55. Nicole Harkin, MD - Part I of II: Preventing Cardiovascular Disease, Cholesterol, ApoB, Lp(a), Statins and more

Hello everyone, I'm Dr. Darsha, and I'm Dr. Altamash Raja, and welcome to Medicine Redefined. A podcast where we will explore the often overlooked but necessary components of health, what we consider to be the fundamentals. We will investigate topics and practices that can give you and your patients the best chance to optimize a healthy lifestyle. It's time to move the needle forward and put the health back in health care. All right guys, do we have a special treat for you today? As you know, we spend a great deal of time exploring how to remain and or get healthy on this show, and one of the leading causes of sickness in the developed world at least is cardiovascular disease. Over the past year or so, we've been looking far and wide to bring on a special guest to take a deep dive into this crucial topic. And our guest today is truly an exceptional person who understands and shares a passion for preventative cardiology. That person is none other than Dr. Nicole Harkin. Dr. Harkin attained her medical degree from Boston University and went on to complete her internal medicine residency at Columbia. She stuck around NYC for a fellowship in cardiology at New York University in which she served as a chief fellow. She went on a complete advanced training in clinical epidemiology, which is where we will spend a great deal of time today. You'll find that this can be a complex yet important topic to understand if one is to prioritize mitigating the risk of the leading cause of morbidity and mortality worldwide. Recently Dr. Harkin moved to San Francisco with her family and founded Whole Heart Cardiology with a mission of providing patient-centered cardiac care, evidence-based nutritional guidance, and personalized lifestyle plans for her patients in a modern setting. So in this episode, we touch on various topics including, of course, her journey and passion for lipidology. We talk about the current state of metabolic ill health and developed countries. We then shift gears and touch on the various ways of risk stratification, which include diagnostics, seeing as she is an expert in lipids, when we discuss, you know, both normal cholesterol and quote-unquote good versus bad cholesterol and some of the basics in that sense. We also talk about routine and more advanced testing, some of which I've become very invested in things like just APOB, LDL, particle numbers, and size, and of course, LP is an extremely important thing for us to understand both for ourselves and our patients. We also talk about other metrics she routinely uses such as imaging modalities. We briefly touch on some treatment strategies, and of course, no conversation of cardiovascular disease and lipids is complete without the discussion of statins, which are highly prevalent in today's society. Overall, I found this to be an extremely enjoyable episode, and there was so much we wanted to cover, but just unfortunately ran out of time. Fortunately, though, Dr. Harkin agreed to sit down for part two, which will be released right after this episode. Now, without further delay, please enjoy this episode with Dr. Nicole Harkin. Dr. Nicole Harkin, thanks so much for coming on to this podcast. You're so welcome. Thanks for inviting me. I'm excited. Absolutely. So, you know, Ultimation Eye have had medicine redefine now for about a year, and for a year now, we've been saying we need to talk about cardiology, right? The number one leading risk factor and death, you know, when we talk about being healthy and lifespan longevity. So finally, you made our way to come true. So again, thanks. But I really want to delve into your journey, right? I think there's a lot of pre-meds and medical students who think about going into cardiology, you know, when they think about medicine. What made you choose cardiology? Take us through kind of, you know, back then, you're a little bit about your journey. Yeah, absolutely. So I started actually thinking, I was kind of a late bloomer into cardiology. I feel like a lot of cardiologists who talk to, they've like known they've wanted to be a cardiologist for a really long time. I sort of came into it later in my medicine training. So early on, I was actually, and remain interested in, but very, very interested in global health and international health and did a lot of work abroad. And so at that point, I really thought I was going to be an infectious disease doctor, which is kind of as a natural compliment to that experience. And so throughout medical school, that's really what I thought I was going to do. And thought I was kind of going to do a public health sort of degree and things like that. And then eventually started kind of getting interested in cardiology. I think a lot of that started actually when I was in Africa. And obviously a lot of my work there was infectious disease related as well, AIDS and TB and things like that. But started to actually really truly understand the global impact that cardiovascular disease has. So it is the number one killer worldwide in every country. And so just seeing just reproving uncontrolled hypertension, lots of premature heart disease and things like that. And started kind of, and that's kind of, I think, when the first light bulb went off, like, oh, yeah, there's a lot else out there. And then I mean, the heart's cool, too. So then I started getting really, you know, I mean, it's the physiology of how the heart works and all the things that happen is really just intellectually very interesting as well. So just really started kind of thinking about that. And then I went to Columbia for intramedicine residency and it's hard not to like cardiology there. The cardiology department is huge there, very influential, did a whole rotation there and just really kind of fall in love. And so ultimately decided to sort of marry my two interests in kind of preventive health and cardiology and really kind of become a preventive cardiologist. So that's when I in fellowship and NYU, they have a huge preventive cardiology group there. So work with them a lot, which was a great experience. And I can talk about that more. And then eventually decided to get boarded in and lipid out clinical lipidology and that's sort of where all of that that experience kind of evolved for me. I love that. I do agree. The heart is very, very cool. And I always tell my colleagues that, you know, in another life, if I didn't go down the sports medicine pathway, which is my calling, I certainly would have done cardiology. And yeah, you've had a long journey, right? I mean, so three years of internal medicine, three years of cardiology and lipidology is that more fellowship time? Or do you just sit for boards on that? How does that work? Yeah, so it's just really independent study and then you sit for additional boards. So the National Lipid Association has kind of some self-study stuff that you can go through and go to some of their conferences. They've got like a crash course for people that are looking to get into lipids and you can attend the conference and then take it and was definitely mentored by by many at NYU. I actually was the first general cardiology at NYU to take those boards and pass them. So that's kind of exciting. That's awesome. And I agree. Now, as you alluded to, that cardiovascular disease is the number one killer globally, right? Particularly in the the developed world. I mean, that's certainly the case and we've talked about metabolic ill health several times in this episode. I think this stat that I've thrown out several times that I wonder if 43% of BCD in this country, United States, right? And the expectation is that in another eight years, that's going to be 50%. And I don't, well, I shouldn't say this, but I think largely lack of education isn't a problem. We spend a lot of time talking about fruits and vegetables on this and we can do all these things yet. People continue to get unhealthy and healthier. Recently, a study that come, I can't remember, but I think it was 2018 is published that 88% of Americans had at least one marker for metabolic syndrome, right? I think that the most recent data, when you look at weight gain during the COVID-19 pandemic over the last two years in just not only the adult population, but in the pediatric population. I think that was some stat that between the millennials, which I think all of us are millennials, probably, it's like 25 to 40 something pounds. So, you know, I say all that to say that it doesn't seem to be getting better despite all the information that's out there. And one of the things that, you know, taking all those things into account, that's important for us to do is spend a lot more time talking about risk stratification and diagnostics and things that how can we identify these things earlier on, which is what you're passionate about, right? Preventive cardiology, rather than later on, sick care, you know? And so, what are some ways that you tend to detect disease much earlier on? You know, maybe not in their people in their 50s and 60s when people really start worrying about their hard health, but 20s and 30s. Yeah. So, I mean, we have a pretty robust understanding of the major risk factors for cardiovascular disease, right? And I think in general, we don't do a great job of employing those tools and using them on a regular basis. So, I think I don't know what the stats are for how many millennials have a primary care doctor, ever seen a primary care doctor, but I'm sure it's like pretty low. So, unfortunately, what happens is a lot of people don't get screened early on and don't identify cholesterol, high blood pressure. All of these things that we should be screening for on a regular basis, right? And so, you know, just kind of even taking some of the traditional risk factors that we know about, high blood pressure, BMI, smoking, you know, all the usual suspects, I think that those don't get identified early enough on. And that's just kind of some of the stuff that we all know, right? And that's even before you get to some of the more advanced stuff, which I'm sure we'll talk about in terms of really fine-tuning risk and looking at different advanced cholesterol markers and in early signs of insulin resistance and all of this other stuff that we should arguably be doing as well. Dr. Hark, at what age would you say you would typically look at risk factors then? You know, I mean, I would assume when you look at the AACVD, it's like 40 to 79, right? I think for optimal results, but now when we see obesity rates climbing so high, are we looking even younger, less than 20 maybe, to kind of look at these lipid panels, for instance? Yeah, no, for sure. So pediatricians are supposed to draw cholesterol panels in all children at some point. And there, historically, it was because we were screening for genetic dyslipidemias, right? So kids as early as eight can go on statins if they have evidence of a very elevated LDL cholesterol, which is diagnostic of familiar hyperlipidemias. So traditionally, that's what we were screening for, but if you talk to pediatricians now, they're actually screening them early for, you know, and they check blood pressure and things like that, but they are seeing what pressure cholesterol, PMI, as you mentioned, in adolescents. And so now we're not only seeing evidence of genetic dyslipidemias and issues of genetic, but really truly lifestyle-related elevated risk of cardiovascular disease. And that's truly scary because in the prevention world, we talk a lot about primordial prevention, which is like really starting young. Well, what's primordial prevention anymore? Is it, you know, utero? So I think that the ball feels like it keeps moving in terms of, okay, you know, in the cardiovascular world, we have lots of conversation about this blurred line now between primary and secondary prevention, based on some of diagnostics and things like that we can do now. But I even feel like we're we're blurring lines completely and totally, and, you know, and we know from studies decades and decades ago that young men and women who died of other causes, if you look at, so I don't know if you guys are aware of some of these studies, but from decades and decades ago, I think it was even the Vietnam War, they would do autopsy studies and look at men and women who had died in war. And there was already signs of atherosclerosis, these young people, and this was then. So, you know, I'm sure that that that is even worse today. Absolutely. I mean, I think in all of our pathology classes, we learn that this, you know, the pathogenic process begins in your teenage years, right? And it's kind of exactly where you're describing here. So let's dive a little bit deeper into, you know, we've talked about the lipid panel, you've alluded to LDL and how that can be diagnostic when it's extremely high and in the pediatric population. For those who might not know, what are the different things that would pop up on a lipid panel, like, you know, total cholesterol, and then from your cardiologist, I, what stands out to you most, what are you looking for? You know, what do you make of the lipid panel? Yeah. So, if you go to your doctor, the traditional lipid panel that you'll get is something that's comprised of the total cholesterol, which is all the cholesterol that we can measure that are contained within the LIBRO protein particles in our bloodstream. And then that gets broken down into HDL cholesterol, LDL cholesterol, which is calculated and triglycerides. So LDL cholesterol is what I mentioned is it's calculated based on the other parameters and that is a measurement of the amount of cholesterol contained within your LDL particles. And that's important and does not get discussed enough and we'll get into why that's important, but, but it is a, it is a lot of people think that that's kind of the end all BL number. And first of all, it's calculated and second of all, it's the cholesterol contained within in the particles themselves. And so the reason we, it is important to look at your LDL cholesterol is that is where most of our data is at this point in terms of if we, what does an LDL elevated LDL cholesterol mean? And we have tons of data, Mendelian randomization, epidemiologic, RCTs, all of this that lines up that shows that elevated LDL, as your LDL cholesterol goes up, your risk of cardiovascular disease and death from cardiovascular disease goes up and as we lower it, your risk goes down as well. And so that's where a lot of our data is and it's a very strong correlation and a very robust correlation. And so much of the drugs that we use are the kind of the first line of defense against cardiovascular disease is working on lowering that LDL cholesterol. And so that is our primary target. And we're probably remains so for for some time in terms of trying to get that to a lower level to prevent cardiovascular disease because it is causative. It is, it is necessary to develop cardiovascular disease. And maybe it's worth briefly going into the pathophysiology of what is atherosclerosis. I don't know if that's worth it or not. Yes. Yeah, yes, please. Yeah, super high level of it is, as I mentioned, these, these lipoproteins, predominantly your LDL particles that contain cholesterol that are thought to be atherogenic. And there's also VLDL and other types of lipoproteins and we can get into those at some point, but, but those are the primary in most individuals, the largest population of atherogenic particles are those LDL. And so what happens when those are those that concentration of apopie containing lipoproteins is elevated that concentration is higher in the plasma and then, you know, defuses across the endothelium into the arterial wall. And, and through complex things that occur, the LDL cholesterol gets oxidized. That's highly proinflammatory and you get the beginning stages of an atheroma. And so, and then as those sort of grow, then you can get either, you can get different complications, either obstructive coronary disease, which is when that plaque becomes large enough that it's obstructing the blood flow to the heart, and that's what we'll get. And, you can also get a myocardial infarction, which is when that atheroma actually bursts. Actually, one of my mentors always compared it to a pimple popping, which I think is absolutely disgusting, but very like you can just visualize exactly what's happening. And then that's off cat the inflammatory cascade and at coagulation cascade and you get a clot that forms kind of on that. And that's a myocardial infarction. And so, so those are kind of what we and and importantly with that, you know, studies have shown and it's somewhat controversial. But studies have definitely shown that it's not always the biggest, you know, we, you know, we're looking at cats and things like that, you know, get nervous about the 80 and the 90% lesions, but sometimes it's those 20 and 30% that that can cause the MI. So, so those are that's what we're trying to prevent. And endothelial dysfunction is important and allows those atherogenic particles to get into the endothelialium more easily. So smoking, obesity, you know, all that kind of stuff can hypertension, make our blood vessels more prone to allowing that cholesterol to deposit, but you have to have cholesterol in order to make a black rate. And so, while it's important, obviously to control these other risk factors, if we really control and lower that concentration of LDL particles in the bloodstream, we can really prevent the deposition and then therefore coronary artery disease. I love that you said that and it's funny because you started off with this is going to be a high level discussion, which it is. And I think that for you, you understand that. And I think for most people, when they look at a lipopanel, they kind of just characterize good versus bad cholesterol, like, oh, HDL high, good LDL high, bad. And it's much more complex than that, as you just briefly touched on. You mentioned LDL particle number and particle size a couple of times, or you alluded to these particle size. And I want to go down this rabbit hole a little bit further, because there are some people who will talk about how it's critical for us to evaluate particle number and particle size, because that's really what matters, right. And you kind of mentioned that LDL is calculated the LDLC that's typically showing on on a little bit panel. And so say a little bit more about why it's valuable. If at all in your experience to check, you know, an LDL particle number and size and what that means, you know, in terms of small, medium and large LDLs. Yeah, so this is somewhat controversial, but and it remains that LDL cholesterol is for many a very good indicator of cardiovascular risk associated with your cholesterol. That said, it misses many people. And in particular, it tends to miss, and I have seen this time and time again in individuals in whom there, there is the risk factors of metabolic syndrome obesity, et cetera. And as you mentioned, now 42 to 43% of our population fits that criteria, at least has obesity and is likely also metabolically has a metabolic issues associated with it. And so in that population, the the association, the discordance between your LDL cholesterol and the number of particles you have is higher. And so you will underestimate their risk associated with LDL cholesterol. If you're just looking at that LDL cholesterol. And so what I mean by that is that in, as I said, for most people, when you measure the cholesterol that's in these lipoproteins, you're getting a good sense of about how many they have. Now in individuals who have very high triglycerides and metabolic syndrome, you tend to get several. So instead of having, say, five large fluffy LDL cholesterol, you'll have 10 small dense LDL particles. And what we've shown in those individuals is that those who have this LDL discordance, meaning they'll have higher APOB or LDL particle, however you kind of want to measure it, then their LDL cholesterol would lead you to believe. So you'll get their LDL cholesterol back, their standard lipid panel back, your LDL cholesterol is 95 or 100 and that's so bad. But then you draw an APOB or an LDL particle on them and their risk associated with that is much higher than you would anticipate based on their LDL cholesterol number. That's discordance. And their risk studies are shown that their risk of cardiovascular disease in those individuals is much more closely tied to that elevated APOB or LDL particle. And so that's where measuring those kinds of numbers can be really important and dramatically impact that individuals risk modification strategy. Now in a standard lipid panel, we're just getting the concentration number correct. We're not getting the particle number. Yeah, so you're just getting the LDL cholesterol is 100 milligrams per desolate or correct. Okay, so then in order to obtain the particle number, is that you would have to do a separate test for that or? Yeah, so you can order APOB separately and many people are doing that. And in fact, if you look at the European guidelines, they really are taking that into account and recommending that you consider it a secondary marker. But the European guidelines do kind of mention APOB as something to follow as well and kind of do outlines and look what we just discussed. So you can order that separately if some people also do what's called an advanced lipid panel and you can get it through quests and lab core and all your usual suspects. And that will give you sort of the LDL particle number and then give you the sizes and things like that. This might not be a great question to ask, but when you're looking at the advanced lipid panel, you're looking at LDL particle number. It shows LDL particle number. It'll show small, medium, large. Am I missing anything? What else will it show? Yeah, and then it does look at like the HDL sizes and things like that. But does when you if you use that to treat, do you ever use the particle number to treat? Yes. Okay, if you're using that, are you more concerned with the small LDL or the number of small LDL or are you looking at the total amount of particle like the So I think the data is stronger when when looking at counting numbers of atherogenic particles. So whether you're using APOB, which is capturing kind of all of the atherogenic particles or LDL particles, that's kind of looking at numbers. That to me has the better data behind it in terms of more closely estimate and cardiovascular risk. And so I tend to pay attention to those more. Typically though in individuals that you see this discourse phenomenon in, in which case, measuring those kinds of things is more important, the little the small they will have a predominant small LDL pattern. So yeah, so you're kind of taking it in it goes hand in hand if you will. I got you. So you're sort of taking into account anyway. You mentioned at the outset that, you know, it remains controversial and you have eloquently described that in cases of discordance, which tends to be high with again metabolic syndrome. And I think for for those who don't know metabolic syndrome. So the five things that you know triglycerides about 150. Oh my god, I'm actually forgetting all somebody. You guys help me out. What are the other four? Yeah. I know your waste or comforts waste or comforts isn't as one. Your blood pressure, right? I'm not sure. Elevated blood pressure, a one C of six, how high is the one CF? It's just glucose. Just glucose. Yeah, what's the last one? Over 100 and then HDL, low HDL, right? Low HDL, lower than 40. Is that what it is? 40 or 50, you on your male. 40, okay. So so and and we mentioned again, you know, recent study showing that 88% we talked about the obesity numbers. Why why not use LDL, right? If we know that if we have compelling enough data to support that when you have discordants and again, we've I think we've all made the argument that metabolic syndrome is on the rise. Why not? Why is it controversial? You know, I'm not part of the guidelines, like him it. I think that so what I would say is that, you know, I think that we do have a robust data set looking at LDL cholesterol. It's what all of our clinical trials for the most part, when you look at, you know, using statins, PCS, can I never just all these drugs, the the targets, the goals, the numbers are all based on LDL cholesterol. And so some of that I think to be fair is because that is sort of what our data is on in terms of of targets and things like that. I think also what's brought up is, you know, cost. Although, true B is not very expensive at all that on. So so that is a little interesting to me. What I also hear is sort of making it more complicated for the average busy clinician to sort of sort of through. We're also, I mean, you see an LDL cholesterol number rate and you kind of intuitively have a sense of, okay, that's high low or not. I don't think average, the average clinician, you know, so we'd have to really switch over our thinking if we were to then focus on particles or able to be or something like that. So, you know, I think that these two things take time to shift over in terms of kind of all of that stuff. I think that the European guidelines, I think are a little bit more reflective of what a lot of us are doing who are really, you know, seeing individuals who, you know, we really want to focus on optimizing heart health and not just like, oh, yeah, oops, you had a heart attack, you know, of optimize it early. Preventing, yeah. That heart attack, right? So, you know, in terms of measuring alpha, little A, they're very, they recommend checking that once and every one, which I think is totally appropriate. So, you know, I think things will evolve over time, hopefully. Yeah, yeah, you know, it's time. Absolutely. Now, I do like that. And, you know, what's interesting, actually, of recent podcasts that Alan Snyderman, on Peter T.S. podcast just a couple of weeks ago, we'll link to that and they go into depth. And a lot of things that you just mentioned right there in terms of, you know, at the individual level, why the guidelines are the way they are. Of course, there's a lot of narrative in that rather than evidence. But, you know, if Alan Snyderman is, you know, you probably, you know, he writes a lot about particularly APOBE, you know, and he's not necessarily on the guidelines as well, but he's got a lot of great work on this. So, we'll link to that. But let's, let's talk a little bit more about APOBE, right? I think that there is probably more of a consensus. You already mentioned that the European guideline is I think you're looting to the ones in 2019. Yeah. It is 2018. Yeah. That are already using that and suggesting that this is maybe a good marker for, you know, cardiovascular health. Some people, again, will argue that hey, non-HDL cholesterol, which I think a standard lipid panel, it tracks it close enough. And I've had a conversation with one or two lipidologists who have made that argument. However, my, just, you know, brief understanding of literature, the issues that you mentioned in terms of discordance for metabolic syndrome tend to be the same when it comes to non-HDL, right? Particularly when triglycerides are high, which we'll talk about in a future episode's Huck can be easily manipulated with diet. Non-HDL does not track well with APOBE. I'm curious to get your thoughts on that. And, you know, when it would be good to use that versus just get APOBE, you know, that kind of stuff. Yeah. So I think non-HDL cholesterol is, so before LDL particle and APOBE became a little bit more mainstream, that was definitely what I was taught to use even more so above and beyond the LDL cholesterol. So I think that a lot of people call it the poor man's APOBE because it is in that panel already. And I think that it can be really useful if you don't readily have and one of those other markers available to you. That said, when you look most of the studies have shown that that APOBE has the strongest association in terms of cardiovascular risk and it counts for all of those other things, right? So, so sure LDL cholesterol is typically associated, maybe non-HDL is like a little bit better, but really APOBE has kind of takes into account all of these things and is probably the most accurate thing to measure in terms of assessing cardiovascular risk. Does that make sense? Yeah, absolutely. And, you know, again, just to kind of drive the home that point, I would argue that APOBE, as you mentioned, it's going to be the lipoprotein that's going to be in all of these markers. You talked about ideal VLDL. And although LDL are primarily the ones as you highlighted that are going to be responsible for, you know, pathogenesis and that process throughout the entire body, there is evidence to support that VLDL does that. I'm in preparation for this discussion right here. I was just kind of doing some light reading and cardiology journals. I'm really reading and lipidology. I don't think there is any such thing. Yeah, if there are, and you know, it can be really fun. Like you said, you would really have to have a passion for it. And, you know, I saved this. It didn't really go through this, but this article in 2020 and actually in Jack was probably talking about how VLDL cholesterol counts for one half of risk of MI associated with APOBE continued lipoproteins, right? And so my thought would be why not, you know, rather than use the poor medicine, why not just get the marker that's going to be and you're going to see, you're going to capture what you're going to see an ideal VLDL. You know, I think in a world where we're getting closer and closer to taking care of our patients at an individual level, like this word precision medicine gets used a lot. And, you know, why not check that? And so I have difficulty from, again, this is a non cardiology bias. This is just a person who wants to optimize health rather than just treat people who are sick. But I'm, you know, from your sense who has the wisdom who've been in the conversation with lots of cardiologists, you've trained in some precision institutions, what's the argument on the other side about not doing it, at least in this country in our health care system? I think it is continuing, it's an evolving conversation, right? I think that it's taken as with all of scientific endeavors, it takes time before something becomes more mainstream. It just does. And so, you know, I don't, there isn't great arguments against it other than the ones, the ones that I mentioned, right? So people argue against cost, people argue against, you know, really having to re-educate the general busy clinician as to what to look for. And so, you know, do we overly complicate it? That's sort of thing. And there are some that say that there's not given our robust data with LDL cholesterol. There's not enough evidence yet that we need to necessarily pay attention to ABOB. I personally find that we have enough. And I think that I've seen it in enough, anecdotally, and enough of my patients. I have seen this major discordance and where I get lots of patients who just had a basic lipid panel. Oh, my docs told me my cholesterol is fine, my cholesterol is fine. And then either they have an event. And so then they come to see me and they're like, what's going on? What happened? Or hopefully not, they didn't have an event, but they eventually found me, and we look at either LDL Particle or ABOB. And it's definitely much higher than you would predict from their LDL cholesterol. And so, you know, I think that given we have so many medications and lifestyle changes at our disposal to really lower risk due to cholesterol, it's just, in my mind, it's a missed opportunity. I love that. And I think as much as both Darshan and are passionate about, you know, optimizing health and practicing precision medicine, you know, I'm, I think, just as passionate about being practicing cost efficient medicine. I think there's something to be said about that. I think in that episode that I referenced with Alan Snyderman, they actually discussed this issue. I'm not sure if you had a chance to listen to it, but Alan Snyderman and practicing Canada, so they have different obviously. But at least Peter T. Had mentioned that he called the lab. And I think it was $250, $2.50 for APOB, right? Something like that, right? I haven't verified this personally with Quest or LabCore or whatever. But, you know, if it is, that doesn't, that doesn't really, you know, so, so I don't want to hold it in every creation in the hospital gets like, you know, the, the regulars that every morning and you're like, you know, yeah, I think that handled the 250. So coming back to your practice, right? If, if a new patient comes in maybe in their 20s, some individual, he's active, he's healthy, she, he, whoever. And they want to, you know, optimize their chances of, you know, living and healthy life and a longer life. What are some of the basic things that you're going to look at? You know, of course, I know you've talked about this. Length family history is, you know, super, super important, you know, back and stuff. But aside from that, when you're looking at objective things, what kind of lab values really stand out in that initial consultation that you'll order? Yeah, so there's definitely not, as you mentioned, I try to practice a, both evident-based and kind of precision type medicines. There's certainly not kind of a one-size-fits-all approach. But certainly we do, I do tend to look at both advanced cholesterol panels, so many of which we've discussed already, the benefits of either an LDL particle number or an ABOB. I also almost always measure an LP little A if someone hasn't had that measured already. And we probably haven't touched on that yet at all, but that's- Let's do that. We're gonna do that now. Yeah. A really important marker. So LP little A, like we've mentioned, LDL particles are kind of, for the average person, the primary atherogenic lipoprotein that's circulating in our bloodstream, for potentially, as much as one in five of us, lipoprotein little A may also be significantly elevated and a major risk factor as well. And so lipoprotein little A, it's basically like an LDL particle, except it has the little A moiety on it, which incidentally is very similar to plasma origin. And so that's thought to be part of why it has increased risk of thrombosis. So what we have found is that individuals who have elevated LP little A certainly have an increased risk of cardiovascular disease. And so LP little A is thought to be atherogenic, just like LDL cholesterol. And it is unfortunately genetically mediated in that it's very much, and this is why the European guidelines recommend checking it once and at least once in everybody's lifetime, because it's genetically mediated. So if you have it, you have it. And it doesn't appreciably change that much over someone's lifespan. In women, it does go up a little bit, postmenopause, but that's really about it. It is influenced somewhat by diet, but not nearly as much as say LDL cholesterol. And so in addition to being associated with cardiovascular disease, after school or specifically, it's actually also, as I mentioned, associated with an increased risk of DBTP. And then it's also associated with an increased risk of aortic stenosis. And so those are kind of the things that we need to just be mindful of in individuals who have an elevated LP little A. And I have a plenty of patients who have had cardiac events, and that's really their only identifiable risk factor is the cell pill delay. And so at the moment, we don't have any therapies for it really. So as I mentioned, diet does not tend to change it dramatically. Stattons, if anything, might increase it. And so really what we're left with is kind of niacin and PCS, kind of inhibitor. So niacin can definitely lower it. It's pretty controversial to use it. I typically don't. But some of my patients have been on it for some time and are pretty, pretty, pretty, want to stick with it. We don't have any outcomes data. So while we know that increased LP little A is associated with cardiovascular disease and causative, we actually don't have any data yet that lowering it will definitely reduce risk. It's, so PCS can and inhibitors are best fed. They can lower LP little A by 20 to 30 percent depending some it depends. And there's some signal that when that individuals who had an elevated LP little A when they're on PCS canine inhibitors, they're, they had lower risk of events above and beyond what would be expected just by their LDL lowering. So when I have patients who meet criteria for PCS canine inhibitors and have elevated LP little A, I definitely encourage them to use them. So, you know, for people who are like kind of anti-medication right and we, we hear about this population all the time, they get their LP little A measured right and it's high. Are we measuring it just to see what type of medication and therapy we can use towards it because you said it's not going to change much really not much effect from diet. So there's not much lifestyle medication that can lower the LP little A. So are we really just drawing it to see what we can give? So, currently how I use it most typically in my practice is really to be able to guide treatment decisions about other risk factors. So, so it is, and in our guidelines it is recognized as a risk modifying factor. So, so certainly in individuals who have an increased LP little A, my threshold for where I'm okay with their LDL cholesterol for instance, or, or credible or epiv is really up right. So, I, I push those people down as well as I can. I really make sure that we're optimizing everything else that we possibly can because of what I've seen LP little A do. Yeah, I, you know, I think it was maybe a different POSCA. I actually might have heard you've said that diet or at least maybe it was diet or plant-based diet tends to increase LP little A. It has. There was one small study where we it actually increased it was it's strange. I mean some of this like I said, but it's it's it's not I mean it it definitely it goes along with the statin data which also increase so paradoxically some of the things that we have that we know that can lower LDL cholesterol either don't do anything to LP little A or make it like a little bit worse. So, I don't want to go too far down this pathway in terms of treatment, but if you did get the LP little A and it was elevated and now you're going to be, you know, taking that information, you'll be a bit more aggressive and everything else that you do in terms of prevention, primary prevention, but also keeping it in the fact in the back of your mind with the statin data. Would you still put somebody on a statin for a protective standpoint because that's strong enough evidence? Yeah, so I definitely definitely and even though I know that it's possible LP little A may increase a little bit with us with statins. If their LDL is not where it needs to be with diet alone, I have a very low threshold to add it. Do you find when you're having this discussion with your colleagues possibly working in academic centers that they are quicker to or they put less of a fight to order this test? Like what's your sense in that? I do think that LP little A is definitely way more recognized at this point. Unfortunately, I still think people are thinking about it too late. So again, but this is true of a lot of medicine and exactly what you guys discuss a lot on this podcast is that, you know, I hear my colleagues thinking of ordering it in an individual who's, you know, 42 and comes in with their first MI and their LDL cholesterol is not so bad, right? Oh, maybe this is LP little A, which is why I think the European guidelines would say we should just all just get it checked at whatever age is a great idea because I'd much rather pick it up before that 42-year-old had the heart attack because, you know, and again, we don't yet have great therapeutics, so I'm not saying we 100% could, but I'd at least like to give it a shot. You know, I find that really interesting because one of the things that we all learn, most of us have to say learned in medical school and during a training is that, you don't order a test unless you're going to know what to do with it, right? Unless it serves their purpose, right? We don't want to do unnecessary testing again for the cost of the healthcare system, what not. And kind of what we talked about, you know, niacin is one treatment. I think that's very, very cheap. PCSK9s can be ridiculously expensive when you're paying out a pocket. And they're only, they're not going to be covered in a 20-year-old for primary prevention. There are some things out there. ASO is, I think, as anti-sense oligonucleotides, right? I mean, but that's like super, super early and for ridiculously high-risk patients and, you know, somebody who's had already had, like the 42-year-old who's had an MI and a couple of stents that you're talking about. But you mentioned that some docs might be quicker to order this test, but at the same time, we don't have much that we can do. Yet people will not order APOB or LDL Particle when we have therapies that we can, you know, target them and kind of modify them, if you will. I find that interesting. I can't say that I am able to explain that phenomenon. Yeah, that's. So, do you want to say something about the ASOs just so people have a sense of what that is and what you're, what your experience is, you know, in terms of where we are with the current state of the evidence with that? So in terms of, there is a one medication that's in kind of late-stage clinical trials that's looking at lowering L.P. Little A in individuals who have established cardiovascular disease and are considered high-risk. And so I think we're at least a couple years out from that clinical data, though, was the last time I looked. I think it's like two years away or so. So, but I definitely, you know, am letting my patients who meet that criteria know, because I mean, and again, to that point of what you've said about feeling like you're drawing something that you can't do much about, I think that's important that in patients who do get this drawn and it is elevated that you are able to educate and counsel them as to what the implications are of this and what they can do about it so that they're not completely totally defeated. So, yes, I let them know that there are some medications on the horizon, but I think just being very aware and not just ordering it to order it and then and then not know what to do about it, because I definitely have patients come to me and they are very fatalistic and they're like, well, I have, I'm gonna have a heart attack like that, and I can't do anything about it and I can't take a medication about. So, you definitely want to make sure that if you are going to order something like this, you do know what to do about it. And right now, the state of affairs is is really helping them get super aggressive about everything else and that gives that does give them a back essence of power, right? Okay, your LDL is currently 130. I wanted this, right? This is what we're going to do to get that down. We might not be able to do something about the LPLLI, but we can absolutely change your trajectory. Yeah, and I think that what you mentioned right there is a really important point that needs to be, I just want to underline a little bit further. I think that, you know, with the cost, the harm of, you know, unnecessary costs aside, the harm that it might increase anxiety in a patient and, you know, Dr. Beth Frady's came out a long time when we talked about her initial passion about what stressed us to the cardiovascular system. I think, you know, we don't want to order a test, and if you're not going to be able to do something about it, and if the patient's not going to receive that well, that hey, you know, I can maybe take care of all these other boxes, that might end up doing more harm than good. So that we got to be cognizant of that fact as well. Absolutely. Yeah, Dr. Harkin, I wanted to take a step back to LPLLI, you know, you talked about how our genes really influence this, and some of our audience might be thinking, well, I wonder if I have the genetics for that, right? Can you tell us which populations typically might have high LPLLI, borcer cholesterol panels, et cetera? That's a great question. I actually don't know the exact distribution in terms of which, you know, ethnicities are more likely to have it or anything like that. I think there are, it is known some populations, but as far as I'm aware, I don't think that it would be able to, you'd be able to reliably say, oh, well, you're ex-wise, so it's super likely, don't worry about it. You know, I think that, as I said, with the European guidelines, they do think that it's, you know, quite reasonable to screen one time and everyone. And again, keeping in mind some of the considerations that we've mentioned, it's very reasonable to check at some point, as long as whoever is going to be checking it has a game plan forward about, about what to do about it. Gotcha. And I just want to clarify, this test is separate from the APOB correct in the advanced lipid panel for listeners. Okay. So, West, there is an advanced lipid panel, so Quest has several advanced lipid panels. They do have one advanced lipid panel that also has LPL little A in it. Labcore, it's a separate test. In Quest, there's one bundle that does include it. And then there's another one that doesn't. So it's highly confusing. So for your average person who's, who's rarely trained in order these. So yeah, but it's something that if, you know, you wanted to get drawn and you felt comfortable understanding like what the implications are going to be, you could certainly talk to your primary care doctor and say, hey, you know, I am concerned about this. I'd like to get a drawn. I mean, I definitely think that the people who should consider getting it is definitely anyone who has premature coronary artery disease. I think that's a given. And then certainly in anyone, any of my patients who have a family history of premature coronary artery disease, that's definitely something that I think should be checked because it's a common cause of familial premature CADs. So those are, I think, you know, your average person, do they need to get it drawn? I don't know that we're definitely there yet, certainly our guidelines don't support that. But I think in people who have some of these family histories or that they themselves do, I think it certainly warranted. Awesome. So we spent a lot of time kind of defining and talking about blood markers that might give us some insight into cardiovascular health, right? What are other tests? Some objective measures, you know, such as imaging and that kind of stuff that you might pull out of your toolbox to give us some insight on how somebody's heart is functioning. Yeah. Or their risk. Right. So I think probably one of the best tools that we have right now that I think bears at least a couple minutes of conversation on is the CACS score, the coronary artery calcification score. So for any listeners who don't know what that is, it's basically a specialized CAT scan that takes picture specifically of and focuses on the heart, especially the coronary arteries, measures and quantifies the amount of calcium contained within the coronary arteries. And so, you know, many of us kind of refer to it as the colonoscopy of the heart in that it's seen very much as a preventive tool. It is not to use necessarily when people are having a chest pain. It's more to look at disease from with a preventive lens. It's sort of widely thought to be picking up quote unquote early stages of heart disease. That's a little bit of a misnomer because calcified plaque is by definition old plaque. It is not new plaque. And so really you're picking up old disease. But regardless, it is a great great tool that we have at our disposal now. And so essentially how many of us use it is when you're trying to sort of further fine tune and assess someone's risk. And it can give you a really good view into what's happening with someone's coronary arteries. So, you know, some of the examples that and in our guidelines, it's very much acknowledged as a great tool that we can use to try to help reset, stratify people, particularly in those individuals who fall at like say a borderline risk like that five to seven and a half percent. Ten year cardiovascular risk. Do we start stands? Do we not start stands? Or if a patient is sort of on the fence, if they want to start them, it can be really helpful to sort of see where they're at. So there's a lot of great robust data that we have at this point that it can really be value added in terms of stratification. Specifically if a coronary artery score is zero, in the right patient that can be helpful to help us say, okay, so far, so good. Let's keep watching if someone is truly opposed to satan therapy. Yeah, I think an analogy that really helped me and I'm still in this one, Peter, I hope all paraphrase because I got, I remember him talking about how a cac will show you after like something after the damage is already done, right? Like for instance, if I did my training and Baltimore and if you go to a place and you go to a home and you see, you know, jail bars on the windows, then you know you live in a bad neighborhood, right? I mean, that's kind of preventative, but a cac seeing a fleck of calcium on a cac score in a young person, it's like somebody's already broken in and there's a glass shattered in the back door. The damage is already done, right? And it's not, so in a 30 year old, if you have some calcium there, then at that point, like the red flag, the alarm bells are ringing, like, you know, something is going on, right? That's an indicative of advanced cardiovascular disease at that point. Is that fair to say? Yeah, so and that's what I meant in terms of a cac score of zero in the rape event, right? So it certainly is, so not only does the cac score give you an absolute number, so it gives you, you know, you're, you're a zero or you're a plan or you're a 400 or then, which means, and that's what I was talking about earlier with the lines blending between primary versus secondary prevention, because of that point, your secondary prevention. So it gives you that exact, that that that number, that absolute number, but that also gives you a percentile, and, and it sort of tells you kind of relative to other people, your same age group and gender, this is kind of where you fall. And so, you know, the cac score is great, but it has to be used in the rape context. And, and that's why I think it's one really important to distinguish that, that this is not, you know, the very earliest stages of coronary artery disease to your point, this is healed up old plaque that has been there for some time. If you're seeing that in a 30-year-old, that's like really, you know, we need to get on this now. That is very highly concerning to me. And also, in by that nature, you have to be careful in interpreting a coronary artery calcium score of zero in a 30-year-old, because it should be 30. It better be 30, right? And so, so just because it's 30 doesn't, or just because it's zero in a 30-year-old, sure, I'm like, okay, this is good. You don't have any cac right now, but it doesn't roll at soft plaque, right? Which is what I would expect that we would have in a 30-year-old. And so, where the coronary artery calcium is cacian score is typically most useful, is traditionally we use kind of 40 and above, and in super-specific scenarios where you're trying to kind of figure out adding therapy or not. So, I want to switch to, because we're talking about satins quite a bit, and I think that we have tremendous data to support their role, you know, in all kinds of prevention, and you've touched on those quite a bit, or at least you mentioned it quite a bit. But I'm wondering before we do that, it isn't worth talking about high-sensity CRP, because I've heard you talk about that quite a few times, and I don't know, use it in your practice. I do. Yeah, I think we can definitely, that's definitely something I also tend to look at, and I think is again something that is recognized within the guidelines as a risk-modifying sort of thing that you can kind of take a peak at and help you kind of make decisions. And so certainly we know, as we mentioned, you know, cholesterol and elevated lipoproteins are a necessary, necessary in order to create atherosclerosis, but inflammation is also critically important as well, because that damages the endothelium, and makes it more likely that we'll see that happen. And so, so we see certainly in, so obesity is an inflammatory disorder, so we see that in that population, we also definitely see it in in kind of the autoimmune population. So we now know that individuals with lupus and psoriasis and rheumatoid arthritis are at much higher risk of cardiovascular disease, likely because of this underlying low grade inflammation, we also see it in HIV and AIDS. So now individuals who are surviving and living long, long lives because of the amazing medications that we have, they tend to have very premature and really just definitely a lot of atherosclerosis, likely because of that inflammation. And so those are kind of examples of people that we that have, you know, known inflammatory disorders that we definitely see that association with, but it becomes just as kind of important in sort of the average person who has the maybe metabolic syndrome or kind of early stages of that or really early insulin resistance or something like that. So, HSCRP can be something that we can measure to get a sense of what is that that in inflammatory state, it's associated with an increased, you know, an elevated HSCRP of two is associated with an increased risk of cardiovascular disease. And, you know, we have Raiders done those studies of, you know, that residual risk, right? So even when people statins, we still see this inflammatory residual risk. Even those statins do, you know, help have in terms of pleiotropic effects. They do reduce inflammation. You know, I think, you know, there's, that's that, that next big area of research is how can we, we modify inflammation in a way that we reduce risk of cardiovascular disease, but also don't impair our ability to fight off infection. And so, so we're still obviously, that that's still kind of in process, but, but it's certainly something that we can, we can look at. And in terms of what to do about it, definitely we do have some, some data to show that eating whole food plant-based diets can help lower inflammation, inflammatory markers, along with lots of other helpful lifestyle changes, which I think we'll get into. I assume I'll come to the next, the next episode. But, so that's one of the things I do, I do look at, because that's something that we, we can definitely work on. Well, I don't think this podcast episode can be complete unless we talk about statins, right? I mean, I think it is one of the most ubiquitous drugs we see, especially ultimation eye in the rehab world, right? I can't name one patient that comes through our rehab doors that hasn't been put on a statin. And I'm sure our audience have heard of statins, probably have, you know, if they're younger, have parents, or grandparents who might have been on it, but just from like a basic standpoint, what are statins? What do they do? Why do we use them? Okay, that's a big task. That might be a three-hour topic, so. Okay, so give me a wee little amount. A couple more minutes. So, statins are medication. Okay, so they super high-level, they essentially block an enzyme within the liver that is necessary to synthesize cholesterol. And so actually the mechanism by which they lower our blood levels of cholesterol is actually because what that does is it makes the liver upregulate the LDL receptors on its surface. So then it pulls more LDL cholesterol from our bloodstream. So that's kind of super basic how how statins work. And as you said, they are kind of the bedrock of preventive cardiology practices all over the globe. They are a class of medications that have been around for quite some time. They were absolute game changers in terms of our ability to lower cardiovascular risk. We now have decades and decades and decades of really sound robust data demonstrating that that in particularly in secondary prevention, we reduce the risk of cardiovascular events. And by as we said, mostly by that LDL lowering effect. And but also well recognized for sort of these pleiotropic effects, which are poorly understood, but definitely we see some anti-inflammatory effects and things like that. Because certainly we see that that you know in trials that where we look at initiating statins the day someone has an MI when you know they get wild in the cath lab, they get their aspirin and they get their statin and they get their statin and they get their hydro statin. And so we know and we know that even within those first 30 days post MI, people that get that hydro statin early on do better. So there's clearly some other effects other than just that that lowering of LDL cholesterol. So they are widely used, widely studied, definitely safe lives. I'd be remiss if I did not mention that they do have some side effects certainly and in some real ones. And so probably the most commonly complained about side effects are the myalgia, the muscle aches, things like that. Some of those are dose response. Some of those are sort of the effects. And there actually was a really interesting recent study which I'm sure you guys saw where they looked at that really they took. So those sort of the nocy, nocy, I can never say that word. Nocybo. Thank you. I say seebo just fine. I don't know why it's okay. It does not go together for me. The nocybo effect. There I said it. So there's definitely been some studies where they have looked at giving patients to seebo and it turns out that we all just have muscle aches, particularly as we get older. And you guys know that there's everyone who has aches and pains. So ways that clinicians can sort of, so anytime before I start to stand, I definitely start at a lower dose possible and work my way up. And then I also actually have patients do a like muscle aches and pains notation. So I tell them to like pay it like right now, pay it into your body of the next stair to what are the aches and pains you get right them down because this is not the statin. And then when we start the statin next week, if you still have those aches and pains, that's not the statin, right? And so actually having people kind of take a catalog of those those muscle pains can be really helpful. And I found that I get a lot less people complaining about those side effects. That said, I have had patients who have had true debilitating myologist because of statins. And so that can be a really limiting kind of side effects. The other one that I do monitor and probably concerns me the most is just the diabetes risk. And it's there. And so we do have to just kind of be cautious and careful and monitor closely for worsening insulin resistance and diabetes. I'm really glad that you brought that up. I think the study that you're talking about was published in BMJ 2020. I came across this one as well. But I think this is worth briefly mentioning. Basically, they took statin intolerant patients, right? And they put them into, you know, they either gave them a placebo or a statin. And they repeated that three times or actually, yeah, they repeated that three times. And there were six periods overall and random order. And the patients either got a statin or placebo. And afterwards, they were queried. And the patients weren't able to tell like when they were getting a statin versus a placebo, right? So they were able to show that, hey, it's not necessarily a statins. That being said, though, there are physicians who will argue that, you know, these adverse events or effects, I should say, are much lower in randomized control trials than they are in clinical practice, right? Because again, the population for RCTs is much smaller than the amount of people in clinical practice that are seen that are taken stands. And, you know, prior to just over the last couple of years, as I've looked at some of the literature, you know, again, clinically, or anecdotally, I should say, I do have a lot of patients in sports medicine and rehab who tend to be maybe a little bit more active, who will say, hey, listen, like, you know, I, I don't like it. I don't like how it makes a feel. Again, we can argue it might be no placebo. But at the same time, you know, there are some statins that are more likely to cause that. I mean, so maybe a case study here would be good, right? So let's say you get a young individual who's highly active, maybe borderline athlete who comes to you and you want to start this because it seems to be appropriate. Is there a one that you might reach for initially, considering that my algeas might be something or, you know, that kind of stuff? No. So I typically use my, if I'm using a statin because I want a desired effect, I, I typically reach for, I mean, and I see a very specific patient population that typically needs a lot of LDL lowering. So I'm not, I'm typically starting with kind of the big guns, if you will. So I usually am using, uh, receive a statin, um, low dose, um, but that's typically what I'm doing. I, I think it's easier to, because you never know who will have a problem and who won't. So I think personally, I start with what I would prefer to use. And then if that doesn't work, you change your game plan. So, um, so as I said, others, and then there's other strategies, you know, you can go to every other day dosing, you can move to a different statin. So I'm proud of Patava, if you need to kind of go to a different statin, you can do that, um, uh, that's, that's lower potency. Or, you know, instead of uptry trading, you like, say, you know, receive a five was fine, but 10, it's not go back down to five and add Zedia or, um, go to every other day dosing and then try to work your way up. So there's different ways that you can kind of modify your dosing schedule, um, as you need to, um, if someone has side effects, but I'd prefer to start with what I want to use first. Absolutely. Well, Dr. Hargit, I want to be respectful of your time. Um, I know a lot of the topics we just talked about today will probably come up again in part two. And I, I'm excited for part two, because we're going to be talking more about lifestyle modification, um, the way you practice, kind of your day to day and what you do with patients. So definitely excited for that. But before we let you go, tell our listeners where they can find you. Yeah. So, um, I am typically most active on Instagram. So Nicole Hargit and MD. Um, and then I also have a website, uh, wholeheart cardiology, all one word, calm, um, and they can sign up for my news letter. Um, I, if patient, if people are interested in becoming a patient, um, I see, I'm licensed in New York, California and Florida. So I paid C patients via telemedicine in those three states. Um, I think those are the main, the main ways to get hold of me and see me. Yeah. Gotcha. Well, awesome. Thanks so much. Excited for part two. Thanks, Dr. Hargit. Sounds great. Thanks so much. Yeah. Thank you so much for listening to the show. I know it may have been a lot to digest, but man is important for us to understand. I encourage you guys to give it another listen and definitely tune into next week for part two where we talk a lot more about interventions and particularly lifestyle interventions for a healthy heart. But before you sign off, please remember the important disclaimer that everything in this podcast is for educational purposes only. It does not cost you the practice of medicine nor should it be construed as medical advice. No physician patient relationship is formed and anything discussed in this podcast does not represent the views of our employers. We recommend that you seek the guidance of your physician regarding any specific health related issues. However, if you enjoy the show, please be sure to subscribe, review and share with anyone who you think will gain value from this. Until next week, thank you for listening.