Paul Ridker and Fatima Rodriguez. Thanks to both of you for joining. For the listeners, we hope you’ve enjoyed it. Please drop us a comment, give us a thumbs up or occasionally a thumbs down, if you didn’t like it. Let us know what we can do better. Let us know what other kind of things you’d like to see us discuss with the experts that I’m always running into at meetings like this.
This is Bob Harrington, from Weill Cornell Medicine, thanking you for listening from Medscape Cardiology and theheart.org.
Robert A. Harrington, MD, is the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and provost for medical affairs of Cornell University, as well as a former president of the American Heart Association. He cares deeply about the generation of evidence to guide clinical practice. When not focusing on medicine, Harrington dreams of being a radio commentator for the Boston Red Sox.
Cite this: Robert A. Harrington, Fatima Rodriguez, Paul M. Ridker. SMuRF-less: CV Prevention Beyond Traditional Risk Factors - Medscape - Oct 29, 2025.
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