Hey everyone, welcome to the Pia Rataea drive. I'm your host, Peter Rataea. 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 pia RataeaMD.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 post-emapazal 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 paddy 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 way. We're going to talk about what the heck it is, why you should care, why it's problematic, like a protein, what some of the potential treatment options are, and what's on the horizon. Now I got to 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 two, zone five, like that kind of stuff, you've just got to be looking at a picture to understand it. 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 Lele. 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 Lele.
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.
I watched four. Well, seven doubles, probably seven doubles, rest of us. That's true. Yeah.
Yeah, that's impressive. So this is the first of what I suspect and 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 Lele or do you want to know about hormone replacement therapy in post-menopausal 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 Lele, which kind of bums me out because I actually really wanted to talk about HRT.
But next time we throw HRT in, we're going to put it up against something like Batchyball. And hopefully HRT comes out ahead and we can talk about it. I think you have been accumulating a bunch of questions that people have also started sending in about LP Lele and I think that's what we're going to talk about. Absolutely.
So a lot of questions are around what is LP Lelele 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. Okay, I was afraid you're 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 of total cholesterol, LDL cholesterol. And if you're really lucky, they'll put bad next to it. HDL cholesterol. And if you're extra special, they'll put good next to it.
Triglycerides and non-HDL 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 you'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 implies that it's a macrostructure. So cholesterol, which is the principle 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, referring specifically to certain organs like the adrenal glands, the ovaries, the testes, turn cholesterol into hormones that are either sex hormones, glucocorticoids, gonadotropens, 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 ion gradient. There are other lipoproteins that don't stick around that long. So VL, very low density lipoprotein and IDL or intermediate density lipoprotein, which is almost non-existent in such a short half-life. And the longer residents of the LDL is probably what explains its atherogenicity.
And that's why LDL is considered the most atherogenic particle after L.P. Lele, 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, 200 milligrams per deciliter. OK? And when it says LDL C is 120 milligrams per deciliter, 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 LDL P, 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 APOLIPA protein that wraps around the spherical LIPA 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, all have the APOB 100. The HDL does not. The HDL has something called APOB A1. It's a different LIPA protein.
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 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 LIPA proteins get through the endothelial space between cells, which is actually not that hard to do. And 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 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 seven-athio 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 seven-athhelial 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 under 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've had so much interest in LPLA 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 and quote, of LPLA and 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 LPLA? Well, in full disclosure, Anahado is a really good friend of mine. 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 LPLA and LPLA.
And Anahado, because he's just such a curious dude, was sort of like blown away at this. He's like, wait, wait, wait a minute. Tell me about it. 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 in 10 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 I introduced him to many of my mentors and he did his own research. And the 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 LPL particle number.
So it's this spherical thing, call it 20 nanometers in diameter. And it has an 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 apo lipoprotein called Apo B 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, this is what probably discussed genetically determined and inherited in a codominant fashion.
A subset of these have something else attached to that Apo B. 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 lipoprotein. And it's called Apolittle A. And this lipoprotein is made in a liver.
And it has a property that it resembles another molecule in the body called plasma antigen. 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 have to miss a picture.
This is one of those things where it's worth looking at the picture. But this Apoliprotein A has a repeated folding structure. These domains are referred to as cringle domains. So we're sort of lost in a nomenclature of Apolittle A and cringle potato chip folds and all this stuff.
It's super complicated. But these repeating structures are organized by cringle domains and there are five of them. Plasmidogen that has five of them. Apo A does not have the cringle one, the cringle two, the cringle three.
It does have a cringle four that very much resembles plasmidogen and it has the exact same cringle five that comes from the plasmidogen. So to distill that again, Apo A looks like plasmidogen and that it has cringle domain five and a cringle domain four that is similar, but it's the cringle domain four that has 10 sub segments. So you have cringle four one, cringle four two, cringle four three, all the way up to cringle four nine and cringle four ten. And if that doesn't have, you're looking to be in your laughing.
It's like, it's hard to believe we're talking about it at this level of detail. But the cringle four two is where you see the greatest variability and you can have a cringle four two with just a couple of folds in it. You could have a cringle four two 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 the story if it weren't for some reason in anticipation of talking about something else.
And with the plasmidogen and the cringles in 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. It looked 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. There's some individuals whose a po a looks more like plasmidogen because everyone's plasmid looks the same, but the a po a is where we see the difference. So we're really dealing with two things, which is how many of your LDLs have those a po a's attached to them and then what do your a po a's look like and what they look like is basically what do your cringle segment four sub segment two's 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 a po little a.
In other words, it's probably the number of the LDL sort of the apolittle particles bound to the LDL particles through the a po b or the number of lp la is that matters more than the mass of the lp little a. So on that note, I was thinking about a po b in that there's one a po b per LDL and then with a po a, there's one a po a per lp little a, but not necessarily not every lp l but every a po a is on an LDL particle. Every a po a is on an LDL, but not every LDL has an a po a 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 a po 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 la, we could probably talk about the relationship between a po e and a po a.
So it turns out that as people may know, you have three different variants of a po e, you have a po e two, a po e three, a po e four, 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 a po b go up and you see triglyceride go down and this is the pattern that has been demonstrated over and over and over again. And what's interesting is why that's happening with respect to the a po a, but 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 la and if you're looking at how it's spelled out, it's capital L lower case p parenthetical lower case a and closed parentheses.
And it's basically saying it's a lipoprotein with an a po a attached to it. Yeah. And if you were going to like come up with an equivalency, you'd do like three little like parallel lines as an equal line and say that's equal to L d l hyphen little a or little a po a would be like the long hand way to write that. I don't know that everybody's ever written it that way in literature, but that's just another way to think about it.
Okay. So piggybacking on that, can you explain the difference between lp little 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 can also be called the different a po a iso forms. 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 Tamika's, 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 check, 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 their lp little a check, it's a mass. I almost never see the cholesterol checked anymore. I think there used to be a company I believe called after tech that did the test. I think they got bought or at least that as I got bought by Vap and now Vap does it.
I'll explain later why I don't think that's such a great test. And then of course there's the Lp little like 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 a boa.
It's measuring the mass of everything, which is the a boa. The a po b, 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 four, subsection two, the more that mass is dominated by a boa.
But you can see very quickly how you could be misled. You could take two people that have the exact same lp little a mass. But if one of them has a very long segment four, sub segment two repeat binding domain, guess what? He's going to have a much fewer particle number or more of the point.
The person that has the smaller segment four, 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. When a patient shows up and their lp little a mass is really, really low, like less than five milligrams per deciliter, 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 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 two by two, which was if both were high, I knew you had a ton of particles, case closed. If both were low, we were off to the races in high fiving. And then when one was high, one was low, we would just 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 lp 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 lp 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 so that reason I really prefer looking at the lp little a particle number, which even though it's reported in animal per liter, to my knowledge is not actually measured via NMR the way LDL P and HDL P were pioneered by liposcience. It's a different assay, but nevertheless, it is counting the apo little a's that are attached to little a po bees.
And so you're getting a number of those. And for that test, we like to see people less than 50 nanomol per liter. When people are sort of 50 to 100, I put them in kind of a gray area. When people are over 100 or certainly over 125 nanomol 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 nanomol per liter. And I've got a few patients that walk around at 400, 500 nanomol per liter. So the lp little a cholesterol, it sounds a lot like when we're measuring LDL C. So if you're measuring all people, a cholesterol, you're measuring the amount of cholesterol that's carried within the lp little a particles.
And similarly with LDL C, you're measuring the amount of cholesterol that's carried within the LDL particle. Similarly, you would rather know the LDL particle. Yeah. So obviously 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. 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 a P.
And I remember thinking, well, I used to be a smart little organic chemistry whippersnapper. I should be able to convert this from milligrams per deciliter into nanomol 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 I forgot his 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 APOAs don't look the same. The whole calculation goes to hell in a hand basket. You can't actually calculate the molecular.
You don't know the molecular weight because of the cringles subsegment. The cringles four segment too because it's got such variability. It's not like you can say the molecular weight of sodium is X. So 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 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, no, you're not going to head. This is being done. But my knowledge is not something that's done clinically.
Whether it will be or not. Again, that's probably a great question for someone like Tom Dasepring or Sam Tamikas or 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 box that I saw slip it. If you normalize that for APOB, you are getting almost a one to one mapping of that because there's another interesting little, it's not a trivial point because trivia tends to be irrelevant. This is actually quite relevant. Apolittle A has lots of lysine.
The immunosublysine and lysine really binds oxidized moieties. Now, APOB does not contain much lysine at all. And therefore, APOB is not particularly effective oxidized moiety scavenger. But APOB is.
And so if you think about your rolling around as an LDL, now you've got a tail thrown on you, which is called an APOB A, right? You got your little disulfide bridge attached to APOB, you got your APOB A tail. Only you can see what my hands are doing right now. That's great.
Yeah, it's awesome. You have pictures. The pictures are definitely worth a thousand words. You can see the crinkle domains.
And if you have a longer, you can see like longer tails and shorter tails. Yeah, that 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 LP 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. It seems to come out of nowhere. They also tend to, you know, if you ask enough, you might even see that somebody has aortic stenosis. And you just know the answer will forget 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 that'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. 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 an LDL, an LPLA of 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 LPLA's must be created equal.
And so the question I'd want to get into with the expert on this is, does it have to do with the lysing binding domains, the affinity for desoxidized moieties? Is there some feature of one person's versus another's that lends to a more aggressive oxidation within the 70th field space or greater retention or something like that? I think that gets into why do we have LPLA? So what would be the evolutionary basis?
What's the function of LPLA? 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 Apo E4, which in today's environment doesn't seem particularly protective, Apo E4 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 LPLA clearly does two things that are 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 plasmidogen. And plasmidogen being a clotting factor means that people with elevated LPLA 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. And 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 OBGYN rounds, how many times was a woman bleeding so sufficiently that she required blood cladding products? It's not unheard of.
And so you think about the benefits this could have had all the way from birth, brilliant but 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 lysing binding domains, that if you're in a relatively low oxidative environment and your LPLA's know where to go when they're done, which is to deliver and where not to go, which is the coronary arteries and the aortic valve, they're actually amazing scavengers. So I'm sure somebody out there has 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 LPLA, 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 systems 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 LPLA's another place to go, which is, yeah, you're ultimately going to end up with the liver, but like 6% of you are going to get stuck in the sub-inventhelial space and wreak havoc.
And on top of that, you're doing a way worse job than the LP because the LP when it gets there is bad enough, but the LPLA is now dragging all that oxidized crap in there with it. So the next question is, what is the problem with elevated LPLA or what are the problems with LPLA 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 LPLA. 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 LPLA 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 the 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. There are blood markers like brain-naturary peptide, BNP or pro-NTBNP that are actually used quite frequently in ERs to assess patients very quickly for cardiomyopathy or cardiac failure. So it's one of those things that we like to look at. And if I see a patient with LPLA, 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 LPLA, 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 sometimes you'll get patients, I have a patient who has a bicuspid aortic valve, which is going to be by itself, that's predisposed to aortic stenosis. And he also has a very elevated LPLA, 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 interventional 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 on all of the above when it comes to why, meaning it's, are these particles more likely to enter the subinithelial 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 cringles oxidized 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-Lil-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-MIs and even suggesting that, well, everybody who has an MI has a rise in LP-Lil-A. And we'll probably get to that later why we think that might be the case.
But the question posed is, well, maybe LP-Lil-A is the result of atherosclerosis and not the cause of it. I don't agree with that because many post-MIP patients don't have an LP-Lil-A. And I think a better explanation for that is that LP-Lil-A also acts as an acute phase reactant, rising with inflammatory responses. But probably not until the antisense oligonucleotide 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 LP-Lil-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 prophylaxis, so deep veins rumbosis, prophylaxis, and prevention. I do take it more seriously in the LP-Lil-A patients. And there are certain strategies you can take around flying.
There's actually a commercial available product called flight tabs, 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-Lil-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 LP-Lil-A is associated with these increased risks?
If we're looking at the epidemiology, what are the associated risks with cardiovascular disease? So with aortic stenosis, the hazard ratios are anywhere from two to four, depending on the studies. The median ends up being roughly two and a half with VTE, but the venous thromboembolism, 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 three X 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 LP-Lil-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 aorticicic 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 looks like a pretty good dose response where it's sort of below about 30 or 40 milligrams per deciliter because unfortunately, all of these studies are done with LP-Lil-A mass and not particle number. And I can't really convert that. We believe that that's probably about 50. That's probably you're going to get comparable in the 50 to 75 nanomole 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 from them and think about that, what should you be more afraid of? A three X hazard ratio for VTE or a 1.6 hazard ratio for atherosclerosis or a 2.5 X hazard ratio on aorticicic stenosis. This is like the advanced clinical epidemiology question.
I think the answer is the 1.6 on atherosclerosis by far the most is concerning 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 effing problem. Whereas a 3% risk on something that's going to 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 out their absolute risk the most with cardiovascular disease. Yeah, we're screening for aortic stenosis, not because I necessarily think it's even 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 in five and one in 10 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 Anahad'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 of taking care of a patient where you have some input into how they lower the 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 LPLA?
Probably what is elevated LPLA? How is that determined? Well, to my knowledge, everything that's done on this that's published is based on the LPLA 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 aphyoresis.
Aphyoresis 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 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 aphyoresis 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 aphyoresis 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 aphyoresis 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 LPLA treated or dealt with? So you just got into the apheresis. Are there other therapies currently available? So apheresis is something that we just really never resort to or very rarely resort to.
And certainly now, now that PCSK9 inhibitors are on the market, I think that apheresis is becoming probably less and less utilized. Historically, the agent for treatment has been niacin. Now niacin's got kind of a checkered history because it's known to lower APOB. So you take niacin, your LDL goes down.
And this is a super contentious topic in lipid circles. But the question is, does niacin 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's HDL goes up. LPLA might go down. So on paper, it looks, at least up to that point, it looks great.
Right. That's exactly right. Those 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'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 LPLA by probably a third.
So see tetheredis? Yeah, exactly. Fifth time's the charm? I think we're waiting for number five.
Yeah. But it turns out that in the trial that basically doomed niacin, the trial probably wasn't designed that well, in that they were giving niacin to patients who were already on a max dose statin and looking for the HDL increase to see if that was adding benefit. And 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, 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 LPLA 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 can't inhibit her. But I guess before I do, I should explain statins because everybody's probably saying where the statins fit into this. And it turns out statins don't clear LPLA, 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. So this SREBP2, which I'll just agree for sure, 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. Now, 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 the 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 lowering of the LDL cholesterol. But it doesn't lower LP-A. 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-A 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 Dasebrang about this because a really interesting paper came out a few weeks ago that actually tried to explain this.
Like all good papers, it ended up leaving more questions than answers. The best explanation that I understood from Tom was that LP-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, yeah, then you might get to the LP-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-A. Whereas a statin by itself is anywhere from no reduction to in some studies an actual increase in LP-A.
And PCSK9 alone also lowers LP-A. So to be clear, PCSK9 inhibitors are not FDA approved for the use of lowering LP-A. But those of us who prescribe these drugs, both for patients with other indications and with LP-A, generally acknowledge that we're seeing about a 30% reduction in LP-A, sometimes as high as a 50% reduction in LP-A when patients are taking PCSK9 inhibitors with or without the same test. And that also probably speaks to the fact that we know that LP-A 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 SRV1. Although I'm not sure of that, and frankly I don't know that anybody is. So what the PCSK9 inhibitor is doing is it's inhibiting PCSK9 and therefore inhibiting the protein that degrades not just the LDL receptor, but these other receptors that clear LP-A. Interesting.
Sure. I was just thinking about something. In statins, so oftentimes I'll read in the papers, just to back up for a second too, I often read in the papers LP-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, Samikas looked at the effect of statins, not only just statins in general, but different statins.
The Torvastatin, Prabastatin, Potipastatin, Livilo, the Rasubastatin and Simvastatin. I think maybe that covers all the statins. If I'm just looking at his data, the LP-A actually looks like it's trending on statins. Not only that, the oxidized fossil lipids to Apo-B are also going up.
Right. Is there any explanation to why that could be elevated? Yeah, because the Apo-B is probably going down. It's probably that you're lowering the denominator.
That's my guess. What's clearly acknowledged is that when you give a patient with elevated LP-A statin, which we do, absolutely, it's not the lower the LP-A, it's the lower the LDL. So actually, I'm glad you brought this up because I missed the punchline in all the detail. At least one of the punchlines is, how do we treat patients with elevated LP-A?
Well, we're probably not going to give them for recess if they can't afford to buy a PCSK9 bit or 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 always refer me to the LP, my LDL-P 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 got an elevated LP-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.
They're not always. I have some patients who don't need a statin to get their LDL-P down to the 10th percentile. But they're the exception and not the rule. So that's where I don't want people to get the impression that if you have an LDL-P, you shouldn't be taking a statin.
No, it's quite the opposite. You probably should be taking a statin, but just understand that the statin is there to control Apo-B and not LP-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 LP-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 the lay and cardiovascular disease and lipid lowering.
And one of the things that they noted was estrogen replacement therapy reduces LP-A levels by up to 50% and there were a couple references there. In effect, it 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 PEPI trial.
However, the clinical role for hormone replacement therapy is uncertain and is not recommended for cardiovascular disease risk reduction. So with that HRT topic, wasn't compelling enough to go over. I think it's 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 were, 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 LP-A, all things equal if they did not receive HRT? I believe so.
Yeah. I'm going to go and look at the LP-A 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-A. So ASOs stands for antisense 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 that's a very well-known obvious fact that I'm just forgetting. But the point is they disrupt the synthesis of ABOA, which is occurring in the liver. So this is a drug that goes right to the heart of LP-A. And I didn't say this earlier, but it's worth pointing this out.
When you go through my whole rigmarole on why do statins probably not decrease LP-A, it doesn't appear that anything that's going to lower LP-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 antibodies, like the PCSK9s, also increase degradation, they reduce the synthesis. They're actually reducing the synthesis of ABOA and the liver as well.
So these anti-sensalconucleotides go right to the heart of that. And they directly stop the synthesis of ABOA 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 we'll be done in five years. Consistent.
Yeah. The frequency distribution figure that will include somewhere. It shows effective anti-sensalconucleotide and it says around 70% up to 99%. So it could potentially wipe out.
Oh yeah. Yeah. Even somebody who's got an LP-litre of 200 and be normalized. I'm a little eerie of wiping out something entirely.
It certainly suggests that if you have this ASO, you can test a hypothesis in terms of LP-litre lay 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 of LP-litre lay? I think we got through a lot of the major questions.
This was 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, like getting into the oxidized phospholipids, how that works in 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 who 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 molecules to dietary intervention. Yeah. In theory, it sounds like you can play around with a lot of lipoproteins. Actually, a lot of the markers.
It seems like with LP-PLA doesn't seem like it can be modified all that much by lifestyle. Is that right? That's the correct thinking. That's absolutely correct.
And probably the reason for that is, as we just learned from the PCSK9 stat and comparisons, directionally speaking, there are two things that are driving LP-PLA, how much you make and how much you clear. But the game seems to be won and lost on how much you make front. How much you clear seems to be a second order thing. Now, when you look at LDL-P, just to contrast it, never mind triglycerides, when you look at at LDL-P, 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 serified cholesterol or non-serified cholesterol rather do you reabsorb after it passes through the biliary system in the inner site? 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 LDL-P 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 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 LDL-C that is known, but it also can have an effect on LDL-P through cholesterol synthesis and absorption. Now I think that the relationship there is much less clearly understood. I've speculated about 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 Dasebrin has written a really eloquent piece on this. So if we can find it, if it's publicly available, we should link to it. 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, does it matter?
We know the answer to that question, but that's a point. I was among them at one point. I think it's you get an NMR and it gives you your LDL-P count. Is it in animals?
It's really early. And it actually reminded me of Fletch and Gillette collecting rent, I believe. And he picks up on a 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 2,500 or? The upper cutoff is 3,500. 3,500.
And it has one of those awesome greater than signs. It's 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 a supposedly a well-formulated ketogenic diet, but it'll coconut away. Maybe some of it was coconut oil, butter, etc. But it was heavily loaded with saturated fat. I would love to read that article and because it's one of those things that's gone around the circles.
Is it good? Is it bad? Yeah, I mean, even 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 can end up asking anyway.
I've probably seen this now 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 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 in the LDL cholesterol and the total cholesterol is actually a good thing.
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?
Was it the total fat? Was it the subset of the fat, et cetera? And it got all but one of those cases of maybe a dozen. When you just replace the saturated fat with mono unsaturated 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 patient that I ever went through this with, my first thought was, dude, we've got to take 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 going off a ketogenic diet. He had all his reasons for why he felt better and performed better on all those things. So I said, okay, well, then we could keep going on a ketogenic diet, but 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 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 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 that replaced the saturated fat and the numbers came down. And everything else, give or take, HDL, triglycerides, all that stuff, sort of in the same ballpark as before, but that LDLP came down.
Yeah. And I got to tell you, I mean, I'm sure that this will kick up a storm of people with very, very strong religious like views on, oh, there's nothing wrong with an LDLP of 3500. 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 in some knucklehead drag racing on 79th? I don't get that. It's most gratuitous in noisy cities. I don't know.
I don't know. I just think we should get involved. We should wrap up 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.
And look, I wasn't that guy. I mean, I probably ate when I was in ketosis, that's probably eating 200 grams 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 trigs were nonexistent. 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 oxidized LDL, you saw oxidized LDL going up. My newbie understanding of this is that oxidized LDL is, in a sense, LPLA.
So that LPLA, well, that's an oxidized phospholipid. Yeah. So the LPLA picks up the oxidized phospholipids from the lipoprotein from the LDL. Yep.
And then that LPLA particle itself is now carrying the oxidized phospholipids, but that's not an oxidized LDL. No, the oxidized LDL assay is different from the oxidized PLSA. The oxidized LDL assay works independent of how many APOAs you have. Okay.
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 LPPLA2, 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 someplace else? This is, you know, 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. And those figures, you just mentioned that the LPPLA2 and LPPLA and then OX, there's another thing called, it's the oxidized phospholipids over the APOB. And in that paper, it's a 2007 paper. And I think Samika's is the last author on 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 dial. So they have, they partition it into six different groups 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 LPPLA. Does he explain why he thinks that's happening? I'm not.
I'm not a fact of APOB being higher possibly. The denominator going up, which shrink the total number. I'll have to look at that. And any other LPPLA 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 LPPLA a little bit prior to Bonnhot'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 it seemed to have quotes that he says, this is Venetian proverb. He 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 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 in terms of the medical knowledge and what's the accepted wisdom and the guidelines and things like that.
So I think LPPLA is one of those cases that's just fascinating. 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'd have 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 when you know like just like the surface level, that's where you're the most confident. You think you know everything. And then as you learn more, it's like the Dunning Kruger, it's like a you. And then your confidence and your knowledge goes down.
Okay, welcome to the 24 hour news cycle cable TV and Twitter, man. I don't know if that's done or 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 will be 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 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 I see the 10 code was actually just issued for elevated LP little 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.