The Peter Attia Drive - #07 - Deep Dive: Lp(a) — what every doctor, and the 10-20% of the population at risk, needs to know

Episode Date: July 30, 2018

Pronounced, el-pee-little-a, this lipoprotein is simply described as a low density lipoprotein (LDL) that has an apoprotein “a” attached to it...but Lp(a) goes far beyond its description in terms of its structure, function, and the role that it plays in cardiovascular health and disease. Affecting about 1-in-5 people, and not on the radar of many doctors, this is a deep dive into a very important subject for people to understand. A quick primer on lipoproteins [7:30]; Intro to Lp(a) [11:00]; Lab tests for Lp(a) and reference ranges [20:00]; The physiologic functions of Lp(a) [31:00]; The problems associated with high Lp(a) [34:15]; Lipid-lowering therapies of Lp(a) [44:45]; Lp(a) modification through lifestyle intervention [1:00:45]; High LDL-P on a ketogenic/low-carb-high-fat diet [1:05:30]; and More Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratia-md.com.

In this podcast, I'm going to be discussing LP Little A. Little while ago, we put up a little question here on Twitter that said, if I'm going to do a solo podcast interviewed by Bob, what topic would you want to hear? And we put up two options. The first was LP Little A. The second was hormone replacement therapy for postmenopausal women. Survey ran for about a day and the results were unambiguous. 80% of you wanted to hear about LP Little A, though many of you did want to hear about HRT and we will absolutely get to that. So on this podcast, we structured it as an interview. Originally, I thought I would just do it as a quote unquote lecture, but I realized that would

just be way too boring and it would be more fun to play patty cakes with Bob and have him interview me. So that's what we did. So Bob put together an interview and he just asked me a bunch of questions about LP Little A. We're gonna talk about what the heck it is, why you should care, why it's problematic, like the protein, what some of the potential treatment options are and what's on the horizon.

Now I gotta admit, this is a bit of a technical podcast, but I also know that this is kind of a technical loving audience. So, don't be discouraged. I also think this is one of the podcasts where you really have to be able to look at the show notes. I find some of this stuff really complicated myself and I find a picture is sometimes worth a thousand words. So, especially when I get into stuff like cringle repeats

and cringle for subsection to zone five. Like that kind of stuff, you've just got to be looking at a picture to understand. And so, if you can't be able to look at something while you're listening to it, that's fine. But maybe go back after the fact and look at it or look first and then listen something like that. But the show notes here will be very helpful.

And hopefully this answers a lot of the questions that people have been asking me over the past year about LP, little A. And again, if this format is helpful, let us know because we're really happy to kind of do one of these every couple of months where we just put up a general topic and Bob grills me on it. So without further delay, here's the discussion with Bob Kaplan on LP Little A. Hey Bob. Peter. How are you? I'm doing well. I noticed you have a coffee there. Of course. What number is that today? Seven. At least. I've watched four. Well seven doubles, probably seven double espresso's. That's true. That's true. Yeah. Yeah. That's impressive. It's a low day. So this is the first of what I suspect, then assume we might do more of where

we threw a question out to people and said, pick one, have a vote. I don't know. We gave him a day or so. And the choice was, do you want to know about LP, little A? Or do you want to know about hormone replacement therapy in postmenopausal women, which by the way, has a more politically correct name now that I can't remember? Endocrine modulating therapies for women in menopause or something. I was going to go with golden years or something to that effect. The point is HRT versus this.

And it was about 80-20 in favor of LP Little A, which kind of bums me out, because I actually really wanted to talk about HRT. But next time we throw HRT in, we're gonna put it up against something like botchyball. And hopefully HRT comes out ahead. We can talk about it. I think you have been accumulating a bunch of questions that people have also started

sending in about LP Little A. And I think that's what we're going to talk about. Absolutely. So, a lot of questions are around what is LP Little A. And I thought in order to explain that, maybe we might need a quick primer on lipoproteins to kick things off. Do you know anyone who can do that? I think I'm looking at them. Oh, okay, I was afraid you were going to say that.

Starting from the basics, if you go to your doctor and you get a cholesterol blood test, they're going to probably show you a couple of numbers, total cholesterol, LDL cholesterol, and if you're really lucky, they'll put bad next to it. HDL cholesterol, and if you're extra lucky, they'll put bad next to it. HGL cholesterol, and if you're extra special, they'll put good next to it. Traglis rides and non-HGL cholesterol, that is a standard lipid panel. Those numbers are largely unhelpful,

but more importantly, they're largely misunderstood. So when people look at LDL and think it's bad cholesterol, that immediately tells you that they're missing what the L and the D and the L stand for. The LDL stands for low density lipoprotein. And admittedly, if you don't have a background in biochemistry or something, you might not understand in looking at that, that that implies that it's a macro structure. So cholesterol, which is the principal molecule that is carried by these lipoproteins,

is something that is made by the body. So every cell in the body makes cholesterol. And most cells in the body make enough cholesterol to meet their own needs at the cellular level. And the single and most important need of cholesterol we have is cellular membranes. So cell membranes must be fluid. They must be able to move. They must be able to facilitate the attachment of one cell to another. They must be able to hold transporters across

their membranes and things like that. And of course cholesterol makes up the bulk of those membranes. So in addition, you turn cholesterol, when I say you are referring specifically to certain organs, like the adrenal glands, the ovaries, the testes, turn cholesterol into hormones that are either sex hormones, glucocorticoids, gonadotropins, these things. So if for no other reason than just being able to have cells that work and have hormones, cholesterol is pretty important because we're not going

to get too far into that. The point I want to make is that you can't traffic or move around cholesterol in the bloodstream because blood approximates water. And so the things that move freely in the blood have to be things that are what we call hydrophilic, or things that would be soluble in water. So something like glucose can move around the bloodstream very easily. But cholesterol cannot. And therefore, it needs to be packaged in something that is itself water soluble. And that something is a lipoprotein.

And the two dominant lipoproteins that are found in the bloodstream are the high density lipoprotein and the low density lipoprotein. And their names are referring to their densities in a type of assay called a gel electrophoresis, which has to do with how far these things move on an eye on gradient. There are other like proteins that don't stick around that long. So VLDL, very low density like a protein, an IDL, or intermediate density like a protein, which is almost nonexistent, it has such a short half-life. And the longer residents of the LDL is probably what explains its astrogenicity, and that's why LDL is considered the most

astrogenic particle after LP little A, which we're going to talk about today. So when you're looking at your blood test, what you're seeing is the cholesterol concentration within the various particles. So when it says total cholesterol, it says, well, if you break apart the HDL particle and the LDL particle and the VLDL particle, and if you can find it the IDL particle, how much total cholesterol do you have? And that's a number.

Call it 200 milligrams per desoleter. Okay, when it says LDL C is 120 milligrams per desoleter, that means if you break apart the LDL cholesterol, that's the concentration of cholesterol contained within them, et cetera. Now in the past, we've talked about the importance of knowing the number of particles you have and how that is a more accurate predictor of your atherosclerotic risk. And so the LDLP, which is similar to the APOB in terms of its predictive power, which is the number of particles. And the reason you can use APOB as a surrogate for that

is that each LDL particle has an APOB, which is an APO-Lypa protein that wraps around the spherical Lypa protein. It's APOB 100 specifically. So by counting those since each LDL has one and only one APOB, you can quantify the number of LDL particles. And again, we care about that because it tracks more with risk. The VLDL, the IDL, and the LDL, I'll have the APO B100. The HDL does not. The HDL has something called APO A1. It's a different lipoprotein.

And it probably explains in large part why HDL is not atherogenic and LDL is atherogenic. The pathogenesis of atherosclerosis is one that's predicated on and we should probably attach and a link to this, the post on heart disease, where I go through this in great, great, and gory detail, the process by which the lipoproteins get through the endothelial space between cells, which is actually not that hard to do. An LDL particle is somewhere between 20, 21, 22 nanometers.

It's probably not an order of magnitude, but several multiples of that is the space between the endothelial cells. So it's the size of the LDL particle really doesn't determine the ease with which it gets through the cell or not, or between the cells. What's much more important is, because most of the LDL that gets into the subendothelial space gets right back out and doesn't cause any trouble. Where the trouble comes is when they get retained and when they get oxidized and when they kick off an inflammatory response. So it is certainly the case theoretically that you could have a very high LDL, but by hook or by crook if your LDL

particles don't get retained in the sub-interferial space and don't kick off an inflammatory cascade, you're not going to suffer the effects that you otherwise would, but all things equal, we would love to see a lower LDL particle number because the process by which those particles enter the space seems relatively stochastic. So, in a few minutes, that's kind of the overview of these LIPA proteins. Okay, so I think one of the reasons why we had so much interest, in LP Little A, is a New York Times article proteins. Okay, so I think one of the reasons why we had so much interest in L.P. Little

A is a New York Times article by Anahado Conner. I think it was January this year that was entitled A Heart Risk Factor, even doctors know little about. And he tells a story of Bob Harper, who was one of the biggest loser OGs. I think it was him and Jillian, were the two trainers. And so Bob had a heart attack at a gym at age 52. And according to his annual checkups, he always checked out very healthy. And as it turned out, according to the article, Bob has, quote, perilously high levels, end quote, of LP Little A in his blood, something that was, I don't think was ever measured prior to his heart attack. So I think this article was an introduction to this particle for many people who read it.

Not only that, it's reported that a small percentage of physicians actually know about it. So kind of going back to the original question, what is LP Little A? Well, in full disclosure, Onohad is a really good friend of mine, and I know he'd been working on that story for about two years actually. I guess I'll take a little bit of credit for getting him interested in APOA and LP Little A,

and Onohad, because he's just such a curious dude, was sort of like blown away at this. He's like, wait, wait, wait, wait, wait a minute. Tell me about, you know, we walked through everything that we're about to talk about today. And he just couldn't believe that something that was so ubiquitous, probably somewhere between one and five and one and ten people walking around with this elevation. And of course, it's a long tail to the right distribution. So where you define the cutoff as perilously high is a function of how many people will be perilously high.

But he just couldn't believe it. And then I introduced him to many of my mentors and he did his own research. And the result of that was a story that I thought was excellent because I can't count the number of patients that sent it to me saying, oh my God, this is that thing you're always talking about. Yeah, so what is this thing?

So we talked about the LDL particle number. So it's this spherical thing, call it 20 nanometers in diameter. And it has a outer spherical structure that is made of lipid cholesterol, phospholipid. Inside it has a core that consists of cholesterol ester. So this is none. This is like the cholesterol without its bulky side chain and the triglyceride. And on the outside, as I mentioned, it has this one apolipoprotein called apob 100. So we'll just refer to that from now on as the Garden Variety LDL. Now a subset of these, and it's mostly, as we'll probably discuss, genetically determined and inherited in a co-dominant fashion, a subset of these have something else attached to

that apob. And it's attached covalently, so that means that it's not an ionic bond. It's an actual, in other words, it's a much stronger bond. It's a disulfide bond, which in amino acids and in biochemistry tends to be a pretty strong bond. So the APO B has this disulfide bond that attaches it to a totally different bipoprotein and it's called APO Little A. And this bipoprotein is made in the liver and it has a property that it resembles another molecule in the body called plasminogen. Now, I suspect that everything I'm about to say is going to not make that much sense until you look at the pictures.

This is one of those things where a picture says a thousand words. So what we'll probably do is, and that defeats the purpose of a podcast, I realize because people want to listen to this, but they don't want to miss the picture. But I think this is one of those things where it's worth looking up the picture. But this April-like protein A has a repeated folding structure. These domains are referred to as cringled domains. So we're sort of lost in a nomenclature of apolittle A and cringled potato chip folds and all this stuff and it's just like it's super complicated. But these repeating structures are organized by

cringled domains and there are five of them. Plasmidagen, that is, has five of them. APOA does not have the cringle one, the cringle two, the cringle three. It does have a cringle four that very much resembles Plasmidagen, and it has the exact same cringle five that comes from the Plasmidagen. So to distill that again, APOA looks like Plasmidogen and that it has Cringle Domain 5 and a Cringle Domain 4 that is similar, but it's the Cringle Domain 4 that has 10 sub-segments.

So you have Cringle 4, one, Cringle 4, two, Cringle 4, three, all the way up to Cringle 4, nine, and Cringle 4, 10. And if that doesn't have, you're looking at me and you're laughing. It's like, it's hard to believe we're talking about it at this level of detail.

But the cringle 4, 2 is where you see the greatest variability. And you can have a cringle 4, 2 with just a couple of folds in it. You could have a cringle 4, 2, with 40 segments that are repeating. And that determines the mass of LP, little A. And that's going to become, I wouldn't be telling this story if it weren't for some reason, in anticipation of talking about something else. And with the plaid's minigin and the cringles and the homology, in other words, how similar are they?

You're basically saying that if you were to look up, like if you were to look at the structures of both of those you could very easily confuse one for the other they look very similar. It probably depends on the similarity during the cringle four because the cringle four tends to dominate it so I don't want to give an answer that could be incorrect because I suspect it depends on the individual I think there are some individuals whose a poa looks more like plasm Engine because everyone's Plasma Engine looks the same, but the APOA is where we see the difference. So we're really dealing with two things, which is how many of your LDLs have those APOAs attached to them, and then what do your APOAs look like? And the what they look like is basically what do your cringle segment for sub-segment twos look like. Now it turns out that between those two factors, the one that probably matters most is the number of your LDL particles that also have this covalent bond to the apolittle A. In other

words, it's probably the number of the LDL- sorry, the apolittle A particles bound to the LDL particles through the apob, or the number of LPLitl A's that matters more than the mass of the LPLitl A. So on that note, I was thinking about APO B in that there's one APO B per LDL. And then with APO A, there's one APOA per LP little A, but not necessarily, not every LDL. But every APOA is on an LDL particle. Every APOA is on an LDL, but not every LDL has an APOA. And that's the

difference between individuals. When you look out at a population is the how many of their LDLs are rolling around with APO A's. Now, I don't think we'll get into it today, but if there's ever an appetite to go ultra deep on LP-LLA, we could probably talk about the relationship between APO E and APOA. So it turns out that as people may know, you have three different variants of APOE. You have APOE2, APOE3, APOE4. Of course, they combine in all six combinations that I'm sure everybody's familiar with. But as you move from the two to the three to the four, you see LP, little A, go up.

You see APOB, go up, and you see triglyceride go down. And this is a pattern that has been demonstrated over and over and over again. And what's interesting is why that's happening with respect to the Apo A. But I get I think that's probably more the seniors course rather than the freshman course. Yeah. On the note of the freshman course, just looking at it and thinking, so we're asking what is Lp little A, and if you're to look at how it's spelled out, it's capital L, lowercase P, parenthetical, lowercase A, and closed parentheses. And it's basically saying it's a lipoprotein with an APOA attached to it. Yeah, and if you were going to come up with an equivalency, you do three little parallel lines

as an equal line and say that's equal to LDL hyphen, little A or little APOA. It would be the long-hand way to write that. I don't know that anybody's ever written it that way in the literature, but that's just another way to think about it. Okay, so piggybacking on that, can you explain the difference between LP, littleittle-A mass, then there's LP-little-A cholesterol, and then there's the LP-little-A particle content. And then as you mentioned, there's the cringle domains, the number of cringles could also be called the different APOA isoforms. Can we quantify those?

How are those measured? Yeah, I believe the first way this was quantified, and again, this will be the type of stuff that I think would be really fun to explore with a guy like Sam Tameekis, who's probably the world's expert on this topic, and we should definitely make sure we get Sam on the show. I believe LP Little A Mass was the first way that this was quantified, and whether it was the first or not, I don't know, but what I can certainly say is it's by far the most ubiquitous.

I'm sure that 19 out of 20 times when a patient is having their LP little A checked, it is the mass that is being checked. Certainly, if a patient comes to me and they've been at least fortunate enough to have had their LP little A checked, it's a mass. I almost never see the cholesterol checked anymore. I think there used to be a company I believe called Athrotech that did the test. I think they got bought or at least that ass egg got bought

by VAP and now VAP does it. But I'll explain later why I don't think that's such a great test. And then of course there's the LP Little A particle number which is just the counting of it. So the LP Little A mass is directionally a reasonable test but it's not a great test. And the reason is it's measuring for particles that carry APOA,

it's measuring the mass of everything, which is the APOA, the APOB, the phospholipids, the cholesterol, the triglycerides, the dogs, the cats, whatever. It's measuring the mass of the entire structure. Now the larger the cringle, section 4 subsection 2, the more that mass is dominated by APOA. But you can see very quickly how you could be misled. You could take two people that have the exact same LP little AMAS. But if one of them has a very long segment for sub-segment two, repeat binding domain, guess what?

He's going to have a much fewer particle number, or more to the point. The person that has the smaller segment for sub-segment two is going to actually have more particles. And so those people are not at equal risk. It turns out that the guy that's got more particles is at higher risk. But when a patient shows up and their LP-little-A mass is really, really low, like less than 5 milligrams per desoleter, the likelihood that their Lp little A particle number is very high is really, really low. And back in the olden days, and by the olden days, I mean like four

years ago, before Lp little A particle number was measured, I used to actually look at both. I'd look at Lp little A mass and Lp little A cholesterol, acknowledging that neither was perfect, but basically coming up with a 2x2, which was if both were high, I knew you had a ton of particles, case closed, if both were low, we were after the races and high-fiving, and then when one was high, one was low, we would just sort of follow-up and test for reasons that we'll probably discuss later around things that could actually change LP, little A, as you marched down the field. But luckily, most patients were either double positive

or double negative and therefore you had a pretty good sense of where their risk was. You then asked about LPL Little A cholesterol. So that basically is analogous to measuring the cholesterol content of an LDL particle number. Except here it's measuring the cholesterol concentration of an LPL Little A particle number. And that, again, in isolation is not very helpful.

I am not an expert in clinical chemistry, but I've spoken with people who are, and it turns out there are some other technical issues with that test that renders it not entirely helpful and also misleading in its own way under certain circumstances. And it's for that reason that I really prefer looking at the L.P. Little A particle number, which even though it's reported an animal per liter, to my knowledge is not actually measured via NMR the way LDLP and HDLP were pioneered by LIPA science. It's a different assay, but nevertheless,

it is counting the apolittle A's that are attached to little apobies. And so you're getting a number of those. And for that test, we like to see people less than 50 nanomole per liter. When people are sort of 50 to 100, I put them in kind of a gray area when people are over a hundred or certainly over 125 Nanomole per liter. That's when I start to get worried because I often get asked this question The highest number I've ever seen on a patient is about 650 to 700 Nanomole per liter and I've got a few patients that walk around it 400 500 nanomole per liter

So the LP little lake cholesterol it sounds a lot like when we're measuring LDLC. So LP little, if you're measuring LP little a cholesterol, you're measuring the amount of cholesterol that's carried within the LP little a particles. And similarly with LDLC, you're measuring the amount of cholesterol that's carried within the LDL particle. Similarly, you would rather know the LDL particle. Yeah, and this is, this is actually what makes it so problematic, is it's even worse than the discordance between LDL, P and LDL C, because at least when you're dealing with LDL, you know the molecular weight. You don't know the molecular weight of LP-lidyl A.

This is actually the point I forgot that I wanted to make a moment ago. I remember once having a patient come to me with everything but the LP little AP, and I remember thinking, well, I used to be a smart little organic chemistry whipper snapper. I should be able to convert this from milligrams per desolate in to nanomole per liter.

And of course, anyone listening to this who knows more about chemistry than me, will remember that all you need to know is like Avocado's number and the molecular weight and you're ready to go. But of course, you don't know the molecular weight. That's the problem. Because the APOA's don't look the same, the whole calculation goes to hell in a hand basket. You can't actually calculate the molecular weight because of that cringlesub segment, the cringlesforsegment too,

because it's got such variability. It's not like you can say the molecular weight of sodium is X or the molecular weight of testosterone is Y. So with the APOA and how it comes in different isoforms, can you measure the APOA? Yes, but it would be for a given individual. That's the point. Yes, you could absolutely measure the molecular weight

of an APOA, but it would be like yours and mine would probably be different. So therefore, at least to my knowledge, and again, I don't want to speak out of turn because I'm sure someone listening to this is going to go, no, no, you knock all head. This is being done. But to my knowledge, this is not something that's done clinically. Whether it will be or not, again, that's probably a great question for someone like Tom Day's spring or Sam to me because they're one of those guys.

But I think that today, the best test we have is the LP little A particle number. And there's a proxy for it, but I'm guessing we'll talk about that later, which is you can also measure the amount of oxidized phospholipid. If you normalize that for APOB, you're getting almost a one-to-one mapping of that, because there's another interesting little, it's not a trivia point because trivia tends to be irrelevant. This is actually quite relevant. Apolittle A has lots of lysine, the amino acid lysine, and lysine really binds oxidized moieties. Now, apob does not contain much lysine at all, and therefore, APO B is not particularly

effective oxidized moiety scavenger, but APO A is. And so, if you think about your rolling around as an LDL, now you got a tail thrown on you, which is called an APO A, right? You got your little disulfide bridge attached to APO B, you got your APO A tail. Only you can see what my hands are doing right now. That's a great idea. Yeah, this is awesome right here.

We're smiling. We'll have pictures. Yeah. The pictures are definitely worth a thousand words. Yeah. As you can see, the cringled domains, and if you have a longer, you can see like longer tails and shorter tails.

Yeah, it all makes sense. And then once you've got your tail in place, now you start to fill that tail up with all these oxidized phospholipids. You can start to measure. If you measure those phospholipids normalized for APOB, you're getting a pretty good proxy also of that. And by the way, this may actually explain, and this is one of the questions, like, you know, when we get Sam on the show, this is one of the questions I want to ask him is just taking a step back from all of this. Sometimes you clinically know when a person has an elevated L.P. little A before you take any blood out of them. These are the patients who don't seem to

fit the classic picture of someone with premature heart disease in the family. Nobody's overweight, nobody's diabetic, nobody's smoking, or even if they are, the disease seems to come prematurely, seems to come out of nowhere. They also tend to, you know, if you ask enough, you might even see that somebody has a orthostinosis. And you just know the answer before you get there, especially if you have their family tree and you can trace it and you can realize that whatever is happening here is coming through dominantly.

Is that something, it's a premature cardiovascular disease? Is that a clinical term? Is there like a cutoff when you call it? Yeah, I mean, I think loosely we would say someone who's having a major adverse cardiac event before 60 would be premature. Of course, I have a different definition of that. I would think a major adverse cardiac event before 80 is premature, but I think someone who's having any major adverse cardiac event

mace before the age of 60, I think anybody would consider that premature. So, what I've never been able to figure out is, you know, that patient of mine that had like an LDL, an LPL of a 650, family history is not outrageous. You know, when people get heart disease, they get it in their 70s. The patient of mine who has the 500, I've tested this patient's family. I know where it came from, I know which parent it came from, and the burden of disease is modest. So, there is something else going on here. And it's just like the case with, we know that LDLP alone is not the issue.

We know that it's just one factor. And similarly, not all LP little a's must be created equal. And so the question I'd want to get into with the next word on this is, does it have to do with the lysine binding domains, the affinity for these oxidized moieties? Is there some feature of one person's versus another's that lends to a more aggressive oxidation within the sub-initial space or greater retention or something like that. I think that gets into why do we have LP-little A? So what would be the evolutionary basis? What's the function of LP-little A? Like, it can't just be some hell particle that's just trying to kill us.

I mean, in theory, it could, because it kills us through basically three mechanisms that don't tend to kill you young. So if you were taking a purely evolutionary standpoint, I think sometimes bad things track. But it turns out that even like APOE4, which in today's environment doesn't seem particularly protective, APOE4 was quite protective against parasitic infections in the CNS. And hell, up until a few years ago, that would have been a pretty good thing to have. Of course, now that we can live long enough, that upside isn't worth the downside of an increased risk of Alzheimer's disease. So L.P. Little A clearly does two things, better separate, and I think we could argue, at least theoretically,

that it would have provided a benefit evolutionary. The first is, if you go back to what we talked about, you have this great homology to plasminogen. And plasminogen being a clotting factor means that people with elevated L.P. little A tend to have what's called hypercoagulability. So they have an ability to form blood clots better than someone who doesn't. Now in today's environment, that's not an advantage because most of us are not in an environment where bleeding to death is a major concern. But you can imagine 50,000 years ago bleeding to death would actually be a significant concern.

So I think these people would have had a trauma advantage with respect to, and I'm sure you could probably pose many benefits during childbirth. When I think about what I saw in the OB-GYN rounds, how many times was a woman bleeding so sufficiently that she required blood clotting products? It's not unheard of. You think about the benefits this could have had all the way from birth, the brilliant of a child right up until getting scratched by an animal or whatever. The second benefit is more of a speculation, I think, but it's probably that going back

to those lysine binding domains that if you're in a relatively low oxidative environment and your LP little a's, know where to go when they're done, which is to the liver, and where not to go, which is the coronary arteries in the aortic valve, they're actually amazing scavengers. So I'm sure somebody out there's got better data on this or has data period because I'm obviously speculating, but you could make the case that being able to have more particles that can scavenge more of these oxidized phospholibids and oxidized moieties and take them back to the liver, which is the ultimate place of clearance for the LP little A, which is a totally safe place to take these things, that

would pose an advantage. And it would be the case today that maybe we're in a higher inflammatory environment. And maybe we've gone too far. In other words, maybe we're overwhelming the system's ability to clear it. And on top of that, we may have other risk factors, hypertension, hyperinsulinemia, other drivers of inflammation that are now giving these LP little a's another place to go, which is, yeah, you're ultimately going to end up at the liver, but like 6% of you are going to get stuck in the subendithial space and wreak havoc. And on top of that, you're doing a way worse job than the LDLP because, you know, the LDLP when it gets there is bad enough, but the

LPLLA is now dragging all that oxidized crap in there with it. So the next question is, what is the problem with elevated LPLLA, or what are the problems with Lp little A elevated. So basically they fit into sort of three categories, the first being enhanced atherosclerosis. The second, I don't know which by magnitude would pose a bigger threat, but probably aortic stenosis given the severity and then the third being enhanced venous thrombosis. So what do those things mean? So basically more atherosclerosis, more aortic stenosis.

I believe about two thirds of the cases of aortic stenosis are explained by elevated L.P. Little A. So you have four valves in the heart and one of them is called the aortic valve. That's the valve that separates the left ventricle from the systemic system, so the proximal aorta. So that valve is under more pressure than the other three valves by a long shot, because it's the one that's directly

in front of the most powerful chamber of the heart. That valve has three leaflets, it's a tri-leaflet valve. And it seems that LP-Little-A has a particular affinity for going there and inducing bone forming proteins to create calcifications. And when that valve loses its suppleness and it becomes calcified, you get basically a blockage of that valve called a stenosis. And so this condition of aortic stenosis is very problematic. One of the earlier signs in the blood that somebody has aortic stenosis would be signs of swelling or enlargement or dilation of the heart. And there are blood markers like brain-naturitic peptide, BNP, or pro-NTBNP that are actually

used quite frequently in ERs to assess patients very quickly for cardiomyopathy or cardiac failure. And so that's one of those things that we like to look at. And if I see a patient with L.P. Littel-A, I'm always screening them for aortic stenosis out of the gate. I don't care if they're 30 years old. I mean, many of our patients are in their 30s and 40s, but if they have an elevated L.P. Little A, we're doing echo at a minimum and preferably cardiac MRI, which is much more accurate

to both look at the morphology of the aortic valve and get a very accurate gradient of pressure. And then sometimes you'll get patients, I have a patient who has a bicuspid aortic valve, which is going to be eat by itself that's predisposed to aortic stenosis. And he also has a very elevated L.P. Little A, about 250 or 300. So even though he's only in his 30s, he gets a cardiac MRI annually. And he's already showing a pressure gradient. So, you know, I've explained to him that he is going to need an intervention at some point in his life, but the good news is we're going to do it long before he experiences any strain on his heart muscle. And the good news again for patients today is this stuff's going to be done interventionally

and not via open heart surgery as it once was. On the atherosclerosis side, I think the Mendelian randomizations, the GWAS, and the epidemiology, all tell a very similar story. I suspect that it's both its ability, it's probably in all of the above when it comes to Y, meaning it's, are these particles more likely to enter the subend-ethereal space? I don't know why that would be the case. Are they more likely to be retained? Probably because they have that whole big cringoloxidized moiety thing there. Are they more likely to kick off an inflammatory response? Very likely because of what they're dragging in with them. And then on top of that, to have the

pro-thrombotic component, I suspect is what's driving the increase in the risk of atherosclerosis. But in truth, we don't have definitive proof that LP-little-A is a more atherogenic particle. And you and I were talking about this the other day that there is this paper that actually was looking at patients with post-MI's and even suggesting that, well, everybody who

has an MI has a rise in LP-Litelae, and we'll probably get to that later why we think that might be the case. But the question posed is, well, maybe LP-Litelae is the result of atherosclerosis and not the cause of it. I don't agree with that because many post-MI patients don't have an elevated LPLLA. And I think a better explanation for that is that LPLLA also acts as an acute phase reactant rising with inflammatory responses. But probably not until the anti-sensoligo nucleotide trials complete, will we actually know the

answer to this question? Because really without a clinical trial, you can't actually infer cause and effect the way we can with other aspects of atherosclerosis, like the LDL particle or inflammation where we have elegant prospective clinical trials that create a relationship between cause and effect. The last thing that I guess I mentioned was the thromboembolism. So I used to have a practice of putting everybody with an elevated APO-A, LP-L-P-L-A on a baby aspirin, just to combat the effect. It turns out that that was probably an oversimplified approach, and that there's only a subset of

people for whom aspirin counteracts the effect. So unfortunately, this is still one of those things, where I don't think we have a great answer. I do take DVT-proful axis, so deep vein thrombosis, prophylaxis, prevention. I do take it more seriously in the LP-little-A patients and there are certain strategies you can take around flying.

There's actually a commercially available product called FlightTabs, which you can buy on Amazon. I was, remember when we did the research on this? I was blown away that you could buy these things on Amazon because they're actually quite potent, but I do recommend that people with elevated LP little A, if they're on really long flights. And again, I'm not recommending that for people who are listening because I can't, but I certainly recommend to my patients to a subset of them that we're particularly worried about, that we look at either pharmacologic agents or even an OTC agent like that as a way to reduce the risk of these types of events.

So do we know how much elevated LPE, little A, is associated with these increased risks? If we're looking at the epidemiology, what are the associated risks with cardiovascular disease? So with the aortic stenosis, the hazard ratios are anywhere from two to four, depending on the studies. And I think they probably median ends up being, you know, roughly two and a half. With VTE, with the venous thrombome embolism,

I think the hazard ratio is about three X. And again, it's important to put this in perspective. We've talked about absolute versus relative risk. So when you talk about a 3x risk of something that occurs like 1% of the time, that means you're going from a 1% absolute risk to a 3% absolute risk. So in other words, it doesn't mean like if you're listening

to this and you have an LBDLP little A, you need to call an ambulance to drive you home because you're afraid you're going to have a pulmonary embolism. And similarly, a hazard ratio of two and a half, three, even four on aortic stenosis. As I said, it probably explains about two thirds of the total volume of aortic stenosis, but it doesn't mean that every patient who's got this is going to get it. I think in the case of that one patient of mine, his bicuspid valve is just a setup to make things worse because he's now got a double whammy on that. And when it comes to atherosclerosis, basically you see odds ratios of about two to four,

depending on the amount. So it's it's it looks like a pretty good dose response where it's sort of below about 30 or 40 milligrams per desoleter because unfortunately all of these studies are done with Lp little a mass and not particle number and I can't really convert that but we believe that that's probably about 50. That's probably, you're going to get comparable in the 50 to 75, an animal per liter is this sort of safe zone, where it's relatively flat, and then it starts to uptick pretty swiftly.

So by the time you're at, call it 200 milligrams per deciliter, you're at about a 60% increase. Now, if you stop for a moment and think about that, what should you be more afraid of? A 3X hazard ratio for VTE or a 1.6 hazard ratio for a throuschlerosis or a 2.5X hazard ratio on aortic stenosis. This is like the advanced clinical epidemiology question,

I think the answer is the 1.6 on atherosclerosis is by far the most disconcerting because atherosclerosis is infinitely more prevalent. So a 60% increase in risk on something that is going to kill a third of people is a big f-ing problem. Whereas a 3% risk on something that's going to, you know, ding 1% of people, yeah, we'll manage it, but that's not what we stay up late thinking about. And even for that particular individual that has that risk profile, that if they look at their absolute risks, that probably bumps up their absolute risk the most with cardiovascular

disease. Yeah, we're screening for aortic stenosis, not because I necessarily think it's even, you know, at the population or societal level cost effective, but at the individual level, we're not going to let that kind of stuff slide. But if you were to think about this at the population level, the thing we have to be most concerned of is somewhere between one and five and one and ten people, and in some cultures it's even higher, in Southeast Asians it's even higher, are walking around with these little time bombs.

And to the point of Anaheim's story, I'm still shocked at how many doctors don't understand this. Now look, if you're a radiologist or a dermatologist, that's okay. I don't think you need to know this. But if you sit anywhere on the front lines of medicine, if you're a family physician, if you're a GYN even, because for many women, their GYNs become their PCPs, the primary care physicians. If you are anywhere in the crosshairs, if taking care of a patient where you have some input into how they lower their

risk of cardiovascular disease, and you don't understand most of what we're talking about on this podcast, I worry that you're missing an opportunity to help patients. Okay, so another question that came in, I think you touched upon it very quickly, is what is the prevalence of elevated LPLitLA? Probably, what is elevated LPLitLA? How is that determined? Well, to my knowledge, everything that's done on this that's published is based on the LPLitLA mass, not the particle number, but the US levels define normal as less than 30 milligrams per deciliter. The European Atherosclerotic Society defines normal as less than 50 milligrams per deciliter.

And I believe both the UK and Germany consider anything over 60 sufficient for state-covered aphoresis. Aphoresis is a type of treatment where a patient has a very large IV put in one arm, typically about a 14 gauge, and blood is taken out, run through a machine machine that spins at a certain frequency to generate a separation of the plasma and you can basically fractionate the plasma and identify something that you want to remove. So back when I was at NIH, I used to volunteer for aphoresis every four weeks to donate lymphocytes.

And then they basically put everything back that once they strip out the piece they want, but you can actually do a ferrisis and remove the apolittle A. The problem is the frequency with which you have to do it is staggering, because the half-life of these particles is a matter of days. So these patients would undergo a ferrisis potentially twice a week. So that's obviously a very difficult way to be tethered. So we got into it a little bit there. How is that normal LP little A treated or dealt with?

So you just got into the a ferrisis. Other other therapies currently available? So a ferrisis is that's something that we just really never resort to or very rarely resort to. And then certainly now that PCS canine inhibitors are on the market, I think that A4esis is becoming probably less and less utilized. Historically, the agent for treatment has been Niasin.

Now, Niasin's got kind of a checkered history because it's known to lower APOB. So you take Niasin, your LDL goes down. And this is a super contentious topic in lipid circles. But the question is, does Niasin save lives? And depending on how you look at the trial data, the answer is maybe or no. It's like a wonder drug.

Theoretically, right? It lowers LDL. It HDL goes up. LP a little A, might go down. Yep. So on paper, it looks, at least up to LDL. HDL goes up. LP a little A might go down. Yep. So on paper, it looks at least up to that point. It looks great. Right. That's exactly right. It does three things that we historically know when they happen. Good things should happen. LDL, particle and cholesterol, APOB, all go down. HDL cholesterol goes up. Although I would argue that that that's not a good thing. I think we have

a pretty good sense of why raising HDL cholesterol inorganically, meaning pharmacologically, is not going to be good. And it lowers LP a little bit by probably a third. So, C-tep inhibitors? Yeah, exactly. Just times the charm. I think we're waiting for number five. Yeah. Yeah. But it turns out that in the trial that basically doomed Niasin, the trial probably wasn't designed that well, in that they were giving Niasin to patients who were already on a Maxto statin and looking for the HDL increase to see if that was adding benefit. So, you basically get lipidologists in two camps. And actually, it's not, it's quite evenly split, at least in my narrow sampling of smart lipidologists,

where you get some who say, niacin should never be used. And then you get others who say, look, it's probably not a great drug, but if you have a patient who can't take anything else, it's still a good drug. And I know lots of lipidologists who are still putting LP little A patients on niacin. Even though there are no data to suggest

that that will save their lives. But I got to be honest with you, I'm not convinced that that's necessarily a bad thing. I generally don't. I now move to the third thing, which is the PCS K9 inhibitor. But I guess before I do that, I should explain statins because everybody's probably saying where to statins fit into this. And it turns out, statins don't clear LP little A, which is kind of counterintuitive if you know how statins work.

So statins work via two mechanisms, what we call sort of the direct and indirect mechanism. So the direct mechanism is that they inhibit HMG-CoA reductase, which is an enzyme that catalyzes one of the early steps, if not the first step, I believe, of cholesterol synthesis. So if you're making less cholesterol, you would have less cholesterol, there would be less cholesterol to carry around. You could require fewer lipoproteins. But that's not really the main way it works. The main way it works is that the liver in response

to the statin upregulates something called SREBP2. And when that thing gets upregulated, it puts more LDL receptors on the surface of the liver. This SREBP2, which I'll just abbreviate for short, is called the sterile regulatory element binding protein. It basically says, hey, the liver is getting less cholesterol, and it wants more cholesterol, so I'm going to put more of these LDL receptors on my surface to pull more in. I didn't know this until recently, but one of the other things that SREBP2 does is

it actually produces more PCSK9. Now, PCSK9 is a protein that degrades LDL receptors. So it's actually a bit of a check and a balance. So you have more LDL clearance because of more LDL receptors, but you also speed up the rate at which those LDL receptors are degraded. So this statin is causing these two indirect effects, but the net tends to be an enhanced clearance of the LDL particle, the APOB particle, and therefore a lowering of the LDL cholesterol. But it doesn't lower LP.lA.

And if you're listening to this, and you remember what we talked about at the outset, you're probably thinking that doesn't make sense. LP.lA is just an LDL with an APOA on it. Why wouldn't the LDL receptor clear it? Because if the LDL receptor clears it, it should also go down. I asked Tom Dayspring about this because a really interesting paper came out a few weeks

ago that actually tried to explain this. And like all good papers, it ended up leaving more questions than answers. The best explanation that I understood from Tom was that LP Little A will get cleared by LDL receptors eventually, but it's just the last in line. So after the LDL is cleared and the VLDL is cleared, then you might get to the LP-little-A. But the problem is, you never get there. So maybe in theory, if you increase LDL receptor expression enough, or if you could knock

out PCSK9 and offset the second piece of what the statin is doing, the statin would work. And it turns out that that is largely what this paper showed. And what we've always known, which is when you combine a PCSK inhibitor with a statin, you actually do get a reduction of LP-little A. Whereas a statin by itself is anywhere from no reduction to in some studies an actual increase in LP-little A. And PCSK-9 alone also lowers LP-little A. So to be clear, PCSK-9 inhibitors are not FDA-approved for the use of lowering L-little-A. But those of us who prescribe these drugs, both for patients with other indications and

with LP-little-A, generally acknowledge that we're seeing about a 30% reduction in LP-little-A. Sometimes as high as a 50% reduction in LP-little-A when patients are taking PCS-Canine inhibitors with or without statins. And that also probably speaks to the fact that we know that LP-Litelae is cleared by different receptors. So its primary receptor is probably LRP2, but it's also probably cleared somewhat by VLDL receptors, and even something called SRB1, although I'm not sure of that, and frankly, I don't know that anybody is. So that what the PCS K9 inhibitor is doing is it's inhibiting PCS K9, and therefore,

inhibiting the protein that degrades not just the LDL receptor, but these other receptors that clear LP little A. Interesting. I was just thinking about something. On statins, so oftentimes I'll read in the papers, just a backup for a second too. I often read in the papers, LP Little A, the words mysterious, unknown,

like in some ways we're in our infancy in understanding this. But I think in one of those papers, Simeaqus looked at the effect of statins, not only just statins in general, but different statins, a torvistatin, pravistatin, pative statin, live-alow, a risuvistatin, and simvistatin. I think maybe that covers all the statins.

If I'm just looking at his data, the LP little A actually looks like it's trending up on statins. Not only that, the oxidized phospholipids to APOB are also going up. Is there any explanation as to why the thing is to be elevated? Yeah, because the APOB is probably going down. It's probably that you're lowering the denominator. Got it. That's my guess.

What's clearly acknowledged is that when you give a patient with elevated L.P. little A a statin, which we do, absolutely, it's not to lower the L.P. little A. It's to lower the L.D.L. So actually, I'm glad you brought this up because I didn't, I sort of missed the punchline in all the detail. At least one of the punchlines is, how do we treat patients with elevated L.P. little A? Well, we're probably not going to give them ferrisis. If they can't afford to buy a PCSK9 inhibitor because it's certainly not going to be approved, you have only one other choice, which is to actually have two other choices, but I'll get to one in a moment.

It rarely works, but it works occasionally. But your real issue is you have to give them a statin because you now have a new LDL target. So my LDL target, when I say LDL, I'm always referring to LDLP. My LDLP target is the 20th percentile or lower for every patient. But how much lower you go than that is a function of other risk factors. So are we talking about secondary prevention? What's the family history? Are they insulin resistant? You know, while there's other factors. But a patient who's at, got an elevated L.P. little A immediately falls into the category of all things equal,

they're at the 10th percentile or lower. And so you will often need a statin to get them there, not always. I have some patients who don't need a statin to get their L.P. little, their L.D. L.P. down to the 10th percentile. But they're the exception and not the rule. So that's where the, I don't want to, I don't want people to get the impression that if you have an elevated LP little, you shouldn't be taking a statin.

Now, it's quite the opposite. You probably should be taking a statin, but just understand that the statin is there to control APOB and not LP little A. Okay. And I don't know if we have enough ammo to cover this, but hormone therapy estrogen, I think it's been shown to lower L.P. little A. I didn't know that actually. This is an up-to-date, which is a nice service that compiles a lot of this information, almost like a review, systematic review,

and they have a section on lipoprotein little A and cardiovascular disease and lipid lowering. And one of the things that they noted was estrogen replacement therapy reduces L.P. little A levels by up to 50 percent. Maybe a couple of references there. An effect that was somewhat mitigated by concomitant progesterone therapy in some reports. I don't know if that's a women's health initiative, so we're probably dealing with different variables, but not the peppy trial.

However, the clinical role for hormone replacement therapy is uncertain and it is not recommended for cardiovascular disease risk reduction. So if that HRT topic wasn't compelling enough to go over, I think this is another reason, another just wrinkle to throw in there. Yeah, I'd like to understand that better. That strikes me as a bit too good to be true, frankly, because certainly there are, I mean, if that's true, that's one, it suggests it might only be, so I guess the question I would want to know is, does that imply that women who go through menopause wouldn't they see an increase in LPLitlae? All things equal if they did not receive HRT? That believes so.

Yeah. I'm going to go and look at the LPLitlae levels of my patients who have gone through menopause while under my care, but nothing jumps out at me. There was one other thing we didn't talk about, which is what's on the front lines here in terms of really interesting stuff, which is these things called ASOs, which is really the first treatment

that is designed specifically to lower LP, LLA. So the ASO stands for anti-sense oligonucleotide. So these are molecules that disrupt protein synthesis. So I can't remember exactly where they ask. I think they act after the messenger RNA between messenger RNA and translational RNA, but maybe they act between DNA and messenger RNA. I should know this. I'm sure there's like, I'm sure that's a very well-known obvious fact that I'm just forgetting. But the point is they disrupt the synthesis of APOA, which is occurring in the liver. So this is a drug that goes right to the heart of L.P. Littelae. And I didn't say this earlier, but it's worth pointing this out.

When you go through my whole Brigham-er-Roll on why do statins probably not decrease LP little A. It doesn't appear that anything that's going to lower LP little A is going to do it on the catabolism side, meaning the breakdown side. It appears to be on the synthesis side, the making side. And so while the monoclonal antibody is like the PCS K9s also increase degradation, they reduce the synthesis. They're actually reducing the synthesis of apolite and the liver as well. So these anti-sensologonucleotides go right to the heart of that.

And they directly stop the synthesis of apolite and therefore you just have your garden variety LDLs. These drugs have been shown to have safety and efficacy, so they have concluded phase one and phase two trials, and they are slowly enrolling in phase three trials. I think three years ago I said they'd be done in five years, three years later, I think they'll be done in five years. Consistent. Yeah. The frequency distribution figure that will include somewhere, it shows effective

anti-sense oligod nucleotide and it says around 70% to up to 99%, so it could potentially wipe out, virtually wipe out LP. Yeah, no, even somebody who's got an LP little A of 200 can be normalized. I'm a little leery of wiping out something entirely. It certainly suggests that if you have this ASO, you can test a hypothesis in terms of LP little A lowering therapy for sure. Well that's what I was referring to at the outset, which was until this trial is done, I don't think we can definitively know the answer of what is the true risk. How do you quantify the true risk? How do you quantify

the true risk of LP little A? I think we got through a lot of the major questions. This is awesome. We didn't have to go for four hours. There's a bonus question. We're in the bonus round. There's some other stuff we can talk about too as well. I think getting into the oxidized phospholipids, how that works, and the LP, PLA2, we could get into. But one of the things that I was thinking about is that with lipoproteins with LDL, with HDL, even triglycerides, you have some tools in your arsenal, just in terms of, let's call them behavioral modifications or things like that. If you challenge somebody or somebody said, I need to lower my triglycerides in 30 days

or else, you could probably do that through diet. Absolutely. I mean, triglycerides by far the most sensitive thing in the blood, as far as lipoprotein lipid-related amolecules to dietary intervention. Yeah. In theory, it sounds like you can play around with a lot of the lipoproteins, actually a lot of the markers, biomarkers, but it seems like with LP-l- LP little A doesn't seem like it can be modified all that much by lifestyle. Is that right? Or at least it's the correct thinking. No, that's absolutely correct.

And probably the reason for that is as we just learned from the PCS K9 statin comparisons, directionally speaking, there are two things that are driving LP little A, how much you make and how much you clear. But the game seems to be one and lost on the how much you make front. That how much you clear seems to be a second order thing. Now when you look at LDLP, just a contrast it, never mind triglycerides. When you look at LDLP, you go back to four things that determine the number of those particles. Three of them have to do with how much you carry. One of them has to do with

how much you clear. So three about the cargo, one about the port. How many triglycerides do you have? How much cholesterol do you synthesize? How much a sterified cholesterol or non-asterified cholesterol rather do you reabsorb in the after it passes through the biliary system in the enterocyte and then what's your LDL receptor profile look like primarily in the liver but also in the gut. Now we just established you can clearly lower triglycerides through nutrition. So you got somebody walking around with a triglyceride of 200 and an LDLP of 1600 and you

do nothing but lower their triglycerides to 50 while I can't predict what their reduction is going to be It's likely going to go down and so that's a lifestyle intervention and that clearly does things and it turns out that we know that diet is also going to lower or raise Certainly it has an impact on LDLC that is known But it also can have an effect on LDLP through cholesterol synthesis and absorption. Now, I think that that, I think that the relationship there is much less clearly understood. I've speculated about what what I see occurring. There seems to be a subset of people who, when they consume high amounts of saturated fat, see a really significant increase in cholesterol synthesis, I think Tom Deisbring has written

a really eloquent piece on this. So if we can find it, if it's publicly available, we should link to it because I think it's a great piece on the hypothesis around why certain people in the presence of high saturated fat just start making much more cholesterol. And then of course the contentious topic is, doesn't matter. I don't know if we know the answer to that question, but that's a point.

I was among them at one point. I think you get an NMR, and it gives you your LDLP count. Is it in animals? It's really. The animal per literate. And it actually reminded me of Fletch and Gillette collecting rent, I believe.

And he picks up one of Gillette's letters and he says, oh, a letter from the Oakwood Potency clinic. We're sorry to inform you we can't process sperm counts as low as yours. So in the case of this NMR, I get the test back. And you probably know the number. Maybe it's like 2500 or And you probably know the number. Maybe it's like 2,500 or... The upper cutoff is 3,500. 3,500 and it has one of those awesome greater than signs. It's just greater than 3,500. It's like, we're sorry our machines can't process

LDL particles as high as you. And I think during the time I was doing an experiment where I was eating a lot of my calories were coming from saturated fat. It was probably supposedly a well-formulated ketogenic diet, but maybe some of us coconut oil, butter, etc., but it was heavily loaded with saturated fat. I would love to read that article. It's one of those things that's gone around the circles. Is it good? Is it bad? But it is definitely something that's seen, you think?

Yeah, I mean, given how amazing we've made progress on this and how we've barely been out for an hour and we're almost done, I mean, I'm happy to expand on this just based on my observations because I'm sure someone's going to end up asking anyway. I've probably seen this now at a dozen times where either someone comes to me already on a ketogenic diet or we put them on a ketogenic diet and they develop this change in their lipids. Now, there are some people who will argue that it's transient and it's going to go away in, you know, a year or two years or whatever. Maybe so. There are others that argue that it's irrelevant, that the increase in the cholesterol

synthesis and the LDL cholesterol and the total cholesterol is actually a good thing and there's some reason that they offer for that that I don't quite buy or understand. But my view is all things equal until I know better. I'm going to assume that high LDL is probably problematic and more importantly the point is are there ways to reverse the diet and reverse the condition and figure out what was the component within the diet that was doing it? Was it the total fat? Was it the subset of the fat, et cetera?

And in God, all but one of those cases of maybe a dozen, when you just replace the saturated fat with mono one saturated fat, even if they stay consuming a very high fat diet, the problem goes away, which has not that that's proof of anything, but that really suggests to me that in those patients, they're getting more saturated fat than they can process. Because I had one, the first patient that I ever went through this with, my first thought was, dude, we got to take you off this ketogenic diet, man. We can play keto camp all day long, but I'm not that comfortable with these numbers. And he was like, but I'm not that comfortable with these numbers. And he was like, but, you know, I'm not going off a ketogenic diet.

Like, you know, and he had all his reasons for why he, you know, felt better and performed better and all those things. So I said, okay, well, then we could keep you on a ketogenic diet, but we got to take, I want to see what happens if your saturated fat goes from 75 grams a day to 25 grams a day. And to do that, you're going to get really familiar and friendly with olives, olive oil, and macadamia nuts. And he's like, I don't care. He was a young guy and he was, he'd do anything. He was kind of like a robot. And so sure enough, in like eight weeks of that change, his LDLP went from greater than 3500 to 1200. Same thing. I had a lot of guacamole,

macadamia nuts, they replaced the saturated fat, and the numbers came down. And everything else, giver take, HDL, triglycerides, all that stuff, sort of in the same ballpark as before, but that LDLP came down.

Yeah, and I gotta tell you, I mean, I'm sure that this will kick up a storm of people with, you know, very, very strong, religious-like views on, oh, there's nothing wrong with an LDLP of 3,500 and, you know, again, I don't buy it. Because the other thing I don't buy is a lot of those times you'll see the oxidized LDL go up as well. And how are we in the middle of Manhattan and some knucklehead dress like

drag racing on 79. I don't get that. It's the most gratuitous. I think we should get involved. For the engines, he likes cars. We just need some jackhammers right now. So yeah, when I see the oxidized LDL and CRP go up as well Which I often see with that then I think you know there's something else going on here This isn't just a cholesterol synthesis problem. It's an inflammatory problem. Something is not here and look I wasn't that guy. I mean I probably ate when I was in ketosis, that's probably eating 200 grams a day of saturated fat. Maybe not quite that much, maybe 150, but I was eating a lot of saturated fat.

But I didn't have any of those response. You know, my CRP was really low. My trig were non-existent. My LDL particle number was probably around the 50th percentile, you know, 12 to 1300 animal per liter. Like, I just didn't have any of those findings. And again, I see a lot of people who don't have those things. So I don't know why.

Some people have these paradoxical reactions, but I also don't think it's safe to ignore them just because insulin levels have gone down. And going back to oxidize LDL. If you saw oxidize LDL going up, my newbie understanding of this is that oxidize LDL is, in a sense, Lp.L.A. So that Lp.L.A. Well, that's oxidized phospholipid. Yeah. So the Lp.L.A. picks up the oxidized phospholipids from the Lp.L.A. protein, from the LDL.

Yep. And then that Lp.L.A. particle itself is now carrying the oxidized phospholipids. But that's not a oxidized LDL. No, the ox LDL assay is different from the ox PL assay. The ox LDL assay works independent of how many APOAs you have. I like to see that number below 40. Again, I think the lab likes to see it below 60, but I like to see that along with the LP PLA2, which you alluded to earlier, these are really local markers of inflammation,

and those are important because if you see a patient with an elevated C-reactive protein, should you be concerned about it? I mean, yes, probably, but the question is, is it cardiac specific or not, you can't really tell. So that's why looking at fibrinogen and C-reactive protein and homocysteine and LPPLA2 and oxidized LDL help you get a better picture of if there's inflammation, how much of this do we think is going on locally at a vascular level versus some play cells?

You see this all the time in people who have food insensitivities and things like that with respect to the Fibrinogen and the CRP. Yeah, it's probably throwing those figures. He just mentioned that the LP PLA2 and LP little A and then ox, then there's another thing called it's the oxidized phospholipids over the apopie. And in that paper, it's a 2007 paper and I think Semeacus is the last author on it as well. He's all over the place. They show the hazard ratios and it as well. He's all over the place. They show the hazard ratios, and it's a J-curve,

so that the very, the lowest, they call it the sex style, so they have, they partition it into six different groups. And on the lowest, if you look at the hazard ratio, the hazard ratio is about two, so the risk doubles. If you have very low LP little A. Does he explain why he thinks that's happening? I'm not. I wonder if it's an artifact of APO B being higher.

Possibly. The denominator going up would shrink the total number. I'll have to look at that. Is there any other LP little A questions that came through the interwebs? Not through the interwebs. Well, then I think we can bring to a close our inaugural chapter one, chapter one, vote on what you want to hear about any final words Bob.

It's interesting. I knew about LP little a a little bit prior to on HOD's article in January and after doing some digging. There's some other thoughts about this stuff that I'm sure we'll get into down the road, but it's that proverb. I think Nassim Taleb quotes, he says this is a Venetian proverb. It says the further from the shore, the deeper the water. And so the more you dig into this, the more you learn the less you know in a sense, you sort of expose yourself to a lot of unknowns. So it's absolutely fascinating. And I think it also gets to how most physicians don't even know about this stuff and you alluded to it in one of our conversations previously that there's this lag, you know, in terms of the medical knowledge and what's the accepted wisdom and the guidelines and things like that. So I think LP Little A is one of those cases that's just it's fascinating and it's the more you learn the less you know, but the more you want to learn. Yeah, and we're really, as you pointed out earlier, in our infancy of this thing, yeah,

if we were just going to put numbers to it, I think five years ago, I had 50% understanding, like one unit of understanding to two units of perceived total volume of content. Today, I'm at 10% understanding, 10 units of understanding to 100 units of perceived total content. So has my knowledge gone up in five years? Yeah, it's gone up 10 fold. The problem is my appreciation for how much information is out there on this topic has gone up 50 fold. So my relative insight has actually gone down five fold. What is that? It sounds like the Dunning Kruger effect a little bit.

It's that when you know, like just like the surface level, that's when you're the most confident. You think you know everything. And then as you learn more, it's like that Dunning Kruger, it's like a you. And then your confidence in your knowledge goes down. Hey, welcome to the 24 hour news cycle, cable TV, and Twitter, man.

I don't know if that's done in your Kruger, but it's on the left side where everybody's very confident. Well, in summary, I'd say the following. If you're listening to this as a patient, you should demand that your LP little A, B, known, it's not negotiable, especially if you have a family history of atherosclerotic disease. If you're physician, and this is your first exposure to it,

I hope that we've invited you to learn to it, I hope that we've invited you to learn more and I hope that we've provided you with enough information that you're sufficiently curious and we'll certainly make a point to link to this some of the what we think are more relevant things. Worth noting, I think about three days ago, an ICD-10 code was actually just issued for elevated LP LLA. That's a pretty big deal. That's like one of the signs that it's not some little nerds only thing. Once you get your ICD-9 code issued or ICD-10 rather, and if you are neither a patient nor a physician, I don't know what you are.

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