FoundMyFitness - #012 Dr. Ronald Krauss on LDL Cholesterol, Particle Size, Heart Disease & Atherogenic Dyslipidemia

Episode Date: August 27, 2015

Dr. Ronald Krauss Dr. Ronald Krauss, M.D. is the director of atherosclerosis research at Children's Hospital Oakland Research Institute, Adjunct Professor at UCSF and UC Berkeley. Dr. Krauss is really one of the pioneering scientists that changed the way we all think about cholesterol and saturated fat. He developed an assay that allows the quantification of low density lipoprotein particle size and concentration (known to the wider world as LDL cholesterol) based on a technique which determines the size of the particle based on physics...meaning the speed at which it flies through the air. In this episode, we discuss... (00:00) Introduction (03:58) An overview of lipoproteins – HDL, LDL, and VLDL  (09:32) Cholesterol is a "passenger" on a train   (12:09) LDL vs HDL - why one is dangerous and the other isn't (17:42) Raising HDL doesn't reduce heart disease risk the same way as lowering LDL  (19:13) Leaky gut and inflammation increase VLDL production to protect the body (30:38) The misconception that dietary cholesterol significantly raises blood cholesterol (40:56) Saturated fats vs carbohydrates in raising cholesterol and CVD risk (53:08) Statins are a reliable, but imperfect, therapy for lowering CVD risk (01:08:20) Measuring cholesterol particle size refines risk assessment and informs medication use If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello, everyone. In this podcast, I'm honored to chat with Dr. Ronald Krauss. Dr. Krauss received his medical degree from Harvard University. He is a board-certified physician in internal medicine, endocrinology, and metabolism, and he's one of the top scientists in his field of cardiovascular research. Ron is really one of the pioneering scientists that changed the way we all think about cholesterol and saturated fat. He developed an assay that allows the quantification of low-density lipoprotein particle size and concentration known to the wider world as LDL cholesterol based on a technique which determines the size of the particle based on physics, meaning the speed at which it flies through the air. Ron and I discuss what HDL and LDL

cholesterol are, what they do in the body, and how they play a role in heart disease. We talk about what small, dense LDL particles are, how they form, what effect eating states. saturated fat versus refined carbohydrates have on LDL particle size and heart disease risk, and more generally, what the main risk factors for heart disease are. Ron also talks about the good, bad, and the ugly of LDL lowering cholesterol drugs, known as statins, and much more. This episode is loaded with so much good information I literally could sit and talk to Ron for hours. Normally, I would take this time to tell you about my crowdfunding campaign,

but I will avoid getting into the details on that right now. you want to learn more about how to support the podcast or what my crowdfunding is about, you can check it out on my website at foundmyfitness.com or on Patreon, p-a-t-r-t-r-e-on-com, forward-slash found-my fitness. Today, instead, I'm going to tell you about a few ways you can stay in touch with what I'm doing outside of these podcasts. The first way is to go download one of my mobile apps. I have both an Android app and an iPhone app that is a great way to receive occasional updates as well as the hottest news in science, health, fitness, nutrition, neuroscience, and aging. To try out one of my apps, search on either Google Play or iPhone app store

for Found My Fitness. The second way you can stay up to date is by following me on Twitter or Facebook, where I try to share one interesting news story every single day and enjoy chatting with many of you almost daily. Head over to Twitter.com forward slash found my fitness and Facebook.com forward slash found my fitness to connect with me there. I hope you all really enjoy this podcast. Welcome to another episode of the Found My Fitness podcast. I'm sitting here with Dr. Ronald Krause, who is the director of the Athlerosis Center at Children's Hospital, Oakland Research Institute, and he is an adjunct professor at the University of California, San Francisco. I personally think of Dr. Krause as one of the scientists that played a very important role in

changing the way we think about cholesterol. And the way that he was able to do that was developing an assay that is able to differentiate between the different sizes of lipoproteins that carry cholesterol. Now, let Ron talk a little bit more about that, but, you know, thanks for being here, Ron. Well, I'm delighted to have this conversation. So for decades, we have, we, meaning, you know, most people have this. This idea in our minds that there are two types of cholesterol. There's the good cholesterol and the bad cholesterol. And the good cholesterol was thought to be high density lipoproteins or HDL.

The bad cholesterol was thought to be low density or in low density lipoproteins or LDL. But we know now from your research and other people's research that it's much, much more complicated than that. And there's actually various sizes and densities of these lipoproteins. Can you explain a little bit about what? the various sizes of these lipoproteins are and what they mean for, what they do in the body, what their normal function is, and what that means for heart disease risk? Yes. As you mentioned, cholesterol is part of the LVL, but it's not the whole story.

When we measure LVL cholesterol, it's really the summation of cholesterol in a whole series of LVL particles that range from very small and compact or data. dense LDL to large and more, more, people use the word fluffy, which is a term I'm particularly fond of. Boient. But it's buoyant. They tend to float more because they actually have more cholesterol and they're larger. So that spectrum of particles, we started to break down with methodology that I was fortunate

enough to have available to me and help develop to show that these different forms of LDL across the spectrum really have very different. metabolic and pathologic properties. And to keep it relatively simple, we initially categorized those spectrum of particles into two major forms, those that are smaller and more dense versus those that are larger and more buoyant. That somewhat oversimplifies the story, but it does capture an important feature, which was what first attracted our attention to this, and that is people with higher heart disease risk and

people who have evidence of heart disease tend to have more of the particles that are the smaller and more dense particles, and those individuals that are more healthy tend to have more of the larger and more buoyant LDL. That became somewhat counterintuitive because when we measure LDL cholesterol in the clinic as the summation of cholesterol in all of these particles, we do know that that is related to disease risk. LDL cholesterol is a reasonable measure of heart disease risk. But what it turned out is that within these particle profiles that we were studying, the highest

risk was related to particles that actually had less cholesterol in them. So it led to a kind of rethinking of the role of cholesterol, not that cholesterol is not relevant to our disease. In fact, it's cholesterol that builds up in the arteries. The question is, how does it get there? And it turns out that even though these smaller particles carry less cholesterol, they do have a greater tendency to wind up in the artery wall. They can be bound more tightly to artery tissue, and once they get into the arteries, they

tend to stick, and they tend to be oxidized more rapidly. All these features we and others help to characterize once we discovered this differentiation between larger and smaller LDL, and it helps to explain the associations that we saw, that is, particles that are smaller and more dense do bring cholesterol into the arteries, but they have other properties that make them more damaging to the arteries, as I've described, versus the larger LDL, but even though they have more cholesterol, do not have the same pathologic features. And that differentiation, although it was a somewhat oversimplification of what is, in fact,

a much more complicated picture, does carry into the clinic. And so we were able to develop tests that have been used clinically in practice. I think more and more over time people are appreciating the value of these measurements and thinking more about lvial particles rather than lvial cholesterol. I usually think of lvial cholesterol, the larger buoyant lvetyl cholesterol as something that's important for cells that need to repair damage to repair the cell membranes, growing cells. What causes the formation of these smaller down cell l.

particles? Well, it is true. We think about, you know, LDL as if it's bad, and cholesterol is bad. It gets into the arteries. But of course, cholesterol itself is vital for every aspect of human biology, ranging from cell membrane functions, point out proliferation of cells, growth, and the health of cells, are dependent on cholesterol. And most tissues, in fact, really, virtually all tissues in human body.

body under normal conditions are capable of manufacturing their own cholesterol. That's really an important system, which relates to some of the other work we are doing when you start to manipulate cholesterol metabolism with use of drugs like statins and also with diet. But the fundamental role of cholesterol is one that promotes health. Where we get into trouble is when it exceeds the ability of cells to take cholesterol out of the blood, particularly through the liver, and it builds up in the blood and gets into the arteries, where it becomes pathologic.

Well, where do these particles come from? That is something that we're very interested in. The origin of LDL particles is in the liver. The liver packages lipids, cholesterol, as well as other lipids, triglycerides and phospholipids, into this spherical particle that also has proteins, and so it's a combination of liposurides It's a combination of lipids and proteins, and that's how we get the term lipoproteins,

lipids and proteins complex together. For the most part, in the form of triglyceride-rich, not cholesterol-rich particles, there are ways of unloading triglyceride from the liver. Triglissoride is a fat that's used also for many positive features of our life, such as energy, storage, and metabolism. In packaging these triglyceride-rich particles, there's some cholesterol that comes along with it, and there are specific proteins that characterize these particles as well. There's different forms of these triglyceride-rich particles.

They're called very low-density lipoproteins or VLVL. And the different forms of VLDL give rise to different forms of LDL. That's one of the reasons that we have these different forms of LVL is that. is that they can originate from different precursors produced by the liver. So cholesterol, in a sense, is a passenger on a train that is mainly delivering triglyceride. But that triglyceride gets used by the body. It gets hydrolyzed. It gets broken down into fatty acids, which are used for energy and for energy storage,

and muscle and adipose tissue, very important metabolic clairs. And as that process occurs through a lipase that breaks down the triglyceride, the particles get smaller and smaller. They lose their triglyceride, but they tend to retain most of their cholesterol. So there is a shrinkage from what is a big, big, buoyant triglyceride-rich-mey-l-l particle to a smaller, more dense l-dial particle. And to the extent that that process can continue to occur during the excursion of lipoproteins in the blood, they can get smaller and smaller.

And that's how you finally went up with the small alveal particles that we've been talking about. So the role of cholesterol in these particles is not a crucial feature of their biological role. As I say, most tissues can, in fact, all tissues, as I say, can make cholesterol, tissues don't make triglycerides. So the triglyceride transport is a main feature, and most people don't understand that.

And the LDL is kind of a byproduct of that metabolic conversion that we just described. And LDL are used by tissues. Adrenel gland uses LDL cholesterol, the gonads use cholesterol to synthesize, for example, hormones that are made about those tissues. So LDL does have a role, and the cholesterol does have a biological role,

But it's not a crucial one. And so that's one of the issues that we have as humans versus almost all other species. We don't have a very efficient way of removing LVL from the blood. So our levels are much higher than almost any other species, certainly most other mammals. You have to feed an enormous amount of cholesterol in order to get anything like what we have in our blood.

So it's this inefficient removal of LVL that leads to the potential for accumulation of the blood and ultimately arteries. And it's really the fundamental reason that we as a species are so susceptible to heart disease risk. I usually think of the HDL as serving that role of removing it from our arteries.

Is that an accurate way to think about it? Yeah, well, one of the, so HDL, and again it's the same general principle that I've just described for LDL is that HDL is a particle or HDL are particles, because again like LDL, in fact, even more so than LDL, HDL is very heterogeneous and there is even more biological variability among the different forms of HDL particles than is the case for LDL particles. But if you group them together and you measure the cholesterol within the collective HDL

particle distribution, that measurement is strongly associated with lower heart disease risk. We know this from countless studies. In fact, HDL cholesterol is a low-Hed cholesterol. It's a stronger predictive of heart disease risk overall than is high aldeol cholesterol. What people don't realize that? So why is that true? Well, certainly one of the reasons that's true is thought to be a process you've just described, which is the ability of HDL, in particular forms of HDL, which are still being studied. to extract cholesterol from tissues. All tissues, as I say, make cholesterol.

And when there's excess cholesterol in the cell, it can be toxic to the cell. So it's an important role for HDL to scavenge cholesterol or to extract it from these tissues that are making cholesterol. And one of those tissues is the artery, and there are cells in the artery, aquifages, that are filling up with cholesterol that could ultimately cause heart attacks through plaque formation, those cells, when they accumulate too much cholesterol, can unload it onto H.D.L. particles, and so it's one of the reasons we think higher HDL is beneficial. However, HDL cholesterol as a marker for heart disease is not saying the same thing as HGL cholesterol. H.D. cholesterol is a causative factor.

The low-hedral actually causes heart disease, because low-h-dl cholesterol is also associated with an increased level of these small l-dial particles. And that was an observation that I first made that led me to realize that these l-dial particles that are small and dense may be associated with heart disease because they were associated with low-h-dil. And that represented really the axis of a larger complex

of metabolic relationships that we've termed cathroogenic dyslipidemia. So what does that mean? That means there is a collection of interrelated traits that are related to heart disease risk, including, as I mentioned, small LDL, low levels of HDL, particularly HDL, cholesterol, and also higher levels of these triglyceride, lipoprines and their remnants.

These partially broken down the l-dial particles are called remnants. All of these things contribute to acrosis risk. So it's a collective of this axis of interrelated lipoprotein changes that is really the important measure of heart disease, risk probably the single most important phenotype or trait related to lipids connected with heart disease in the population. It's not high-LD cholesterol, but most commonly you see. It's this metabolic trait, athergenitous lipidemia, of which the small LDL is a marker for,

and is almost certainly a causative feature of the disease associated with risk. But the HDL may be coming along really as just a covariate. We don't know that the HDL has the same important causal role as LDL. And the reason for saying that is a couple of lines of evidence, but the one that's most compelling is that efforts to reduce heart disease risk by treatments that raise HDL cholesterol have failed, whereas almost every treatment that has been aimed at lowering LDL sufficiently has been successful. So as a causal factor, high LDL and particularly small LDL, is unquestionably a pathologic agent that is worthy of therapeutic low lowering, whereas the role of HDL is a bit more complicated.

The removal process is important. There's no question about that. The removal of cholesterol is important. But HDL is also a marker for this other syndrome. And trying to raise HDL cholesterol is not necessarily guaranteed to reduce heart disease risk the same way alone the LDL is. There's also genetic arguments that have been made. Genes associated with high LDL are associated with heart disease risk,

that's a very important pathologic connection because genes ultimately are the blueprint for our biology, and if the genes associated with high LDL are also associated with heart disease risk, it says that the LDL was really the causal agent. The genes associated with variation in H.L. cholesterol have almost in every case not been associated with heart disease risk. And that is another argument that has sort of cast the HDL on a somewhat different gl like an LDL, certainly as a target for therapeutic intervention.

Yeah. You mentioned the generation of the small LDL particles, the small dense LDL particles, which, you know, through normal biology, these LDL particles are donating triglycerides to cells and become smaller and smaller. I've done a lot of reading directed from Mark Shignaga. He had talked about some very interesting mechanisms and directed me into the literature on the role of inflammation.

And inflammation in the production of VLDL, so as inflammation goes up, VLDL production is increased. And at least in a couple of studies that I've read in literature, it seems to be implied. the reason for that is that inflammation increases the release of endotoxin, which is a lipopolysaccharide from bacterial cell walls in the gut, that gets released and it binds to lipoproteins, to all lipoproteins. And it's sort of like an adaptive response to make sure we don't get sepsis or some sort of very toxic infection. And so I've done some reading on a few studies that have shown that endotoxin does bind lipoproteins. And I'm wondering if you've looked into that at all or what role the endotoxin in binding

these lipoproteins seems to play in keeping the small or dense lipoproteins in the circulation longer or... Okay, all right. Well, those are... That's a very interesting topic. And just take a step back regarding the role of inflammation in lipoprotein metabolism. because that's something that is not widely appreciated. We know that inflammation is an important feature of many chronic diseases,

including heart disease and the artery wall inflammation. It really is the major factor that converts a relatively benign cholesterol deposit into a much more nasty and dangerous form that can cause blood clots and rupture and black formation and blocks arteries. Inflammation is a key feature of that. So inflammation is really an important feature of many aspects of the processes we're talking about. But biologically, again, inflammation is not designed to cause heart attacks. It's designed to help us with host defense.

So there's a very interesting argument that has been made that part of the physiological driver for VLTL secretion by the liver, the production of these pregnancy-strivedged particles, is really not a nutritional, although I think it does have an important nutritional law, but perhaps even as importantly, it may serve an important role in host defense. And so I come to the LPS question at the end of this discussion because a really interesting sort of corollary of that is what role does the lipoproteins have in the host defense mechanism. And what's intriguing, and it's sort of a like a broadoproteins have in the host defense mechanism.

of a biological fact that we don't want to make too much out of, but I think it's very intriguing, is that the liver constantly makes the major protein that forms the backbone of these VLVL and ultimately LVL particles called APOLB. Apoprotein B. It's a very big protein that is biologically ancient. It goes back to lobsters. It's a very important and complicated protein that gives the... integrity to lip protein particle, it helps keep all the fat contained and allows the fat to

be soluble in the bloodstream. That's the secret of lipoprotein particles, is that there is a soluble protein that helps to keep the fat from forming droplets like you see in chicken soup. It helps to dissolve the fat in the way. Anyway, the APOB protein is constantly synthesized by liver. It's under a tonic stimulation. It's not much regulated. It's just continually being produced and degraded, which seems like a very inefficient process.

But one of the thoughts that has intrigued me and others is that the regulation of APOLB and the particles performed on APO B, the LVL particles, is really to get these particles out in a hurry when they're needed. Because VLDL, it's a huge particle, relatively speaking, to most other biological proteins. It's molecular weight as can be tens of millions as opposed to 50,000. So it takes a lot of work for the liver to make one of these VLVL particles. And what the liver doesn't want to do is spend hours making a VLVL particle if it needs to come out in a hurry.

But why would it need to come out and hurry? Well, one of the arguments is it may be because it contains components, which it does, that help promote inflammation in the circulatory system. Why would that be important? Well, because when you have an organism, a parasite or an infectious agent in the vascular system, malaria parasites, antipanosomes, whatever you care to mention, viruses, one way the body has of eliminating them is by setting up an inflammatory response and an immune response related to that.

And VLDL carry pro-inflammatory proteins. They carry also prothrombotic proteins. They actually are a very efficient delivery system, sort of like a fire truck that carries a lot of things that we can use to fight off infection. Now biologically, in our current era of antibiotics and antipsis, that function has a function has sort of faded. But the rapidity of this response and the fact that it's regulated not by production of APO B,

but by degradation, suggests that this is designed to come out in a hurry. And so degradation of APO B is inhibited when there is lipid to be released. So the ability of the liver discrete APO B and the lipids associated with the LDL is increased when there is this additional lipid production that occurs. And that lipid production is stimulated by cytokines.

So it comes back to the body having a foreign agent in it. That foreign agent these days is more likely to be a plaque in the artery rather than a bacterial agent. But the response is the same. Says we got cytokines, we got inflammation. Those come to the liver. And one of the early studies that got me interested in this aspect of things is that we showed collaboration with people at UCSF that cytokines such

as TNF alpha in particular but interferon as well stimulate the production of VLVL secretion by the liver and so again infectious agent inflammatory signals cytokines are produced increasing lipid synthesis reducing the degradation of APO B allowing the rapid export of these VLVL particles. All of that occurs in minutes. And so that's the sort of thing you want the fire engine to get out of that fire station in a hurry.

It's an intriguing argument that is consistent with the notion that inflammation is a key regulator of lipocotein metabolism in a positive way, historically evolutionary-wise, but in an adverse way in our current environment. So where does LPS come in? Well, these particles that are secreted, as mentioned, who gets smaller and smaller. LPS, produced through this infectious inflammatory signal, does bind to these particles.

They're binding to VLDL and LDL is partly, I think, a protective mechanism. It's a sequester the LPS. Again, this is somewhat hypothetical, but it's a plausible scenario, which requires a lot more study. study to really get the molecular basis of this interaction understood. But from a physiological standpoint, there is evidence that if you increase the clearance of LDL from the blood through drugs like statins, which lower LDL by, we can talk about this perhaps later, the role of LDL receptors in the liver is crucial to regulating LDL in the blood, because the LDL receptors, particularly in the liver, remove LDL from the blood.

So it has been shown that if you increase LDL receptor activity and increase LDL uptake from the blood, you can lower LPS levels. So it's consistent with the idea that one of the protective mechanisms, in addition to the secretion of these anti-inflammatory, these inflammatory molecules that can kill bugs, One of the other ways that we are protected from the effects of sepsis by lip protein metabolism is probably through the transport and ultimate removal of LPS by these particles. H.DL does that to some extent as well. As I mentioned, all lip proteins are capable of binding LPS.

Where that comes from and what's a molecular basis for this is what regulates that binding I think it's an important question that we really need to have more work on. I agree. And also whether or not the binding of this LPS to these lipoproteins stimulates more of an inflammatory response. Right. And the other thing you mentioned, which I come back to, is that the smaller particles, in fact, this is an important feature of these small particles that I didn't mention earlier,

that may actually be one of the more important reasons that they're associated with heart disease risk, is they have less affinity for the LDLBL receptor. That's been shown by us and by others that as the particle shrinks to a smaller size, the region of the particle that is recognized by the LVL receptor, which is actually a region of the APOB protein that is the receptor recognition site for the whole particle, gets to be obscured. It gets to be less exposed. And that's one reason we think that these particles

are less capable of being removed from the blood by the liver. There are other features of these particles that contribute to that, including changes in other proteins, that may inhibit receptor-mediate uptake of these smaller LDL. So they hang around longer. And that may be one of the more important reasons that they're bad, is not because, partly because of the binding to the artery wall,

and the oxidation, all of that's important. But the fact that they're circulating so much longer, gives them much more opportunity to interact with the arteries and undergoal transformations that can be pro-inflammatory themselves. And the ability of LPS to stick to the VLDL means that some of that LPS remains on the particle as it gets smaller and smaller. And if that particle isn't being cleared rapidly, the LPS will be circulating even longer, and it may be part of the whole process by which this contributes to acrosis.

And I think that makes perfect sense, and that's a really elegant way of explaining. it. But the inflammation brings me to another topic and that is diet. So I think you mentioned earlier that we're producing cholesterol. We produce cholesterol in ourselves. We're making cholesterol ourselves. Absolutely. And I think that most people think about cholesterol in their body as originating from the food they eat. They think, for example, if they eat an egg, egg yolk, which is high in cholesterol, if they eat six of those eggs, then their cholesterol, blood cholesterol is going to go up. But that's not necessarily true. Can you explain?

So one of my multiple lives has been in the world of nutrition. And early on, I've been interested in nutrition virtually all my life and really came into the lip protein research because I felt the diet had a very important role in heart disease and the lip protein effects of diet, I thought were really important. And I've been studying that now for a long time. So I became involved not just on the research side of things, but also more on the public health side through my work with American Heart Association. I became chairman of the nutrition committee quite a few years ago now.

And I remember that committee, which is now morphed into a larger organization that I hope to establish within the H.A. It's an important part of American Heart Association's messaging to the public. You were involved in the dietary guidelines, right? Yeah, from the American Heart Association. We did that, I actually did that twice. And so I was forced to sort of deal with translating the science, such as it is, about diet and heart disease risk, into something that could be actionable.

And that's tough because the data linking diet to heart disease risk through any mechanism, lipids or otherwise, really doesn't necessarily establish a causal role because there's so many features in diet. You can't just easily pick one thing or another. But cholesterol was on the radar screen. So when I became chairman of the nutrition committee on my first cycle, there was a lot of media. I spent a lot of my time dealing with the media. And I was just astonished by the questions I would get about dietary cholesterol

and blood cholesterol. And as you say, people just conflated those two terms. And I had to spend a considerable portion of my time trying to educate the so-called science Well, the science writers who were often not trained in science at all. Actually, I'm sorry, I'm trying to understand this, and they just simplify this story to the point where it becomes totally meaningless. The body makes cholesterol, it regulates the absorption of cholesterol from foods, and the contribution of dietary cholesterol and blood cholesterol.

I was actually forced to address this in a very rigorous way through a committee that I was on for the Institute of Medicine and the National Academy of Sciences, which established dietary recommendations for macronutrients, which was the first time that anybody really did that seriously. It's really this enormous volume of committee looking at every aspect of macronutrients and health. And my topic, which I had to take on was cholesterol, dietary cholesterol. And when I went through the literature, I was just astonished at how small the effect is.

And it's very difficult to even imagine how an effect of excess dietary cholesterol could influence heart disease risk unless one just either had a mutation that caused the cholesterol to build up or when it was an enormous amount of dietary cholesterol. But for the most part, the effect was so small that it was almost unmeasurable. So we wrote that report and it sort of made that point. And then 15 years later, the current dietary guidelines come out saying, well, you know, after all these years of recommending keeping cholesterol less than 10 million milligrams a day, we realize there's really no data to support that.

So it took a long time for the U.S. dietary guidelines to catch up. And I was really in a bind because there was this historical precedent of living dietary cholesterol because of its potential role in blood cholesterol levels. And it's really not even worth talking about. But the idea is still out there, and physicians still even recommend not eating eggs. Yeah. So eggs isn't a whole other story. And so again, one moves from dietary components to the foods that those components are

contained in, which is really one of the messages that I've tried to emphasize in all the work that we've done, trying to reach the public, which is, again, a nice opportunity here for me to do this with you, is that we should be thinking about the overall context in which those nutrients are adjusted, foods and dietary patterns. And finally, the US dietary guidelines are beginning to think about dietary patterns rather than just individual nutrients. However, they still have not abandoned focus on measuring disoherent. that fatty acid, we should be thinking more about the overall food context.

The important regulators of heart disease risk from a dietary standpoint are way beyond the effects on blood cholesterol. We have to think of a lot more complexity in the role of diet. Not that cholesterol and lipoporting effects aren't important. And here we can point to saturated fatty acids, for example. We can have a discussion about that, if you wish, raising blood LVL levels. Does that translate into higher heart disease risk? Well, it's very hard to show that.

In fact, there's almost no evidence to support that relationship. And parenthetically, it may be importantly, we've shown that the form of LVL that increases with saturated fat is not the small LVL but the large LVL. And in fact, that led me to question whether or not saturated fat was really an important in factored disease risk, because our studies did not show that it was increasing small LDL in the majority of the population. There may be, there are individuals who are hyper responders who probably ought to stay away with saturated fat.

But for the general population, I began to suspect that this relationship was not as strong as people thought because it was the less dangerous form of LDL that was increased by saturated fat. And in fact, that's what we've shown. And I've gotten involved now in a lot of, I've taken a lot of heat for that. But as time has gone on, we first published this with Dr. Siri Torino in my group about five years ago now. And it was, we were really hit hard when we published that first paper, questioning in

relationship of the fat, heart disease risk. I'm glad to say that over the last year or two, there have been a number of a couple of that have supported that absence of a strong relationship. And the algae-article story, I think, may be part of the reason for that, but there may be other factors as well. Again, it may not be the saturated fat itself that should be incriminated here. It should be the foods in which that is consumed. And there may be, for example, in fact there is evidence from epidemiology

that red meat, could be processed red meat, which contains saturated fat, may have adverse effects on heart disease as well as life itself, when life expectancy and other diseases. And it may not be the saturated fat that's the most important factor. We don't know. What about carbohydrates, process for fine carbohydrates and their effect on small then cell, lb-al work? So you're talking about context.

Right, that's right. So that takes me back to the nutrition committee again. I started, as I said, I've been involved in lip protein research for a long time and dietary effects on lip proteins as part of our program. And I got into the American Heart Association nutrition activity really as a result of that, of that interest. And in addition to inheriting this confusion between dietary cholesterol, blood cholesterol and the general public, I also inherited from my colleagues and predecessors in the field,

the mantra that we should be going for low-fat diets. There was a very strong campaign to keep the message simple and stay away from fat. There were a lot of forces in society as well as in the academic and industrial worlds that had an interest in pushing that message as a way to keep the public focused on what they felt was the most important thing they should be doing, was restricting fat and saturated in particular. But what nobody really thought about seriously was the unintended consequence that that message,

which the food industry responded to in a very responsible way. They said, well, the experts in the field are telling us to use low-fat products. We're going to make low-fat foods. We're going to make low-fat cookies. We're going to make low-fat, snack wells, brownies, and butter. And so there was this tremendous response which led to a reduction in fat intake and saturated

fat levels that did go down on the diet. But the trade-off was an increase in carbohydrate. So getting back to your question, we became very interested in studying the effects of a low-fat diet on lipoprotein metabolism. And so the very first study I did when I came here to Berkeley and started to do this some dietary work, was to test the effects of a low-fat diet, the traditional low-fat diet. This is again when I was trying to get involved with the heart association.

I was still in that mode. I was thinking, well, low-fat diets are good. This is what my predecessors had said, and so maybe that's what we should be studying. And the hypothesis was that people with small LDL would have a good response. That we put on low-fat diet, their heart disease risk should go down. Well, it turned out that it was actually the opposite. We had a completely contrary result. We found that people who started off with large LDL when they were put on low fat diet

actually made their LDL smaller. So it went exactly the opposite direction. And that was like an eye-opener to me. And I think it's still sort of somewhere percolating through the nutritional world. Not everybody has really understood the implications of this. But what we found shortly thereafter is it wasn't so much the low-fat aspect of the diet that was causing this to happen. It was the fact that we were substituting carbohydrates.

high carbohydrate diets can promote the production of these VLVL particles from the liver that make small LVL. So high carbohydrates clearly push lip protein metabolism in the direction of atherogenic dyslididemia. All the features, high glyceride, small LVL, and system makes sense of lower HDL. And so we've tried to sort of break down the dietary response into a more specific role of particular carbohydrates, As you know, carbohydrates cover a wide range of food substances ranging from simple sugars like fructose and glucose to complex starches and fiber that are less easily metabolized and do not raise blood sugar levels the way the processed starches do. So we have been very interested in remembering that down and we and others have

pretty much come to the conclusion that probably the chief culprits in the production of this atherogenic, this lipidemic trait, low-fat, high carbohydrate diets, are probably the simple sugars, and fructose in particular among them, which is, of course, a component of naval sugar and added sugars. Half of that is fructose, the other half of glucose. So we think all carbohydrates have this potential for pushing lipid metabolism in that direction. But sugars, and particularly fruit drugs, we think, are the most potent. And this has flown in with a huge popular tension.

Now, people really do understand, I think for the most part that dietary-headed sugars have adverse effects, not just on lipids or heart disease risk, but on many aspects of health and obesity, for example, being perhaps the biggest public health issue that has been associated with. added sugars, particularly from liquids. But when you're saying fructose, what about fructose found in fruits or is that as much of a problem? Well, fructose is, of course, a fruit sugar.

That's how it gets its name. But when it's, again, in the context of a food, like a, let's say even an orange or an apple, you are not getting either the dose of fructose or a, you are not getting either the dose of fructose or the packaging of fruit dose that you get when you add sugar to a Coke. Right. And you're drinking it in a concentrated form. It's absorbed more rapidly and there's much more of it. You have to eat an awful lot of food to get the amount of fruit dose that you get from

a single can of Coke, for example. But also importantly, it's the fiber and it's the overall packaging of the sugar that can sort of buffer its metabolic effects. and fruits that I think make it much less of a problem from a diverse point. So just so that people understand, you know, it's your research and others have shown that it's more of the foods that have a high glycemic index, maybe? Foods that are more refined, have added sugars, added fructose. Well, I've been kind of carefully avoid that issue because I think there's still a lot

of uncertainty on that score. I think that the effects of fructose, the metabolic effects of fructose are unquestionable. I don't think there's any doubt that this fructose makes fat. It makes the liver, when it encounters fructose, makes fat, and that starts this whole process in motion. Starches, again, coming in various packages ranging from more easily processed and more rapidly broken down starches that makes glucose because that's the breakdown product of the starch they're considered high glycemic index, ranging in starches that are less processed and consumed

in the context of high fiber, which are less rapidly broken down, have lower glycemic index. That's all, no question about the differences in those characteristics of those starches. However, it's been difficult to show that glycemic index itself is an important influence on Lachrotein metabolism work for that matter on heart disease risk. We sort of vilify processed foods, which I think there's a good reason to do, and that spills over into vilifying processed starches. And I don't have any reason to recommend.

I see patients. I certainly told them to say away from that stuff because it just adds calories and doesn't have all the nutrients that are contained in a fiber-rich, whole-grain form. But whether the glycemic index itself or the glycemic load, which is the total amount of those carbohydrates that are consumed at raised blood sugar levels, whether those are really harmful or not, I've tried to stay out of that argument because I don't think there's really been a compelling amount of evidence. either way. In fact, the study was just reported by a colleague of mine from Harvard, in which

they failed to show a relationship between glycemic index and LVL levels, or liquid levels. So I'd say that's an open question. I think focusing on sugars and added sugars is a way that we can all come together. People that have been focused on fat as the culprit, for the most part, are also acknowledging that added sugars is a big problem. So we've come together on this issue. Beyond that, I think we still have a lot to learn. And the combination between the added sugars and the saturated fat, is that perhaps the worst combo?

That would be, that's the one study that I would like to see somebody fund. I've been trying to do nutrition research in a controlled way. for a number of years. And we sort of worked our way to that question. Could there be some combinatorial effect that could explain what I would call sort of the Big Mac effect by having your red meat, your bacon, and your cheese on a white bun with a milkshake? Right. So I think that might be true, but it really hasn't been studied.

And it's something I really would, it's very hard to find sponsors. These studies are hard to do and are expensive to do. And we haven't yet found anyone interested in that question enough to seriously consider funding it. Because it involves doing, when you get into combinatorial nutrition, it gets really expensive. Because you have to have an arm where there's a high saturated fat with no, you know, with lower carb, high saturated fat with higher carb, low saturated fat, et cetera. You get into a very big production in order to do that study properly. Plus, which we think there is heterogeneity in the population, that there are some people

that are more sensitive to these adverse effects. So you have to have a large enough study population, 40, 80, 100 people, minimum, to be able to sort out these effects. And I'm somewhat, actually I say, frustrated that that question may go unanswered. It's a very important question when we're talking about. You mentioned that you think the role that nutrition plays in cardiovascular health is very, very important. So people need to know what to eat.

Well, you know, I'll just say this as an editorial comment. It's the fact that NIH, which has been the major funder of biomedical research, which is the major fund of biomedical research in the world, has basically pulled the plug on clinical research support in general as a general area of emphasis. The infrastructure for doing good nutritional studies in particular has relied on a mechanism that is now being withdrawn, due to funding constraints, and it's affecting our ability do good nutritional research. So we have to rely on other sources.

And when we rely on industry, I've done a lot of work that's sponsored by the National Dairy Council. I'll say that, you know, acknowledge this a disclosure. But they haven't told me what to find. They haven't, they didn't tell me that my first study was going to come up with a completely opposite result from what I expected. And nothing I've done since then has been dictated by the dairy industry, but they've been very good about funding the work because we've been able to sew that saturated

fat is not as maybe the evil agent of doom that has been made out to be. And others have shown that when saturated fat is packaged in a dairy product, particularly a fermented dairy product, there may actually be some metabolic benefits. So we've been on a sort of a parallel course, not because they've told me what to do, but because we've been very interested in pursuing work that really, I think, justifies a somewhat more relaxed approach to consuming dairy fats than has been generally recommended. Having said that, I think that the sponsorship for research of this scale has to come from other sources.

And so I'm very glad that I'm involved in an advisory role to some such work that's going on, through philanthropy. And I think that's one of the best ways to do research for the type we're talking about is through philanthropic support. But we still, I personally have not yet gotten to the point where I see the potential for doing these large studies with the kind of support we need. And as you say, I think it's really important to figure out ways of getting that support. Well, you've certainly pioneered much of the research on, that you've been a lot of the research that has changed the way the public thinks about cholesterol and, you know, LDL, cholesterol

in particular, and also the foods we eat and how the foods we affect cholesterol. It's becoming more and more popular now that saturated fats aren't the culprit to heart disease. As such. As such. But here's my next question for you. So we spend, as a country, you know, tens of billions of dollars every year on this drug that you mentioned. and LDL lowering drugs like statins. And this, as far as I understand, is on the premise,

mostly that when someone goes to get their lipid panel measured from their doctor in the primary care physician, it's based on their total LDL cholesterol because most physicians do not measure all the different particle sizes of LDL cholesterol. Yeah, and it's not always... I just say it's not somebody that has to be done across the entire population.

But certainly when we're considering treatment, there I think it does have a role. Yes. And so what are the effects of statins on the small dense algae particles and health in general? So you've hit on another one of my lives because more than half my research program, and in fact the majority of my research program now that's NIH funded is through a grant statin effects and the basis for response to statins and the basis, particularly for differential response across the population. So as we've gotten deeply involved in studying statins effects, we certainly have had an interest

in determining how that relates to the levitin profile. And if you think back to what I described about the role of the LVLBOLF. receptor in clearing out of the particles and the fact that the small lvial particles are less efficiently removed by the LL receptor. And one accepts the well-established fact that a major mechanism by which Staten's lower LDL is by increasing LFEO activity. If you take all that information and put it together, you come out with a conclusion, or the hypothesis, perhaps, to start with, that statins would

have a lesser effect on smaller lvial particles because they're more dependent on receptor-mediated uptake. And in fact, we've shown that. So we've done now, we've studied almost every statin and shown that the effects on smaller lvL particles, particularly the very smallest lvL particles, are blunted compared with the larger LVL. It's not as if there's no effect at all, but they're less efficiently cleared. So statins tend to work primarily on the larger cholesterol-rich-el-dial particles, and the lowering

of LDL cholesterol by statins is more strongly related to that effect than the effect on the smaller LDL, which are cholesterol depleted. Now having said that, there is absolutely no doubt that the LDL-L-lowering effect of statins contributes to reduce heart disease risk. I think that's unquestionable. There are other mechanisms involved. I'm sure that we've been studying that can be influenced by statins, including adverse effects, which are very important part of our current research.

But the benefits are absolutely well established. One of the most effective treatments we have for any medical condition other than any antibiotics for infections are statins for lowering LDL, 30-40 percent reduction of risk. time. And so that's because there are a set of LDL particles that are lowered by statins that are bad. And so it's not as if it's all or none. It's just statins could be more effective if they were able to lower the smaller particles. The ones that play a bigger role in heart disease risk. Well, the way I think about it is if you're lowering the larger LDL particles, even though in a way I don't think that's good because you need larger LDL, but you're also

lower, you have less of it around to be processed into lower, smaller. Yeah, although part of that effect, yeah, that's right. Although part of the effect in the small oe al is coming to the triglyceride axis, which we're very interested in that effect as well. Stan has may affect triglyceride metabolism in ways that could affect small oeuvre production. But the net effect is less than it could be if we had a drug that lowered the small alveal product. more effectively. What do you think about dietary changes compared to using statins?

Like if a person, I know not everyone's going to do a dietary change. So statins obviously have their place and they are probably saving a few years on people's lives that wouldn't otherwise make any dietary change. But what are your thoughts or, you know, on dietary changes and that modulating heart disease risk as opposed to taking statins? So I have to have a disclosure here, you know, spending a lot of my time and still doing a lot of work in nutrition. It's been frustrating to observe how limited the evidence is that making dietary change reduces heartaches. The strongest evidence that we have for any kind of treatment is based on randomized controlled trials.

As I mentioned, dietary studies, even though I'm measuring lipids, let alone heart attacks, required in enormous investment of time and energy and funding. So there's been very little basis for concluding that a dietary modification, lower fat, lower carbohydrates even, reduces heart disease risk. And it partly is because the studies haven't been done. And partly because the studies that have been limited by a number of issues. Compliance to these studies, and is always decay over time, and you need to be on these diets for long periods of time to see an effect, plus which the actual dietary effects are not huge. They vary among individuals, so there's people that are really responsive to diet, and

I see these in my practice, from whom diet is extremely important, but if you ever did out over the population, the effect on markers of heart disease risk, lipid, small o'euvre, or blood pressure even, they're measurable. But in terms of the magnitude of those effects across the population, they're much smaller than what can be achieved with statins and their effects on LVL levels. It's disappointing to have to say that because I'm a firm believer in lifestyle and a lifestyle intervention, both diet and exercise for reducing heart disease risk and promoting health overall, but when it comes to people who are at high risk for heart disease, diet alone

is frustratingly difficult to show that there can be a long-term benefit, not because there isn't such a benefit, but the studies just aren't there to help support that. Staten trials supported by industry, big studies, tens of thousands, hundreds of thousands. We've assembled data from 40,000 people in statin trials looking at, you know, and the studies, genetic effects on response. Huge amount of data, beautiful data. Millions that have been used to support these studies. That's disappointing to me.

Yeah, right. Well, that's right. So the money has been coming where the profit comes in. And fortunately in the case of statins, it's been okay because the statins, by and large, have fulfilled their expectations. With the proviso that there is a huge variation in response, and even though there's a 30% 40% reduction in heart disease, risk in patients who are at risk. Or even in the general population, it's been applied, statins that have not been studied,

just huge segments of the population, men, women, different ethnic groups, different lipid levels. And they seem to have a similar benefit across that population. But it's not 100%, and it's not even 50% for the most part. So there is a residual risk on statins that we still have to solve how we best approach that. I think lifestyle is important. I think if we were all fit and lean, a lot of that residual risk would go away. Very hard to prove that, but that seems like a very plausible, and certainly in my case, actionable advice to give to patients is to work on things that you can

control in your lifestyle, but if you remain at risk for heart disease as a physician, I'll write a stand prescription if I thought it was needed. Not to guarantee you that people are going to live forever or anything close to that, but it has a statistically real effect on risk, and we haven't gotten there with diet. We don't have that kind of data for diet. So this sort of leads me to my next question is, do you think that statins are overprescribed in a way based on the fact that most physicians don't look at all the LDL particle sizes, don't look at all the genetic factors, they just look at, you know,

you know, total LDL cholesterol, and if it's really high, you know, and maybe they have high, it will be APOB, they may prescribe a statin, you know, whereas if you look at two people, they may both have high LDL total cholesterol, but one may have no small, you know, dense LDL and one may have high. So, and then what about the side effects of statins? So are they over-prescribed and not the side effects? These are great questions which have a lot of implications. Starting the prescription of statins, depending on which hat I choose to wear, I could argue

that statins are overprescribed because a lot of people are taking statins who are not likely to benefit. But I can put on another hat and say there's a lot of people out there who should be on statins who aren't because physicians aren't really sufficiently aggressive in taking high-risk patients and lowering their LVL in a maximum way that still is safe. So there's subsets of the population that are underfeited, and there's a large segment of the population who are taking statins prophylactically based on guidelines which have continued to evolve, which I was part of that process for a while, and then I grew from it because

I realized I was not happy with the way things who are going in terms of the recommendations, which have evolved to identify even larger segments of the population that should be taking statins to the point that I think there are a huge number of people that are going to be taking statins who really don't need it. And that's where the adverse effect problem comes into place. So my current NIH rant, which is again the biggest part of my program right now, is to identify markers for susceptibility both to the benefits of statin as well as to the adverse effects.

And those adverse effects, people tend to minimize because the benefits in the benefits and the for high-risk patients are so evident from the clinical trials. But as you look at the data, there are some pretty surprisingly adverse things that are out there that are a little bit below the radar screen. One of them is muscle effects, which certainly have been recognized, and people tend to think about them in the more extreme case where people get muscle damage and life-threatening complications of muscle breakdown. very rare, fortunately, otherwise statins wouldn't be out there in the way they are.

But we and others begin to develop evidence that may be effects on muscle metabolism that may be much more widespread that could accumulate over time in a way that may not be manifest in an obvious symptom, but could lead to changes in muscle function, muscle strength. This is a hypothesis that underlies the work between now in terms of the adverse effects of statins on muscle. But there's an even bigger problem, which emerged a few years ago, from one of my colleagues actually, at Harvard who discovered a clinical trial that he organized, and then it turned out to be in the literature, people just hadn't really recognized it, a significant percentage of people taking statins are going to develop diabetes.

Diabetes is not something you want to acquire as a result of drug treatment. It, of course, increases heart disease risk. The magnitude of that effect turns out to be surprisingly high. It's something on the order of 11 to 12 percent of Stanton users are at risk for developing type 2 diabetes. In women, in particular, we published the paper that sort of opened this up, actually. In women, the evidence is that maybe two or three or four times that, it may be as many 30 to 40% of otherwise healthy women who are put on statins could go on to develop type 2 diabetes

over time. That's a very unacceptable number. Now if you're a woman that has a high LDL or a woman that has a very strong, a predisposition to heart disease risk, that shouldn't stand in the way of treatment. But because our guidelines have opened up a statin use to a much larger percentage population as a prophylactic, what's called primary prevention, that is in healthy people who have not yet had this heart disease but who are considered at risk, because a high percentage of those individuals and women, I would point out in particular, have a relatively higher

likelihood of an adverse effect, type of diabetes in particular, than benefit. I think we have to look seriously at finding ways of improving our selection of patients for statin use. And that, again, is driving my research. And fortunately, again, as much as I'm wedded to nutrition and its role in health and heart disease in particular, statins are a lot easier to study. And so, and I think from the public health standpoint, especially Especially now with widespread use of statins, almost like a dietary supplement, like people

take statins, as if they're like a vitamin. We have to be really careful about that. And that's where I think, hopefully the studies we're embarking on this year in the current phase of our grant cycle, which is starting to do this work, I really feel very committed and passionate about using the tools of what we call precision medicine or genomic medicine, as more defined laboratory tools such as this particle measurement is not going to be at in minute to better identify those people who are most likely to benefit. So I think physicians getting back to your question, who are using LDL cholesterol as

the barometer of statin efficacy are potentially going in the wrong direction. And we need better attention to the particles and the measurements of the particles themselves rather than alfuel cholesterol, when we as physicians are recommending, particularly drug treatment, and we should be monitoring those particles as the primary target of treatment, because there are the, particularly smaller particles, give us a much better handle on therapeutic benefit of any treatment. So the test that you played a role in developing, which is, I believe, used by Quest diagnostics, it's like based on physics, essentially, right?

You're just throwing these particles through the air and based on the way they're going through the air, you can figure out their density. But why is that not used in medicine? And can we get physicians to start adopting this? I mean... Yeah, well, of course, I disclose here that along the way, because of my interest in life-prachin metabolism and where I've been able to do my work and initially at the Lawrence Brickley Lab and not here at Children's Hospital, I've been able to

work with people that have had analytic capabilities that have led to methodologies of the most recent, as is one you'll mention, I'll come back to a minute to that particular method. But I, you know, we've brought this to the public through industry. And so, you know, you have patents and they've been licensed to do this methodology. So that's a disclosure. But that's the way you get things out there, is through that kind of partnership. And it has penetrated a certain segment of the preventive cardiology community. There are lipidologists in particular who are proliferating.

Fortunately, there's a lot of lipid education going on. And the people that are really skilled and understand lipid metabolism are at least thinking about lipoprotein particles, not necessarily yet about sub-fractions, but that's not necessarily about sub-fractions, but at least a particle versus the L-Vial cholesterol is taking you in the right direction because that's really the first step in terms of narrowing down to focus on what you should be treating. That's being understood, but it's still a relatively small percentage of the entire medical community that they consider themselves lipidologists or cardiologists.

What about the rest of the physician community? Well, they've been confused. And part of that is because there's been a number of methods that have been out there, not just the ones that I developed, but others that have used different systems and different calibration, different ways of organizing the data, different ways of trying to educate the public lot of it, but driven by the companies that have promoted these methods. And so physicians were getting barrage and so are with competing claims for this or that method, not as well standardized, certainly as the LVL cholesterol measurement.

So it's been kind of given a backseat in part because of that confusion, in part because because a lot of people still not convince them. But even my colleagues, even the lipidology community, is not fully convinced that the smaller particles are that much worse than larger particles, despite all the data we have. So I'm always on the trail trying to sort of remind people of what the data show.

I give a talk called not all alveol particles are created equal. People just need to understand that. So there's been a slow uptake because of the confusion, scientific confusion of the methodological, confusion and at one point it was a price issue as well is it really cost effective to be using this test and you know hundreds of thousands and millions of people but across an arm or leg well this new method that we it's not too new anymore

I've been looking at it for like over ten years but Quest did partner with us and has been now more actively engaged in supporting the development of this methodology and improvement and methodologies to be more refined. So this is one of the more refined measurements. In fact, it is the most refined measurement we have for light protein analysis using this technique called ion mobility, which spays particles into air.

And then we count them as a function of your size. And it's very elegant. It's based on physics. And it works, and it gives us data that is entirely consistent with everything we've known from our previous methods. It's standardization is in progress, but it's relatively easily standardized.

And its cost has come down to something that's not that much more than doing the standard cholesterol panel. So none of those things should be barriers anymore. So I'm hoping that as time goes on, hopefully within my lifetime, that physicians will see the role of this in their clinical practice. Certainly when they're trying to make a treatment decision that they're considering a patient for some sort of intervention, I think that's where the particle analysis really is important. For screening the population, I think what can argue, the standard lipid test do a fairly

good job, but if you're having somebody view or, in my case, patients are on the cost about whether they should be dealing with their lipids, I think these measurements have enormously to our ability to target those people who would benefit from certain kinds of treatments, statins, diet, and then monitoring them as they're undergoing fees. So if anyone that's had a standard lipid panel done and let's say their LDL cholesterol was high, they can go to Quest diagnostics and get that test done or do they need a doctor's prescription first? No, no, yeah, no.

This is all done by medical orders. There has to be not only a doctor's prescription, but there's got to be a diagnosis. Yeah. To get insurance reimbursement, you have to have a defined basis for doing those tests. Insurance policies, Medicare are starting to, have been re-imursing for those tests, but you have to have a medical reason. And that gets back to the issue of what criteria should be used to identify someone who should have this test done.

One could argue that if one has a really high LDL cholesterol, we might not even need this test because if the LDL cholesterol is high enough, it's almost always going to have some of the small l-dl particles in it. I'm talking about very high l-del. The people that really are most likely to get benefit from knowing what their particle profile looks like are those that have sort of the garden variety levels of Ldial cholesterol. What's that considered to be? Well, the average in the population is something like 115 or 120 milligrams per deceditor.

If you take a population of heart attack patients, it's only slightly higher than that. So that's another one of the important messages that me and others try to convey is that LDL cholesterol, because of this particle difference, does not discriminate heart disease patients from the general population as well as those the particle measurements, which are more specifically related disease risk. So in those individuals who have LDL cholesterol in that sort of borderline range between, quote, normal, you know, unaffected people at low risk for heart disease versus those that have heart disease, there is a relatively tight range occupying the middle of the cholesterol distribution.

That's where I think this particle measurement, though, you have the greatest potential for refining risk assessment and identifying people that should be considered candidates for with whatever one can use to help lower those particle concentrations. I don't want to take too much more of your time because you've been so generous and we've covered so much, but this brings me to one, this, what about someone, as a follow-up to that, what about someone that has, you mentioned genetic risk factors? Let's say they have a genetic risk factor like, you know, there have an APOE4 allel, which means they can't recycle the LDL, you know, cholesterol back to the liver as efficiently.

So they have more LDL cholesterol around. And they have a level of, let's say, 150, which is much higher than what you said the average would be. But they don't need a lot of refined carbohydrates or added sugar or things like that. Do you think they could still benefit from this particle test? Well, those that have APOE4 have a sort of additional dimension to risk. We don't understand all the reasons for that. But the determination of small LDL particles is driven by many other factors, including other genes.

that are probably even more important than APOE, actually. So the APOE4 axis sort of amplifies the risk associated with small LVL or any other heart disease risk factor. But the recommendations for trying to monitor and manage small LVL particles, I thought about this a lot recently. I think they represent sort of a separate axis from the APO-E. I think the APO-E axis amplifies the risk, but it doesn't necessarily change the fundamental biology for production of the small product. But if someone were to have their lipid panel done by their physician and it was 150,

that said they didn't know their APOE-4, their physician would look at that and go, whoa, that's really high. Right. And I think, you know, if there's, it depends not just on the LDL, but there's a range, if you want to actually pick a number, the sort of consensus number that the lipid community, the cardiologic community, has accepted as mandating attention for genetic reasons. It's an LDL actually at 190, so it's even higher than that. So I'll start with that.

If your LDL is 190 and greater, the particle measurement, probably, isn't going to affect the treatment decision because in almost all cases those patients have genetic epidemiology, but maybe part of it, but not the cause of those very high levels. That's usually an LDL receptor epidemic. Those patients are sufficiently high lifelong risk of heart disease that they are candidates for statin therapy almost in all cases. It's very difficult to achieve a significant approach towards optimizing LDL levels in those patients.

So that's 190. 150, sort of halfway in between. So that's a gray zone. And so it depends not just on the LDL, but the overall risk. Blood pressure, diabetes, family history. Triglosterides? And triglycerides have not entered into the equation.

So there's epidemiologists that do all this number crunching and they come up with risk assessment tools. Triglacly hasn't entered into it because it's so tightly related to everything else. It's a very bouncy measurement. It's much less stable over time, even from day to day as LVL cholesterol and H.DL cholesterol, so it sort of falls out of these equations.

But it's part of this aftergenital pneumonia of phenotype. It's part of that trait. It's important, but as a measurement, it doesn't stand up to the LVL particles in terms of its association with the scurine HDL. So anyway, this risk assessment is done, and then you decide, well, is this patient at sufficiently high risk using these,

you know, if you're in the swing of things With the guidelines, you do these assessments of likelihood of having a heart attack for the next two years, and if it's high enough, then you jump in with aggressive treatment. And I think the risk is high enough. You probably use that as a patient as well, but it's not an automatic decision. That's where the particle measurement hasn't yet achieved the level of acceptance to enter into this risk calculation formulas, partly because the risk assessment tools that we have work pretty well of themselves.

This is actually a very interesting point from a sort of a conceptual standpoint, so I'm just going to say this because that's maybe a little bit complicated. But when you have some very strong predictors of heart disease risk, blood pressure, diabetes, even out of the cholesterol, HDL cholesterol, these standard measurements, and you throw them into a risk formula, and you add in age and sex. you can explain a lot of risk that way. You can argue what that explanatory number is, whether it's 50% or 70%, it's very high. So if you add lVL particles or these more defined measurements of particle concentrations into

those formulas, you don't get much additional explanation of risk because a lot of these things are interrelated with one another. And so there is a confusion between the magnitude by which you can improve risk prediction by these measurements versus what's really important biologically that you should be treating. And so people think, well, because your particle measurements don't add that much to the risk assessment. But it adds a measurable amount. It's just not a lot.

People say, well, let's not worry about that. But from a biological standpoint, that may be the driving factor. So if you turn that whole process around and you throw off the standard factors and you just use the particle concentrations and maybe a few other things like agent sex, you can also expand a lot of the risk. So you can choose your weapon, but don't confuse the ability to predict risk with what you should be treating because those are not always the same. I hope that's not too complicated.

But that to me is a very interesting point. It is very interesting. It is a little complicated. It is complicated. So you may not want to get too far into that. And then there's also the issue of relative risk versus absolute risk, which isn't important. That's something that I think people should be able to understand because it's really important as well.

If you're absolute risk of heart disease is very low, if you're like a super healthy person that has immaculate blood pressures, lean, fit, blood sugar is great, and their lelio cholesterol, or even small ovia particles are elevated. may increase the risk by two or three full. But if it's two to three times a very small number, that's still a very small number. And if people sort of confuse that with how much benefit you're likely to get from lipid lowering, it really depends on the absolute risk. Right. No, that's actually a really good point. And I think we'll end on that point. Ron, thank you so much. I know that you don't have a website, but you are, you know, people

can find you at Corey. What about talks? You mentioned not all LDL particles are the same. Are there certain talks people can look up and find, they want to hear you speak? Yes, there have been some webcasts that I've done. I can't give you chapter and verse, but I'm Googledable, I guess. Ron Krause, Google? Yeah, something like that. And also they can find you at cory.org. Right.

So, exactly. Thank you so much, Ron. Really, really interesting conversation. Great questions. Okay. and usually if you tweet at me, I actually do read it and often reply. I'll catch you guys next time.