#334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, cholesterol, brain health, and more | Tom Dayspring, M.D.

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My guest this week is Tom Dayspring. This may be a familiar name to you as Tom has been a guest on a podcast several times already.
Tom is a fellow of both the American College of Physicians and the National Lipid Association, and he is certified in internal medicine and clinical lipidology. He was the recipient of the 2011 National Lipid Association President's Award for Services to Clinical Lipidology and the 2023 Foundation of NLA Clinician Educator Award.
Boy, have I known Tom for a while. Tom and I met back in 2011.
At the time, I had a budding interest in cardiovascular disease and lipids. Tom took me under his wing and has been one of the more important mentors I have had in the field of clinical lipidology.
In this episode with Tom, we talk about the foundations of atherosclerosis, why it is the number one killer in the U.S. and abroad, both for males and females, and how the disease works from a pathologic perspective.
We talk about the various risk factors for cardiovascular disease and the role of insulin resistance and chronic kidney disease, which are two things that don't get talked about quite as much as high blood pressure, smoking, and lipids. We then do a bit of a dive into cholesterol and lipoproteins, discussing the role of ApoB, the development of atherosclerosis, and also talking about other particles that make up ApoB, so LDL, VLDL, IDL, in addition to HDL and their associations on cardiovascular risk.
Talk about testing the various biomarkers as well as the impact of nutrition, particularly saturated fat and fat consumption on lipid levels. We then talk about the impact of cholesterol in the brain, where cholesterol in the brain comes from, how it's synthesized there, how that differs from the periphery and the role of pharmacology in that.
So without further delay, I hope you enjoy my conversation with Tom Dayspring. Hey Tom, thank you so much for joining me.
It's actually probably been a while since we've done an actual podcast together, though, of course, we speak so frequently that it almost feels a little strange to be talking in this way. But anyway, thank you for joining us.
Now, it's a thrill to be back on the podcast series. It has been a while and there's always stuff to talk about in lipids, as you and I know too well.
So, Tom, we're obviously going to talk about cars today because that's no, I'm just kidding. Everybody knows what we're here to talk about.
We're here to talk about ASCVD, cardiovascular disease. I think in part, I'd like to do this because there aren't many people who probably heard our first podcast series together.
I think that was a five, seven part series, something of that effect. I still obviously get many notes from people who are just discovering that or who listened to it way back.
But I also think if I could be critical of that discussion, as much as you and I enjoyed speaking for what I think amounted to eight or nine hours, it's a little bit intimidating for someone who's trying to understand this topic. And so the two things I would like to accomplish today

would be to sort of bring a little bit of brevity to what we discussed then. And of course, also to update people on all the things that have changed since then, because that's sort of the beauty of this field is that a lot has changed in the probably six years since that discussion.
But maybe we should at least start by letting you define for people what is meant by atherosclerotic cardiovascular disease. That's a very specific type of a vascular disease.
And that means arteries throughout your body acquire a pathology. And that pathology is simply the deposition of cholesterol in the artery wall.
I always joke, there's like one sine qua non for atherosclerosis, and that says, do you have cholesterol in your artery wall or do you not? If you don't, you don't have atherosclerotic heart disease. And of course, we have many, many arteries in our body, and some are much more afflicted than others.
And the ones of most concern are typically the smaller ones that are supplying our heart and our brain, because those are sort of essential organs that need a profuse blood flow with all the nutrients and oxygen in the blood. So small arteries, if pathology is afflicting the artery wall, can cause trouble before the big arteries.
You can get atherosclerosis in your big abdominal aorta, but that takes an awful long time before it's going to get to the point where you have an aneurysm and explodes. But the coronary disease of the cerebral arteries, because their lumen is so small, and the lumen of a coronary artery is like the dot of a pencil.
So it doesn't take much to affect the blood flow that's going through it. And over time, this deposition of cholesterol has two things that can happen.
It can build up, and the artery lumen starts to narrow, narrow, which would interrupt the blood flow. But all too often, probably more often, is the deposition of cholesterol in the artery wall, and those collections are called plaque.
That plaque can become very inflamed and rupture or erode, and that sets off the coagulation system in the arteries, which rapidly cause narrowing or obstruction of the coronary artery. So atherosclerosis is the deposition of cholesterol in the artery wall.
As you know, and we'll get into it likely in some parts is, well, how did that happen? The artery is not oversynthesizing cholesterol. My joke is it's a dump job.
Somebody brought cholesterol into that artery wall. I just want to reiterate a few things you said there, which is probably the role I'm going to try to play today is play the interpreter sometimes.
So we talked about how, you know, obviously we have arteries in all shapes and sizes, largest artery in the body, of course, the aorta coming off the heart, running up in an arch to supply the vessels of the head and then down into the abdomen where every artery of the body arises. And as you point out, it's not that the arteries of the heart are uniquely susceptible to this process you just described as atherosclerosis.
It's just that two things are conspiring against us. The first is that they are very small arteries and therefore it does not take a significant amount of obstruction or occlusion to create ischemia, which is just the technical term for when oxygen is no longer able to perfuse the tissue.
And then of course, at the risk of stating the obvious, the second fundamental problem is it happens to afflict an artery that is, let's call it specifically sensitive to the demands of oxygen. I remember explaining this to my daughter when she was in grade school and I came in to do a little dissection for her seventh grade class.
And I explained that part of the reason we don't have butt attacks and we have heart attacks is that the glute muscles are not quite as sensitive to oxygen and there are many forms of collateralization. And of course, saying that to a group of seventh graders or fifth graders or whatever turned out to be maybe not the best judgment because that was all they remembered for the rest of the class was butt attacks.
So head or brain and heart have this issue where tiny blood vessels, not a lot of collateralization, catastrophic things happen. And I also want to highlight the other point you made, which was, look, this can happen in two ways.
One tends to be catastrophic and one maybe not as frequently catastrophic. The gradual occlusion of the arteries is probably what more often leads people to complain of chest pain under demand.
You know, gosh, I was climbing the stairs or I was at the gym and I just felt a tightness in my chest and under normal circumstances, I don't feel it or maybe I do feel it, but then I take a nitroglycin and everything grows away. We'll talk about why all of that's happening.
But it's that really frightening scenario where a person in a moment has a complete occlusion of a coronary artery when a plaque ruptures. And as you explained it, the clotting system of the body responds in the way that it should respond when damage occurs.
If you, for example, cut your skin, but it turns out to be absolutely the worst thing the body could have done. And in an ironic way, the body kills itself.
This clotting response is what creates a sudden occlusion. And if that occurs in the wrong part of the anatomy of the heart, that person will be dead within a matter of minutes if an intervention is not performed.
So with all that said, anything you would add to that, Tom, as far as just setting the stage for what we're about to talk about? No, you explained things very well from my physiologic or pathologic explanations to really drive home why those two vascular beds are so important. Brain and the heart can't go very long without the nutrients.
That was a great point, too, that the obstructive part of coronary artery disease, or even carotid disease, extracranial disease, the bigger arteries that are bringing blood to the brain, they're pretty asymptomatic until studies have shown that the arteries have to be almost 75, 80% occluded before those organs are deprived of the nutrients they need. So you can go a long time building an expansion of an artery that's going to occlude your artery without knowing it or so.
And I don't know whether that's good or bad, but ultimately, if you at least report chest pain, you will get diagnosed in time to do something about it. It's not like you said, a plaque rupture, you got four minutes for somebody to dial

911 and hopefully somebody can CPR you till you can get and take a clot buster. Yeah.
So let's talk a little bit about the pathophysiology of this. Before we get into what the non-modifiable and modifiable risks are, because we have two categories of risk.
Let's just talk a little bit about the timeline of events. Of course, I'm spoon feeding you an answer here that I know is a very important teaching point.
But when we think about atherosclerosis being the leading cause of death, which it is, I guess we should have stated that at the outset. This is the leading cause of death in the United States.
It's the leading cause of death globally. It's the leading cause of death in men, and it's the leading cause of death in women.
So it's hard to really imagine anybody listening to this who shouldn't be concerned by it. I suppose if you're a squirrel, you can probably skip this podcast.
So given that it's the leading cause of death, it doesn't exactly show up as the leading cause of death in people too young. It's not like we're watching teenagers, 20-year-olds, 30-year-olds, or many 40-year-olds, although there are some tragically, who die of this disease.
This is largely viewed as a disease of the elderly. Does that give us any insight into the time horizon of this disease or the pathophysiology?

I think it clearly does. So if the deposition of cholesterol is the problem, if you ran to your doctor tomorrow and got your cholesterol checked and it's very high, you don't have to rush out to see a cardiologist to check your arteries that day because it takes a long, long time for this cholesterol deposition to occur.
We're talking about very small molecules here. And even the way that it's being deposited in your artery wall are very, very tiny dump trucks.
They don't each carry four pounds of cholesterol. So if carriers of cholesterol are invading the artery wall, it takes decades for this plaque to finally get to a point where it's noticeable on some diagnostic image.
Certainly, it would take even longer for symptoms to occur and everything. So it's a slow-so process.
But we know this is occurring basically from childhood on. There are pediatric studies, P.
Day, Bugaloosa Heart Study, where young children have died of this or that, and they get autopsied, and they have fatty streaks in their aorta at ages 4, 5, 7, and 8. We know from autopsy studies of military personnel who unfortunately get killed in their job that these young men, many of them robust in great shape, have subclinical atherosclerosis, but none of them are dropping dead of heart attacks while they're serving in the military with rare exception.
So it takes a long, long time. So that's the point.
Ultimately, yes, you will pay the price. And most of the heart attacks are men after 40, women after 40.
But we are recognizing now the real opportunity is to sort of diagnose who might be having cholesterol deposition at a much younger age when we can just arrest it with various modalities. Yeah, I've told this story before, but it probably bears repeating.
In medical school, so now this is almost 30 years ago, the pathology professor, this is first year of medical school, said, what is the most common presenting sign of myocardial infarction? This was true at the time. I don't think it's still true today, but it's close.
And everybody, of course, every medical student put up their hand and went through the litany of symptoms that you might have, chest pain, shortness of breath, left shoulder pain, nausea, et cetera. And he said, no, it's actually sudden death.
The last thing I read suggested slightly fewer than 50% of people's first MI will be a fatal one. Do you happen to know the most recent stats on that, Tom? No, but it's still quite high.
It's very high. Yeah.
It's just not more than 50%. The majority do survive and get to a husband, but it's got to be close to 40% that just don't have that opportunity.
Yeah, which is staggering. And to think that only 25, 30 years ago, that number was north of 50%.
The other statistic that I've shared before, but again, it always bears repeating, is that if you take all of the men who are going to suffer a major adverse cardiac event, so heart attack, inclusive of stroke, cardiac death, etc., you take that whole group of men, and that's a pretty big number, 50% of them will experience their first event before the age of 65. And 33% of women in the same boat will experience their first event before the age of 65.
Now, the older I get, the younger 65 feels. So there was a day when 65 seemed, those are old people.
I don't think of 65-year-olds as old people anymore. I'll tell you that much.
And therefore, to think that 50% of men and a third of women who are going to ultimately suffer a cardiac event will suffer their first one, which could potentially be their only one if it's fatal prior to that age, also I think puts in perspective the temporality of this condition. So we've just established that this is a disease that begins at birth.
This is largely established through autopsy studies where children, teenagers, people in their 20s die for other reasons, car accidents, homicides, war. And in the process of doing an autopsy, we begin to see the early stages of atherosclerosis, I think is quite conclusive that this is a disease process that might be inevitable to our species if we live long enough.
And what might separate the people who never get it or the people who die from something else at old age versus the people who do simply has to do with the rate of the accelerator and the rate of the brake application vis-a-vis these modifiable and non-modifiable risks, which I guess we should talk about now. One addendum to that is just to show you how early this can start.
There are fetal autopsy studies in mothers who have familial hypercholesterolemia, and when they look at the little fetus's heart, they actually see the beginning of plaque development in that instance. So it occurs early, and this is why pediatric guidelines have now at least encouraged lipid testing in the pediatric age group, probably age eight or nine.
You don't wait till you're 40 or 50 like you just implied because, yes, we can still help that patient, but we're moving into what's called primordial prevention. Discover the risk factors early and whatever ones you can modify earlier rather than later is the time to do it.
Yeah. Thank you for making that point.
And I was actually not aware of the fetal studies in FH. We're going to obviously come back and talk about FH or familial hypercholesterolemia, as it is sadly not as uncommon as one would wish.
So let's talk about the risk factors here. There are a solid seven or eight really, really well understood risk factors.
Many of these are modifiable, but some are not. So take them in any order you like, Tom.
Yeah. And the one thing we've been trying to exemplify later is the difference between risk factors and risk modifiers, risk markers.
Risk factors have pretty much been shown to be causal of the disease through the ways you do that, Mendelian trials, a ton of randomized trials, and even observational trials, whereas the risk markers are not causal per se, not to say they're not important and we should attempt to modify them all. So there is that little bit of distinction.
So let's start off with the risk factors, things that are no doubt about it. Let's not argue about these.
And age is one. Now, we can't modify that, so fine and dandy.
But the things we can, smoking, of course, is really at the top of the list, and that can be modified with the patient's cooperation. Lipid disorders are certainly in the causal risk factors and high blood pressure.
You can say things like diabetes and everything, but they bring basically the hypertension and the lipid disorders to the table. So the risk markers would be a long list of other things.
And there are ones that are biomarkers. Others are not, like coronary calcium, CTA.
If you see that you have atherosclerosis, there's certainly a risk marker. But homocysteine, omega-3 issues, vitamin D, a lot of the bioinflammatory markers that we can look at that would be, if you have risk factors and you have these risk markers on top of them, the worse gets worse.
It's like a Chinese menu. The more things on there, it's going to be more expensive at the end of the day.
Of course, my world is lipidology. That's what I focus on.
But I know in your practice, you're super aggressive with blood pressure management. It doesn't seem like there's too many smokers in your practice, which is good.
Maybe they don't want Peter as their doctor if they're puffing away. You can take it from there with that little introduction.
Yeah. I like that distinction of looking at the causal and the non-causal as you could almost have a two by two causal versus associative and modifiable versus not.
So I would say two of the most important non-modifiable or really three would be obviously age, one particular gene that we don't yet have the ability to fully modify its phenotype, which is Lp little a that we'll talk about. And then of course, there are other very strong lines of family history that aren't necessarily transmitted through lipids the way the FH gene or sets of genes are.
In other words, there seem to be other polygenic causes here that run very strongly in families. I would argue that I have some of these genes, Tom.
As you know, my family history is riddled with cardiovascular disease, and yet it doesn't come in the flavor of profound dyslipidemia. I have a normal LP little a.
I never actually had a very elevated ApoB. And in fact, when I had that first calcium score at the age of 35 that already showed the presence of calcium, it was in the context of an LDL cholesterol at about the 50th percentile.
It was about an average Joe as you could be. And yet there was clearly something else going on.
I wasn't insulin resistant. I wasn't a smoker.
I had none of the risk factors, normotensive. There was something else going on.
We could probably spend a minute on talking about why I've had zero evolution of that disease over the past 16 years, which also speaks to the nature of interrupting causal pathways. and now on the causal side, I don't think there would be any dispute from any reasonable person on the causality of ApoB, hypertension.
Let's talk about two other things though specifically. Let's talk about insulin resistance per se and chronic renal failure.
Do we have strong enough evidence on the causality of these, which are clearly highly associated with the condition? Or how do you think about that? Well, the chronic kidney disease is a super major risk factor for there, but probably primarily through virtually everybody with chronic renal failure has lipid disturbances, high APOB, which you just mentioned, and they have a high degree of serious hypertension. So you got two really causal things that are basically present in everybody with CKD.
So is that the only reason CKD is doing it? I suspect that when your kidney is not getting rid of a lot of things, there are other things floating around that are irritating your arteries for sure. One other thing I might add there, Tom, is when we do see people with even compromised kidney function, we generally see homocysteine go through the roof.
And while it might be a bit of a stretch, as you recall, we used to spend some time looking at markers. I don't even want to get into it because it's such a mouthful, but you'll recall the days of asymmetric and symmetric dimethyl arginine.
And we would see these things skyrocket in people with high homocysteine because homocysteine impaired their clearance. And of course, there's at least reasonable mechanistic data to suggest that high amounts of symmetric and asymmetric dimethyl

arginine impaired the enzyme nitric oxide synthase, which produces nitric oxide, which leads to

vasodilatation. So to put that entire path together, there's a very clear link between

kidneys that don't work fully, high homocysteine, and then the buildup of amino acids that prevent

the body from making a vasodilator. I don't know that the causality of that has been clearly established in humans, but it would serve as at least one additional plausible mechanism for why renal insufficiency could be leading to an increase in vascular disease.
Yes, it's sort of what I said. Hey, there's other things floating around when you have CKD, homocysteine, which certainly would be one you could throw uric acid into that equation probably also, and other metabolites, ceramides, and things that are beyond what we want to discuss today.
So multifactorial CKD as far as atherosclerosis. Yeah.
And then let's talk a little bit about hyperinsulinemia and insulin resistance. Again, let's try to disentangle what's obvious, which is, as you pointed out already, that condition tends to traffic hand in hand with hyperlipidemia and hypertension, which are clearly and independently established as causal.
What do you make specifically of hyperinsulinemia and hyperglucosemia as independent risk factors beyond the lipid and hypertensive components? I sort of don't accept that. And it goes back to this incredible study in the 90s by Steve Garvey when NMRs came to the table, nuclear magnetic resonance analysis of lipoproteins.
And there are distinct lipoprotein signatures associated with insulin resistance. They can go back and listen to our original podcast.
But basically, if you look at certain characteristics of the low-density lipoprotein, the very low-density lipoprotein, and the high-density lipoprotein, you will see distinct patterns that appear in insulin-resistant people. You would have bigger VLDLs because they're triglyceride carriers.
You would have smaller LDLs because the triglycerides convert big LDLs into small.

Likewise, you would not have big HDLs because triglycerides enhance HDL catabolism, making the HDL small. So if you look at all those distinct, and they're easily measurable by NMR, if you have those patterns, and this was corroborated doing insulin clamp studies.
So if we saw these type of lipoprotein signatures and we looked at the insulin clamp studies, they're all insulin resistance. And the interesting thing was these signals occur before postprandial insulin goes up, certainly before fasting insulin goes up, decades before glucose goes up.
So I think it's just impossible to separate insulin resistance and lipoprotein abnormalities. Those type of lipoproteins that I just discussed are the ones that are delivering cholesterol to your artery wall.
So we also know not everybody who has atherosclerosis has insulin resistance. So there are people out there who believe, boy, if you don't have insulin resistance, you cannot get atherosclerosis.
That's silly, but it's still promulgated out there. So I don't know.
And maybe it's my little sphere of lipidology. I look at everything as related to lipids maybe too much.
But there is that very early on, before at least insulin levels start to go up. Now, we even know before insulin levels goes up, there are other cellular mechanisms that are going on in insulin-resistant people.
So I don't know. They're together.
I don't know what purpose it serves to. Hey, whether you call insulin-resistant causal or non-causal, it's a very serious abnormality to be taken, incredibly serious.
I think I tend to lean towards some independent causality there. And I point to some of the diabetic research where they look at studies where you take two different approaches to maintaining euglycemia.
So as you know, Tom, there are obviously pharmacologic aids that can do that without the use of exogenous insulin and with the use of exogenous insulin. So in other words, you could have two different ways to bring glucose down, one by increasing insulin sensitization and one by actually just giving more insulin.
And interestingly, when you parse apart the results of these studies, you see something something interesting which is that there appears to be some vascular damage that is mediated by just the hyperinsulinemia alone even in the presence of normal glycemia. Of course we would understand why hyperglycemia is problematic for microscopic vessels but it's kind of these larger vessels that seem to have a negative response to hyperinsulinemia.
It almost comes back to this idea of what's going on with uric acid and homocysteine. Are these things somehow inflammatory to the endothelium and therefore render the endothelium even more susceptible to a given concentration of lipoproteins.

Again, it might be a moot point because I think when it comes to ASCVD,

the goal is probably to address everything,

and therefore we might be sort of having more of an academic debate on this. I think the other point that is probably worth mentioning to people

when we talk about causality in biology is distinguishing between things that are necessary and things that are sufficient. And obviously, once in a while, you find something in biology that is both necessary and sufficient, but many times it's neither and it can still be causal.
So I'll use the example of smoking. So is there any doubt that smoking causes lung cancer? There's no doubt in anyone's mind.
Anybody who doubts that probably shouldn't be having a discussion at this point. So smoking is causally related to lung cancer, but is it necessary for lung cancer? No.
Only about 85% of people with lung cancer are smokers. 15% have never smoked.
Is it sufficient for generating lung cancer? No, it's not, because there are many smokers who don't go on to develop lung cancer. So in that sense, you can have something that is very causal, meaning it's about a thousand times increasing the risk of lung cancer, but it's neither necessary nor sufficient.
This will be relevant when we pivot to our next topic, which is ApoB. It'll be interesting to talk about ApoB through the lens of necessity and sufficiency.
So before we do that, maybe give folks the little explanation on what ApoB is and maybe why we shouldn't think of it as synonymous with, say, LDL cholesterol. Yes, well, ApoB is the ballgame nowadays.
It's not widely tested like it should be. But anyway, cholesterol has got to get in your artery wall to cause this disease, atherosclerosis.
We know cholesterol is an organic molecule that is in the lipid classification. There are many other lipids, but the definition of a lipid is it's a molecule that's not soluble in water.
And the dilemma is our delivery system of everything in the human body is a water solution called plasma. So how in the world are lipids trafficked in plasma? That's basically a physical chemistry impossibility.
You know, you've heard me say this many times to patients, evolution had to develop a lipid transportation vehicle. So these hydrophobic lipids could be trafficked in aqueous plasma.
And the solution was very simple because proteins are soluble in water. So if one just combines a collection of lipids to a protein carrier, lipids can go wherever the human body wants them to go in plasma.
The things that traffic lipids in our body are protein and wrap lipids. The proteins are called apoproteins.
Once they bind to lipids, they're called apolipoproteins. And the whole macromolecule, once it's fully developed, is called the lipoprotein.
So lipids go nowhere in the human body unless they're a passenger inside of a lipoprotein. Now, there are many proteins that can associate with these lipid collections, but there's two we're going to put at the top of the list.
They're the structural apoproteins. These proteins provide structure, stability, and water solubility to the lipids.
There are two basically categories of lipoprotein families in our body. We're talking about the ApoB family right now.
So ApoB happens to be the largest of all the apoproteins that the liver and even the intestine can produce. By the way, no other cells in the human body produce ApoB.
It's the liver and the small intestine, very high molecular weight. So, particles that are wrapped with ApoB, and of course, they're full of thousands of molecules of triglycerides or cholesterol, phospholipids, and other lipid moieties.
The ApoB family, we have other ways of classifying them, and that's in the centrifuge. So the ApoB family consists of what everybody has probably heard, low-density lipoproteins, the LDL, very low-density lipoproteins, the VLDLs, which are our triglyceride-carrying particles.
IDLs, I'm going to mention them for completeness, intermediate-density lipoproteins. They're very transient characters in between VLDLs and LDLs.
They're not a consequence other than some very rare lipid disorder. So that's the APOB family.
But the really good thing and what makes APOB so valuable is there is one molecule of APOB per APOB containing lipoprotein. And this is great because it's a very easy assay for labs to do.
It's an immunoassay, well standardized. So we can have on our patients, hey, go get an ApoB concentration.
And when we get that number back, we know we are actually counting the number of ApoB containing lipoproteins. And that's so critical because the particle that can leave plasma, enter the artery wall, and start off this atherogenic process are the ApoB family.
The other family of lipoproteins are our high-density lipoproteins, our HDLs. Their structural protein is apoprotein A1, except there's from one to five copies of ApoA1 per HDL particle.
So that doesn't become a useful biomarker

to get an HDL particle concentration. And the HDLs, until you get into the

sub-discussions of them per se, are not atherogenic. So don't worry about them too much.

It's the ApoB particles. And to just complete this discussion on the importance of ApoB, what makes an ApoB particle decide to leave plasma and crash the artery wall rather than go back to a receptor in the liver that can bind it and pull it out of plasma in a process called clearance? Because if all your ApoB particles are being cleared in the liver, there would be none to invade your artery wall.
So what forces them into the artery wall, and depending on other factors, there are threshold concentrations above which the odds are good ApoB particles are crashing your artery wall. And because unless you have horrific other risk factors, that's why atherosclerosis takes decades to develop, because it takes a long time for these tiny apobie particles to keep crashing the artery wall.
And maybe later we can discuss what happens to an apobie particle once it's in the artery wall. But step one is crashing the artery wall, traversing the endothelial barrier, the one cell lining that's on every artery in our body, and going in.
So it's particle number. And the best and easiest way and the most tested way to get an accurate atherogenic particle number is to measure ApoB.
You'll hear even statements say ApoB is causal. You'll hear LDL cholesterol is causal.
Because of its very long plasma residence time compared to the short plasma residence time of VLDLs, about 95% of our ApoB particles are LDLs, hence LDL-P, another way of checking particle number, is really what drives total ApoB. Not that the VLDLs are not important, And they can be.
But it's the LDLs that are doing most of the cholesterol dumping in the artery wall. So ApoB really gives us a good handle on LDL particle concentration.
So, and yes, ApoB bringing that sterols into the artery wall is causal, but it's really the sterols that do the dirty work once the ApoB is in the... So you can't separate ApoB from cholesterol.
So I don't care whether people say cholesterol is causal or ApoB is cholesterol, because you can't separate the two in physiologic circumstances. So let's maybe go a little bit further into that process just so folks understand it.
So let's, for the purpose of this discussion, assume that it is indeed the most common ApoB bearing particle. It's a low-density lipoprotein.
So an LDL molecule carrying its load of cholesterol, maybe a little bit of triglyceride to boot, makes its way from the lumen of the artery through the endothelial barrier between a couple of cells into a potential space called the subendothelial space, what set of factors increase or decrease the probability that it is there long enough for its cholesterol package to begin the process of oxidation? Do we have any sense of this idea of retention? Yes. And it's always subject to new data coming in because this is under a long time and continuing investigation.
One little minor correction, you called LDL a molecule. It's a macromolecule.
And I'm a stickler for terms, as you know. So once the ApoB particle traverses that endothelium, and that can happen even if you have a normal endothelium, and it certainly can happen easily if you have a diseased endothelium.
And probably worth noting, Tom, that's almost assuredly where things like smoking and high blood pressure make your odds worse. Those are things that are damaging the endothelium, making that barrier more permeable, which is simply a probabilistic game.
This is all probabilistic. What increases the odds of an ApoB getting in? More particles, that's higher ApoB.
More porous endothelium, that's what happens with smoking, that's what happens with high blood pressure, that's in my view probably what happens with things like high homocysteine, high insulin, or renal insufficiency, high uric acid, all of those things. So anyway, yeah, it's all about the probability of making the gradient such that the APOB is going where it's not supposed to go.
Yeah, you mentioned that ADMA before, that's basically a regulator of nitric oxide, probably the most crucial molecule that an endothelium produces to defend the integrity

of the artery or so. And once that's out of whack, the endothelium is not functioning like it should.

There are receptors that can get expressed there that can pull these particles in.

But okay, the ApoB particle is in the wall of the artery, the intimal layer there.

One of my jokes is usually it's like once a fly hits flypaper. If there is such a thing anymore, it's stuck.
Then what happens to it? So when an ApoB particle enters the artery wall, it has a high affinity to bind to collective tissue molecules called proteoglycans, syndectins, there's a whole subfamily of them. And now you have that ApoB particle that is just stuck there.
Now, look, the number of LDL particles floating around your plasma, we're sort of talking like ApoB, you can count the number of particles. And now, well, there actually are quadrillions and quintillions of these particles.
And that's how many are crashing your artery wall

too. So there's a lot of them in there.
And they're all right next to each other, bound to

these proteoglycans. So it's now believed the next step that happens, what's on the surface of all

these ApoB-containing particles? It's phospholipids. The cholesterol and triglycerides are inside

these particles. There's a little bit of unasterified cholesterol on the surface.
But these phospholipids are very susceptible to two things. One is ultimately going to be oxidation, which is a big, big role in atherogenesis.
But the first is there are enzymes called mutases that somehow realign the phospholipids that are on the surface of these particles. And when distinct phospholipids are put next to each other, these particles have a high affinity to stick to one another.
And that's called LDL or ApoB particle aggregation. And that is believed to be the first step.
So what you ultimately have is a lot, zillions of these ApoB particles in a big mass of cholesterol and all the other lipids that are inside that particle. And that's where the oxidation starts to occur because sterols get exposed, the phospholipids, many of which have double bonds, are highly susceptible to oxidation.
So now you have this clump of gooky cholesterol and phospholipids, which are oxidized. Well, oxidation is a major signal to the immune system.
The immune system is going all over the body. And when things get oxidized, that means it's on fire.
It's often an infection or some other pathology, and here come the white blood cells to put out the fire. So once you get this aggregated mass of oxidized, whatever you want to call it, it's way beyond cholesterol, white blood cells start traversing that endothelium, the monocytes, and they come in and they transform into macrophages, which express receptors that can start ingesting all these aggregated ApoB particles.
And the next step, and this was seen by the great Russian, I think in 1913, a Nitchkoff, when they overfit rabbits, pure cholesterol, and they developed atherosclerosis, something rabbits normally don't get. You drown them with that type of cholesterol.
And under the microscope, he saw all these things that there was some long German name. I wish I had it for it's basically cells that are full of cholesterol lipids.
So this was what we now call the foam cell, which is just a lot of cholesterol in the interior of these macrophages. And under the microscope, they look very foamy.
So that's how they got their name foam cells. And as you can imagine, all these masses over the decades we've talked about, now you have plaque.
But as this plaque is being formed, that immune system is still trying to put out the darn fire. So what the next thing the immune system does is once the macrophages have eaten it and sort of organized it into a pool of cholesterol, is smooth muscle cells are recruited from the external surface of the arterial wall.
They migrate and they start covering this gook, this mass of cholesterol and other lipids. And now you really have a distinct plaque where you have a cap on it.
And the cap is simply smooth muscle cells originally. But these smooth muscle cells transform into more complex cells that can

start secreting calcium. And that gives this cap plaque a fibrous integrity.
And what is the purpose of that? To prevent what Peter and I talked about early on, you don't want this plaque to rupture. It's like putting a heavy mounded dirt on a volcano, I guess.
It's less likely to rupture if you can cover it. Ultimately, the type of cytokines and chemokines that are being produced by these white blood cells, some of them have bone forming ability.
And that's why much later in the disease, calcium starts to get deposited in this cap plaque. And that's maybe somewhat fortunate because being radio

opaque, that enables the type of imaging studies we have now to say, oh my goodness,

there's calcium in your artery wall, which there's only one cause and that's atherosclerosis.

So those are the several steps maybe you want to elucidate them on further, Peter.

But none of this happens like you overeat a lot of cholesterol tonight,

and boy, next week you're going to have a heart attack. It takes decades.
That's a great explanation. Maybe I'll just summarize it a little bit.
So we already talked about how we get into this process where you have the APOB-carrying lipoprotein. Let's again, just simplify it and call it the LDL in this situation.
Although, as we'll talk about, I'm sure that can also be an LP little a. It enters that subendothelial space and its presence alone makes it susceptible to have its contents oxidized.
Cholesterol is a rich target for oxidation. And as that happens, we once again have this example of the immune system, which is out there basically surveying, constantly looking for things that are bad, usually in the form of monocytes.
And they're sensing, they're seeing a chemical signal for that oxidation. And as they enter that space, they become this other type of cell.
They metamorphize into something called a macrophage. And the job of the macrophage is to literally consume, to phagocytose, to eat the thing that it is concerned with.
And when it begins to eat that oxidized cholesterol, that produces the foam cell. I want to pause there for a second and talk about how way down the line, when we ultimately have that calcification, as you said, that's actually quite visible.
A calcium scan is exactly looking for that phenomenon. But I often get asked the question, Peter, is there anything I can do today to know if there is any damage to my endothelium? Are there any foam cells in me? Are there any fatty streaks? And then, of course, the next thing we kind of talk about is a CT angiogram, which in its first phase, when it's run without contrast, which it usually is, you have the opportunity to potentially see calcifications.
And then once the contrast is injected, you get a higher resolution image that shows more anatomic detail of the lumen. But in my experience, Tom, you have

to have a reasonable amount of soft plaque, non-calcified soft plaque to show that, suggesting that there's probably still quite a bit of damage that could occur before you would see anything on a CTA. And of course, I realized there are some people listening to this saying, well, what about newer tests clearly that are using a fat attenuation index to look at the changes in the character of the fatty tissue in and around the adventitia and to see if that is in and of itself predictive of damage.
So I'll just kind of let you take that in whatever way you see fit. Outside of research-based tools, such as intravascular ultrasound, do we have tools to really understand these early stages of disease? If a person says, look, I don't want to get treatment now, but I don't want to wait until I actually have calcium.
Is there a middle ground? Not definitively, but there's two things. Certainly, there are these advanced imaging techniques, and that's one where they're analyzing certain characteristics of the artery wall.
I think still not ready for primetime play yet. And certainly, because of its course, it's nothing the average person's going to run down and get tomorrow or so.
So we go back to then, hey, these macrophages that

are sending out these signals, recruiting more and more white cells to get in there and help me.

It's like a fire department calling for a second, third, fourth alarm. We need more immune operators

on the system. Are there immune markers we can perhaps measure in the blood? And that's basically

what we're doing right now. So obviously, these would be different types of inflammatory markers, and they're looking at other type of biomarkers that might signal this type of pathology going on.
These are the ones that are readily available to most people. And these are risk markers because by themselves, they're not causal and they have other etiologies or other causes that might explain why they're high.
The first and the one with the most evidence is the C-reactive protein test. That was used for years to help diagnose rheumatic fever, which obviously had a lot of inflammation.
Down the road, Paul Ritker was the guy who did this. He discovered, well, the type of inflammation that goes on in the artery wall is incredibly subtle at first.
So you're not going to see a C-reactive protein of 22 or a sedimentation rate of 55 in the blood test, the old time markers of inflammation. He says, can we analyze C-reactive protein at heretofore trivial, not even looked at levels? So they started looking at extremely low C-reactive protein levels.
And lo and behold, he showed, and it's beyond debate now, that yes, they call the test high sensitivity, but it's actually the same damn assay that checks for CRP if you have rheumatoid arthritis. But the high sensitivity has a different reference range that they relate to atherosclerosis, and obviously much lower than you would have with some rheumatic disease.
So subtle elevations of this C-reactive protein, the rule is, hey, above two, you're at worry. Above four, you've got some serious inflammation in your body going on.
It's not necessarily

cardiovascular, but could you be in an early stage of some other inflammatory disease? Sure, that's why it's not specific. But you know we look at levels even less than two as a signal to us to start worrying.
So that's the first inflammatory marker. I just haven't been that impressed with HSCRP's specificity.
There are too many people I have seen who have a normal HSCRP, and I actually define normal as less than one. So I'm not even talking about the actual assay cutoff of two.
So these are people that walk around with an HSCRP of 0.8, and yet you actually do a calcium score on them and you find they've got a calcium score of 10, which again, this is not a person who's going to die anytime soon, but they've already progressed to a calcium score of 10. This is a person who might be in their 40s.
So this is a person who's actually on the path towards premature atherosclerosis. So I just think that inflammatory markers are probably not specific enough, or in the case that I just gave, even sensitive enough at low, low levels of this disease, in particular, because I think that this disease has multiple paths.
Even though we're not going to talk about it today, another topic we love talking about is Alzheimer's disease and brain health, and how there are different paths that patients will take to get Alzheimer's disease. Some patients come at it through almost a genetically pre-programmed path.
Others come at it from much more of a vascular disease path, and yet others come at it from a more metabolic and an inflammatory path. And there are all these different paths.
And I almost wonder if there are similar paths towards atherosclerosis. And there are some people who are arriving at it.
It's almost genetically programmed in them. And then there are others who are showing up through this very lipid-based path.
And yet there are others for whom inflammation is the dominant path. And maybe those are the people where the HSCRP shows up very early in the process.
Again, I'm completely making this up as an analog to what we see more commonly in the paths to dementia. But I guess what I'm saying in a long-winded way is I find myself rather unconvinced that we have great tools to measure the phenotype of early atherosclerosis.
That's so true. And it's the specificity, as you said, I can name two or three other inflammatory markers that would have the same weakness.
You could have a fatty liver and they're elevated or so, or subtle infectious disease somewhere. So they're not specific.
You could say, and Ritker would tell you in the scenario you described where, well, got coronary calcium is there already, but their CRP is perfect.

Maybe that's a stable plaque that's not going to rupture herself. You can get into those type of debates.
Maybe they had a CRP blip five years earlier when that plaque was still being oxidized. Yeah, I understand that for sure.
So I think the only way we can use these inflammatory markers is, Hey, if ApoB is high, LP little a, two major risk factors, and these inflammatory markers coexist with them, I worry about you perhaps a little more. But that doesn't mean if ApoB is high or LP little a is high and your inflammatory markers are perfect that we dismiss you as, aha, you're the one who's not going to get atherosclerosis because that's not a game you want to play.
So that is the weakness of those type of markers. I don't have any other markers that I can tell you to check on inflammation other than there are 10 other subtle, rarely tested inflammatory cytokines and chemokines that can be measured.
Same, hey, if your ApoB is whatever and your homocysteine is high, we worry a little bit more about you. We have to maybe attack that because it's modifiable.
So I'm not sure what the other markers would be outside of you wait long enough, you're going to get some imaging thing that's positive. Or do we just start respecting ApoB? And that's basically where the lipid world is going.
And that's where this new concept, primordial prevention, has come into play. In the old days, it used to be primary or secondary prevention.
Hey, you've had a heart attack. Thank God you've survived.
We're going to try and prevent the third heart attack, secondary prevention. Or once imaging came along, then we can say, aha, your CTA or your CAC is positive.
To me, that's secondary prevention right there. I wouldn't call that primary prevention.
So what is primary prevention? You have a high APOB, you have high blood pressure, but we're not talking about that aspect and what we would do with that today. And therefore, what is primordial

prevention? People with physiologic parameters in the lipid and lipoprotein sphere. So we're still going to check them because we think at a certain age or depending what else goes on in that person's life, they will enter that primary prevention.
And then once that is, if that's defined as escalation of ApoB, then you're going to get into the decision of what sort of therapeutics might we want to offer this person whose ApoB is just slightly high. We don't wait till the ApoB is in the 80th or 90th percentile because I think if there was a way of getting into those people and looking for this pre-imaging atherosclerosis, we might find it.
And some we would not. There are no doubt there are some people who, just as you said, not every smoker gets lung cancer.
There are people with high ApoB who live long and healthy lives, but I don't know what else is going on in their artery wall. And I have no way of measuring that to assure them, aha, you're the exception to the APOB rule.

Well, there's a lot you said there

that I think is a great place to go next,

but maybe just to finish a little bit of housekeeping,

we've now both brought up LP little a at least twice.

So I think we've done many podcasts on this,

but what would be the three minute explanation

for the person who either needs a refresher or maybe who is new to this and hasn't heard of what LP little a is yet, and why should they care about it? We've defined an LDL particle as a collection of cholesterol, a little bit of triglycerides wrapped by one peptide called apolipoprotein B. In some people who have the genetic machinery, their liver makes another protein called apoprotein small case A.
The guy who discovered it thought he discovered a new antigen. A was the signal for antigen.
So that's where the little a came about. Again, capital A is the apoprotein A that is on an HDL particle.
So there are distinctions between small APOA and capital A. All right.
So if your genes tell your liver protein matching apparatus to produce this APOA, within the liver, it binds to the APOB that's on a primordial LDL particle that's being produced in the liver. So now some of your LDLs, apolittle a binds to it and the liver just secretes them into your plasma.
So that's what an LP little a particle is. It's a low density lipoprotein that is carrying another protein that should never be on an LDL particle.
That apoprotein little a has some characteristics that make it extremely atherogenic. Much of it ties into the oxidation that we mentioned before.
So if that particle enters your artery wall, whatever oxidative forces are at play are going to get much worse, which is not good as far as atherogenesis is concerned. So if you have these LP little a particles, and it's not a concentration gradient that drives them into your artery wall, that's sort of an inflamed particle carrying some oxidized phospholipid that can be pulled in by receptors that are still not defined, but it can easily get into your artery wall.
So it's like, hey, we got a little fire in somebody's backyard and somebody brings a can of gasoline and throws it on the existing fire. So the atherosclerotic process occurs much more rapidly earlier in life.
It's bad news. Now, the good news perhaps is 80% of people don't inherit the gene that makes you produce the sapoprotein little a, but 20% do.
Now, people are, 20%, no big deal. Look at 20% of the world population.
You're talking billions of people who have what's now recognized to be the number one lipid lipoprotein disorder associated with atherosclerosis. So my goodness, and this is why there's now a call for it.
Let's everybody get that checked once in your life early on because you either have it or you don't. And if you do have it, then we can start looking at ways to perhaps modify some of the bad news risk that's going to occur with that process.
Right now, we can't get rid of the apolittle a particle. That's perhaps coming.
There are drugs under investigation to do that. All we can do if we discover this LP little a is look with a magnifying glass at every other risk factor or risk marker you have and do what we can to control those.
So LP little a is a bad news, LDL type particle. It's not atherogenic because of the amount of cholesterol it's carrying.
It's what I call a minor LDL particle, but particle for particle, it's seven to eight times more atherogenic than an LDL particle. So even now, you have way, way, way more LDL particles.
An average person might have an LDL-P of 1,200 nanomoles. So you might have an LP little a of 100 nanomoles, and you would say, oh, that's a minor particle.
Yes, but if it's eight times more atherogenic than an LDL, it's a bad news particle. Not everybody's a criminal in our country, but it doesn't take a lot of criminals to cause a lot of havoc.
So it's a terribly dangerous inherited type of lipoprotein. That's a great analogy to think about it.
You don't need a lot of something that has high virulence and potency to cause a lot of difficulty. Let's pivot for a minute to talk a little bit about something you also touched on briefly, which was that when we're young, we have what's referred to as a physiologic level of ApoB or LDL cholesterol.
So the concentration of LDL cholesterol in a child is low. The concentration of ApoB is low.
We don't see this very often because we're not used to checking these things in kids, but occasionally you'll even notice it as a parent. If your kid gets sort of a comprehensive blood test, their total cholesterol might be 60 milligrams per deciliter with an LDL cholesterol of 30 milligrams per deciliter and an HDL cholesterol of 25 milligrams per deciliter.
Very, very low levels of this. Why does this change as we age? Why is it that aging

seems to be associated with a monotonic increase in lipoproteins? And this is absent something that we could even get to later if we have time, which is what happens during menopause for women, which is more abrupt. But just talk to me about ages 10 to 50.
Why does everybody seem to go the wrong way? Well, a lot of, of course, is the multitude of things we subject our bodies to. If you want to encompass that with the environment or a lifestyle, you quote unquote, whatever, and you can throw probably whatever you want into that category of things that might cause your body to, as ApoB goes up, it's almost all related to your liver is losing the ability to clear these particles out of plasma.
It's not like you're overproducing 10 tons of them. It can happen, but that's rarely a contributor to the high ApoB levels.
So scientifically, we have to zero in on what regulates clearance of these particles. And the simplest thing is to say, well, the only way these ApoB particles get cleared is our liver produces something called an LDL receptor, which migrates to the surface of the liver cell that interacts with the blood flow, the plasma.
And these LDL receptors are engineers to recognize any ApoB peptide that floats by it. So if an LDL particle containing ApoB floats by an LDL receptor, it will get grabbed, and then it gets internalized into the LDL receptor, and it gets catabolized.
And then the liver can take whatever cholesterol, triglycerides, fatty acids, blah, blah, blah, is in that molecule and use it for other purposes or somehow get rid of it in the biliary system if the liver doesn't need it. So it's going to come down to what are these factors that I called, hey, environmental lifestyle that affects what we call LDL receptor expression.
And it's a lot of things. One of the things you mentioned before, insulin resistance would affect that.
Numerous components of the diet express, are you regulating LDL receptors or not? How much cholesterol your liver is being told it needs to put in the next VLDL particle or more importantly, the HDL particle going out. So lipid balance in the liver is regulated by a bunch of things called nuclear transcription factors.
They actually sense, hey, the liver needs some lipids or the liver's got too much lipids and we got to get rid of it. Those nuclear transcription factors migrate into the nucleus and the nucleolus of our cells, and they bind to specific parts of the DNA and tell our genes, produce this protein, produce that protein, this enzyme, that enzyme, this receptor, that receptor, that can go out and help restore sterile homeostasis to this human body.
So probably every adversarial thing you've been told in your life not to do, gain weight, don't eat this,

don't eat that, are all affecting these nuclear transcription factors that are going to regulate clearance of these ApoB particles. And it's a long list of things that can probably do that.
It is interesting that on average, more of the things that we do that are quote unquote less healthy, whether it be gain weight, eat a certain way, tends to result in decreased hepatic clearance. So on that topic, one of the questions you and I get asked all the time is, look, hey doc, I buy your thesis that ApoB is bad.
I buy your thesis that mine is too high and I buy your thesis that I should probably lower it. I'd really like to start with my diet before I turn to pharmacology.
Typically, there's two things I tell patients here. The first is I think your two best levers nutritionally to reduce ApoB are lowering triglycerides and lowering saturated fat intake.
Now, of course, this assumes that you have high enough triglycerides that lowering them further will indeed lower ApoB. And it of course assumes you're eating a high enough amount of saturated fat that reducing it significantly will lower ApoB.
So let's assume for a moment that those things are true. We're talking to a patient, Tom, whose ApoB is 100 milligrams per deciliter.
You and I have just, I don't want to say read him the riot act, but we've given him the education that says, look, you'd be a heck of a lot better off if you were at 60 milligrams per deciliter. His triglycerides are sitting at about 162 milligrams per deciliter.
And when we query his diet, we realize it's pretty high in saturated fat. He's probably getting, call it, I don't know, 40 or 50% of his calories from fat, and he's probably getting 50, 60 grams per day of saturated fat alone.
So in other words, he seems like a really ideal candidate if he's willing to switch more of his fat calories to monounsaturated and polyunsaturated, or even just reduce fat altogether. And he's willing to take the dietary steps to reduce total calories and maybe even carbohydrates specifically to kind of bring down his triglycerides.
So without getting into how he's going to do that, can you explain why lowering triglycerides and lowering saturated fat intake, those two things could bring this guy from 100 down to 60. Sure.
The saturated fat is a little easier to explain. We have plenty of studies that show excess saturated fat, those nuclear transcription factors that are regulating lipid balance in the liver.
And the liver is the master controller of lipid homeostasis in the body. It works hand in hand with the intestine, but the liver is sort of the brains of the operation.
In many, many people, exposure to saturated fat, the nuclear transcription factors realize, oh my God, fatty acid toxicity is going to occur to this liver. We have to take our defensive mechanisms on that.
First thing they do is say, my God, we don't want more lipids being pulled into the liver by these LDL receptors. So the nuclear transcription factors go into your DNA and say, stop making these LDL receptors.
Stop sending out the signal that will be translated into an LDL receptor. So of course, if you eat saturated fat and your liver stops expressing LDL receptors,

your ApoB is going to go through the roof.

What is the ApoB particle carrying cholesterol?

And above the threshold concentration, it's going in the artery wall.

Typically, if that person does follow your advice and restricts the saturated fat,

they will go back to some more increase in their LDL receptor expression.

Saturated fat in some people, too, also turn on the enzymes that induce cholesterol synthesis. Now, if the liver starts overproducing cholesterol, then the lipid pool is out of whack.
The same nuclear transcription factors go in and say, stop making LDL receptors. We don't want to pull in more cholesterol into this liver that's oversynthesizing cholesterol.
It's another whole story, as you know, Peter, why we don't necessarily tell people you have to restrict cholesterol in your diet. We're talking about saturated fat here.
And the absorption of sterols in your gut has nothing to do with the absorption of fatty acids in your gut. Totally different mechanisms that pull them in.
The triglyceride story gets much more interesting

and maybe much more important because it's so epidemic in the world now. We know triglycerides is a poor man's biomarker of insulin resistance.
Two things I wanted to say, if you're measuring triglycerides in the blood, personally, I believe the only things you need to measure in the blood are ApoB and triglycerides. There are basically two categories of hypertriglyceridemia.
One is at above 500, 1,000. If it is, you have some crazy genetic disorder that is involved with your high triglyceride, and most of those are not associated with atherosclerosis.
But nonetheless, they are associated with pancreatitis and other pathologies. So you would want to lower what's called a very high triglyceride level.
But the average doc who's out there doing lipid levels is going to see a triglyceride maybe between 130 and 160, 180. So every once in a while, you'll see a 3, 400, but they're less common.
That almost is always insulin resistance as the etiology of that through many factors. So once you have too many triglycerides, and where are those triglycerides being made in your liver? Other cells don't produce triglycerides other than an adipocyte.
But if your liver is overproducing

triglycerides, the liver says, oh my God, I got to get these out of here. Because if the liver retains triglycerides, you know it's going to get fatty liver, not a wise thing the liver wants to do.
So the liver then packages them into the triglyceride containing lipoprotein, the very low-density lipoprotein. Why do we even make VLDLs? What purpose do they serve? Even if you have a physiologic VLDL concentration, it must be doing something once the liver makes it and secretes it.
And that is very similar to the big chylomicron particle that comes out of your intestine. These are the triglyceride-carrying vehicles that are bringing fatty acids in the form of triglycerides to the tissues that need to grab the triglycerides, convert them to fatty acids, and oxidize those fatty acids to make ATP.
They would be our muscle cells, the heart being a very important muscle that you want to keep beating. It's a big consumer of triglycerides.
The muscles, the big chylomicrons, the big VLDLs coming out of the liver, they go into beds that express the triglyceride-dissolving enzyme lipoprotein lipase, muscular beds or adipocyte beds. The triglycerides are hydrolyzed to fatty acids.
They enter those muscular beds, and then they can be oxidized for ATP. In an adipocyte, the fatty acids are pulled in, reconverted to triglycerides, and stored for future energy needs.
So that's what VLDLs do. But if you have way more triglycerides in your liver because you're insulin-resistant and your liver is overproducing them, the liver makes very big VLDL particles.
Earlier on, I talked about, hey, there are certainly NMR signatures of insulin resistance. The big VLDL is one.
A normal person with physiologic triglyceride never makes big VLDL particles. There's no need for them.
That person makes smaller VLDL particles that carry

just enough trigs to be sufficient for energy needs of the muscle. But in an insulin-resistant person with high triglycerides, here come these big particles out.
Now, insulin resistance is not only associated with too much triglycerides, there's another apoprotein that is made in excess, and it's called apoprotein C3.

So the VLDLs coming out of the liver are now carrying something they shouldn't carry very much of, apoc3. Make a long story short, it retards the catabolism of these triglyceride-rich VLDLs.
So it blocks their attachment to lipoprotein lipase. So the plasma residence time of a VLDL or chylomicron, which should be extremely short, is now prolonged.
What is the consequence of letting these triglyceride-rich VLDLs float around longer than they should? Number one, if you measure triglycerides in the blood, it's going to be higher than it ordinarily would be. And that's why if you look at a certain triglyceride level, you might suspect this is happening.
But here's the continuing bad news. When these triglyceride-rich VLDLs are floating around in plasma, they bump into the much, much, much more numerous LDL and HDL particles.
And what happens? We carry a lipid transfer protein that actually locks LDLs and HDLs into VLDLs or LDLs into HDLs. It's called cholesterol ester transfer protein, CETP.
It really should be called CETTP, cholesterol ester triglyceride transfer protein, because what happens is when these two particles, my joke is they're mating because they're now connected with this little canal, they exchange one molecule of triglycerides for one molecule of cholesterol. In essence, the VLDLs and chylomicrons become triglyceride poorer but more cholesterol-rich, whereas the LDL and the HDL become cholesterol-poor and triglyceride-rich.
Any doctor who does a lot of lipid profiles knows, yeah, you're right, Tom. I notice every time triglycerides goes up, LDL cholesterol doesn't necessarily go up, but almost assuredly, HDL cholesterol goes down.
And that's because HDLs, which should really carry almost no triglyceride molecules, have now sucked in a lot of trigs, but they've given up cholesterol. If we were measuring HDL triglyceride levels, we would see it's very high, but we just see the HDL cholesterol is low.
The last step, What happens to any triglyceride-rich particle? There are lipases ready to dissolve it. Endothelial lipase and hepatic lipase attack triglyceride-rich HDLs.
By extracting and hydrolyzing the trigs, the HDL particles become so small they break apart. ApoA1 goes down to the kidney where it can be catabolized into amino acids and excrete it.
Hence explaining why diabetics, people with high trigs have such low HDL particle counts and low HDL cholesterol. But basically here's what happens to the LDL now.
The LDL is sending cholesterol in exchange for triglycerides to the VLDL or the chylo.

So the little LDL particle, much smaller than those monsters, becomes triglyceride-rich and cholesterol-poor. So what is the fate of that type of LDL? If we could only measure LDL triglycerides, it would be by far the best lipid metric we could ever measure.
So Tom, it seems like the reason ApoB is going up in a high triglyceride environment is because you need more LDLs to carry the same amount of cholesterol ester because so much of their carrying capacity is going towards also managing the transport of triglycerides. And therefore, while LDL cholesterol might remain constant, it's being spread out over more particles.
Therefore, ApoB, which is the marker of particle concentration, is going up. And of course, that's the metric that matters.
This of course is the classic example of where we see discordance between LDL cholesterol and ApoB particle concentration. So we were talking about the triglyceride rich LDL particle.
And what happens is the lipase is mostly hepatic lipase takes the trigs out and then the LDL particle becomes very small. So you have a small LDL particle, which per particle can't carry many cholesterol molecules.
But the major reason APOB goes up is an LDL that is small, the APOB assumes a different confirmation on the surface of the LDL, and it is no longer recognized by the LDL receptor. So you have markedly delayed clearance of the small LDL.
So yes, whether your LDL cholesterol goes up or not, the cholesterol is spread among more LDL particles because they can't be cleared anymore. So that is why lifestyle can work very good.
Anything that lowers trigs can interrupt this pathologic lipolysis or catabolism of these ApoB particles. If we could make those small LDLs disappear and they would assume they're more circular shape, they conform to the LDL receptor more.
So this is why if you look at the ApoB or even the LDL particle count in diabetics, it's through the roof or in people with high triglycerides due to mostly decreased clearance. So the LDL-P goes up.
But what's driving the total LDL-P? It's the small LDL-P. They would have some large LDL still floating around.
There's never going to be anybody who has 100% small or 100% big. But the predominant species when triglycerides goes above a certain threshold is the cholesterol-poor small LDLs that have decreased clearance.
So ApoB goes up. When ApoB goes up, where do these small particles go? It's an ApoB particle.
It crashes the artery wall with relative ease. So that's the basic explanation there.
The other thing I should tie into this, at what level of triglycerides can this occur? The silly guidelines have put, hey, a triglyceride of 150 above is where it's high risk. And that's what the average practitioner or patient believes, because that's what the labs report on the lipid profile.
This transformation that starts to delay the lipolysis of these particles occurs somewhere at a triglyceride 100 or above. You don't have to have a trig of 150.
That's the 75th percentile of a population triglyceride distribution. My God, we don't wait for any other lipid metric to hit the 75th percentile.
So I'm not sure why they still do that other than perhaps they didn't have enough to tell people what to do about it. But you and I know when we look at it at the lipid panel, we're a little nervous when trigs start to go much above 80, never mind 100 to 120.
I often use myself an example. I've been a lifelong, very insulin resisting guy, always had a pretty decent LDL cholesterol.
My trig was always in the 102, 105 range, which I dismissed as being normal. But of course, once NMR came around, I saw, oh my God, look at your LDL particle concentration.
Look at the number of small LDLs. And this is why triglycerides cannot be unlinked from APOB2, because the real pathology of high trigs, it's just creating too many cholesterol-carrying particles that can invade the artery wall.
It's not triglycerides in the artery wall that are generating atherosclerosis. It's the delivery of cholesterol.
But as trigs go up, you have a lot more ApoB cholesterol-carrying particles. Even though each particle is carrying lesser numbers of cholesterol than before, there's just many more of those LDL particles that are crashing

your artery wall. When we do come up with a way to lower triglycerides nutritionally, or even if we wanted to use a drug, virtually every single one of our lipid-modulating drugs is FDA-approved to lower triglycerides.
You can't look at it and say, oh, I've lowered your trigs from point X to X minus whatever. You have to lower ApoB to see event reduction with trigs.
Now, most of the time when you lower trigs with proper therapies, lifestyle or drugs, you will see a drop in ApoB. But there have been several trials that dramatically lower triglycerides with the fibrates that did not reduce MACE because although they dramatically lower triglycerides, they're not the greatest ApoB-lowering drugs in the world.
So respect triglycerides at much lower levels than you've ever been taught. But your goal of therapy, be it lifestyle or drug, is did I normalize ApoB? I think that's a very important point, which is it's always worth taking a shot at modifying your nutrition to fix ApoB, but don't forget the goal.
The goal is lowering ApoB. We have these two proxies that are quite helpful.
Triglycerides, if they're high, great, great way to approach. Usually in most people, caloric reduction is the key of doing that.
And therefore, if you have a person who's eating a lot of saturated fat, a lot of carbohydrates, low quality carbohydrates, sugars, hypercaloric, that person can actually do a lot of ApoB reduction with nutrition. Conversely, when you see a person whose trigs are 50 milligrams per deciliter, who's not mainlining saturated fat and eating in relatively normal amounts, I typically advise those people against draconian fat reduction, which admittedly will indeed lower cholesterol, but often comes at the consequence of something else nutritionally.
And so we tend to steer clear of that and save that for people who have an obvious reduction. I think this point, by the way, about the conformational change in the relationship between the LDL receptor on the liver and the LDL particle is a very interesting one.
Of course, it begs the question, Tom, do we believe that LDL particle size should be of concern, given that you just acknowledged that these smaller cholesterol depleted LDL may linger longer? Or can we largely ignore that if we have a good handle on ApoB? In other words, is all of the risk of everything you just discussed captured in the ApoB marker? Yes, but if you were doing everything you say nutritionally or pharmacologically to do it, you would see a transformation of those small LDLs. You wouldn't find them anymore, and you'd have a normally sized and ApoB composed particle.
But what I should introduce into this discussion is the nonsense going out there that these big LDLs, often called fluffy buffy, are cardioprotective. But guess what happens on a big LDL? The ApoB gets distorted on the big LDL too.
And those particles are far less compliant to the LDL receptor. It's one of the reasons people with FH have such, because they all have very big particles, and their high ApoB is due to defective LDL receptors, but it's also due to defective attachment to LDL receptors, because the ApoB is no longer in the proper conformation.
And the last thing I'm always going to sneak in on this

triglyceride topic, I did mention it's the chylos and the VLDLs that carry trigs. They're the big triglyceride-carrying particles.
Yes, they screw up the HDLs and LDLs by sending trigs over there, but normally those particles should deliver the trigs to the muscle cells where they lose trigs, and then they get smaller, the chylos and VLDLs.

Smaller chylos and VLDLs are called remnant VLDLs or chylos. But when they shrink, the main reason they get cleared from the body is they carry multiple copies of apolipoprotein E.
And ApoE is the apoprotein on VLDLs and chylos that binds to a very specific hepatic receptor in the LDL receptor family called LRP, LDL receptor-related protein. But when ApoB is on big VLDLs and chylomicrons, it's contorted.
It doesn't bind to the LRP. But once the chylos and VLDL shrink down,

the ApoB assumes a confirmation, and that's why their plasma resonance time is so short. It's all ApoE-mediated, and each of those particles carry several copies of ApoE.
But in some resistance where the VLDLs and chylos can't get rid of their trigs, then these people have what is called increased remnants. Now, they're nowhere near the particle number of remnants.
It doesn't even come close to an LDL particle number, but it's up way more than it should be. And particle for particle, remnants carry five to six to seven times more cholesterol per particle than an ApoB LDL particle.
So if you let these remnants float around, they get pulled into the endothelium. They're a very inflammatory particle in part because of the ApoC3 on them.
They get internalized easily into the artery wall, which is another reason people with high trigs have so much atherosclerosis. It's not only because they have too many LDL particles.

They got too many remnants.

And if they're losing HDLs, if HDLs perform a cardioprotective function by extracting cholesterol

they no longer have enough HDLs to do that.

That's why you and I get very nervous when we start to see trigs exceeding 100 because we assume some of these pathological pathways are at play. A couple of very important points there, Tom.
The first is, yeah, it's true that the remnants, just like the LP little a's, are captured in the ApoB concentration, but it's almost like you have three populations, for lack of a better really four populations that are buried within apob you have the majority of them which are ldls you have vldls your garden variety vldls you have your lp little a's if you have too many of those and then you might have too many remnant vldls and of these four it's that that remnant VLDL and the LP little a that pack more of a punch than their counterparts, the regular garden variety VLDL and the LDL. And so this is where I think ApoB by itself can be a bit misleading.
In other words, you could have two people that both have an ApoB concentration that's identical, but if one of them has it in the context of basically it's all LDL cholesterol and some VLDL, yeah, they're okay. And then the other person might actually have a disproportionately high LP little a and or remnant concentration.
And you won't know that unless you're doing some of this additional analysis. Is that a fair rationale for saying why we want to look at everything? Yes.
So you measure LP little a, that's easy. And you see, it's not a major contributor to ApoB, but it's a terribly atherogenic particle.
So we get nervous with it. With the VLDL particles, measuring ApoB tells you nothing about the number of VLDLs have, because although they can be particle for particle more atherogenic, there's not very many of them.
So what's a poor doctor do? Here's my little pearl. So there's another metric people should look at.
It's called non-HDL cholesterol. Think of what that means.
That's the cholesterol that's not in your HDL particles. In essence, it's your ApoB cholesterol.
So how would I know if your ApoB cholesterol is up? I can't look at ApoB, but if I did that calculation, non-HDL cholesterol, if your ApoB is looking good, but non-HDL cholesterol is still a little high, I'm suspecting you got some of them remnant VODL particles floating around. Now, it's not 100% true, but it's about the only thing you can do.
There are no accurate remnant tests that are available to the run-of-the-mill doctor. So, look at non-HDL cholesterol.
And by the way, for the listeners, that's a freebie on the lipid profile. It's basically total cholesterol minus HDL cholesterol.
So that means it's the cholesterol that is in your VLDLs and LDLs. So if your LDL cholesterol, ApoB is looking good, but your VLDL cholesterol is still high, that would drive non-HDL cholesterol to be higher than it should.
And that's why Peter and I also have very aggressive goals for non-HDL cholesterol also. We don't always discuss it with the patient, but we would if it was still elevated within the face of a normal APOB.
All right, let's talk about HDLs, the most confusing of the lot. Now, we've already done dedicated podcasts on this topic.
We've spoken at length about this. So we're not going to be able to obviously cover this in too much detail, and we'll point people back towards the previous podcast where I've done this.
But you've already alluded to the fact that HDLs can be protective. This has led many people to refer to HDL as the so-called good cholesterol.
And if your quote unquote good cholesterol is high, yeah, you don't need to worry about anything. I'm not going to ask you to debunk that because the tone of my question already suggests that that's nonsensical.
So let's have a modest but brief discussion on how HDLs work and why is it that when they're functioning, they can be quite protective, but at the same time, maybe say a word about why, unfortunately, we can't figure this out or discern this from blood tests. Yep.
And it's so important and it's so unknown out there in the real world. And in the layman's world, it's probably not known at all because they keep reading these idiotic missives in newspapers or magazines that, boy, check your good cholesterol.
And even if it's high, you don't have to worry about your bad cholesterol, LDL. It's so sad.
Even sadder that some providers still believe this and tell their patients that. So basically what we say very quickly to any patients is, as we're teaching them about lipoproteins and what they do and what they carry, we get to a point where we say we're not going to talk about HDLs anymore.
Now, don't get me wrong. HDL particles are incredibly important to both your cardiovascular system and probably many other tissues in your body.
And that means HDLs perform a lot of functions that, especially with the heart, may be very cardioprotective. We also know that some people have the type of HDLs that don't perform those cardioprotective functions.
They actually perform bad functions to the artery wall and plaque and the heart. So the important thing is you can understand, boy, what HDLs do, let's call that HDL functionality.
And to make a long story short, whether your HDLs are doing those cardioprotective functions or they're doing bad things to your vasculature, whatever they're doing has zero relationship to their cholesterol cargo, meaning your HDL cholesterol level in the blood. There are people with low HDL cholesterol, often a signal for a high cardiovascular risk, but not everybody.
And there are people with very high HDL cholesterol have been told they're protected, and we know they are not. A group of them gets atherosclerotic disease.
A group of them have been described with breast cancer, dementia. So obviously, you can't look at an HDL cholesterol in an individual patient and make extrapolations on what the heck the HDLs are doing in that person.
The reason HDLs have these either miraculous or disastrous properties comes down not to their lipid content, certainly not their cholesterol content, but to two things. Their protein content, over 150 proteins have been found to be associated with various HDL particles, and they perform an immense number of likely very necessary actions that need to go on in certain tissues where things may be going wrong.
We also know that the coat of an HDL, apart from its proteins, is virtually all phospholipids. So the exact phospholipid concentration of an HDL surface has tremendous amount to what to do.
Can an HDL do wonderful things or bad things? Those phospholipids really determine what an HDL can bind to in various tissues. Now, of course, we can't measure HDL phospholipid content.
There are hundreds of phospholipids. You would get a lipidome coming back that you couldn't even pronounce half of the phospholipids or at least the fatty acids that are in those phospholipids.
And same with the protein. If there's 150 of them, I guarantee the average doctor might be familiar with about 10 of those proteins and not with the rest of them.
So I don't know how to determine a patient's HDL functionality. Clearly, the people having adverse effects with high HDL cholesterol have dysfunctional HDLs probably related to that proteome or their phospholipid content and vice versa.
So what we tell a person right now is in the year 2024, we didn't always believe this. This bad cholesterol had an origin that everybody believed way back when.
Framingham, Mr. Fit, the earlier observational trials, nobody ever adjusted for APOB in those trials.
It wasn't even available when they were doing it. So we now know that the people with low HDL cholesterol who do get atherosclerosis always have high APL-B.
And why? Why do those people have low HDL cholesterol? I've already told you it's the trigs that knock the HDL. And the trigs may not be 400.
The trigs may only be 130, which are being ignored. And what is high in them? APL-B.
So the proper treatment of low HDL cholesterol in the person you believe has cardiovascular risk is just like Triggs, lower APOB, lower non-HDL cholesterol if you can't get an APOB. If somebody has a high HDL cholesterol, I don't know what blood tests to tell you.
I would always check an APOB. We do that in 100% of people.
And if it was high, we would treat APOB regardless of an HDL cholesterol level. But I can't look at a man or a woman and say, oh my God, you're the one with high HDLC who might wind up with dementia or some cancer or something.
I don't know. So we'll track those other diseases with other modalities that we have at our beck and call.
I don't know what to tell you about your cardiovascular health if you have high HDLC, but I can guarantee you it is not a declaration of cardiac immortality. So it's HDL functionality.
And you recall we had a nice email exchange about a friend of mine who I've known for many years. He's always had a very high HDL cholesterol and a very low LDL cholesterol.
In fact, his HDL has routinely been above 100 milligrams per deciliter, and his LDL cholesterol has always been below 100 milligrams per deciliter. So this is a guy that by anybody's metric looks like he's in tip-top shape.
But I did suggest to him at one point, it would be reasonable to at least do a calcium score because I've seen these case studies of individuals with high HDLC, low LDLC, who still end up having atherosclerosis. And it can be quite aggressive because it could be that that high HDL cholesterol is actually a marker of dysfunctional HDL that are having a difficult time clearing it.
To make a long story short, he ended up having quite a high calcium score. And so now he's on very aggressive treatment to take any residual risk out of that ApoB.
So he's on double therapy now and he walks around with an ApoB in the 20 to 30 range. And hopefully that's going to be sufficient to retard this.
But again, always a great story. I remember you sharing that case with me and I, my God, why the heck did you do a CAC? Because you've heard me spout enough, you learned your lesson.
I don't use HDLC to make any decision. Yeah.
I distinctly remember reading a case study 10 years ago about a woman who looked just like that and ended up having very advanced atherosclerosis. Let's pivot and talk about the brain a little bit.
This is an area where your own knowledge has grown rapidly, Tom. This is clearly an area of immense curiosity for you, for me, because cholesterol plays an important role in the brain, I think to put it mildly.
And people have many questions about the role of cholesterol-lowering therapy and brain health. So let's just start with a basic question, which is what role does cholesterol play in the brain? And what do we know about the different pools of cholesterol? We have cholesterol outside of the central nervous system, cholesterol inside the central nervous system.
Can they move back and forth? Can lipoproteins go back and forth? Is LDL taking cholesterol into the brain and back? Tell us about how that whole system works. So important.
I'm glad we're going to chat about this a little bit. And it's obviously so complex.
Really, I'll almost give you credit. You're the guy who got me

interested in lipids in the brain probably 15 years ago when you introduced me to Richard

Isaacson at the Cornell Dementia Clinic. And he was very interested in lipids because he just knew

lipids are part of what's going on in the brain. And I better learn more about lipids.
And you were

good buddies. And I got pulled into that circle.

I like how you said dragged initially.

I mean, pulled slowly, yes.

No, you're a strong guy, Peter.

You've motivated me to study a lot of things that maybe I wouldn't have tripped into.

I would have never met a Richard Isaacson had it not been for you, but thank God you

did. And so we've been trying to learn about brain and the lipids so often.
The last thing I'll say, you did that great podcast with Dan Rader on HDLs, and it's a podcast everybody should listen to. At the end, you sort of turned to Dan, you said, where are we going with lipids, Dan? We've solved the APO-B.
We're learning a lot about HDL. And Dan said it's lipids in the brain is the next frontier.
And why has that not been studied very much until now? Because you can't stick a needle. You have to go into the, get cerebral spinal fluid to analyze what's going on in the brain.
And most people are amenable to a venipuncture in their elbow, not a spinal tap.

So here's what's going on.

Cholesterol is almost certainly the most important molecule in the brain.

The brain is by far the most cholesterol-carrying organ in the body.

The brain actually makes more cholesterol than any other organ per se, way more than the liver even.

So if I gave you a dumb question, I got this body here and I want to find out where all the cholesterol is, where should I go?

Thank you. organ per se, way more than the liver even.
So if I gave you a dumb question, I got this body here and I want to find out where all the cholesterol is, where should I go? Open his skull and take out the brain. That's where you're going to find the most cholesterol.
Wow. So obviously, cholesterol is crucial to the brain.
And that's because the brain is made up of a lot of cells, all of which have important functions, especially those neurons that shoot off all the action potentials that make our body function and everything. And what's on the surface of a neuron? Free cholesterol and phospholipids.
So evolution, I guess, figured out a long time ago that the brain needs cholesterol. So we're not going to make the brain dependent on cholesterol that's floating around the plasma or what's in your liver or your intestine.
We're going to let the brain make all the cholesterol it needs. So we're going to really drive the enzymes that synthesize cholesterol in the brain.
So the brain needs cholesterol. To make a long story short, every cholesterol molecule that's in the brain got there by de novo synthesis in the brain.
Not a single molecule of cholesterol was delivered from the periphery, meaning that floating around our plasma leaves the plasma and enters the brain. Now, by the way, where is all the cholesterol in our plasma? I've already told you it's got to be inside of a lipoprotein floating in plasma.
That's where we measure cholesterol. That's where we measure lipids in the plasma.
But I can assure you there is no cholesterol-carrying particle in the plasma, be it a VLDL, an HDL, or an LDL, that crosses the blood-brain barrier and says, okay, brain, here's your cholesterol for today. Doesn't happen.
There is a rapid turnover of cholesterol in the periphery. Cells make it.
They get rid of what they don't need. It's brought back to the liver for the liver to decide what to do with it.
The turnover time for cholesterol in the plasma is two to three days. So if a cholesterol molecule synthesized in the brain.
What is its half-life? Five years. Now, half-life, if a half-life is a given number, the total brain residence time of that cholesterol molecule is you multiply that by seven.
So some cholesterol molecules last up to 30 years once they're synthesized in the brain. And that's why cholesterol synthesis in the brain starts in utero.
Early on, mom's supplying the little fetal brain with a lot of cholesterol, but very rapidly, second, third trimester, those brain cells start making their own cholesterol. Once a child is born, there's a lot of cholesterol synthesis going on by virtually

every cell that exists in the brain. There's only like three of them.
But at a certain point,

somewhere between the ages of five and 10, the brain has made all the cholesterol it needs.

So then only two cells continue to make cholesterol. So lesson number two, what are the

cells in the brain that we're in this conversation with? Neurons I've mentioned. In utero and in childhood, neurons produce a lot of cholesterol.
But at a certain age, the neurons got more work to do. They don't want to make cholesterol.
Why? Because every cholesterol molecule requires 27 molecules of ATP to produce. It's a super energy-driven process.
Neurons need ATP for a lot of other functions, those electrical charges they make. All right.
So what are the other two cells in the brain? Oligodendrocytes make the most cholesterol. And where does the cholesterol they make become? Myelin, which coats every nerve ending, every axon and dendrite in your body.
Those oligodendrocytes are big-time cholesterol producers. But they make all their cholesterol go to myelin.
They don't send any cholesterol over to neurons. So what is the other cell? And it's astrocytes.
In infancy and childhood and utero, oligodendrocytes, astrocytes, and neurons are making cholesterol like there's no tomorrow. Once the neuron stops making it, astrocytes are the sole maker of cholesterol that supplies the neurons.
But how would an astrocyte synthesize cholesterol and send it over to the neurons? Aha, the brain has to have a lipoprotein system just like the periphery does. Now, between astrocytes and neurons, basically, it's brain interstitial fluid, sort of a loose connective tissue.
It's called the matrosome. So if astrocytes synthesize cholesterol, they obviously have to package it inside of a brain lipoprotein, secrete that lipoprotein, which swims through the matrosome and goes over.
And guess what the neuron expresses? LDL receptors, LDL receptor-related protein, or something called the scavenger receptor, all of which can bind to the type of lipoprotein that an astrocyte produces. So the brain also has a lipoprotein delivery system, but here's the difference.
What is the main structural protein in the periphery, ApoB or ApoA1? What is the main structural protein in the brain? ApoE. So when an astrocyte makes a lipoprotein, it's an APOE containing lipoprotein.
And by the way, they're smaller, much smaller than the particles that we find in the periphery. If we put them in a centrifuge, they have the density of a high density lipoprotein that floats around the periphery.
So they're often called brain HDLs, but don't confuse brain HDLs with peripheral HDLs because most of the brain HDLs have ApoE as their structural protein. In the periphery, they have ApoA1.
Here's where the story gets a little more complicated, as always. What is the smallest apoprotein the body can make? It's actually apoprotein A1, which is why an HDL needs four or five of them.
So if ApoA1 can dissociate from an HDL, and we do have free HDL in the plasma that's measurable, it is small enough that it can cross the blood-brain barrier. And once it joins the blood-brain barrier, what is the small APOA1 looking for? An HDL buoyancy particle.
So it joins with the APOE particles. So the brain lipoproteins are all APOE, or they're all APOE plus APOA1.
And you can have multiple copies of each of those on those particles. So now, as long as

the ApoA1, by the way, which can bind to an LDL receptor or the scavenger receptor, same with the

ApoE, the neuron can grab them and either internalize them or delipidate them, and the

neuron gets its cholesterol, and the neuron's happy. And then the delipidated particles can

go right back and fill up at the astrocyte again. So that's brain cholesterol transformation.
But Peter, I know you check ApoE genotype on your patients, and you do worry when certain ApoE genotypes come back, especially those carrying the E4 allele. Because we know that's associated with AD, and we have enough knowledge to know that, God, those brain apoproteins, the brain HDLs carrying ApoE4, are, guess what, dysfunctional HDLs.
Just like we've discussed, you can have dysfunctional HDLs in the plasma. So if your brain makes ApoE4 instead of ApoE3 or ApoE2, you are not going to have the best brain HDL particles.
And not only do brain HDL particles carry cholesterol back and forth, if amyloid or tau is being produced in a neuron, they can grab it and transfer it over to microglia, which are brain immune cells, which can get it and take it down and get rid of it in the brain lymphatics. So your ApoE genotype certainly affects our VLDLs and chylos in the plasma.
That's a lecture for another day because that's not that common. But in the brain, the ApoE4, you only have ApoE containing lipoprotein, so you don't want to have it.
I just want to make sure people aren't confused on that point. So definitely people listening to us are familiar with the APOE4 gene.
But just to reiterate, you're going to have two copies of these genes, just as you do for every gene. This is a gene that exists in three isoforms.
So none of these are considered mutations, meaning there are three types that occur in nature, the E2, the E3, and the E4 isoform. So you have six combinations of these, and therefore three of these combinations include at least one copy of an E4.
So there's the 2-4, the 3-4, and the 4-4. So we know epidemiologically that there's a clear increase in the risk of Alzheimer's disease as you move from 2-4 to 3-4 to 4-4.
And I just want to make sure people understand that we're kind of going back and forth between the gene and the protein. If you have an E4 gene or a E3 gene or a 2 or whichever combinations you have, you still make an ApoE protein.
What is different is what the protein looks like in response to the gene. And what's very interesting is, if my memory serves me correctly, I believe it's only a single amino acid substitution between each of these.
In other words, one amino acid difference between the one made by the three isoform and the four isoform results in what you just said, which is individuals who have the ApoE4 gene have an ApoE4 protein that wraps their brain lipoproteins that gives it less affinity for doing this job of transferring cholesterol from astrocytes to neurons. So this is a very important explanation of why it is that people with an ApoE4 gene are at an increased risk.
This is not to say it is a causative gene. It's not a deterministic gene.
It's not a gene that if you have a copy or two copies of the ApoE4 gene, you're going to get Alzheimer's disease. This just explains why there's a greater susceptibility and why an individual who has one or two ApoE4 genes needs to work that much harder on all of the other variables that factor into AD.
And again, to your point, why does this not really play as much of a role in the periphery? We could save that for another day, but it sort of does in the edge cases. And that's why we see a higher incidence of ASCVD and APOE4 carriers.
You did already allude to it, but only the astute listener will remember it when you talked about the APOE and the conformational change of lipoprotein. I'm not going to go back to it because I want to stay on the brain.
But anyway, I just wanted to interject that point so people knew the relationship between the genotype and the phenotype of the structural protein. Very much.
And even that single amino acid change just affects the shape of the protein. So it no longer binds where it should, and it screws up its so-called

functionality of the particle. One amino acid in a peptide, you wouldn't think, but it's true.
Now, there's one other part of the brain lipid story, and it gets deeper. And remember, in the brain, we're on our infancy.
So much of what I'm going to tell you now is not carved in stone, end the discussion, but it's how we understand it in September, October, November of 2024. So it's the cholesterol story.
We know if the brain can't get rid of cholesterol, that is associated. One of the characteristics of people with dementia or Alzheimer's disease.
So there comes a point where too much cholesterol in the brain can be

bad news. But we also know, and I'll discuss it in a moment, but because cholesterol synthesis

is so crucial to the brain, you would never want to restrict cholesterol synthesis to a severe

degree. That wouldn't, or just suggesting that you would say, yeah, that doesn't sound too bright.

So let's get into cholesterol homeostasis in the brain. Now, the neuron is an interesting little

Thank you. suggesting that you would say, yeah, that doesn't sound too bright.
So let's get into cholesterol homeostasis in the brain. Now, the neuron is an interesting little cell there because it gets its cholesterol in adulthood from these ApoE-containing particles.
But if the neuron wound up with too much cholesterol, just like too much cholesterol in any peripheral cell, the liver is lipotoxic. It by itself would kill the cell.
So the neuron is the one cell in the brain that was given an enzyme that it can transform cholesterol molecule into a metabolite that's called an oxysterol. We have another name for oxysterols, and this will make you scratch your head.
Yeah, they're bile acids. The liver, by the way, can change cholesterol to an oxysterol, which means sends it right down the bile acid synthesis pathway, and the liver dumps it in the bile, and we excrete it fecally.
So if the neuron can change cholesterol to an oxysterol, is it possible for that oxysterol to leave the neuron and enter the plasma? And that would be a way of the central nervous system to get rid of cholesterol. Now, wait a minute.
That's a lipid. Lipids can't pass through that blood-brain barrier.
So the neuron makes these oxysterols. That's basically a sterol with extra oxygen molecules attached.
So the neuron makes something called 24-S hydroxycholesterol. For those of you who've listened to our first podcast, you know cholesterol at one end has a hydroxy group.
That's what makes it somewhat water-soluble. But the other end of the cholesterol molecule has no hydroxy, it's all lipids.
But if we could stick another hydroxy group on the tail of the cholesterol molecule, it has a hydroxy group at both ends. It actually becomes a rare hydrophilic lipid.
It's a lipid that's soluble in water, and it has no trouble passing through the blood-brain barrier. Once it enters the blood-brain barrier, it's in plasma, and it either rapidly binds to albumin or to any lipoprotein that's passing by.
And both the albumin or the lipoprotein brings that oxysterol to the liver, which converts it to a bile acid and excretes it. So the brain can actually get rid of sterols in a fortuitous way by sending it down to the liver, which makes a bile salt from it.
So 24-S hydroxylase is the enzyme only neurons have. People think if we measure 24-S hydroxycholesterol in the bloodstream, and it's high, we know the brain's trying to get rid of cholesterol, and it's a marker of brain cholesterol health, because you really should have trivial amounts of that in the bloodstream.
And it is, with mass spectrometry, easily measurable. All right.
But let's get back to the astrocyte and the neuron making cholesterol. Our cells, Peter has talked about this many times, there's a bunch of original steps that go to a linear molecule

called squalene, and then it starts to form a cyclic molecule that are called sterols. And the ultimate sterol is cholesterol.
But there's many steps of the sterol. One sterol becomes another one, becomes another one, becomes another one.
The penultimate, next to last sterols that ultimately will transform into cholesterol are either lithosterol or desmostrol. As it turns out, and it's lucky for us, lithosterol is the major pathway of peripheral cell cholesterol synthesis.
When your liver makes cholesterol, it goes through the lithosterol pathway. Same with most of the cells in your body.

Who uses the desmostrol pathway? Why did evolution give us two cholesterol synthesis pathways? Because cholesterol is essential for human life. God forbid you had some genetic defect where you knocked out one synthesis pathway, you've still got another, so you're still survivable.
So the The desmostral pathway, although it could be used by any cell, is primarily used by the brain astrocytes, also in the periphery by the steroidogenic tissue. So very interesting.
So in your brain, can we measure serum desmostral? Would it reflect what's going on in the brain? Actually, we know it does, because people have done the studies where they've done spinal taps, analyzed CSF desmostrol, and it correlates incredibly well with serum desmostrol. So serum desmostrol is a biomarker reflective of the desmostrol synthesis pathway.
By the way, for the nerds, that's called the block pathway. The lithosterol pathway is called the Can-Dutch-Russell pathway.
Astrocytes predominantly use the block, the desmostral pathway. And in adults, astrocytes are the supplier of cholesterol to the neurons.
If for some reason the astrocyte fails and the neuron in an emergency how to make cholesterol, it actually uses the lithosterol, canned Dutch-Russell pathway. But in adults, that pathway is for the most part not at play.
It's inactive. So again, that's why we don't measure lithosterol.
Lithosterol is telling us anything going on in the brain because it's all coming from peripheral cells. It would be a minuscule amount that might be brain.
All right. So why am I telling you all of this? My speculation has been that the reason that the place we see desmostrol in the periphery in the steroidal tissue is that that's the tissue that has the highest demand for cholesterol production may be suggesting that the desmosterol pathway is more suited to a high demand pathway vis-a-vis the astrocytes and the steroidal tissue.
Again, we're so far in the nerdy stuff on this now that it's just a speculative comment. Listen, it's the AT of brain that thinks of stuff like that.
That's why I love that I've known you for 15 years, because many of the things you tell me, I got to go look up and say, God, that sounded logical. Let me check if there are any truth to it.
And I think you're absolutely right with that statement. So before I get more into that, anybody who's ever prescribed a statin to people knows there's a very small amount, and it's even in the package insert that comes back and tell, doc, since you started this, I'm not right.
I'm not thinking right. I'm not calculating right.
My brain is in a fog. And we use the word brain fog.
Again, an extreme minority of people given statins have that. We had no clue what caused that.
Invariably, it would stop the statin, try another one. It

usually occurred. If it didn't, fine.
But if not, then we'd have to figure out other ways to lower LDL cholesterol, which was not easy years ago. But anyway, my hypothesis nowadays is these small number of people who get brain fog, I wish I had dysmosthrol levels on them, could some people be very sensitive to the effects of a statin? We know in the periphery, hypersynthesizers of cholesterol respond incredibly well.
Or excuse me, oversynthesizers do, hyposynthesizers do not. So who knows? But that being said, now here comes the next part of that epidemiologic study where they correlated low desmostrol with serum desmostrol.
People who had low serum desmostrol had a much higher incidence of cognitive impairment and Alzheimer's disease, which would lead simply to the hypothesis that serum desmostrol is a usable biomarker to, say, is somebody at risk for Alzheimer's disease. And this goes back to when I met Richard Isaacson with Peter.
We started throwing these hypotheses around, and we've watched that ever since. Where would it come into play? Until recently, statins were our only game in town.
So if we write a statin, especially if used it at a

higher dose, if desmostrol was dropping low and we use an arbitrary cutoff point, the 20th percentile, would that be maybe you don't want to inhibit cholesterol synthesis in the brain to that degree? Might we want to attack APOB with another agent? All hypothetical reasons I'm putting on the table here right now. And I think right now we look at that, especially in who? Who are the people that we know are likely prone to dementia and cognitive impairment? The E4 carriers, people maybe with strong family histories, people that have other identifiable traits that make us think they're prone to AD.
we would watch Desmosthrol incredibly closely in that population.

So... identifiable traits that make us think they're prone to AD.
We would watch desmosthrol incredibly closely in that population. So now the last thing I'll tell you, if the astrocyte is not making cholesterol because of its being oversuppressed by a statin, the neuron would be getting less cholesterol.
The neuron would convert none of that cholesterol to 24-S-hydroxycholesterol because it's trying to conserve every cholesterol molecule it can. So I think if you were somebody who could measure 24-S hydroxycholesterol in the serum, you would not see it in somebody who had cholesterol synthesis suppression in the brain.
This all has to be worked out in future clinical trials, but there are looking at this in some clinical trials right now. So one day we'll be a lot smarter on this.
Right now, if you want, you could measure desmostrol and perhaps use that as a cautionary marker. Number one, if they're not on a drug and it's low, if you haven't done an APOE4 genotype, you might look at it.
But if it is somebody who has a propensity to desmostrol and you have to use a statin, maybe you want to watch that. The good news is, and I think it's why our mantra is, if we have to use a statin, we start with low-dose statins.
We have very little use for the high-dose statin in the year 2024 because none of the other APOB-lowering drugs, via benpadoic acid, ezetimibe, certainly PCSK9 inhibitors, get into the brain and suppress cholesterol synthesis. So we have many ways of lowering ApoB if we were a little fearful of low desmostrol in a patient prone to AD or so.
So that's about as much as we want to get into probably with brain lipids right now. Understand APOE is a big player up there, and there are different types of the APOE protein, but understand cholesterol homeostasis has a lot to do with what is in the peripheral cells.
We can look at markers of synthesis. The markers of cholesterol absorption that we use big time when evaluating peripheral cholesterol homeostasis obviously is not at play in the brain.
The brain is not absorbing cholesterol from your gut. Before we leave that, Tom, what is our hypothesis around the hydrophobicity of various statins? And do we think that certain statins are more likely to cross the blood-brain barrier? Are there certain statins that should be ignored in patients with marginal desmostrol? Great question.
And the thoughts have changed on this too, because early on, if you go back, probably maybe even listen to the podcast you and I did in 2018, I believe, we were talking about hydrophilic and lipophilic statins. And the lipophilic ones can pass right through the barrier a little easier than the hydrophilic one, which need receptors to pull them in.
But subsequent analyses has shown all statins get into the brain. Ultimately, once you have a steady state statin level in the blood, they all will get into your brain, and they all have the ability to suppress cholesterol synthesis in the brain.
Now, the last thing I want to say about statins before everybody says, oh my God, I'm stopping my statinomar. I can't get a desmosterol level.
Well, they're available if you look for them. But in general, if you analyze all of the statin data, the many trials, be they observational or randomized control, there is no signal whatsoever that in a population statins worsen or cause cognitive impairment of Alzheimer's disease.
There's a few studies that even suggest perhaps some lowering, maybe that's through atherosclerotic cerebrovascular disease, who knows. But don't worry that statins in the overwhelming vast majority of people are not hurting the brain.
But I think we've introduced perhaps a biomarker that you might know with a little more certainty if you have to write a statin in somebody subject to dementia. Yeah.
We actually covered this at length in one of the previous AMAs, and I went through every meta-analysis on this topic, it's important for people to understand that at least at the time, and I don't think this has changed, there has not been any statin trial where the primary outcome was dementia. The primary trial is always cardiovascular disease, but there have been more than a dozen such trials where the secondary outcomes are dementia.
It's worth noting that in every one of those trials, regardless of statin used, there has either been no change in the risk of dementia or a reduction in the risk of dementia. Now, it's interesting.
These studies were almost all done in the setting of trying to determine if lipophilic versus hydrophilic statins were more, less, or better. And the answer always emerged, it didn't seem to matter, which of course makes sense if you understand now that they probably all crossed the blood-brain barrier.
So the question remains, will there ever be a study done that tests this question specifically as the primary outcome? In other words, where the study is powered to ask the question, does the use of a statin increase, decrease, or have no effect on the risk of Alzheimer's disease and dementia? Or will we instead be forced to rely on these secondary outcomes, which are always subject to some potential misinterpretation. Again, I take much more comfort in knowing that they are all either neutral or favorable.
That would certainly be better than the opposite. But again, that remains a bit of an unknown.
And you might be right, Tom. It might be that on average, it's having no effect on the brain.
On average, it's having a beneficial effect through the vascular system. But then there might be edge cases that are not being captured in large clinical trials based on hundreds of thousands of people.
And it might in fact be those patients in whom a little extra knowledge goes a long way vis-a-vis cholesterol synthesis in the brain. And the final point I'll make here is what a privilege it is to be practicing medicine in 2024 when we don't have only statins, but we have ezetimibe, we have benpedoic acid, we have short-acting PCSK9 inhibitors, we now have long-acting PCSK9 inhibitors.
We have ASOs around the corner. There really is no need for a patient to ever endure a side effect of lipid-lowering medication today.
We can lower everybody's lipids without side effects, and that's only going to become more and more true in the next decade. Couldn't argue with anything you said there.
It's brilliant what you said. And also, this is not a reason not to use statins.
We're not evaluating populations. We treat people one at a time.
So in somebody we're worried about dementia, we have a biomarker that's probably usable. And if, God, you can't take the statins, so what? We can get your ApoB gold pretty easily with the other things that we know are not affecting the brain.
What Peter said, wouldn't it be nice to have a randomized blinded trial to answer this question? All statins are generic. I don't know of any pharma company that's going to spend a billion dollars to prove or disprove what statins do to cognitive functions of the brain.
So it's not going to happen. So if it's not, we can use in individual patients these oddball biomarkers that is what I think is part of medicine 3.0, where we maybe use a little smarter knowledge to try and do a better job.
The last thing I'm going to, and Peter has harped this enough to, maybe I bad mouth high dose statins. We don't use them.
We're not treating acute coronary syndrome patients where maybe you want to be on a high dose statin for X amount of time. You can get most of the APOB lowering with a statin with the baby dose.
This has been proven in trial after trial. Most of the LDL receptor upregulation occurs with the lowest dose that inhibits cholesterol synthesis.
You start doubling, tripling, quadrupling, you might get another 6%, 7%, not the original 30% lowering or so. So in today's world, why do you ever have to double, triple, or quadruple the dose of a statin when we have all these other additive drugs that You take a baby statin, my acronym for a low-dose statin, and you combine it with a zetamide, benpidoic acid, or PCSK9 inhibitor, you've got a military machine that can destroy APLB.
So that should be the thought processes about attacking APLB nowadays. We have so many options, which we didn't have in the heyday.
I always say one last thing, because I'm old enough to remember, where did all this hydrophilic, lipophilic stuff come from? The first two competitive statins on the market were simvastatin, which was Merck's most potent statin, more potent than their lovastatin or Mevacor. So everybody jumped on zilcor or simvastatin,

but Bristol-Myers squid made pravastatin, hydrophilic. And there was a lot of thought looking at other biomarkers and even catabolism that the hydrophilic statins were safer than the

others. Was there a little more brain fog with mevacor or zilcor than there was with pravacol?

Anecdotally, people said that. I never saw a trial that looked at that.
But that's where it all came from, pharma competitiveness, hydrophilic versus a lipophilic statin. Well, Tom, my final question, I guess, really comes down to what are you most looking forward to in the next three to five years? I have an answer for what I'm most excited about, but I'm obviously more interested in hearing what you're most excited about in the entire field of cardiovascular medicine.
Is it something on the drug side? Is it something on the diagnostic side? Is it something else? What has you most excited? Well, most excited is I hope I'm still here in five years, and I hope I'm still capable of having these discussions with you. Peter's working hard to make that happen with me, so I high-five him on that.
But if I do make it that long, look, I think we've got ApoB solved right now. They're looking at even other types of PCSK9s coming down the pipe, a little more potent on LDLC than the current ones.
There's an oral PCSK9 that they're working on. Would you rather swallow a pill than take an inch? But you're still just chasing ApoB.
And we can pretty much, with rare exception, get that to goal now. So I'd be more excited about for the people with the rare genetic disorders that are driving their lipids and lipoproteins out of whack.
There are drugs coming that attack other apoproteins that are there. But again, that's going to be a minority of patients on that.
Diagnostically, I would hope, I can't ever see it coming, but I couldn't see a lot of things coming, that there might be some usable HDL functionality tests, which would make us a little smarter, perhaps, on giving a patient some insight to their HDL markers or so. Would there be other types of earlier markers? I don't know that we're going to get an earlier imaging marker than a CTA right now without being invasive or maybe optimal tomography and stuff is showing us stuff within the vessel wall.
So who knows what imaging is going to bring to the table, but that probably won't be in widespread use when it first comes out. Would there be other inflammatory markers we have now? Fine, you can use them.
You can look at them. I didn't say it before, but does everybody understand that whatever inflammatory marker you're looking at, that is not the goal of therapy.
ApoB is the goal of therapy. The thought being, if you make ApoB low enough, the atherosclerotic process in the artery wall would dry up, scar up, and there'd be no more inflammation in the artery wall.
But there are other things going on, as Peter alluded to. So there are other biomarkers coming in.
Certain amino acid biomarkers are being looked at or so that might give us other types of insight, looks at the arterial wall pathology that might be going on. I would love to see some of these synthesis and cholesterol markers, perhaps even LDL and H-triglyceride levels, the latter two are just simple assays being made available to the general public.
And I would like to see more widespread availability of the sterile biomarkers. And you need some education on how to use them, but that would be all great.
And the last two things, I guess about two weeks ago, the NLA published their first statement on ApoB. And we've given you a lot of info why we use it, but you want to get down into the weeds.
That's a statement to read. And they do mention as good as it is, it can't happen tomorrow.
No guideline is going to tell you to make APOB for the simple reason is the overwhelming majorities of practitioners really don't know what APOB is, including those in the cardiology community, for goodness sake. You can't get a guideline declaring everybody stop doing lipid profiles, just get ApoB because nobody would know what you're talking about.
Sadly, today, the NLA put out a secondary expert person statement on LP little a, and they get into the same thing. Yeah, everybody should get an LP little a once in your life, but right now in 2024, there are Several drugs drugs coming to lower it.
We have no idea whether they're going to reduce MACE or not. So stay tuned.
We're going to get to read out on one next year. What if it failed? Then LP little a just becomes a risk marker like CRP or something.
It's not a goal of therapy. So stay tuned for that.
But they also get into it. A lot of labs, they're not doing the right type of LP little A testing.
I was shocked to hear it because it's kind of a cheap test, but apparently there are third-party payers giving doctors grief for ordering it, for God's sakes. And again, the overwhelming majority of PCPs and a heck of a lot of cardiologists have no idea what LP little A is.
What good does it tell you to go get it tested and you show up in your doctor's office and goes, who that's nothing, don't worry about it. So I'm hoping for better education among doctors in the lipid world.
God knows, Peter, you've done your part. And I just always like to pat you on the back.
Last year, Peter was made an honorary lifetime member of the NLA.

And I would suggest you go to their website and see who else has ever achieved that title.

It's the giants of the field who invented the centrifuge or that type of serious analyses.

Why did Peter give it?

Peter has probably brought more lipid education to more people than any of those gigantic thought leaders ever did. So I high-fived my buddy for doing these type of things and giving lipid its due presence on his missives, his Instagrams, and his podcast for sure.
So like always, Peter, we're going to know a lot more. Some of the stuff we said today is probably going to sound like idiocy in five or 10 years, but I think a lot of it's going to be right.
If I look back at my life and I prognosticate about a lot of stuff, I've been a lot more right than wrong. So I'll pat my own back.
It was a huge honor last year to receive that award from the NLA and no small part at all. That's obviously due to your mentorship and the mentorship of others.
So thank you very much. And thank you obviously for your continued education, both for me personally and also for everybody listening.
You're an absolutely tireless educator. Your zeal for teaching, your generosity of knowledge is really unparalleled.
And you and I joke all

the time about that first time we met way back in Reno, total chance coincidence, and certainly one of the more fortuitous things that's happened to us both. So thank you again.
I think this was a great discussion. I know that at times it got a bit technical, but I would encourage people to maybe go back and listen to this again, really go through the show notes on this one.
All the stuff we talked about, you'll find summarized there and links to other studies

if you want to be able to go into some of the details. So thank you once again, Tom,

for everything you've taught me and obviously everything you've taught the listeners.

Vice versa, my dear friend.

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