104. The Future of Cardiovascular and Metabolic Health Through the Lens of Lipidology | William Cromwell, MD

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 healthcare. Hello everyone, our episode today is a wonderful delight and a true treat. Our guest is the one and only Dr. William Cromwell. He is a clinical lipidologist from Rally, North Carolina, and he has been a tremendous voice and an academic leader in the fields of cardiovascular disease and lipidology and metabolic health. He's also the chief medical officer of Precision Health Reports. If you are a recurrent listener, that company may ring a bell because the chief executive officer, Matt Martin, was previously on this show. Today we have his partner in crime, Dr. Cromwell. If you aren't driving, I highly suggest you get a notepad and a pen or pencil because you're probably going to want to take a lot of notes on this. Dr. Cromwell has been one of the most popular themes of our podcast, Dr. Nicole Harkin, who was previously on our podcast, is one of our top ranking episodes. We decided to deep dive lipidology again, but this time we're going to look at it through the lens of precision medicine and metabolic health. While we're going to be talking about markers like LP Little A and APO B and bust the myths on LDL and HDL, we're going to get a little nerdy. Having a notepad might be useful. You might gain things that you're going to want to bring up to your doctor or that you might want to Google and go down the rabbit hole a little bit later. This episode is full of information. It's super practical. It's things that you will look into. I promise because this is the future of medicine. All right, let's get to it. All right, Dr. Bill Cromwell. Thank you so much for coming onto the show and sharing your expertise. Thanks for having me. Absolutely. Not too long ago, we had your counterpart, Matt Martin, come onto the show to talk about precision health reports. We covered the basis on that, but now we have you to really deep dive into the science of lipidology and so we can nerd out on that. One of the things we love to really ask our guests is their journeys. What might have been those key events that got you into cardiology and then more specifically lipidology that kept you on the straight path and maybe even led you a straight for the better? That's a great question. Actually, it's a funny story because I started as a physical chemist to went to medical school. I was a young guy. I got to medical school and so I just asked a couple of questions. What kills people? Bascular disease. Well, how do you stop that? We're not entirely sure. What options do you have? As they were ticking off things from hypertension to diabetes, we got to this thing about lipoproteins and cholesterol. I said, I want to make you measure that, right? Well, yeah. Well, I'll do that. And they said, nobody has that. That's kind of a crazy thing, but at the same time, I thought to myself, if the number one killer of Americans is still obtuse and there's something about analytics that could play a role in this, that seems like a good place to start. So very intentionally in medical school, I was very interested in lipidology and through my residency and fellowship, I just charted a b-line straight to a lot of protein disorders. I started my first lipoclinic in the late 80s at which point very few people cared. If you can think back that far, we really didn't have statins to speak of. They had just launched an evagore. We didn't have very many outcome studies. We didn't really know of doing things in this field was going to help people. And sometimes you get lucky. And so that's basically what happened. I had a passion about something. I invested my time in there and lo and behold, it became to be something of importance. So that's been the short story of 30 plus years. I love that. It's a very logical progression. And it's like, yeah, that's what I'll do. We'll measure it. And yeah, I can only imagine because it's especially the United States, right? We dragged our feet when it comes to measuring, um, L. P. Little A and people in the younger population of these earlier in their lifetime, especially April B with the guidelines. And so I can only imagine what it was like 30, 40 years ago. Now you're, you're not the first lipidologist that's been on here, right? We were talking about that offline, Dr. Nicole Harkin shout out to her, um, but in long-term listeners, certainly, are familiar with that concept. We've talked about that time and time again, but maybe for those who haven't, um, heard the term lipidologies or lipidologists, could you define exactly what that entails, um, and what type of specialties go into, to be board certified of biology? Well, just think everything cholesterol and triglyceride related is lipidology. Lipidology is about the blood fats and the major blood flagots are cholesterol and triglyceride. Uh, then you kind of go rings out from that. The next ring out is, uh, how cholesterol and triglyceride are trafficked in the body and particles called lipoproteins. And what that means for both health and disease, um, then you get into the various things that can mess that up and there's a wide range of stuff from other medical issues people have such as diabetes or insulin resistance to genetic causes, sometimes medicines are taking. Uh, so it's, it's a very rich, uh, area that you can simply say it's about cholesterol and triglyceride, but as soon as you start unpacking it, uh, you realize whenever you see somebody, there are 70 plus potential things going on, what combination of the 70 to this person have? Yeah. Yeah. Now, most people who've ever been to a doctor or really talked to anybody about nutrition or been associated, they've heard the term cholesterol. And historically, people used to say good cholesterol, bad cholesterol. We know that's not really a thing, right? It's, it's, uh, really the particles that are good or bad in terms of how they interact with our physiology, but you've brought the term lipoprotein a couple of times. That's your Twitter handle for those who don't know and I absolutely love that. Now, can you define a little bit what lipoproteins are and what purpose do they serve, uh, within our bodies? Sure. So, um, going back to cholesterol and triglyceride, these are fats and these fats don't dissolve in water. So since our blood is mostly water, how would fats move in water without just being like a little slime layer on the top? And the answer is there are these lipoprotein particles. So lipoprotein looks like a tennis ball. It's got, uh, various fats on the outside, it's got proteins embedded on the outside and the center is hollow and what gets stuffed in the center are varying amounts of cholesterol ester and triglyceride. So lipoprotein particles are those things that move cholesterol and triglyceride to different places in our body for different reasons. Now the, the interesting thing is that it's the particle that gets the letter name. So your viewers are very familiar with LDL, HDL, LDL is bad, HDL is good. But what that means is low density lipoprotein, that's what LDL is. So it's a type of particle that carries cholesterol. Um, as you said, there has been the nomenclature of good and bad cholesterol, but that's because cholesterol has been easier to measure than other things. And we have used the amount of cholesterol in an LDL particle as a way of quantifying things. Not 100% will probably get into why it's not 100% but that's where the term bad cholesterol came from because it was a bad particle LDL and the cholesterol and bad particle must be bad cholesterol in if HDL is a potentially good particle, then the cholesterol in HDL must be potentially good cholesterol. So let's do that now. Let's talk about a little bit more what makes the LDL particle bad? What is it about the LDL particle that's quote unquote bad? What is about the HDL particle and then are there other lipoproteins, which is really what I want to get into that might be for bad actors that we should really care about? Well, that's a little question and it could take us a little while to unpack it. So good and bad actually come from the way in which these particles were first identified. So you could ask yourself, when did we first know anything about human lipoproteins? And that was in the early 50s. John Golfman and Linda again were the guys who characterized human lipoproteins. They did so with ultra-centrification. They found that some particles were heavy in dense and others were light and buoyant. And so they first categorized these by their flotation. High density lipoprotein was the more dense and low density than very low density. So these names actually were characteristics of the way they floated in an ultra-centrifuge. The next observation was that if you look at the association of these particles with people who are having heart disease, there was clearly the case that a subset of lipoproteins were strongly associated with the risk and another subset was strongly associated with less risk. So those that were associated with risk are called the apobias and boy containing lipoproteins. Apob is shorthand for apolipoprotein B. It's a structural protein that's on the outside of many populations of particles. The entire apobipool is considered potentially bad. And a high number of those particles, a large amount, would accelerate blockage formation. Now what's curious about the apobipool is that over 90% of all apobiparticles are LDL. So it's not wrong to say that LDL is a bad particle. And it's not wrong to say that LDL particles are the key drivers of blockage formation. But to your point, they're not the only ones, but they certainly swamp out and dominate the apobipool. There was a time where when we were doing that, I remember you mentioning that you are on a different podcast that you had a partnership with Jemot Post, right, who came with them or you guys together came up with the NMR profile and they were measuring LDL particle number as well as the size of the LDL, which also matters. So I'd love to hear you briefly talk about that. And then I'm also noticing at least both in mainstream and a lot of, you know, among the lipidology folks that LDL particle number is really not emphasized anymore in terms of what we're tracking. And apobip is more favorable. When did that fall out of favor? Or is there still a role to check for LDL P rather than LDLC instead of maybe, or is apobip just good enough? All good questions. So a little story. I was actually in an election rally in North Carolina. I had some downtime and the guy who was driving me around for the day said, do you want to be a man who can measure lipoproteins? Now that's a trick because a lipoprotein particle is a mixture of phospholipids, free cholesterol, proteins, cholesterol, estrogen, and triglyceride, there's no chemical thing that makes one particle different than its neighbor. So historically, quantifying a unique lipoprotein is very difficult. So we went to an office and I met this tall guy in Blue Jeans and Arachis looking at Intermar spectra. And I said, what are you looking at? He said, I'm looking at these signatures from these lipoprotein particles. And we talked for a while and I said, so you can resolve the downfield shifts that are this close to one another. He said, well, you know something about this. It doesn't seem like you should be able to do this. And so over several months, we had a lot of correspondence. And indeed, he had found one way to uniquely quantify individual populations of lipoproteins. And so we started working together and the question was, would any of that information clinically make a difference? And how would we determine that? And the short answer is a whole lot of clinical trials. So now 18 million samples, 700 peer-reviewed papers later, we learn a lot. And what we learned is that golf and a litter gun were right in 1952. And what they observed back then was that you could measure cholesterol or you can measure particles. If the measurement of cholesterol and the measurement of particles agreed, that's called concordance. And they both were equally associated with risk. But if the measurement of particles was different than the measure of cholesterol, discordance, risk tracked within particles, not with the cholesterol, that observation has been true every time it has ever been looked at since 1950 and every people grew in every trial. So at the end of the day, it is the particle that is responsible for interacting with the artery wall to affect blockage formation. It is the number of particles that drive that process forward. And cholesterol is just a way to try to infer how many of those things you have. So when you ask, how do you measure the number of particles, you can do it by ApoB. And that's been around since the 80s. You can do it by NMR LDL particle number. That is another valid outcome proven way to do it. ApoB had a good 20 year head start, so to speak. And so a lot of people would use ApoB and that's fine. In my opinion, ApoB and LDL particle number are alternate measures of the number of particles. And either one can be used for good utility. It's a matter of what's available, what's easy for the practitioner to get. We have reports that embed both of those in our credit metabolic report. Many more people get the ApoB version and the LDL P version and that's fine. But it's just two different ways to get to the number of particles instead of relying on cholesterol to infer that. I'm glad you brought up concordance and discordance. You know, at least as I mentioned, I'm a novice in this field. And at least over the last two years, I've had chat with at least three lipidologists. And at least one of them has mentioned that when we're looking at authentic particles, ApoB is really not necessary. And people at this point are thinking about their cholesterol panel and they get that you have a comarcus as non-HDL cholesterol. And at least the first person said, well, you know, non-HDL cholesterol is a good proxy for ApoB. Both you and I know that that's a good proxy is not good enough when you can check the all the other genetic particles. But what I've come to learn is especially in folks who have at least multiple factors of metabolic syndrome, that discordance becomes greater and greater. Would you care to just elaborate a little bit on that? Why a non-HDL cholesterol isn't necessarily the best thing to look at. And ApoB is truly what we want to track if that's the mark you're going after instead of LDLP. Well, so either way that you measure particle number, ApoB or LDLP will be a definitive answer to a definitive question. How many of those particles do I have? When you're using something that's cholesterol based to answer the question, you run into a couple of problems. The first problem that you run into is that the amount of cholesterol in a particle is not constant. So let me show you an example. So I've got a bottle of water. Now this bottle of water has not been opened. It says it's a 500 ml bottle of water. All right, so if I have one liter, I have two bottles, simple math, right? So two is a half and a half. But what happens if I have a particle that looks like this? See now the water inside is much, much less. And to get a liter with containers with this amount of water would be many more than to get a liter due to two full bottles. This is the dirty little secret of cholesterol testing. The amount of cholesterol per particle is highly variable. And it becomes more variable when you get into issues such as metabolic syndrome, insulin resistance, type 2 diabetes. There are physiologic exchange reactions that take place where cholesterol is taken out of some particles and give them to others. And triglyceride takes the place of the cholesterol that was removed. And this two directional exchange is done by cholesterol ester transfer protein, CETP. So what happens is as you become more insulin resistant, metabolic syndrome, diabetes, high triglyceride, the characteristic of APOB containing lipoproteins is that they become relatively cholesterol deplete, not all of them, but most of them. So the amount of cholesterol in the particle has now gone down. That's why the LDL cholesterol and the APOB or particle number can be discord. Because I'm measuring the amount in an unknown number, but what's in the particle isn't constant. The second challenge is that total minus HDL cholesterol is the cholesterol supposedly in all the APOB containing lipoproteins. But remember, I just said that under physiologic conditions, the amount of cholesterol in these particles is highly variable. And so when you look at diabetes or metabolic syndrome, you can ask the question, how discordant is 9 HDL from APOB or how discordant is 9 HDL from LDL particle number? And the answer is you can get up to 40% discordance in those settings. That's why 9 HDL, though it is better than LDL cholesterol, is not the same as knowing the absolute number of particles, especially in those settings where you have more cholesterol depletion as we call it or less cholesterol for particle. Yeah, that's awesome. Thank you for that analogy. It really makes sense. So those who are watching will certainly get a chance to see that. This might be a bit too much in the weeds, but APOB, as I understand it, they're at least APOB 100, APOB 48. When we're talking about the athergenic particles, and all the APOB family, which one of those is it? And what are the differences? Well, APOB 100 is synthesized and liver. It's on VLDL, all the breakdown products of VLDL, on LDL and the breakdown products thereof. V48 comes from the gut. And it is embedded into a very, very large lipoprotein called chylomicrons. Chylomicrons are the way that we take that's, and initially, from the gut, package them, and send them into the circulation. V48 is very, very small as a contributor to the APOB pool, which is about 2%. It's a very small contribution. So V48, while you may find it under certain conditions in athletic clacks, it is not a primary player. The APOB containing particles that are much more injurious are the LDL particles, and there's a family of those. Remnant lipoproteins are very injurious, and remnants are the breakdown products in between VLDL that leaves the liver, and LDL, which is formed after many breakdowns of VLDL through the remnants until it gets to LDL. Now, these remnants are usually cleared very quickly from the blood, but in the occasion where it is not, then you have a problem that they can rapidly accelerate blockage formation. And there are some unusual genetic disorders that are remnant abnormalities. They don't have an LDL problem. They have this breakdown product. They didn't get clear properly and just hanging around and as a result, this is causing blockage formation. So that's a little bit about V48, V100, and of the APOB pool, it's the remnants and the LDL family, which are the worst actors. What percentage of the population have that genetic variation where they're accumulating a lot of remnant particles, do you have a sense? Yeah, well, it's 2% have the genetic predisposition, and then a subset of that go on to develop the full-blown syndrome. So what we're talking about is, despite a lipoprotonemia or type 3 hyperlipidemia, that is a two-hit problem. The first hit is you have to have an abnormal APOE. APO lipoprotine E is responsible for clearing remnant particles. There are major phenotypes of that or genotypes, and genotype E2, E2 happens about 2% of U.S. population and that's the setup for not being able to clear. The second thing that has to happen is you have to overproduce VLDL or very low density lipoprotine out of the liver. If you overproduce VLDL and you can't clear the remnants, that's what sets you up for persistent remnant elevation and blockage formation. So it's 2% have the genetic predisposition and a subset of that go on to develop full-blown dispatile lipoprotonemia. Wow. We always hear about APOE, particularly APOE-4, and it's linked with Alzheimer's. But I did, at least I remember reading at one point that APOE is implicated in cardiovascular disease, so thank you for that because now I can kind of wrap my mind around that. Now the other lipoprotine that I think is really worthwhile for people to know, especially if you're a South Asian ancestry, which Darshan IR here, is lipoprotine A. So could you talk a little bit about that? That's the other side of the family, right? But also maybe independent risk factor for mace. So what is that? How is it different and why is it important? So low density lipoprotine, as I said, is a family of particles. And that family has different characteristics. You can have smaller ones, larger ones. You can also have those that have an extra protein on the outer surface called apolipoprotine small A. Now that is a long protein that has several repeating cringle units or circular things that it was actually named because I guess it reminds somebody of a Danish pastry. Jevne's cringle repeats in this long protein called apolole. When that is attached to APOE, it's like pin the tail on the donkey, and that particle has many attributes that make it much more injurious than just a regular LDL particle. So how frequently do people have elevated LPOE? Well, most common reason for it to be elevated is genetic. As you said, Asian Indians are ethnicity with many more problems with LPOE, the many other ethnicities. In the US, the frequency is about 20%, one in five individuals in the US has significant LPOE elevations. We know from a number of studies that risk scales by quantity, and as you go higher and higher and higher, not only is LPOE contributing to risk, but at some point, it can be its own independent causal risk factor with no help from anybody else. And the thresholds that people typically talk about as being of interest, if you're using animals per liter, it would be above 125. And then when you start getting over 150, 200, you're really picking up steam, and there's a population that's definitely has a risk due to LPOE. There are other reasons why it can be elevated, but you don't see that often. Hypothyroidism can increase LPOE, you know, renal insufficiency can increase LPOE. Transphanantake will increase LPOE. So there are some other reasons for it to be high, but most commonly it's genetic. You know, something David comes at, Dar's comment on this, if you remember, I remember Dr. Harkin mentioning that there was a study published somewhat recently that a vegetarian diet or a vegan diet can increase LPOE, do you remember that vaguely? Are you familiar with anything like that, Dr. Kama? Those types of studies are small, and they're hard to draw a conclusion. So we have a lot of signals out there, as I would call them, you know, you have a population, they do a certain thing, there's a signal for change, whether that's a significant association or causal is less than clear, but that's something that some people are interested in. Yeah, absolutely. So we spent some time talking about the atherogenic particles, rightfully so. Is there anything else that we have uncovered that you think is worthwhile for listeners to understand and really advocate for themselves when they are looking at cholesterol panels when they're considering their cardiovascular stroke, just risk in general? Yeah, I don't want to get us off topic too much, but just introduce an idea. And that is that whether it be punitive lipoproteins like the apobipul or hypertension or diabetes or any major causative risk factor, risk is a function of magnitude over time, how bad for how long? And this is critical. This is why people with familial hyperclestrolemia and born with very high LDL levels end up with disease very early in life because they've been that way since birth and they have been bathing their arteries in these increased numbers of they would be particles, LDL particles, and it takes its toll over time. So the first question I have when I see somebody who has an abnormal value for apobipul or LDL cholesterol is how long has it been that way? The longer the worse. And many times we don't know. People oftentimes, especially men, they don't seek health care very frequently. Sometimes they only do it because their wife seems in the office. And so the wife has made you come to the doctor. Now you're 45 years old, you're getting your lipid panel and it's abnormal. And you chase that with an apobipul and it's it's high. And I say, well, how long has it been that way? Well, we don't know. Now you're left in a quandary. What do I make of this? Why is it high? How long has it been high? Are your vessels already demonstrating evidence of plaque formation? These are critical questions and get us into the precision medicine field. This is how we should be taking care of people one at a time. The three of us on this call could have the exact same apobipul and wildly different cardiovascular risks due to the duration, the magnitude, comorbidities, other factors. And this is where the guidelines have over the past several years made a little dog leg to the left. And that is they've said it's not good enough to calculate risk. It's not good enough to try to make a number go from A to B. You really need to know much more about an individual. And so this includes their clinical history, their biometrics, their biomarkers, 30 plus risk enhancing factors. You're supposed to integrate all of that one person at a time and then harmonize it with six different U.S. and international guidelines. Now when you do all of that, then you come up with a, so here you are. Here's what I can tell you about you. And this includes things like L people lay and apobipul, but it also includes do you have autoimmune disease? Do you have chronic inflammatory disease? R-A, sorry, agarthritis, and closing spondylitis. Do you have HIV? If you're a female, did you have premature metapause before 40? Did you have preeclampsia during pregnancy? I mean, the number of risk enhancing factors is very, very, very broad. And that's the way that you bridge the gap between, here's my number. And what do I need to do about it? So the logical question becomes, in your ideal practice, when would you first check these markers? Teens? 20s? Yes. So this is now getting a lot of steam and preventive cardiology. Alan Snyderman, who is a senior of mine, he's the guy who came up with the term hyperbeta lipoprotonemia in 1984 with P. Quittervitch. So he's the godfather of apobin and estrogen of parable number. And Alan for years has advocated, if we have a punitive risk factor, the sooner you find it, the sooner you can fix it. Now, we said that risk is magnitude over time, benefit is how much improvement over time. So if you can make a significant improvement at an early age, keep it. The decades of improvement are what act by compound interest to give you the best outcome. So small changes earlier in life and sustained have great impact on long-term risk versus finding people later on 50s, 60s. We can still do something to help them. But a window that we could have done a better job would have been in their 20s. So finding people earlier in life is critical. And when you find them, you want to at least make sure that you have evaluated alternate reasons why the numbers can be bad, things like liver disease, renal disease, kidney disease, thyroid disease. You want to make sure that they have an appropriate therapeutic lifestyle, diet, exercise. You want to make sure that they're trying to maintain a reasonable way. You're doing these things that short of medication could have a big impact. And then as they go along, if you happen to run into these risk enhancing factors and abundance, that's where you're supposed to have a shared conversation with the patient. And you and the patient talk about it and say, you know, if I leave you the way I find you, your long-term risk is relatively high. If we do something to mitigate the factors that are causing some of that risk, we have the potential for benefit. But success is promised to nobody, failure is promised to nobody. I can't write it on a rock that somebody's going to have a heart attack at a given time, but I can say the first step in deciding who a good candidate for medical therapy is, ask yourself the question, what happens if I don't do anything? What's the natural history of leaving people the way you find them? And if I have a 30-year-old with a family history of early disease, high LPLA, high APOB, and I leave them that way, I am leaving them in the CN box of anthal sclerosis for them to get more disease than they need. And that's not a reasonable thing to do. Now, while we're on the topic of risk, I was curious to know whether there are other tests that we could do within the lipidology world that would help us understand disease states, for example, LDL receptor account maybe. We know that if you take that in, what we're doing is clearing the LDL by up regulating those receptors. Aside from just starting early from a prevention standpoint, getting a lipid panel, maybe getting the APOB open little A, as well as the intervention from a lifestyle perspective, is there anything that we know of that can also help elucidate whether somebody would be at a higher risk moving forward that might not hit them in their teens or 20s, but maybe when they're 40 or 50? Yes, great question. And it goes back to risk enhancing factors. So this is where the guidelines say, we have equations that were developed in order to take a population and stratify them into big buckets. High, moderate, low risk, let's say. And that's a nice way to segregate people, but within each bucket, there's a lot of heterogeneity. So not everybody in the high risk bucket is truly high risk. Not everybody in the low risk bucket is truly low risk. So how are you going to try to do a better job? You're going to look for the factors that have, as part of their physiology, they play in the sandbox of making a blockage. So the things I was just going through with you, which include, you know, chronic inflammatory diseases, etc. These are all things that when she start finding multiple risk enhancing factors, I have found the individual who needs a close look, who needs, if necessary, pharmacologic intervention to reset their APOB level to a place where they are less likely to develop blockage. Now, the corollary to that and one that has also been very important in the past five years in preventive cardiology is imaging. If I image your vessels, not invasive, and I find plaque, I have found disease. I don't have to worry if we're about to start something, you already have it. And that puts a sense of urgency in getting everything that's modifiable to an optimal place. So existing blockage will be stabilized, new blockage would be slowed down or stopped altogether. And so how one images is its own conversation and topic, but increasingly, imaging is part of the discussion of, you come to me with a number which is unfavorable, we don't know how long it's been there, we haven't found a secondary reason for it. My next question is what's up with your vessels? Do you have plaque? Yes or no? I don't need flow limiting disease, I don't need an abnormal stress test, I don't need something ready for a stint, all I need is objective evidence you have plaque. And if you have plaque, and I do this with the guys, it's funny. So guys come to my practice, kind of shaming in and by the wife many times. And we go through this work up and I find blockage. And so the guys looking at me and saying, well, okay, you got this imaging study and you say there's plaque. So what does that mean? So well, I want you to practice saying this, what's your name? Say the guy's name is Bob. My name is Bob and I have vascular disease. So that's harsh. No, you got to say to him, I got to hear it because until you own it, you can't fix it. Because the wife is going to say, what doxay? Doc said, my name is Bob and I have vascular disease. We're proudly so we can fix it. If we can't find it, we can't fix it. If we don't own it, you're not going to keep it fixed. So first step is we got to find it and then I got to get patients to admit that this is something where I could leave you the way I find you, which is with disease. Or we can do something about it. Another way to put it sometimes and people aren't getting it with that as I tell them, your house is on fire. Now, it may be confined to the closet in your bedroom right now, but there's a fire in your house where it's not supposed to be. You'd probably like to put that out or you can watch your whole house burn down. It's up to you. And so they kind of get it, like you're talking about real stuff here. I'm talking about a vessel that's got blockage in it. And you can either let it grow in misbehaved, you can stabilize it, but the choice is yours. Yeah, the imaging that I imagine you're referring to is either a CAC, CT NGO, or non-invasive ultrasound, right? Yeah, anything else that I missed there? Those are the non-invasive imaging techniques along with ABI. So ankle-breakial index is a means to check blood pressure in the arm and the ankle. And if it is a low average of less than .9, you infer there to be decreased flow. That's a good screening test. It's not a definitive test, but for many people, that's another way that you can non-invasively begin to steer toward an answer. Is there evidence of something that needs my attention? So since we brought up Sennaraman and all of us are interested in the preventative aspect, right? Dr. Al Sennar talks about the 30-year risk, right? Which is, again, stuff that we're interested in, you know, the ACVD is really looking at your 10-year risk marker. Dr. Sennar, we're not 40 years old, so it doesn't even qualify. We can't even put our numbers in there. But what would you let's us say that person that used before somebody in their 30s, high LP-little A, maybe borderline to high EPO B, some risk enhancing factors, other risk enhancing factors in terms of ethnicity, and whatnot. What would be the non-invasive imaging modality of choice for the BCT and Ju? Good question. I would add one thing before I answer that, and that is that the risk calculator can give you a lifetime risk. So you have 10-year risk and lifetime risk, and so even at your age, you can get an estimate of lifetime risk. For men, if it's elevated, if it's high, you by definition have high risk. A colleague of mine, Sergio Fasio once said, you're never lower than your highest risk. So if you calculate your 10-year risk is low, in your lifetime risk is high, you're never lower than your highest risk, which means you're high risk if we just leave you the way we find you. So thanks for bringing up the age component of long-term lifetime risk as being more meaningful than 10-year risk in individuals under the age of 50, okay? Now when you're in the age group that you talked about, 30s, maybe early 40s, if you have access to high quality B-mode ultrasound of the carotids that can quantify plant, that's a very good imaging study, but it's very operate or dependent. So the person doing the ultrasound has to do it well, they have to take their time, they have to free hand through the bulb and the internal carotid defined areas that look thick, then you have to measure it and you have to measure it in multiple different planes of image acquisition, and ultimately you're looking for confirmation that there's something reproducibly 1.5 millimeters or greater in thickness. And if you have that, you have a plaque. That is much more sensitive than a CAC score. So a CAC score, a corner area, a calcium score detects calcified blockage, but calcification occurs late. So you have a lot of different blockages that are not calcified, a zero calcium score, and you end up saying, oh, I'm good, I have a zero calcium score. The other test you mentioned to CTA is like a virtual angiogram, and you can see the plaque, even though it's not calcified. Many, many different series out there have taken cohorts of people with a zero calcium score and then submitted them to CTA and found lots of disease. So a cornyardial calcium score is best for individuals who are a little bit older middle-aged side, so men 45, 50 or older, women 55 or older. That's a good place for you to consider CAC score. In the 30s, CAC scores are just to get the swings one way. An abnormal number gets you noticed, and a zero value doesn't rule anything out. Because of the radiation exposure and whatnot, CTAs are probably not a great first step for young people. They can be done for good indications, but in my hands, if you are able to do a high-quality B-mode ultrasound and demonstrate plaque, that's very valuable. As someone who does a lot of ultrasound in the musculoskeletal realm, the operator-dependent piece is critical. I try to explain that too, and I guess the challenge would be is how do we identify what high-quality or who the operator is and how good they are. Any tactics on how somebody can tease that out is it just really worth of mouth or any other way for us to know? It's not easy. So there aren't metrics out there and there aren't societies out there that you can go look up a center or a tech or a physician and say, you know, where do they land? I would ask a few probing questions. Number one is crowded ultrasound can be done as a B-mode or as a duplex scan. A duplex scan is looking for flow velocities. How quickly is the blood flowing in different spots? And they'll get spot, spot, spot, spot, spot, spot, spot, spot, spot. And they're looking for a change in velocity, a gradient. And that would infer that there is a blockage that is limiting blood flow there. So if you're using duplex scan, you're getting a relative potential plaque assessment. They may say 0 to 25%, 25 to 50%. That's not really measuring plaque. It's measuring a phenomenon that could be related to a plaque. If you look at B-mode ultrasound, you can do what's called a crotted Entema Media Thickness Test C-I-M-T. And what you're doing there is you're looking at the first two tissue layers, the Entema and the media in the distal common here. And what that will tell you is how thick or you compared to H-matched peers. That also is not the same thing as a plaque. Now if you're doing a B-mode ultrasound and doing a C-I-M-T exam, you can also look at the ball where the internal, the external, and the common crotted all come together. And you can look in there to find cross sectionally and longitudinally, any areas that are thick. You can do that in the internal crotted. And so many times, people do both a C-I-M-T and a plaque assessment in the same study. And the questions that you could ask if you're interested, if you call somebody and say, call hospital X, do you do B-mode ultrasound? Yes, I do. Do you report plaque in millimeter thickness? And there's a pause. You either do or you don't. If you report plaque in millimeter thickness, then you are actually looking for evidence of what we would call 1.5 millimeters greater thickness plaque. If they say, no, we don't report plaque in millimeter thickness, then that's not the same quality exam. So that's one discriminating question that could help you as you're looking for a center. If they say, oh, yeah, we report plaque. It's there in millimeter thickness. That's a much better place to start. Love that. Thank you for that. Now, this might be a silly question. So pardon me if it is, but once the logic behind only checking the crottids, right? Somebody could be absent of disease from crotted arteries and still have coronary disease, right, and be more susceptible to heart, heart attacks versus strokes. Is that the case? Or if you have any pathosclerosis, crottids is the first place that's going to be or something like that? Yeah, so disease anywhere is the same as disease everywhere. For the purpose of saying, do you have plaque formation? Any arterial bed that can be shown to have definitive plaque gets you checked into the box of, okay, the process has started. We need to turn it all. Now, we learned a lot about this from the Bogolusa heart study back in the 70s, in Bogolusa, Louisiana, where they were doing crotted ultrasounds in high-risk teenagers, and they were finding plaque in high-risk teenagers. So we know that this is a methodology, which is particularly sensitive at a younger age, and that's the reason why in, you know, 30-year-olds, if there's something there, you're likely to see it. You also made a good point that every vascular bed is its own time clock and its own independence, that the problem with coronary arteries, not only are they very small, but they are sheltered under, you know, bone and muscle and all sorts of layers of things, being able to visualize that is very difficult. You're not going to see it with ultrasound. You're going to see indirectly the calcium in a plaque by CACscore, and really, CTA is one of the few ways that you're not invasively going to be able to see details of a plaque without actually doing an invasive calf. Now, there are things you can do if you do, you know, a catheterization, but nobody wants that for screen. Yeah, certainly another first step. I want to come back to HDL for a moment. You know, we touched on in the beginning talking about good versus bad cholesterol. Hopefully, we've dispelled that, and we've certainly talked about that before. But, you know, often people will go to their providers, whether they're primary care cardiologists, and they'll say, look, your HDL divers are high, you're doing really well. That's protective, this cardioprotective. I think we've all known that for quite some time, but the problem is trying to raise that, you know, intentionally hasn't really panned out as well. So, can you talk a bit about HDL and how that turns out to be protected, protective, rather? And then why haven't we been able to manipulate it, or why haven't the outcomes approved after we manipulated it? So, this could be a whole day's conference. HDL is complicated. APA-V is easy. APA-V is bad. A lot is real bad. Don't have a lot. HDL, on the other hand, is complicated. If you look at our understanding of HDL cholesterol, the first came out of things like the Framingham Heart Study. And what they found was an individual with low HDL cholesterol, where it's significantly higher risk of vascular disease. And the people who had higher HDL had lower ASCVD risk. So, that kind of made sense. The problem was that what was considered high in the early studies was up to about 80 to 85. We really didn't look much past that. What has happened over the past 15 to 20 years is there have been very large populations, which allow us to see people that are higher than 90, 95, 100, 105, etc. And what is true, and I just did a grand round on this not long ago, the higher the HDL, at some point you not only are not cardio protected, but it's associated with increased events and increased mortality consistently. So, high HDL is not only not going to buffer your LDL. High HDL, when you get into the hundreds, is going to potentially put you at increased risk. How can that be? How can a particle that's supposed to be good put you at risk if you have greater than expected amount of it? Because what's really happening with HDL are the functions that HDL carries out more than the quantity of cholesterol in the HDL or even the number of particles. There are ways in which the HDL particle can be a good actor or it can be a bad actor. So, to make it simple, the HDL particle has about 100 plus proteins on the outer surface. It's a proteome. It's got all these proteins and these proteins do a variety of things. Reverse cholesterol transport. They pick up cholesterol from other tissues like macrophages and get rid of it so that you can decrease blockage formation. Anti-inflammatory functions, antioxidative functions, anti-infective functions are all sorts of things that these HDL particles do. And what we know is that those complex functions are highly modifiable. They are specifically modifiable when there are comorbidities such as diabetes or when there's high systemic inflammation. Many elegant studies have directly shown, for example, that you can take human aortic cells and you can put a constant HDL quantity in this media. And as you increase the amount of inflammatory substrate, you directly decrease HDL function. You no longer have endothelial nitric oxide production. You have increased free radicals. You increase adhesion cell molecules like IKM and DKM that start the process of recruiting monocytes to become macrophages that start the blockage formation. So, take away from this that the function of the HDL particle is the more important entity. And we don't have any commercially available test for HDL function. It's a research tool still. But that's what the feature of HDL therapies may look like is how do we one way or another improve a meaningful aspect of HDL function, such as reverse cluster transport. And there are studies of agents that are ongoing now. But to your point, bulk raising of HDL, NISM, with vibrates, with CETP inhibitors, has never demonstrated clinical benefit. And that is because it's not the bulk of the HDL that is going to confer benefit or risk, it's the function of the HDL. Awesome. Well, yes, it's a complex topic, but you've distilled into some core concepts that I think hopefully people can take away. I certainly feel a little bit smarter, but I'm sure there's a lot more under their surface that we haven't been able to touch. I want to switch to triglycerides. And I think that'll bridge really well in talking about metabolic syndrome. We've talked about a lot of different lipids and other genetic particles. Triglycerides is another marker that ties into metabolic syndrome, sign of inflammation and just long-term adverse outcomes. Can you talk about triglycerides a bit in terms of how are they distinct from the other particles that you talked about? I know the lipoproteins will carry them, but what is their role specifically and how are they a proxy for just overall metabolic ill-help? Well, so triglyceride abnormalities are complicated. And most commonly what you're talking about when you see high triglycerides is either you're producing too many triglyceride-rich particles. You're not clearing the particles after you make them or both. So to talk about high triglyceride and what's happening and why it's bad, you have to think about production and clearance. Overproducing particles occurs, for example, in insulin resistance in the metabolic syndrome. To have two diabetes where you are flooding the liver with free fatty acids and building blocks for triglyceride. And as the liver is a master carpenter, it's taking these substrates, it's making lipid. You package that into a VLDL particle, which is triglyceride-rich. And so we're overproducing and that shows up as a high triglyceride. Now the clearance of triglyceride is through enzymes called lipases. And lipases chew up the triglyceride inside a particle, much like air leaving a balloon as the triglyceride is liberated from the particle it shrinks in size, like air leaving a balloon. And this is how you go from a VLDL particle to different remnants all the way down to LDL. So what's happening in real time when you see a high triglyceride is some amount of production, some amount of clearance, or a problem with both. And that gets us into understanding why is triglyceride a signal for risk? When triglyceride is high, many things are happening. The first thing that happens is the amount of cholesterol in the particle changes. This is what it looks like with a normal triglyceride. This is what it looks like with a very high triglyceride. So as triglyceride goes up, the cholesterol in LDL goes down. Your measured LDL cholesterol looks okay. But because you are overproducing these apobie particles, your apobie is actually high. So now we have this discordance again. We have too many of the bad particles. The triglyceride is changing the composition of the LDL so you don't see that the LDL is really high when it actually is. And so one of the things which commonly happens as triglycerides go up is that there is an increase in the number of apobie particles, which is directly anthropogenic. And that is a large part of triglyceride's relationship with risk. It's not all of it. It's a large part. The second part, as you said, are the more dynamic physiologies that have high triglyceride as part of it, insulin resistance, metabolic syndrome, diabetes. And that's a very, very early finding. If you look at all the things that go wrong with people who are trending toward metabolic syndrome, it's abnormalities of lipoproteins that predate even arise in insulin. And specifically what happens is you have increased numbers of large LDL particles, increased numbers of small LDL particles, decreased numbers of large HDL particles. And when you put those along with the size of these particles into a multi marker called the lipoprotein insulin resistance score, the LPR score is highly predictive of future diabetes, independent of glucose, independent of insulin, independent of waste circumference, independent of triglyceride, independent of triglyceride HDL ratio. So many of these biomarkers overlap with the condition that they are giving visibility to, when triglyceride is high, it's giving visibility to, in many cases, metabolic syndrome and insulin resistance. But there are so many other things that are also pointing in that direction, you have to ask, is triglyceride a marker? Or is triglyceride a mechanism? And we have more data to say it's a marker than to say it's a mechanism. The mechanism side is when you have these remnant particles, right? So when remnant particles are high, triglyceride is up, you have type 3, despatal lipoproteinemia, okay, there's a direct causal relationship. But outside of the situations like that, triglyceride is more of a marker of disease and specifically commonly found in metabolic syndrome and insulin resistance diabetes. It's very interesting, you know, I think as we learned in medical school and then internearing onwards, when we look at metabolic syndrome, we really look at it from a checkbox perspective, you know, if you hit the blood pressure, if you hit the waste circumference, or the fasting glucose, we're just going to check it off and if you have one three or more, we're going to bucket you into the metabolic syndrome. What you're saying that there is a difference between what causes those markers versus, you know, the risk that brings those to kind of come up from an inflammatory standpoint. You mind touching on, especially from your company, PHR standpoint, some of the markers that you're checking to assess that risk to see if a patient is on the trend to metabolic syndrome and the importance of those. So it's a good segue. We have this categorized mentality about metabolic syndrome, three or five features or more, you've got it, right? Now, the interesting thing is what happened long before any of those features came out is that you had this perturbed metabolism with the lipoprotein insulin resistance scores, a very early proximal sign of insulin resistance. Now, you could also look at insulin levels, insulin levels will rise within insulin resistance, but it's a lagging indicator behind lipoproteins, but it's still relatively early. You can do a home insulin resistance score, which is a mathematic combination of insulin and glucose, another way to infer insulin resistance. So there are several ways to infer that. If all you had was a lipopanel triglyceride divided by HDL cholesterol over three to three and a half in first insulin resistance. So there are many ways to infer insulin resistance. I think the question that you were getting to is what can we do to discriminate the risk for diabetes heart attack and stroke that people have in the insulin resistance state? So let's say the three of us on this call all have two of five features for metabolic syndrome. Does that mean that we have equal diabetic heart disease and stroke risk? And the answer is no. Well, what's a better way to discriminate? And one way to do that is called the metabolic syndrome severity school. It was developed by researchers at the University of Virginia and the University of Florida. And what they did was with access to large well-vated datasets. They said, let's take the absolute value for your waist circumference, your triglyceride, your HDL cholesterol, your glucose, and your blood pressure. And create a multi marker which will wait these things and give you a continuous variable from one to a hundred. And what you will find is that when you're above the 75th percentile, you're significantly increased risk for diabetes heart attack and stroke. I will tell you that we have that in the precision health report, cardiac metabolic risk report. I have seen so many examples of people with one or two factors, 60th percentile, two or three factors, 30th percentile. So the number of categorical features you have does not bear resemblance to the impact that the actual numbers have. So the bucket categorization gets you in the right direction. You need more detail to unpack the contribution to risk of these individual markers like metabolic syndrome severity score. And if you're at specific question is, what is my risk of diabetes down the road? The curious thing is that the lipoprotein insulin resistance score, as I said before, is uniquely robust in determining incident diabetes. We did all 26,000 of women's health studies. It was not made inaccurate or not predictive by adjustment for the entire kitchen sink. You adjust for waist circumference, BMI, glucose, insulin, et cetera, it still predicts. It's true in prevent, it's true in cardio, it's true in nasa. So if the purpose is, what are my cells doing insulin resistance score? How is my body doing metabolic metabolic syndrome severity score? What's my diabetic risk? Bluecoast LPI R school. And if you look in nasa, for example, the multi-ethnic state of the athlete's growth is we have a cohort of otherwise healthy well people, followed for a very long time, a certain number of them develop diabetes. Well, it's very interesting. So how can I predict who did or who did not? Well, the reason that we transition from normal glycemia to diabetes is that as we become insulin resistant, our body increases insulin production. So if the liver muscle and fat cells are not responding to an insulin signal, just repeat yourself. If your child didn't take out the garbage, just repeat yourself. As soon or later it's going to happen, right? Just keep repeating yourself. So insulin levels are going up. We are compensating for the lack of peripheral sensitivity, this peripheral insulin resistance. Glucose gets to some number usually between 100 and 110, and it hangs there for a really long time. And as we continue in this insulin resistant state, eventually our pancreas begins to decrease its insulin production. And glucose like a hockey stick rises very precipitously, right? So that's the half of physiology of what's going on between normal glycemia, the diabetic threshold in insulin resistance in the middle. So if I were to plot for men and women separately, what does your diabetes look like as a function of your glucose? I got an 80, a 90, a 100, a 110. Well let's pick 110. At 110 you can have either an ideal insulin resistance where you can have a maximally high insulin resistance. And what I'm doing with my hands demonstrates the difference in risk at any different given glucose. Wherever your glucose is, your actual risk of progressing to diabetes is how insulin resistant are you at that glucose? The more insulin sensitive, the less the more insulin resistant, the more. And to put some numbers to this, you might range from a 10% at your risk to a 45% at your risk. That's huge. And if I tell you specifically giving your numbers, you're at 40% risk, you can do something about that. You can change diet, lifestyle, etc. And you can bring that risk down. How do we know that works? The diabetes prevention project. In DPP, using lifestyle, there was a significant reduction in people transition in diabetes. And what was the most predictive marker of who did not develop diabetes? Change in LPR school. Love that. Now I've had the chance to use my own report and look at some of the different markers. All the ones that you're mentioning to me actually went through all that this weekend. So it's all fresh in my mind. But one of the things that was somewhat new to me was the systemic inflammation, right? Historically, we've talked about high-sensitive CRP. How that's a good marker. But you guys use something called Glyke A in my sanguite or is it Glyke A in our GLYC? Can you do you care to just talk about why you guys favored that over HS CRP? So we're talking about systemic inflammation. And total body or systemic inflammation can occur for any number of reasons. But at the end of the exercise, the liver is producing a family of acute-phase proteins. And these acute-phase proteins include things like interleukin six, interleukin one, high-sensitive CRP. After gliding on a whole bunch of them, right? So we have all of these acute-phase inflammatory proteins that are being released. And they can be look-full. HS CRP was one that was of interest to Paul Ricker and others. It was very well characterized. We know the story of HS CRP and its relationship with risk. But the challenge with that as a biomarker is its biological variability. So if you look in the same person over time, there is a significant biological variability day to day week to week. If you are going to use that biomarker, you're advised to do more than one and average them in order to get a more representative measure. There's a gender bias with higher HS CRP and women versus men. So this is a biomarker that's a little clunky and doesn't lend itself to the degree of reproducibility that would allow it to be used as a single test. And with one blood draw, how's my inflammation? That's just not what HS CRP allows you to do. Glike A is an inner-marre signal, which is the composite of five to seven different acute-phase proteins. And because it is the integration of multiple acute-phase proteins, its biological variability is less than 5 percent versus HS CRP whose biological variability is over 40 percent. There's no gender bias. When you look in populations like women's health, or you look in Mesa, or others, the performance of these head-to-head, like a outperforms HS CRP. If you look at some specific examples of outcomes like mortality, Glike A is a much better predictor of mortality. If you asked the question, what about unstatin therapy? And in the Jupiter study, your viewers may remember, Jupiter was a study of Resuvistatin versus placebo. It was particularly helpful because the Resuvistatin group got so much benefit they stopped the trial early for clinical benefit. Now, that doesn't mean that everybody on Resuvistatin was protected. Some people on Resuvistatin went ahead and had a heart attack anyway. Did HS CRP discriminate people who developed heart attacks or not on Resuvistatin? It did not. Did Glike A? Yes, it did. Glike A is a more stable biomarker that can only have to be measured once to be accurate. It doesn't have a gender bias. It outperforms CRP and disease associations with mortality, diabetes, heart attack, stroke, and it specifically gives a unique reading people who are on statin therapy regarding Resuvist. That's why we chose. Love it. Well, Dr. Carmel, we spent an hour talking about diagnostics. I'd love to switch if you have a couple more minutes to talk about management strategies. I think that this conversation will be complete unless we do that. The best is probably to start is to talk about lifestyle interventions. I know we touched on that earlier on how that's probably going to be where all of us are going to start. This piece is interesting because anybody and their mother will come in and talk about nutrition and sleep and just feel that they're a subject matter in these experts. When I look at the literature, it's a very muddy to me in terms of which one of the levers is the best to pull on. I also understand that context is everything. For what might be the best lever for Darsch, it might not be the one for me. It might not be the one for you. I suppose when you look at the data, you've been doing this for 30 plus years longer than that. Which one of those lifestyle interventions, and I put that in quotes lovers, is the place to start pulling in order to make significant changes in somebody's arthrogenic lipid particles? You teed it up correctly. It depends on the physiology we're talking about. Different physiology respond to diets differently. If we start with the elephant in the room, insulin resistance, metabolic syndrome, these individuals benefit more by a therapeutic lifestyle diet change than they do from exercise. Both are helpful, but the diet is more important. What part of the diet has been shown to be most impactful? Some version of carbohydrate camping, some version of intermittent fasting, some version of calories to maintain ideal body weight. There are three characteristics that would be the ideal diet for an insulin resistant individual. Carb camping does not mean that you have to be ketotic, and that's very controversial. There are people who will look at keto diets as potentially helpful for a variety of reasons, and that is true. But keto is a principle. There are many ways to try to carburestrict and be in a keto diet. If you were to overeat certain fats as a percentage of calories, many people go on to have very high LDL, which is unproductive. There was even data at ACC that indicated that individuals on a keto diet with high LDL have increased athletic event risk. So it's not benign to do that. So you want to cap carbs, but you don't want to go full out to the point that you're getting deleterious effects when they were being part of them. I have found that a 75 gram carbohydrate cap is a good starting point. A lot of people can operationalize 75 grams without really fighting too difficult, but that's just a number. It doesn't have to be 75. They can be at 50 to 100 anywhere in there, but it doesn't have to be a keto diet either. Intermittent fasting. There's a lot of very good data that an eight hour eating window, followed by a 16 hour fasting cycle with no calories, has significant impact on insulin resistance and heart attacks. Now, again, some people would do great with an eight hour window. Some people need to go to a six hour window. Some people even want to go to a smaller window. It's just harder to do, right? But those are things that many people haven't ever tried. So keeping your total carbs is 75, stepping your way into the point where you're having your first calorie intake between 10 and noon and cutting off between 6 p.m. and 8 p.m. That's a good eight hour window. And then you operationalize that. And the next thing is in combination with exercise, tune your calories to maintain an ideal body weight. On the exercise part, it's basically time under tension and high intensity interval training that have the best insulin sensitizing effects. And your viewers are probably familiar with those. But I use time under tension a lot for people who are somewhat limited in what they can do, right? And the concept is let's just take a squat, for example. If I do a squat, I go down, I come up. Well, time under tension is I take an eight count to go down and an eight count to come up. And I never release the tension. And then I go back down for an eight count. So it's keeping muscles under tension for a longer time. If you're in the gym and you're doing bench press, go with a lighter weight and then start with it off your chest. So you still have a load, eight count out, eight count back, don't let go of load and repeat that. And so you either hit exhaustion or you've gone 30 seconds, right? So time under tension and high intensity interval training are really very helpful in improving muscle insulin sensitivity. Love that. I did want to ask about lean mass hyperresponders. And I know this could be a whole nother conversation as well. But you did mention people in keto diets. Sometimes they will see their particle numbers jump up. Can you just briefly explain what the lean mass hyperresponder means? And any any type of comment that you have on it for people to kind of learn and to be aware of? Well, it's a term that was used by David Feldman to give a monocle to people who on a keto diet had a low triglyceride, a higher HDL cholesterol, and their LDL cholesterol, particle number, and total cholesterol might not decide it. And it can go very high and go over 200, ignore 400. I'm making really really go up there. So this phenomenology of people who are lean and on a keto diet are having this type of lipid change has been called a lean mass hyperresponder. As I said, there are data sets out there that would indicate that on a keto diet, high LDL over time is associated with increased event risk. There is a study going on now looking at arteries to see what happens with imaging of arteries over time and people who are so-called lean mass hyperresponders. The key thing is that persistently high numbers of April B particles is potentially dangerous. It does not have associated with it a benign characteristic. And I think one of the things to be very, very careful about is the persistence of that for a long period of time. Now let's say that you're a lean mass hyperresponder and you jumped up and then over time it comes back down. That's fine. Let's say you jump up and you change your macros and it comes back down as you adjust your macros. That's fine. But to have it go up and stay at a really crazy high level and say that's fine. I think I'm okay for the next 20 years like this. We have no data and we have no model of anything like that that would support that it's a benign condition to maintain numbers like that for a long period of time. So there are people who are trying to get a better understanding of when and how things go bump in the night that way. But I would simply say if one of your viewers finds themselves as lean mass hyperresponder, a couple of things to think about. Number one, non-invasive imaging. Do you have plaque? If you have plaque, don't feed the plaque. APOB is wood that you put on the fire bathless grosses to watch it burn bright. Don't feed the plaque. Number two, if you don't have plaque, that doesn't mean that you are clean. It means that this is also a potential factor going forward and you can keep an eye on it. You need to do serial imaging studies or something else to detect when a change is occurring. So you don't let things get out of control. Number three is what's the value in maintaining an APOB that's super high. If you can just simply change your macros a little bit and bring it down to a more modest range. You're still having keto principles. You're still on a carburestricted diet. You're still ketotic. But by changing the macros to keep the APOB less daunting, you're benefiting and you're not losing anything. So the people who are resistant to changing anything and believe that maintaining a high ethernet particles for a long time is innocuous. I feel uncomfortable with that. I think it's important to note for the listeners that all the things that we're talking about in terms of markers and wrist tracking, as you mentioned, we're looking at APOB and the LDL particles, the things that are going to be authentic. The other thing that we did talk about earlier is healthy little way. Selfishly, this one is super important to me as somewhat frustrating because there's really not a lot out there, at least that I'm aware of in terms of how do we work with these folks? How do we talk to the people in terms of interventions who have an elevated LP little A? Especially that threshold that you mentioned above 125 animals per liter. What type of medications I understand? PCS K9s, there's some ASOs that are kind of in the pipeline. But somebody, let's go back to that 30-year-old, 40-year-olds, really not going to qualify for those agents just because in the clinical trials, it's going to take decades before that's even valid. And I even think about, well, let's say if we try to address residual risk, it will be in particular. There is some evidence to suggest that statins actually paradoxically increase LP little A. So I'd love to get your thoughts on what do you do in that type of conundrum and is statins still an approach that you'd like to take despite the fact that it might increase all people of the life you're tracking it? How do you handle that? Well, so there's a lot in your statement and your question. So starting with what can we do to lower LP a life? PCS K9s will lower it, but over a highly individual range. You could say average 25 to 30%. I've seen some people who have had a great response to PCS K9s. I've seen some people who have had no response to PCS K9s. And so there's a wide range of individual variability even with that as an example. Nice and in high dose, can reduce LP a life, but it doesn't give cardiovascular benefit on top of the statins, so it's not something which is commonly used. Statins can, in certain cases, raise LP a life, but not by an amount that would be problematic. And if you look at outcomes studies of individuals on statins, those who have an LP a life should continue to have cardiovascular benefit on a statin. So I don't think statins are contraindicated in people with an LVLPLA to the contrary. We use all the tools available to us to bring the APOB pool, including LP a lay down as much as we can. And one of the things that we haven't talked about specifically, but it tees up with this conversation is, what would you reach or what is your goal for an individual with high LP a lay? What number are we trying to get to at least keep the company that LP a lay is keeping in a better place? Short answer is there's no too low APOB or LDL. There is no too low. If you have an LDL cholesterol on PCS K9 of 20, God bless you, keep it there. Do not back off. Why do we say that? In the Fourier study, 13,500 individuals on statin plus placebo, 13,500 people on statin plus repatha. If you compare them, the group that had statin repatha had an median LDL cholesterol of 26, 26, many of them below 20, and they were left that way for years. What did that teach us? It taught us that as you continue to drive LDL and APOB down, there is more event reduction. There is no level below which further reduction doesn't give you additional decrease in heart attack and stroke. Number two, there were no more adverse events in individuals in the 20s than those at 57 year 100. They had no cognitive dysfunction. They had no difference in safety signals. There was no safety downside. And this is why all of the guidelines have transitioned from a stopping point, a goal, to a threshold, a starting point. As the guidelines are now being harmonized, we want people to stay as far below their threshold as possible. Let's take a very high risk person who has a high old people lay and they already have lockage. Well, the minimum threshold that's harmonized now is less than 55. And as far below that as I can get is where I want to be. You give me LPLA. If I get you down to 30, I'm a happy guy. Now, there are specific LPLA therapies that are coming. And there are clinical antibodies. They're small interferion RNAs or others. And the phase two data shows extreme efficacy. We're talking like 80 plus percent LPLA reduction. So there is the potential to have agents that are effective. Would that translate into reduced heart attacks and strokes? We don't know. There's the problem. It should. We believe there are small data sets that indicate it is very likely. But we are looking in the development pathway, not only to find agents that work to lower the number, but also that are safe and that have outcome improvement when exercised in midway. So I find it interesting that study about monotherapy versus stool therapy. And so my question to you is now with changing guidelines possibly. I don't know how long it's been since we've for me at least a look at the guidelines and say, Hey, this is now what we're doing. From your perspective, what are cardiologists doing now as far as the treatment algorithm goes? Are we still just starting statins and then seeing what happens or are some cardiologists jumping towards like stool therapy or does it just really depend? Well, the guidelines would ask you to several things. Number one, you would start with a comprehensive evaluation and decide if this patient is a candidate for statin therapy. And that would include LDL cholesterol level 190, plaque in your vessels, diabetics 40 to 75 years of age, high lifetime or calculated risk, all of those are statin eligible patients. And the choice of agents is largely predicated on their demonstrated outcome improvement. So the reason statins are chosen as the usual starting first line agents because they have the largest body of data to demonstrate reduction and heart attack and strokes. Now, if you're on a statin and you need further LDL reduction, the next question is what agents have been proven on top of a statin to further reduce risk. And that would include a cytomide, which is the generic frazzetia. That would include PCSK9 inhibitors, the monoclonal antibodies. That would include bethinoic acid, which was just shown at ACC to have a significant reduction in events. And so with the guidelines which came out just a few months ago say is start with a statin. If you need more than a 25% additional reduction to get to your threshold, go to PCSK9 monoclonal antibodies next. And if you still need further reduction, add either a cytomide or bethinoic acid. If you need less than 25% on a statin to get to your threshold, the world is your oyster. You can use either a cytomide or PCSK9 or bethinoic acid. So you've got four different agents with outcome proven benefit that you can mix and match for a variety of reasons. Awesome. Options are good. They're always good. Well, Dr. Kramel, I want to thank you so much. I'm looking at my notes here and I only got through or we only got through about 50% of what I wanted to ask you, but we want to be respectful of your time. I know you're a wealth of knowledge. And I hope that you'll consider coming back on here because there's just so much more that we can touch on in this world and and all the experience that you have. You know, we'd like to close with our little tradition by asking this important question because I think that's essentially the theme of the show. And a lot of things that we touched on here and there in terms of our conversations about precision medicine and you know, patients advocating for themselves, but the question for you is what does it mean to you or how do you think we can add the health back to health care? I think two things. Health is a function of maintaining the quality of life that people are really looking for. I see people all the time who come to me and they're a little ambivalent. Should I be on a drug? Should I not be on a drug? Should I start a standard? Should not start a standard? And my question to them is what does a great day look like 10 years from now? I don't answer. Just think of it in your mind. A great day. And then answer the next question. Is that great day more likely or less likely if you have a heart attack or a stroke? Probably not more. So we need to get into the habit of making sure that the endpoint that we're looking for is health spam, unrestricted ability to do activities that bring joy and meaning to our life, living in such a way that chronic disease is identified as early as possible and intervened on as definitively as possible with therapeutic lifestyle first and then medications if necessary. The earlier we find people who are trending in the wrong direction and we have as you know a huge problem with insulin resistance obesity metabolic syndrome. We find this in kids all the time. The time to intervene is them to help them to change their trajectory to a better health span. So when they get into their 20s now we're moving in a better direction a more sustainable direction versus I've seen people have kind of a nihilistic approach that they see a large family with a large child and they just say oh well that's just the way they are. I don't agree with that. I think we have to be proactive in creating opportunities to identify people early and then we have to come up with some real world solutions. You know unfortunately in inner cities there are food deserts where are people going to have reasonable non McDonald meals right they have fixed income or a limited amount of money they can't go out and spend it a whole foods on the best foods they're going to find something else. What about physical activity and how many people just aren't active at all and how many times can we get people into a more active lifestyle. You know these are the things in my world that I see as low-hanging fruit. You know find people early find the first manifestations of them moving down this metabolic pathway, intervene so they don't have to stay there and help them understand. You know down the road the quality of your life is something that you have a lot of control over and I would hate for you to be a victim of chronic disease in such a way that you are missing out all the things that you envision as being a great day 30 years 40 years from now or if you're you know in your middle eight years 20 or 10 years from now just keep in front of you that you know the quality of our life is really going to trump the quantity of life. I don't want to be that guy who's hanging on at the end of my life with the last 20 years of my life being awful because I was the victim of some you know series of ill events from a chronic disease. So I think if we just keep the mindset of you know early identification, early management, find solutions before things get to be embedded problems that gets us a long way down the road. We've got to work out of us. Amazing. Thank you Dr. Cromwell. Thank you. Before you take off if you are interested in learning about your liquid markers, the numbers and the metabolic health profile, I did link precision health reports into the show notes so be sure to click that. You'll get a full report. It's very easy. Ultima and I have done it. We've absolutely loved it and we're excited to track our numbers as we progress on our own health journeys. If you did like this episode, if you think it will value somebody else, please send it to them. And if you've been enjoying this podcast, if you really enjoyed this episode, please do us a favor and leave a rating and review. We are trying to get to 50. So if you could help us out with that, we would truly appreciate it. As always, the medical disclaimer, everything in this podcast is for educational purposes only. It is not constituted to practice the medicine that we are not providing medical advice. No physician, patient, patient, patient, is formed and anything discussed in this podcast is not representative views of our employers. We recommend that you seek the guidance of a personal physician regarding any specific health related issues. The last but not least, thank you to our team, Ethan Zhu and Harita Yapuri. And with that, wish you the best week ever.