 Thanks, everyone. It's my first time here, so it's an honor to be here. And I realize that speaking right before lunch is an unfortunate slot. So what I think we'll do is my talk will probably take the 35 to 40 minutes that's allotted. But if folks want to stick around after, I'm happy to answer questions. There aren't many things I enjoy talking about more than cholesterol. And with my wife not here to kick my shins under the table for going on and on, I might be a little unencumbered. So this is one of my favorite quotes, and really it speaks to a lot of things that we've already heard about today, such as the role of dietary fat and things like that. But I think it's particularly relevant for what we're about to talk about today. We must admit that our opponents in this argument have a market advantage over us. They need only a few words to set forth a half-truth, whereas in order to show that it is a half-truth, we have to resort to long and arid dissertations, which I promise not to do today. But if folks are interested in this topic, there is just a wealth of information out there, good information, and I'd be happy to point people in the direction of that. So rather than talk about the obligatory 30,000-foot view I'm about to give, I think it's probably more accurate to say it's going to be about the 220,000-foot view. So there's a lot of stuff here that I won't get into that's really interesting, and perhaps it'll come up in Q&A, but perhaps we can talk about it offline. Okay, so let's start with the jugular question, because any discussion of cholesterol has to begin with a discussion of atherosclerosis. So if I took a group of medical students or physicians, or lay people for that matter, and I said, what causes atherosclerosis? You'd get a lot of responses. You'd say, well, maybe it's caused by low HDL or high LDL or obesity, even metabolic syndrome, high blood pressure, smoking definitely causes heart disease. Maybe it's just the elevated triglycerides in our blood. And while it's true that all of these things are related to atherosclerosis, and some even play a very strong role, it's important to keep the actual definition in mind, which unfortunately is recognized by very few clinicians. The synquanon of atherosclerosis is the presence of a sterol in an arterial wall macrophage, nothing more and nothing less. So it has nothing to do with how much you smoke, how high your blood pressure is, or how high or low your HDL or LDL are. If you do not have a sterol, or a laser pointer that works, inside an artery wall that gets engulfed by an arterial wall macrophage, you do not have atherosclerosis. What we're gonna talk about today is what gets the sterols in there. Now you notice I use the term sterol. The reason is I'm being much more broad than just talking about cholesterol. Cholesterol is a form of sterol. It's the sterol that comes from the animal kingdom. But of course we also know that there are phytosterols, which are the sterols that come from the plant kingdom, and you can see the chemical structures of those. So one of my favorite questions is, but what about good cholesterol and bad cholesterol? Thank you so much. Wow, nice. Turns out this is a very misleading term. There's actually no such thing as good or bad cholesterol. All cholesterol is good. Cholesterol is essential for life, not important for life, essential for life. There are a number of functions that couldn't exist in the body without cholesterol, but perhaps two of the most obvious are demonstrated here. The first is the production of very important hormones in our body that we've already heard a little bit about in the past two days. And there's very complex pathways that will turn cholesterol into these really important hormones, androgens, et cetera. The other one is in the presence, in the role that they play in the bilayer membrane of a cell, virtually every cell in the human body, for that matter. In fact, when you look at a cell in cross-section, you can see that it's not only composed of a bilayer, two lipids opposing each other, but these lipids create a transmembrane environment and hold within them complex proteins that play an essential role in everything our cells do. So if you didn't actually have cholesterol in the wall of a cell, and in a moment I'm gonna tell you how much cholesterol you have in the wall of a cell, these cells wouldn't be able to move, they wouldn't have the fluidity to interact with each other, nor would they be able to contain these very important and necessary ligands that control permeability. So if you remember one thing from this slide, no cholesterol means no life, and in fact there are rare genetic disorders where endogenous production of cholesterol is severely limited and these patients do suffer early morbidity and mortality. So where does this stuff come from? So there's two ways to really think about this question, I'm gonna try and answer it in two halves. The first is thinking about the actual production, the chemical production of this stuff. So the first is endogenous consumption, or pardon me, exogenous consumption. So the cholesterol that we eat. And you notice I have pictures of both eggs and corn here, why am I doing that? Because remember, we eat both cholesterol and phytosterol from plants. Most people don't realize this, but corn actually on a per gram basis has far more phytosterol than any other plant except one. And eggs of course contain cholesterol, that's why they're so bad for us, right? So we consume an average of between 300 and 500 milligrams of cholesterol per day. That's the diet of some people, people like me probably consume closer to about 600, 700 milligrams per day. Endogenously, the cells of our body produce about 800 to 1200 milligrams per day. Now the liver does the lion's share of that at 20 to 25%, but it turns out virtually every cell in the body is able to produce sufficient cholesterol within itself, de novo, to sustain its function with two exceptions, and these are two really important exceptions ironically. One is the adrenal cortex and the other is the gonad. And if you think back to what I showed you a moment ago, the importance of cholesterol as a precursor in the important hormones, it's kind of ironic that both the gonad and the adrenal cortex can't produce their own cholesterol at sufficient levels or even at all, that's somewhat debatable. The fact that they can do it at all. What's not debatable is that they clearly can't do enough. Okay, so what role do the liver and the gut play? It turns out they play a very important role. So remember, the liver not only is synthesizing 20% of your cholesterol, but it is also the place where that cholesterol aggregates, gets deposited into bile salts, which by the way you couldn't make without cholesterol, but that's another story, and gets dumped through the biliary system into the gastrointestinal system, into the gut. The gut then becomes the ultimate regulator, if you will, of how much of that cholesterol that we ate plus synthesized gets reabsorbed in the body. 85% of the cholesterol in the gut is of endogenous origin. So it's the endogenous cholesterol makes up the largest pool of what's there. So 15% is coming from what we ate, 85% what we recycled that we made, and then the gut does something I'm gonna show you in a second. The other thing I wanna point out here is remember, we talked about, call it 300, call it 1200 milligrams here. The total body store of cholesterol is between 40 and 50 grams. So it's sort of like the total body store is a swimming pool and we have two other things that contribute to the swimming pool. One is a little internal hose and the other is an external little drip thing. So if you think about biology, what have we learned? We've learned a few things, right? Whenever you have a system that has an enormous internal store of something and minuscule a little external and internal contributions to that, it's a highly regulated process and it's very unlikely that the inputs on the little side are moving the needle and it's probably the case that something else is. So we just talked about how we synthesize and we absorb cholesterol and as a general rule, people actually differ. We fall into, broadly speaking, one of two categories. People tend to be more the synthesizer, meaning you start with these two carbon units and you go through 37 different steps of carbon fixation to make this 27 carbon molecule called cholesterol. So people either predominantly do that in their cells or they predominantly, they don't make much but they sure are good at absorbing it. Now there are people who do neither particularly well and there are people who do both of those particularly well but on average that represents about 80% of the population. The absorption story is a fascinating one and I wanna touch on it for a moment despite the ungodly diagram here. I couldn't find a better one. So this is your gut cell. This is an enterocyte. This is the lumen, meaning it's the sort of tube surface of the gut. This is the inside of your body. The blue thing is a transmembrane complex called a nemenpick C1 like one receptor, obviously. And it's sort of like the ticket taker in a bar. Very little discrimination whatsoever. If you have the money you get in the bar, right? So it basically lets everything in. Cholesterol, phytosterol, doesn't matter how much. By the way, it's worth pointing out and it's kind of an interesting point. Phytosterol on a molecule per molecule basis is actually far more athrogenic than cholesterol. So some of you may know this, but people have in the past taken huge doses of phytosterol because if you took enough phytosterol, you would over occupy this and prevent cholesterol from getting in. So phytosterols were viewed as a way to prevent absorption of cholesterol. It turns out that's interesting if this guy is defective because now, and I'll tell you in a moment why, you're selectively bringing phytosterol in the body and these patients actually ended up getting a higher incidence of coronary artery disease because they, on a per molecule basis, were bringing in a more athrogenic particle. So once everybody gets through the ticker-taker and they're in the bar, the bouncer, the ATP binding cassette G5G8 has to do his job and the bouncer has to make sure, one, that there's no bad people in the bar. So he works very hard to selectively kick the phytosterols back out so that they can leave our GI system and if there's too much cholesterol being absorbed. I mean, there's too many people in the bar. It's just a fire hazard. It's not just that we've got guys who wanna start fights, but it's just too crowded in here. You'll also see a selective reduction of cholesterol content in the gut. So you got a ticker-taker, you got a bouncer. It's a highly regulated system. Okay, so everything we've talked about so far has been cholesterol and I didn't get into this detail but it's important to point out here. When cholesterol has nothing attached to this last carbon, it's called a free cholesterol when it just has that OH group there, but most of the cholesterol we eat actually has big bulky side chains so R just represents some big other chemical structure. We call that cholesterol ester. So you have these cholesterol esters and free cholesterol. We also have triglycerides. Most people appreciate what that is, right? The three carbon backbone and the three tails and then we have these things called phospholipids. These things are all essential. Think of them as cargo. The reason is they're all hydrophobic. They repel water. So if our vascular system is thought of as sort of the waterway, you can't actually put the cargo in the water because it won't float down the river like normal cargo will. It just sort of bounces around and doesn't go anywhere. So you have to put the cargo in a boat and the boat is called the lipoprotein. The lipoproteins transport the cargo and the lipoprotein as you can see and again as its name suggests is part lipid, part protein. So it has a lipid monolayer, which is of course composed of cholesterol and inside it has a core and the core contains a combination of things including all of these guys. And in a moment I'll show you how they vary by the different type of lipoprotein. You'll also notice there's a ring around the protein and that's an apolipoprotein and that apolipoprotein is what allows the lipoprotein when it reaches its destination to interact with the cell it needs to interact with and frankly even before it gets to its destination allows interaction between lipoproteins. Now the lipoprotein on here is called B100, apob100. That's a very common one. We're gonna talk a lot about that later. There's also an apob48 and there's an apoba1 which we're gonna talk about as well. That's the one that resides on a certain type of lipoprotein called a high density lipoprotein. The apob100 resides on the one, the one called a low density lipoprotein. So think about boats, think about cargo. Cargo doesn't go anywhere without boats. Now a moment ago I started this talk by saying that you do not have atherosclerosis without having a sterile in an artery wall. But to get to an artery wall I just told you that the cargo can't do anything on its own. Meaning the free amount of cholesterol that I measure in your bloodstream or my bloodstream is as relevant to your heart disease as perhaps your eye color. Now technically there's a pretty strong correlation and we'll talk about that. But the point is unless the boat delivers the cargo to the artery wall you don't have atherosclerosis. So just for the sake of understanding the nomenclature I'll just go through this really quickly. We have things that everyone's probably heard of. We have these things called kylamichrons. They're the largest of these lipoproteins by far. They contain mostly triglyceride. In a moment I'll show you a diagram that tells you where they all come from. We then have the next ones down, the VLDLs, their sons are the IDLs and their grandsons are the LDLs. These guys get all the bad press because they're the bad cholesterol. And then down here you have a totally separate lineage of different family called the HDLs, the good ones. And so remember the HDLs have ApoA1s. All of these guys have ApoBs. And this is what I mentioned a moment ago. We export triglyceride in the form of VLDL from the liver and we also do the same in the gut. So the gut captures, remember on the back side of the bar you had that kylamichron that was picking up the triglycerides. The kylamichron and the VLDL both shed their triglyceride pretty quickly thanks to lipoprotein lipase and give off triglyceride to their cells. They're delivering it. Keep in mind we don't even have free floating triglycerides in our blood. At best they have to be bound to another protein called albumin. And so what are we doing with this triglyceride? We're doing two things with it and it's highly dependent on our metabolism and what we're doing. If we're active and we're metabolically flexible we're using that triglyceride to be delivered to a muscle because triglyceride is obviously the preferred fuel in an abrobic situation. If we are metabolically inflexible and we are metabolically deranged we are actually delivering that triglyceride to an adipocyte to store it. So once the VLDL and the kylamichron shed their trig they become an IDL and that becomes an LDL. Okay, LDL. Let's talk about the chicken and the egg problem which I contemplated taking this slide out but it's worth having because I think this is a more sophisticated audience than I would normally give this talk. A lot of people will ask the question but what about inflammation? You haven't said anything about inflammation and I mean I sort of did because I said that the sterol has to be in an artery wall macrophase which is obviously an inflammatory cell. There's no perfect way to answer this question. There's no experiment we can design in humans that would answer this question. So we have to look to the natural experiments and I'm a big fan of Stephen Levitt and I had dinner with him about a year ago actually and we were talking a lot about the field of microeconomics and how they have to rely exclusively on natural experiments and I think this is an example of how we have to do the same thing here. So let's take a look at two. The first which was reported in the New England Journal of Medicine a couple of years ago looked at a type of a very rare genetic mutation which is a nonsense mutation in something called PCSK9. So PCSK9 is an enzyme that results in the degradation of LDL receptors on the liver. These are receptors that clear LDL particles from the body. We all have this enzyme and it works really hard to break those receptors down. Some people who have this nonsense mutation have less functional versions of that receptor. The net effect of that is they have more LDL receptors on their liver and they clear LDL much more. So they're taking more of the boats out of the river, the boats that are carrying the cargo that we wanna keep out of the artery wall. As a result of that, these people have almost a super human immunity to atherosclerosis. So these people walk around with an LDL cholesterol level between five and 40 milligrams per deciliter, very low and probably harmful for many other reasons. But nevertheless, these people have a totally normal immune system but they are deficient in boats and cargo and as a result they don't get much heart disease. Conversely, we have a condition called familial hypercholesterolemia, which is a very complicated disease with many variants but the recurring theme here is the opposite problem which is a paucity of LDL clearance capacity and therefore they have very high, both total cholesterol and cholesterol carrying boats which are really the bad guys here in this disease process. And they get the opposite issue, right? Which is if they make it into adulthood they are far more susceptible to atherosclerotic disease. So the point I wanna make here is this, atherosclerosis is not a lipid mediated disease. It's not a disease of cholesterol. It's a disease of lipoproteins. The lipoprotein mediates it. If you don't have the boat, you don't have a problem. So how does it end up in the artery wall? So this is a cross-section view of an artery wall, kind of a lousy figure, I'm sorry. But you can see here that you have an endothelium which is that cellular layer that is right there exposed to the blood going past it. And then you have the media, the muscular layer, et cetera of the artery. There's a little space between the epithelium and the media called the, appropriately enough, subendothelial space. In a normal circumstance, you don't want anything in your sub-epithelial space. In fact, you want that space to be gone. You don't want a space there. Various things increase that space. Various insults to the endothelium both increase the permeability of it, meaning the ability for boats to slip past the dock, if you will. And then the capacity for them to take up residence there. So what happens is a lipoprotein particle carrying an ApoB lipoprotein, and that's mostly the LDL particle, gets in here and kicks off an inflammatory response because we have immune systems that are largely doing the right thing. You're not supposed to be in here, I'm going to get you out. So the macrophages arrive, the process goes on, we get proteoglycans that get up-regulated, all sorts of things now make it harder for them to leave because now they're sort of stuck there while the immune battle is going on. It ultimately switches over from the humoral side, the B cell side to the T cell side, the cellular side, and it becomes actually a bit of a spiral of death because the moment you start getting them in there, the inflammation creates an environment that makes it easier for other ApoB carrying particles to get in, right? If you were going by a dock that didn't look like it was open and couldn't attract anything in, and all of a sudden now there was mayhem and ruckus and you could get in, more of these particles get in. This is what it looks like under a microscope, I think for the sake of time I'll just be real quick, right? This is normal, these are three different types of stains and over time you can see the progression of initially the lipid, eventually the macrophage. So again, it speaks to the sequence of events which is the lipoprotein gets in first, the inflammatory response exacerbates it. Okay, one of the most contentious topics in this field comes down to the size of an LDL particle. Most of us probably at some point have believed or do believe that a smaller LDL particle is more pathologic than a large one, right? This so-called pattern A versus pattern B. So for those who aren't familiar with that argument, here it is, right? So both of these particles have the same content of cholesterol, meaning if you add up all the cholesterol in these and these it's the same, but clearly there are more particles here than here and they happen to be smaller. So we have two things going on. You have the pattern A person and the pattern B person. Here the LDLP, the number of particles, is five, here it's nine. There is no dispute that this person is at greater risk than this person. That's not disputed. The debate centers around why. Is this person at greater risk because they have smaller particles or are they at greater risk because they have more particles? So let's take a look at that. This is from a very large study, the Quebec Cardiovascular Study published in circulation. This shows you a two-dimensional odds ratio, which I'll walk you through very quickly. We use APOB as a surrogate for LDLP, the number of particles. So a bigger APOB means more particles because there's only one APOB per particle. And it shows you in two dimensions, particle size versus particle number. And this is a relative risk ratio. So you can see that for people with a low particle number, there appears to be no difference in risk between small and large. And if particle number was high, high APOB, it appeared that the smaller particle had a 6.2 relative increase in risk versus 2.0. So this would certainly suggest that a smaller particle is more pathologic. What the authors put not in this figure, but unfortunately only in the text, was that this was based on a discrete division of size, sort of like dividing people up as tall and short, using six feet as the cutoff. When you actually looked at particle size as a continuous variable, this effect completely vanished. Let me repeat that. If you don't just arbitrarily determine what the cutoff point is, and you do this over a continuum, size no longer matter. Let's look at it in a different patient population. Let's look at the MESA trial. The MESA trial looked at a different metric. They looked at changes in IMT. So this is the thickness of the media wall in carotid arteries. This is a very good non-invasive test for atherosclerosis. And in the first analysis, they said let's not adjust for size, pardon me, let's not adjust for particle number. So they looked at LDL size and they said sure enough for every increase in a standard deviation of particle size, the intimal thickness went down, less atherosclerosis, which again suggests in the unadjusted analysis, bigger is better. When you adjust for the particle number, and this is the important part, not only did that effect vanish, it actually bordered on being the opposite direction, meaning for every increase in particle size, you saw an increase in atherosclerosis. Again, P-value 0.05 doesn't quite pass the test, but the point is the effect vanished. Let's look at this yet another way. Let's take a look at MESA data cut a different way, which shows years of follow-up five versus cardiovascular events based on the division of LDL particle versus cholesterol. Because the question I think a lot of people ask at this point is okay great, but how do I measure that risk? And the point I wanna make here is you measure that risk only by measuring the number of particles, not the concentration of cholesterol within the particle, which is what the standard test is. So when you divided people up in this category based on their LDL particle number and their LDL cholesterol, and I won't get into the details of what the cutoffs were, they used 30th percentiles, you can see here that the people at the lowest risk had low levels of particle numbers, but high numbers are not low numbers of cholesterol concentration. The next group at the best risk had low particle numbers and low numbers of cholesterol concentration, and you can see this effect all the way to the top. So the group that was at the highest risk by mortality had high numbers of LDLP and actually low numbers of LDLC. It's very counterintuitive. You might think it's a freak event. So let's look at the Framingham data. This is a 16.7-year average follow-up of 2,400 patients. They used a different cutoff point. Here they used a cutoff point of an LDL cholesterol of 131 milligrams per deciliter. It's a little elevated. And an LDLP of 1,400, the units of that are nanomoles per liter. And you see the exact same thing. The people at the highest risk, the people who died the quickest, this is a Kaplan-Meier survival curve, were the people that had the highest LDLP, independent of LDLC, and the reverse was true. So we have this issue called discordance. Discordance is a statistical term that means two variables are not predicting the same thing. We were taught that LDL cholesterol is the big risk, right? If your LDL cholesterol is high, you were at risk for heart disease. And yet we're seeing that some of the time, in fact, depending on the population, as I'll show you in a second, that turns out to be patently false. This is a study that looked at 136,000 patients admitted to the hospital for a coronary artery event, meaning these people were having chest pain and or actively having heart attacks. And in these patients, they looked at LDL cholesterol level. And you can see that nearly 50% of them had what you would consider a low LDL cholesterol level, below 100 milligrams per deciliter. Tim Russert is included here at the time of his death. His LDL cholesterol level was 69. So what's going on here? How is this happening? Let me just show you another slide or two on that point to illustrate this discordance because it clearly is related to some metabolic syndrome. Most of us know that there are five criteria for metabolic syndrome. If you have three of the five, you have the syndrome. If you have none of them, the blue number, which is your LDLC and the red number, which is your LDLP, largely predict the same thing, meaning they're at the same percentile risk of predicting an adverse cardiac event. If you have one component of metabolic syndrome, remember what these are, right? Elevated triglycerides, elevated fasting glucose, elevated blood pressure, truncal obesity, et cetera, all of a sudden the discordance, the gap between these widens. If you have two, if you have three, so now the people with three, four and five actually have metabolic syndrome, right? That's the diagnosis. Look at the discordance between them. In these patients, LDLC is of no value. In fact, it's harmful because it gives you a false sense of confidence. Why is this happening? There are a lot of reasons, but by far the most important is this one. Remember our good friend, the lipoprotein particle, the boat. The boat's job is to carry cholesterol and triglycerides in a very delicate balance depending on which lipoprotein it is. If you are a VLDL, you're supposed to be carrying four times the triglyceride to your amount of cholesterol. Because remember your job. Your job is to provide triglycerides to hopefully muscle cells, but also fat cells for storage. But if you're an LDL particle, you should be carrying 75% of your cargo in the form of cholesterol. But what happens if you still have so much triglyceride kicking around that you can't do that? You make more boats. So the discordance is a result of having too much triglyceride that needs to be mobilized and it's crowding out what you're supposed to be carrying around which is the cholesterol. So if you're sitting here in this room asking the question, golly, how do I make sure I don't have too many boats and I'm optimizing my cargo? It's a good question to ask. We indirectly have to answer this question through a couple of different types of evidence. The first is looking at clinical trials that indirectly measure certain aspects of what I just said. The A to Z trial, which I'm sure many of you are familiar with, this is the trial Christopher Gardner published about five years ago, took a group of 312 patients, I believe, followed them over a year on four radically different diets that span the spectrum of relative restriction of carbohydrate ranging from the Ornish diet which is obviously the least restrictive. That's a pure fat restriction diet up to the Atkins diet. And you can see both at two months and at 12 months far and away the greatest reduction in triglyceride concentration was in the group that was paradoxically eating all the fat and none of the carbs. Okay, not a surprise to you guys. Let's look at the workplace diet trial in 2008. This was a trial again that looked at 322 patients divided into three groups. These patients were followed for two years on one of three diets. The first group was given a calorie restricted low fat diet. The second group was given a calorie restricted Mediterranean diet. And the third group was given an ad libitum Atkins diet, meaning eat as much as you want as long as you don't eat carbs. And again, you can see the only group that experienced a significant reduction in triglyceride, not only relative to its baseline, but even to the others was paradoxically this low carb group. And most recently Peter Havel and his colleagues up at UC Davis did a study that took this one step further. This was a study that took a group of healthy volunteers and after an induction period put them on one of three diets. The diets all consisted of the same macronutrient breakdown. Believe it was 30% protein, 55% carbohydrate, 15% fat. So very close to the standard American diet. But there was a substitution made in the carbohydrate group. So group one got all of, sorry, pardon me, got 25% of their carbohydrate purely as glucose. Group two got 25% purely as sucrose, so 50, 50 glucose fructose. And group three got 25% purely as high fructose corn syrup. And I know what you're thinking, 25% of your carbs in the form of sugar, it's actually not that radical. If a person's eating 24 to 2500 calories a day and they're getting 25% of their carbohydrate intake in the form of sugar, that's only 120 pounds of sugar a year, which as I suspect Rob Lustig will tell us tomorrow is actually below the national average. So we're not talking about doing crazy stuff like mainlining people full of sugar here. This is the standard American diet. So look what happened, I'm sorry, I'm gonna have to look at my screen because I don't can't see that. So the first graph up here, graph A shows you the triglyceride area under curve over a 24 hour period in this group. Keep in mind this intervention was only 10 to 14 days. This is a very short period of time. And yet look at the change in both the pure fructose group and the high fructose corn syrup group relative to the pure glucose group. Now a lot of people say, well, isn't that amazing? I would have expected the glucose to go up. And I probably would have too until you realize that most of these people coming on this diet, transition to all glucose instead of glucose and fructose is actually an enormous improvement in diet. It is for most people. When you look at other metrics of triglycerides such as fasting level of triglyceride, interestingly, everybody skyrockets. And when you look at post-prandial triglyceride, everybody goes up. Now we can debate for days which of these is the most accurate assessment of cardiovascular risk. And there are great arguments to be made for all of them. From a practical standpoint, it's very difficult for you to go to your doctor's office and have them measure your 24-hour triglycerides. So we tend to refer to these two. But what happens if we look at something even more important, which is particle number? Now remember I said you can use ApoB as a surrogate for particle number because a lipoprotein particle only has one ApoB. And here they did just that. So when they looked at fasting ApoB levels over here, you can see that the glucose only group had a very slight bump in their number of particles. The group consuming fructose had a very big jump. It's important to keep in terms what you're looking at here. You're looking at grams per liter as opposed to milligrams per deciliter. This is a very significant jump. And the high fructose corn syrup had an even greater jump. Now I'm looking actually forward to talking with Rob tomorrow about this because as most of you know, the difference between fructose and high fructose corn syrup is very little. One is 50-50, the other is 55-45. So it's interesting to note that there's a difference. And it may be the fructose because of course high fructose corn syrup is technically made up of 55% fructose and 45 glucose. But nevertheless, I'm sorry. Oh, I'm sorry, my mistake. Fructose here, all fructose versus high fructose corn syrup and corn syrup. Yeah, yeah, thank you. So it's interesting to note that somehow the presence of glucose may be making this worse. And again, I think there may be an issue of insulin sensitivity that's resulting from that because we know that fructose, even though it doesn't stimulate insulin, does worsen insulin resistance. Whether we're seeing that effect in a short period of time remains unclear, but what does not remain unclear is that either pure fructose or high fructose corn syrup is dramatically worsening your lipoprotein. Forget lipids, we don't care about LDL cholesterol. It's actually worsening not only your absolute amount of apoB, but it's also worsening your apoB relative to your aproA1. In other words, what does this mean? It means you are building up more LDL particles and fewer HDL particles. Perhaps during the Q&A we can explain why the fewer HDL particles is a bad thing, but the point is in a very short period of time in healthy volunteers, you're able to observe this effect, ask yourself what that's doing over the course of your lifetime. So what do we know? Cholesterol is vital for life. The cholesterol we eat actually has very little to do with the cholesterol in our body. The problem actually occurs when cholesterol or another sterile gets into an artery wall macrophage. The only way this happens is if they are carried there by an apoB bearing lipoprotein. A particle is a particle is a particle, so please don't fixate on the size of the particle and don't fixate on the concentration of cholesterol within the particle. You need fewer boats if your boats can carry more of their intended cargo. Last point I wanna make is something that's not clear to me. So just to sort of bear my insecurity, there's a very important question I don't know the answer to and I've not been able to find this answer yet. Which is an LDL particle count of 2,000 millimoles per nanomoles per liter is very high. It's the 99th percentile. So if a card carrying lipidologist encountered a patient with an LDLP of 2,000, they wouldn't let them leave the office without two drugs. It's simply, it's malpractice, right? The question is, what does an LDLP of 2,000 mean in someone who is heavily restricted in at the very least sugar, if not carbohydrates in general? Does it portend the same cardiovascular risk? I don't know, but what I do know is I have seen a subset of patients that I've worked with who despite a low carbohydrate diet still maintain a high particle count despite a profound improvement in other metabolic factors, including a reduction in CRP, a reduction in perhaps the most specific inflammatory marker I can think of, which is LPPLA2. That's a marker of inflammation right at the wall of the artery. Myeloproxidase, you name it. So everything improves, their insulin sensitivity improves, their inflammation improves, and yet they still have a ton of particles. And again, the question I don't know the answer to is, does it matter? Maybe. I wanna just quickly thank the folks who have basically taught me everything I know about lipoproteins, and obviously, if people are interested in learning more about these topics, I would highly refer you to Dr. Tom Dayspring, Tara Dahl, and Jim Otvos. And with that, thank you for your attention.