The Peter Attia Drive - #24 - Tom Dayspring, M.D., FACP, FNLA – Part V of V: Lp(a), inflammation, oxLDL, remnants, and more

Episode Date: October 19, 2018

In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part V, Peter and Tom talk about inflammation, endothelial health, and oxidative stress as they pertain to cardiovascular disease, and our attempts to monitor them using biomarkers. They also discuss a couple of very important risk factors that too few people (and doctors) know about. Tom closes the five-part series with a tragic story about his good friend that is likely all-too-common for many practicing physicians, that both haunts and motivates Dr. Dayspring to learn as much as he can about the number one killer in the United States. We discuss:     Lp(a) [2:30];     Inflammation [17:15];     Oxidative stress markers: Lp-PLA2 and oxLDL [20:45];     Endothelial health markers: ADMA and SDMA [34:30];     Remnants [43:45];     Omega-3 fatty acids (EPA and DHA) and apoC-III [55:30];     Red blood cells and cholesterol transport [1:07:45];     Tom's friend Earl [1:10:00];     Peter's friend JP [1:18:15]; 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.

Hi everybody, welcome to the fifth and final episode in the week of Tom. This is the tour de force magnum opus course on lipidology. As we round this out, we talk about a number of things. We talk about LP, little A, inflammation, oxidized LDL, remnants, red blood cells in cholesterol, a biomarker called LPPPLA2 that you've often probably heard about, another biomarker that you may have not heard of called ADMA or asymmetric dimethylarginine and SDMA, symmetric dimethylarginine. And then we kind of bring it back to what is one of the more tragic stories in Tom's life,

which is a friend of his who unfortunately probably had FH wasn't treated. And in many ways is sort of one of those patients that still kind of haunts Tom. And I think, you know, we open this back in part one by talking about Tom's passion for two other things, firefighting and hockey, and how that passion is what really got him into or basically allowed him to apply himself to this new field once he became obsessed. But also, I think most physicians listening to this will have a similar story where there are certain patients or there are certain personal relationships where a loss of life stays with you for a very long period of time. And in many ways it colors what you do over time. So I hope you enjoy this fifth and final installment of the lipidology advanced course and next week we'll be back to our regular scheduled programming where

we're just doing you know one podcast a week. So I hope you've enjoyed this and I hope you find the show notes very helpful. I can't express how much work has gone into it. So without further delay here is the final episode with Dr. Tom Dates. This will be a nice way to dovetail niacin, statins, and PCSK9 inhibitors. What lipoprotein have we not discussed today that would tie in a discussion of those three? Well, the astute listener realizes it's our good friend Lp. Little A. All right. Why do I bring this up? So Lp. Little A, there are some people who still argue, hey,

niacin makes sense because it lowers Lp. Little A. I'm going to save everybody on this podcast, the brain damage of listening to us discuss that for the next 20 minutes and just bypass us to the more interesting question, which is why don't statins lower LP little A? Well, first of all, we need a better understanding of LP little A clearance and personally of the belief that it is the LDL receptor. There is a plus-minigin receptor that could clear some things and there are macrophage

receptors that, depending what else is going on, might internalize some LP little A and get rid of it that way, but it's the LDL receptor that clears it. The other two. Let's pause for one second, because I realize even though we've already done an entire podcast on what is LP little A, there's someone listening to this who hasn't heard it, you'll go back and listen to it,

I'm sure I'm gonna do future podcasts where I interview the world's expert on the topic, but Tom, can you give in two minutes a description of what LP Little A is? Yeah, it's an LDL-like particle to which is it here in another apoprotein that shouldn't be there. It's called apoprotein, little A, and you must pronounce it as little A. That means small case rather than capital A. Lipoprotein capital A is apoprotein A1. That's the main apoprotein on an HDL particle. So if you tell me you got Lipoprotein A, how do I know what are you talking about? You got HDL particles? Are you talking about LILA, which clearly identifies

to me this potentially pathogenic, atherogenic LDL particles. So use the correct terminology with everything. And Peter's got that nice podcast on it. Our metrics of, is that present in you or not is most labs will run in LPLidlally, mass, which is the weight and a desolate of plasma of the weight of your entire, all your LDL particles, everything that's in them, their triglycerides,

their cholesterol ester, their phospholibular sir. Meaning any lipoprotein that is carrying an apolipolittle air. Yeah, and you weigh the entire. That's all of the LDL density. Yeah. So, but you're weighing everything. You're not weighing apolittle air. You're not measuring apolittle air per se.

Yes, that has a molecular weight, but the molecular weight of apob is way higher than the molecular weight of apolittle A, but you're measuring that too when you do an LP little A mass. But the molecular weight of apob is known because it's pretty much the same, whereas the molecular weight of apolittle A is very important. It's very variable, so that's another reason

LP little A mass becomes a useless metric. And how do I know how many cholesterol triglyceride phospholipid, 10,000 other lipid moieties, other proteins are on that particle? I don't. And you have the heterogeneous mixtures of particles that would have variable amounts of all of those constituents. So you can see there's going to be a weakness to measuring L.P. Littlae mass. Now, if it's really high, you probably got too many LP little A particles. But since there's almost no more debate that the best metric for our LDL particles is low density lipoprotein particle number, there's no debate among those who will truly understand that HDL particle numbers are your best, available metric on

quantifying the number. And that is a better metric than guessing that using HDL cholesterol or LDL cholesterol. When you rather have a really nice finite count if LP little A particles are dangerous, wouldn't you like to have a excellent accurate concentration in them? Well, the only way you can do that nowadays, NMR provides those other HDL in NMR cannot assay LP little A particles because NMR assays lipid content of particles, not protein content. So the only way I can give you an LP little A particle count is I have to separate all lipoprotein's electrophoretically and they all, you'll see little bumps on the electrophoretogram, VLDL's congregate here, LDL's congregate here, HL's congregate there, and what's that little bump

that is in this person, but it's not in that person. Oh, that's LP-LitLA, because that's due to its surface charge, where it migrates between the cathode and the anode and the gel that you separate them on. So if I then take that LP-LitLA hump, and I immunostain it with an antibody that binds to APOB, you've just counted

number of particles that are in the LP little A distribution range. I theoretically should not call that an LP little A particle count. I should call it LP little A APOB. That's too much of a mouthful. It doesn't fit on a request form. So of course, it's abbreviated LP little A dash P. And to me, the downside of that is most people think it's an NMR measurement, which it absolutely is not. Basically, if you want that metric, and we've already announced I do work

for true health diagnostics, I was working with a different lab before that, the lab that actually did the development of the LP-Lylae APOB assay which true health absorbed and got proprietary rights to when he did it. So that's it. And believe it or not, there are people who are going to have discordance with LP-Lylae mass, the weight of the whole kitten caboodle versus the number of LDL particle counts in generally carly. But if you really want to know, and also I find it useful, at least those of you who are doing LDL P by NMR, you have your total LDL particle count. But what does that really include?

It includes LDLs that don't have APO, little A attached, and it includes LDLs that don't have April Little A attached and it includes LDLs that do have April A attached. Now I throw a stat in it you and we started to talk about this, that statin is not going to budge your LP Little A particle count at all, but the statin is going to dramatically lower your LDLs that don't have, LL attached to it. So your LDL total particle will get down a little bit, but part of that is your LP, LL A particle count, but this shows you you are getting benefit when you give a statin to somebody with high LL A.

You're gonna have to go after residual risk. You know, one of the best examples I saw of this was an unusual case where a guy had an LDL particle of 1600-ish Nanomol per liter, but he had an LDLP little A of 600 nanomol per liter. So even though it's an apples and oranges assay directionally speaking he's got 600 LP little A particles Nanomol, so nanom particles per liter and a thousand non

L.P. Little A's. But when you give him that statin, you're really only targeting the thousand. Correct. And so you'll be surprised at the lack of response you might see because you're not getting to target those things. No, but you still get your 3040 here, but your total L.D.L.P. may still be higher than you wish it to be and

Unfortunately, that is LP little A particles Then you can get into the theoretical discussion right now that if I could get rid of them and Basically the only way you can do that now is the maybe try nice in which is a weak lowering of a 20% or a PCSK 9 inhibitor which Seems like 30 to 50%. Well, it would be an individual response, but it's a nav range. So if somebody could at least afford that drug,

you can't get it covered by third party because they don't have that indication to help you manage LPLidolate patients. So, and that'll never come. Because could I ever prove to anybody that the PCSK9 inhibitor, because it's lowering LP-LitLA is reducing events? No, because they're gonna turn around and say,

all its event reduction is they're just getting rid of the remnants in the LDL particles. That's nothing to do with lowering. And how would you argue against that? We need a drug that only lowers APO-LitLA or LP-LitLA and does nothing to LDL particles. And that drug is under investigation right now. It's an apoi synthesis inhibitor, where your liver is going to stop making the vast quantities

of apoi to these people who genetically inherit that propensive. This is courtesy ISIS. Yeah. Again, not to be confused with it. Let's hold our breath. But so until then, are there people in the lipidology world who would say, Tom, until then I'm going to continue to use knives and because lowering it has to work. I've been around too long things seeing lowers this and lowers that and they don't work. So, I, is nice and going to have the same toxicity and I think it has another people in LP

little, I don't know. But if you want to use that because you want to make a patient happy because you're improving some metric be my guess I would not I know many lipidologists who would not But there are ones and look Sam Simeekis is probably the world authority on the Sam uses nice and in his practice too And I hope Peter has him on one day with a podcast He would tell you until we did our dad on his other drugs I'll try and lower it a little bit. If nothing else, I'm Hill, Hashtag, I'm lowering

April B a little bit too. And I'm, I don't know if it matters, but I'm raising whatever HDL metric. But away, although fibrates are probably our best available drug now to raise HDL particle count, Niasin, which blows away fibrates on raising HDL cholesterol, does nothing to HDL particle count. Niesin, which blows away fiber, it's on raising HL cholesterol, does nothing to HDL particle counts. I didn't mention that before.

It's an added, because Niesin makes the HLs bigger. I was just about to say that could actually suggest it's worsening LDL, HDL functions. Yeah, you're right. So, but the Niesin people will convince you that the big HDLs are protective, it's laughable and the small HDLs are harmful, it's laughable, and the small HDLs are harmful, whereas the VA has really- Probably the other way. It's the opposite, because the lipid-pore HDLs are the ones that can go onto the work.

One thing can go onto the work. So, you know, you're never gonna have definitive answers on any of that, but yeah, there's a lot of BS around. So, what's the best explanation for why a statin, which causes the liver to upregulate LDL receptors, does not lower LP-little A, whereas a PCSK9 inhibitor, which also net results in more or longer transiency of LDL receptors, seems to lower LP-little A, even though that's not its primary objective. And by the way, the data certainly tells us now that the main determinant of LP-little

A mass or LP-little A particle concentration is APOA production in the liver, not clearance. So until we can really inhibit production of APOA, who knows what you're doing. But until then, let's see, so how do LDL receptors clear these particles? Well, earlier I think I mentioned that LDL receptors looking for apoe or a section of the apoe that it can latch onto. There's a very specific area on the apoe protein on any of the apoe particles that because of surface charges will bind to a specific part of the LDL receptor. That area on apoe is called the LDL receptor binding domain.

So if here comes an LDL particle, that domain is sticking right out. It'll stick right to any expressed LDL receptor. But what if there's something camouflaging that APOA or that LDL receptor binding domain on APOB, such as an interloper like APO protein, little A. I could see where that would slow the clearance of an LP little A particle, because it's not going to bind as rapidly and as vividly to an LDL receptor. So most of these people have to wait

to many LDL particles. We express whatever LDL particles we want. We try and express more with the statin. What are they going to grab first? The LDL particles that don, we try and express more with the statin. What are they going to grab first? The LDL particles that don't have apolitellae attached. And only then would they maybe then start even grabbing apolitellae particles or so. And do we all really have enough LDL receptors? Most of this for a variety of reasons do not. Other things retard the clearance too.

You know, with the APOC3, I talked about other proteins that may be affecting clearance too. So there are just other factors that play. But right now, my guess is APOA is affecting totally efficacious binding to an LPLATO-A particle. It's camouflaging the LDL receptor binding domain on APOB. And therefore, I better learn how to inhibit synthesis of it. So, Sam will obviously, hopefully, we do get Sam on the show and we'll talk about this, but that this any sense, all you're going to include, height is basically going after

the jugular issue, which is you inhibit the synthesis of APO little A. Yeah. And hopefully, you do that. You know, the million dollar question has always been, why do we even have APO little A to begin with? Did it ever serve some physiologic function? Or is it important in any other aspect of human life? I guess we'll know it if we eliminate it and there's some bad outcomes in that trial. And obviously it absolutely will be looked at for every safety aspect anybody can ever think of right now as you're developing that drug.

So right now, I don't think there's anything they're worried about, say I'm with no more than I. But yeah, so if we can reduce that in, I don't know that we can shut it down completely, but he can drastically lower apolilate and LPLate levels to, you know, everybody thinks eat or have it. There's a lot of people who have what's considered a physiologic or non-adversarial concentration of LP-lilay in your system. So, you don't have to make it go to zero, you know, where risk is concerned. In fact, the only people they're ever gonna study to stroke is in people like you just

mentioned, who have an LP-lilay mass or particle count up and at 600 range or something. You're not gonna take people people with borderline LPLittle a's and risk a clinical trial on them. Just like the first statin trials were done in sort of FH type people or so. Yeah, they're enrolling for phase three on that trial, aren't they? And is it secondary prevention or primary prevention? I'm pretty sure it's secondary prevention. Yeah.

And remember, there is some data in the Aferesis world that if you pull out LP little apodicles, there is event, they're not randomized by the trials because how would you do that with aporesis, that aporesis for the nonphysioresis? It's a dialysis where you're clearing your blood of, you take the blood out, you get rid of the LDL particles and you give the residual blood back. And for at least a week or two, they have less. But there's so many other things you're clearing, the regular LDLs, all sorts of rheological things, all sorts of other hybrids, modic proteins and things that who knows

what the Y-Aphoresis really works. You know? I don't want to get us too far off our main theme of lipidology, but because they're both quite recent, let's just really, really briefly talk about two other interesting drug trials, which look at a completely different component of the atherosclerotic mechanism pathway, which is the inflammatory pathway. So there was an agonist to IL-1, I believe, or maybe it was that IL-1 or IL-6.

Yeah, IL-1, IL-6. And then there was also a trial that looked at using low dose of methotrexyl. Which is still ongoing. There was some preliminary words that it had. This is looking good, but it's not been definitively- That's where we want to know, tell the fall. But there is the theory, this, hey, reduce inflammation,

and you will certainly help vascular health in capacities. Maybe even I have nothing to do with lipids or so. And so what's a great anti-inflammatory drug? Well, we've been using low dose methodorexate in people with inflammatory disorders without a lot of toxicity for a long time, rheumatoid arthritis, et cetera, culture scene, very powerful anti-inflammatory. There's a big outcome trial undergoing with that.

And I believe, within the next year, we're going to have that on both of those trials. So in the problem, this IL-1 inhibited at Peter talks about, which has already published a nice outcome data by inhibiting that, but it's a $30,000 drug. And there was downside to it, because by seriously inhibiting the inflammatory system

there was a slight increase in cancers in some people. Your immunological system has uses in the body, so you better be careful how much you knock it out. Because of course, because of that downside, it will never get an indication for me and you to use it. Again, if you're some multi-billionaire, it's already been approved for certain type of conditions, you could use it. Yeah, and I think the bigger issue is really, as more and more of these drugs become available,

hopefully it leads to a more and more personalized type of intervention, where, look, if you got somebody who's walking around with a low C-reactive protein and a low fiber in origin, and their issue is elevated, you know, LDLP, I don't see why you'd want to use an IL-1 agonist on that, or antagonist rather on that patient. So yeah, it comes down to basically stratification of what's the driver? What, again, this comes back to this idea of necessary,

but not sufficient, sufficient, but not necessary, neither necessary nor sufficient. Inflammation is necessary, but not sufficient. You do need an inflammatory response, but you can have an inflammatory response, and that by itself doesn't necessarily. Well, and a certain degree of inflammation is critical for you to get rid of a certain pathologies or so, so you never want to stop the immunological system. Yeah, look, I believe like Peter does.

These are multifactorial diseases. We've spent a lot of time on apobelia, but the many other contributors that go into this. So I believe the better we can evaluate using biomarkers, the better we can identify many of the known existing pathologies. I'm sure there's many we don't fully understand yet. And then perhaps we can better individualize our therapeutic suggestions to these people and know what we have to do both nutritionally and pharmacologically if that's necessary to normalize whatever you're trying to normalize. Yeah, that's a complex world out there, and you got to look at a lot of things.

So we've already discussed many biomarkers on the lipid front, and we've alluded to some of the biomarkers on the inflammatory side, C-reactive protein, fibrinogen. But what are some other biomarkers that you find helpful as far as understanding even more diffusely endoth you'll dysfunction or other markers of Oxidized states that can give us more of an indication and say look you might have two people with the same degree of Dislipidemia, but one has a greater burden of oxidation going on than the other which would be presumably worse Presumably yes, and the problem is going to be when you even start expanding. And I can throw some markers at you that you want to measure it. It would tell you there's a pro-oxidative state going on. If your mission is to reduce after-pharmabotic events, trials that show, yeah, if we improve

this oxidative marker at oxidative matter, people do better. They've never, have ever been adjusted for APOB or LDL particle count. So even though you may show some nice data on them, if you really just normalize APOB and LDL particle counts, would it even matter? I mean, and don't tell me what common sense suggests. And look, I'm all furred. I use oxidative markers now mostly to try and convince people to do certain nutritional therapies rather than I got a wonderful drug for you to reduce inflammation.

Because right now, I really don't. I know if I lower APOB, I reduce inflammation. So that's one perhaps, that's your first therapeutic initiative lowering APOB by nutrition or if the risk category is high enough a drug fine. But if I could I measure something that tells me you have a prooxidate of state. Yeah, and people do ox LDL levels in the blood, but they have no idea what they're measuring. Remember, an LDL part out truly oxidized LDL particle, which is the only type that a macrophaging or arterial walkin internalize is oxidized

in the wall of the artery. And what is oxidized? It's the phospholipids on their surface. Or maybe some free starols be it a phyto-stero cholesterol. That oxidized surface lipids is what the scavenger receptor on a macrophage is going to pull that particle into it. And then you start accumulating cholesterol and you have a sterile laden fault cell bingo, you got the disease. So, but can I measure oxidized LDL in plasma? No, LDLs don't get oxidized

in the plasma. There's too many natural antioxidants in plasma where they don't occur. So, what you can measure in plasma is what's called minimally oxidized. All right, there's a little bit of oxidation occurring, but it's not the phospholipids. It's some of the structly proteins on the APOB segment are being changed into aldehydes, which is what the monoclonal antibody picks up. It picks up aldehydes on APOB, but those aldehydes wouldn't have formed if there wasn't a little bit of a prooxydate of state.

So when you're measuring ox LDL, it's really APOB, a measure of LD, APOB oxidation, but where is APOB? It's on remnants and on LDL particles. So just understand what you're measuring. But of all the LDL particles that are floating around, if you get an abnormal ox, you're looking at maybe 5% of the total particles. Now, you might make the case that when they do enter the artery wall, force them by the particle number, they're going to be even further in hand. So maybe

they got all leg up on an unoxidized LDL particle. Okay. So I would use that as a measure of a prooxydate of state. and I'd try and give you whatever nutritional things I believe might fight oxidative states or so. I'm not known that I got a drug, including a supplement that ensures me it can do that or not. Other than, if I had to reach for a supplement, it might be an omega-3 fatty acid, but it's another story. So that's what you're measuring with the oxyldial.

I think there are better markers of prooxydate of states. And look, a lot of oxidation is the granular sites oxidizing a variety of tissues. So myeloprooxydase is a granulicycreted prooxydate of enzyme. We can measure that easily in the blood that would be a signal of a prooxydate of state. And I think the best of all is as fatty acids get oxidized, derivatives form, they're short of chain fatty acids and they're put in a big group called isoprostanes and you can easily assay something called F2 isoprostanes,

which have clearly been linked to prooxidative states. Now, it's a urine test, it's not a serum test, but it's a small urine sample, it's not 24 hour urine. So I like to do F2isoprostanes. So whatever you like to do, be it ox LDL, be it myeloproxidase, or be it the F2isoprostanes, I can use that as useful information and maybe even convince you

that nutrition is important here and that is the best way to try and change them around or so. So those are some of the prooxydative mark. What I would not use is the prooxydative biomarker that way too many people are is lipoprotein phospholipase A2. First of all, the data is pretty poor. Most people don't even know. The only thing the FDA has given that approval for is as a screening test in primary prevention never ever for anybody on a lipid modulating drug or on a who has known coronary atherosclerosis. For the simple reason, at Mendelian randomization has shown the level of LPPLA to activity or mass has nothing to do with outcomes, sort of like the HDL

cholesterol story. And even more important, there have been two megatrives where pharmaceutical industry has developed LPPLA to inhibitors, gave them to patients, shut down LPPLA2 activity, drastically reduce LPPLA2 mass, levels plummeted, no outcome reduction whatsoever. And LPPLA2 is an enzyme made by the endothelium. No, it's made by macrophages. It's a macrophage. It's just like myeloproxies and made by brand new sites. The MPO data are equally unimpressive,

aren't they? Well, if you want to come down, it depends what you're using it for. If you, I stopped using MPO, two years ago. So look, and I agree with you. I think I don't know myself. I do the, look, oxyldial, I do it. It's easy to do. Yeah.

It's there. And it's more linked to the process that I can see MPO. I don't know. You could have some other vasculitis going on. Yeah, it might take on MPO as I found it to be unhelpful. And I agree with you that LPPLA2, it's one of those things you only really need to check once, where I find that actually somewhat helpful. And again, I could be just diluting myself is you take the patient with an elevated LPP

little A, who has an elevated LPPLA2, and not only do you have a tongue twister, but you also have a patient that might be a little higher risk. And I wondered if I whispered that into Peter's ear over the ear. I knew you knew you knew. But anyway, I would tend to agree with him. So here's why.

LPPLA2, which is an enzyme that does oxidize those phospholipids on an LDL-win. After that LDL enters the arterial wall, is exposed to reactive oxygen species, and some of the fatty acids on the phospholipids start oxidizing. Then LPP-LA2 activity kicks in, and it de-asturifies the fatty acids from the phospholipids. So now you've got oxidized phospholipids floating around, and a byproduct called lysolessid, which is a pretty pro-authorogenic molecule.

So LPPLA2 is involved with the production of them in the arterial wall. That's not where we're measuring LPPLA2. But hey, if it's on the particle when it goes in the artery wall, whose artery is wall in today's nutritional environment doesn't have reactive oxygen species sitting there waiting to attack something. So, boy, what particles entering order in your wall are going to have the most LPPA-LA2 mass on it when that's where you're going to turn on LPPA-LA2 activity.

And by the way, the new assays available everywhere, they no longer measure the mass, they measure the activity. We were the last company who finally ran out of reagents and we're going to activity now. So across the board, the study show either LP, PLA2 mass or activity are identical in predicting risk if that's what you're using it for. But believe it or not, the activity, I say, is so much easier technically to do less costly. That's what all labs are doing nowadays, the activity. So back to LPPLA2, jumps on LDL, he is a little bit on HL particles, but most of it is on HDL particles, but HDLs are heterogeneous species of normal size, big and small LDL particles. You'll find way, way more copies of LPPLA2 on the smaller LDL. Perhaps one of the reasons if people believe small LDLs are more arthrogenic than larger sizes. I don't know, once they're in the artery wall, which is driven pretty much by particle number,

but everybody with small LDLs has probably got too many LDL particles. So they're very prone to oxidation when they do go in the artery wall, not that a big LDL particles. So they're very prone to oxidation when a dooglyene artery will not get a big LDL campy oxidize. It could be, but it would have less LPPLA2 on it. But if I really wanted to know the number of copies of that enzyme LPPLA2, where would I find it in the blood on LPPLA particles? Well, that's where it's all carried.

So I think Peter hinted on it in his LP, a PLA-2 podcast, that there's another attribute to LP, little A, other than quantifying it or weighing its mass. And that's, we do know there are people with high LP, little A who do not get up. And they may be a minority, but they're out there. Just like not everybody with FH is gonna have a heart attack. Some go through life with that. And most get some events, but many do not. And clearly,

there are people without LP, little A who get heart attacks for other reasons. So if you came to me, with a very high LP, little A, whatever, do I just say, life's over, get your willing order, no drugs that can really help me with this and you can't afford a PCSK 9 and Hivers, I can't even experiment there. Maybe the ones who are at most risk, part of the functionality, part of the atherogenic potential of an LPLitl-A particle is one of the functions, perhaps a vapolidl-A, is it's a garbage truck that scavenges oxidized lipid moieties phospholipids, starroles, and it brings them back to wherever maybe it's Macrophages that clear them and detoxify them. So it's a

Some sort of a little rescue truck garbage truck of clearing it, but what happens if you got way too many LPL Little A particles too many LPL particles. So some of them are going in your artery wall. Now you have an LPL, LAParticle that's not only got a potentially proethrogenic apolilate protein on it, but that thrombotic, if it is a pro thrombotic protein, there's plenty of evidence suggesting it is. By the way, with arterial, not so much venous thrombosis. Many people have dismissed LP little a's, being linked to venous thrombosis. I don't know if this sort of, but if you talk to Sham on it, he will tell you. Oh, that's interesting.

So I stand corrected because I think I was probably quoting some old data when I said that the VTE hazard ratio is about two. Yeah, but it's just weak sort of data. So when you talk to Sam, talk to more about that. So maybe it is, maybe it is. After all, but the order is to know. Where are you after all first? Yeah, no order. No order.

And part of the pathology, maybe it's just trafficking these oxidized lipid moieties into your particle, which is going to just stimulate this whole inflammatory mess that's going on your itari wall. And maybe it's a pro thrombotic mess if that's a pro thrombotic protein, too, the double whammy going in with it. So and I think Peter covered it nicely in his discussion here. There are any segments on apolidolacyl cringles. And there are a couple of cringles that have a large essence of lysine and amino acid that is like fly paper for oxidized lipid moieties.

So they really bind to these lysine rich segments on April, little A. So if we could start measuring oxidized phenomenon and tying it into. Now Sam has written about this in his papers. Well, and Sam has published a data showing that's who you worry about with LP Little A. If they have oxidized APOB phospholipid-delevated, Sam's got an acid, so that's not a hell of a widely. Yeah, that's a shame. And, and he'll Sam will tell you that yes, we're measuring it on APOB particles, but

the APOB particles that carry the vast majority of these oxidized are LPL little A particles. Yeah, it could be a red, inner, to be odd ball LDL particle, but mostly it's your LPL. So that is, again, a double whammy. So I think maybe in the future we're going to be screening with whatever you want, LPL little A mass, LPL little A particle count. I hopefully never LPL little A cholesterol. It's like all cholesterol metrics should be. And the only way you can assay it is a poor assay nowadays.

Anyway, is all right, you do have excess LP little A, whatever in your system. Let me now do this follow up test. And if that's also up, let's discuss everything we can possibly do until that miracle drug, hopefully miracle drug comes along and we got a cure for you. And maybe it'll be covered in host people because the data will be strong because like all these new anti-sense drugs, it's gonna come with a price.

Yeah. Before we leave biomarkers, anything you wanna say about asymmetric or symmetric dimethylarginine? It's a very interesting biomarker also where we talked about endothelial function. Perhaps even some of the antioxidant function is this miracle molecule. Every endothelial cell makes extremely transially, makes an ins gone.

It's nitric oxide. Nitric oxide is a powerful regulatory molecule that regulates vascular reactivity, but oxidation, the thrombotic potential of an endothelial surface initiating a thrombus is highly dependent on nitric oxide. So, when endothelial cells make nitric oxide, which is by far the most important molecule they make, where does that come from? Arginine, the amino acid, arginine. So, arginine gets converted into nitric oxide.

So last thing I want is things that are going to screw up arginine pools, which is needed to make nitric oxide. And two proteolytic molecules, we know byproducts of basically catabolism of nuclear proteins is something, one is called symmetric, and the other one is called asymmetric dimethylarginine. There are isoforms of one another, so if you, you know, there are mirror images of one another,

but there are actually different molecules. One directly and the other indirectly inhibits the synthesis of arginine. So if I measured ADMA or... The synthesis of nitric oxide, do you mean? Right, yes. Well, ultimately synthesis of Arginine. So if I measured ADMA or... The synthesis of nitric oxide, do you mean? Right, yes. Well, ultimately synthesis of Arginine, which results in the synthesis of nitric oxide. OCEI always thought that S-DMA inhibited the synthesis of Arginine, but ADMA inhibited

NOS directly. I should correct what I said. One inhibits the synthesis and the other enhances the catabolism ofism of our gene so the end of the day you're gonna have less And less on nitric oxide and they're both Markers that we can easily measure so and if we measure them in their high You might presume hey, maybe that's a blood test that actually tells us something about endothelial function. I don't think we have another that has anything close to it. Maybe that high thought. I think the nice thing about the ADMA-SDMA is it creates a biologically plausible mechanistic

explanation for why we see an association between high homocysteine and greater disease, because homocysteine really inhibits the clearance of ADM and STM and that's very clear when you correct it. Which would therefore screw up nitric oxide production. Correct. So it brings even oxidation into the process would disturb that process too. So if prooxydate is state, if hyper homocysteine Amy is adversarial to the vascular, that's one of the pathways in which it is.

So what can we do? Well, we can measure it. So who would I measure, ADA? So if you came to me and you're on your third bypass or fourth stand, I think it's pretty safe assumption you have screwed up endothelial function. So I don't think there's anything to do. The first thing you're questioning is,

what do we do about it? So one thing is, look, if they have impaired renal function, hypertension, those are things that you go after. The homocysteine, especially in the MTHFR mutation patients, you give methylated B vitamins, which is still controversial in mainstream circles, because even though it lowers homocysteine, some will point to that and say, well, you have no outcome data on lowering homocysteine. But you have plenty of data that in people with hyper-homocysteine-uria, lowering homocysteine

drastically improves their vascular alchemy. So it's plausible that a certain threshold of homocysteine that there's probably make sense. And if you really understood the pathway of catabolism, a mothion, and you'd understand it's better, remember, in that pathway is going to be the production of a lot of neurotransmitters. Two, so there's a lot going on. If you have the genotype that's going to screw up methylation or the enzymes involved with that. That's another story.

But perhaps the best use of ADMA, SDMA is in the primary prevention setting where you got a little borderline, APOB, LDLP, you're not going to do lifestyle and do I really want to throw you on a drug or something? If those markers are up, that tells me whatever is going on in you, you have endotaly of this function. So you're down the road towards vascular pathology. So it might be a marker to kick you in the rear, to at least be super aggressive nutritionally. Even, hey, I'm sorry of whatever nutrition we tried,

you still have abnormal endoteliophunction. It's time for us to, here I would rather improve these markers that will take a drug to get them to where I want them to be. So maybe we can use it in that setting. If you also want to tell it to me, time you say, hey, if you've been through a bypass or a stent or something, why do it? But what if I have such a patient who have maxed out on a statin z-mi, by not everything

I else to almost sustain or insulin existence and they're still up? Should I lower APOB even further with a PCS? Because I mean, you use it for what you want to use it for, but as a marker of endodilial function. And very interesting of the two, you get both, and you also get an arginine level in the same assay. And SDMA is cleared by your kidneys. ADMA is catabolized in the cells.

So kidney function has nothing to do with ADMA. But SDMA, one of the things that I elevate it, is renal disease. And when SDMA goes under serum, it it comes back flux right into the cell and decrease nitrocoxide production, probably part of the pathology and people who are renal failure. It's just about to say, the thing I like about the ADM-STM A.S.D.F. even though we don't have all this great long-term data is it's one biochemical pathway that provides very clear evidence for two observations that are undeniable, elevated homocysteine and renal function.

Yeah, the estimated, not the ADMA. But you get both out of the, but you get both. Yeah, you get both. It's not like you're running selectively. You order, you get them all three of those moments. And they're addressing both sides of that equation. So it's a very interesting little biomarker there. And hey, who doesn't want another renal function test?

Most are using creatinine. That's kind of a poor you should be used as a statin Yeah, I'm sure and SDA will be further enforcement that and mild degrees of renal impairment go ignored in this country and if you're even in the early Even stage two, but certainly by stage three, which could be a clearance of seven day or something or sixty people that gets ignored, even though EGFR is being reported to people. And that's a major league risk factor that you ought to say you're a vascular path, you're at risk for vascular disease.

I got to see what I can do to you therapeutically to lower your risk, but it gets ignored until a creatinine clearance is thirty two and you need dialysis or something, you know. Yeah, this is one of those things I do talk about with a subset of my patients, especially these young patients in their 40s, 50s who buy, sustain, see, and create, and then maybe even a touch of microalbum. And, you know, their GFR is 80. And I say, if you're 40 and your GFR is 80, there's a problem if you want to live to be 100 because I don't know where you're going

to be at 80. Yeah. And look, if you got album in your year and you got a serious vasculopathy someplace, maybe it's just your gomerulus and you got a kidney disease, but you probably have some other vasculine disease too. So albumin is just asking something else about something as big as a protein to escape it in New York. And you've got some membrane problems that are lining some eat or go marialists or a blood vessel someplace. The other ones are and it's interesting because Peter in his little world sees a lot of these people who are well trained athletes take

care of themselves and some of them in Peter probably encourage them to build up muscle mass in which can influence creatinine and makes it far less usable as a mark of renal. So statin C has not influenced by muscle mass. So that's where it picks up some of the imperfections the weakness. We just both. Yeah. And if you do both, which is by the way, if you read the American, the kidney guidelines, they've actually developed a nice equation where your clearance, and we provide this at THD, and I don't know any other lab that does,

we give you a clearance based on creatinine, we give you a clearance based on systatincy, and we give you the best clearance of all based on both of those parameters. And then you segregate biophrican American and the african American. And that's because creatinine you segregate by African-American. And you can see it, because creatinine is very different in African-American.

So there's a lot more to those EGFRs. If you haven't studied it lately, then it might be going on. And if I'm going to do a biomarker, if there's no other restrictions, and looked at might be a third-party payer or somebody else, I'd rather do the most informative biomarker. And that would be the dual EGF4

and maybe some SDMA, or SDMA thrown in as a real marker anyway. And that SDMA ADM marker, I really wish we could take you to just be five or six PowerPoint slides and you'd see these pathways. And maybe I'll tweet them in the next week or so in the next slide. Yeah, we can just attach them here easily to the show. And you'll really, it's not a high, highly,

it's staring right in the face how they work and what they're doing. Now, we touched on something earlier that I know you wanted to come back to and we were deliberately short on it, but I'm trying to kind of think about how to land this plane here. You want to go back and talk a little bit about what a remnant is. It gets so much confusion about remnants. They're talked about like they're one homogeneous entity. Yeah, like there is a person, well, every known lipoprotein class, including LP little A,

has remnants. All a remnant is, is a smaller part of its sister particle that's in the same density class. So VLDLs come in multiple sizes. You got the big ones which are only found in people with triglyceride abnormalities. If you don't have a triglyceride disturbance, you will never have a big VLDL particle. You'll have medium size and very often just small LDLs. But if you look at your LDLs,

there's a normal size particle. There's a big LDLs and a small LDLs. Everybody has a heterogeneous mixture. There's no human on particle, there's a big LDLs and there's small LDLs. Everybody has a heterogeneous mixture. There's no human on the planet who has 100% exact diameter of every single sub-fraction of a lipop HDLs, very widely in their density and their size and their diameters. Even IDLs, there's a certain diameter range or density range where here's the upper limits of what you would call an IDL and here's the lower limits of Wendy and I call it an ideal, an LDL. Or when does a small VLDL?

I can't call it a small VLDL anymore, or it's called an ideal. But wait a minute, wouldn't an ideal be a remnant of a VLDL? If that LDL has a VLDL or IDLR, and is in an LDL, a remnant of a IDL or maybe a VLDL or IDLR, a gene is in an LDL, a remnant of a IDL or maybe a VLDL, calymicrons, as they lose their triglycerin, some phospholipid, as they become smaller calymicrons. Calymicron remnants, which are, for the most part, if you're lucky, cleared by APOE receptor somewhere, but there's calymicron remnants floating around. So, what is the only particle I really care about?

A part, an APOB particle I can wind up in your artery wall, get oxidized and deliver the starroles and you oxidize them and then you got plaque. So what forces them in? It's particle number. Now I've also explained, all right, if that's a APOB particle number, LDL P is your first biomarker. APOB is simply an LDL P biomarker. It's not counting VLDL particles because there are so few of them. You're certainly not counting chylamicrons because they're even fewer of those.

So APOB is identifying to you way too many LDL particles in this person. But there is absolutely no doubt. Even though you have way, way more LDL particles than you do have VLDL particles, because VLDL particles are two or three times bigger than an LDL, the volume of the spears, the third power of the radius, they do carry more cholesterol molecules per particle than an individual LDL particle. But of course you have so many more LDL particles than even VLDL or whatever you think a VLDL remnant is. Most of the cholesterol getting into your

audit wall is still LDL delivered, but I am not denying that VLDL particles cannot deliver cholesterol and get oxidized into the audit wall. they can. So what has been the classic definition of a VLDL remnant? Well, they've always said, well, do that conversion factor. We told, divide triglycerides by five. If it that's high, the VLDL cholesterol is high. Those are, they have too many VLDL remnant. And no doubt, if we really had a VLDL remnant test, that's true.

But it would not be true in other people. So, and our support man's perhaps estimate of remnant. It's trying to clarify what you're saying, right? Because I think it's a bit confusing to the listener. You can estimate VLDL cholesterol in two ways. You can take triglyceride and divide by five, and the higher the triglyceride level, the less accurate that becomes. You can take non-HDL cholesterol and subtract LDLL cholesterol from it and you'll get an estimate as well.

Those two don't often agree, by the way, but nevertheless, you have two estimates, but that still doesn't answer the question. Which of those go on to become pathologic remnants? Correct. So all your identifying errors, you have increased cholesterol content in VLDL particles, and because the ones we fear the most are remnants, we're just presuming, oh boy, there's got to be remnants here. So whatever therapy you're thinking of doing in this person, you better get rid of some

remnant therapy too. Well, all of the FDA approved drugs at lower APOB, it's statin, azetamib, fibrates, which are approved to lower the whole cholesterol, even though they don't really do it that much. Pieces cannot clear, all apobie particles, including remnants. So your ultimate solution, now your first solution might be nutritional,

if it's not somebody coming off their bypass who is in the nightmare, risk range classification, where I think you need a lifestyle and pharmacology day one. You just don't have too many decades have passed. You shouldn't be puttin' around on a real short time. You know the nutritional therapy. If I think you have remnants is gonna be, I'm gonna address insulin resistance in you. And so I'm being an advocate of some degree of carbohydrate restriction and certainly a clear advocate for a lot of reasons, apart from even APOB would be the fasting as part of your diet and so great. If you want to use your VLDL cholesterol and it makes you

think there's remnants and you're going to suggest the therapy, I would tell you if you're a total drug guy that I had a drug, then that's the person you give a vibrate to with your statin because that's where what the vibrates really do well. But I can show you that is that I might have to statin clear as many remnants as that combination too, but I think vibrates bring other things to the table that perhaps that he does in people with triglyceride rich lipoproteins. And what it is going to be, so it's how I really think we're going to have to identify remnants.

So just to even tell, there's a laboratory that produces, they separate VLDL particles by ultra-signification. The NMR people used to report total VLDLP, but they would also give you large VLDLP plus medium VLDLP plus small VLDLP. And we used to say, well, the small VLDLP, those are the remnants, that's the mark. Well, they don't do that anymore. They only give you the large VLDLP anymore. Those animal generating labs that have the proprietary ability

to release VLDL particle data, and that's not all animal data. Is that liposcience or lab quarter? There is no more liposcience. It's lab quarter. So you will get a large VLDLP, and it has one reason and one reason alone. It's a lipoprotein marker of an insulin resistant state. That's it.

It's not a goal of therapy. It's nothing. There's no data that, what you do to VLDLP affects outcomes, although I'd make the case that maybe it does. But it's just an IR marker. I can measure small dense LDL cholesterol, HDL2 cholesterol, just small LDL particle concentration. I can do an insulin level in 10 other tests that tell me you're insulin resistant. So I don't need any VLDLP. Mark, I mean, they were using that as part of their IR algorithm score.

Yeah, so if you don't have that, and they use, they factor in VLDL size there, because the big triglyceride rich VLDLs are Markov insulin resistance. But if you're measuring insulin levels and other insulin biomarkers, they're no better than that. I don't know if they're any better than just measuring small LDL particle concentration,

at least than a drug naive person. So fine, it is a marker of insulin resistance. But this other lab, the centrifuge, and they tell you, ah, look at our smaller VLDL cholesterol, those are remnants. How do they know? All they know is that person has extra cholesterol in their small VLDL particles. But VLDLs, depending on two things, it's ApoE content and it's ApoC3 content, is going to be virtually instantly cleared. So if your small VLDL particles are being rapidly cleared by your ApoE, ApoB100 receptors, what I'm talking about. So in other words, if you took a bunch of small VLDLs and some of them had lots of ApoE, APO B100 receptors. So in other words, if you took a bunch of small VLDLs, and some of them had lots of

APOE and very little APO C3, those aren't remnants. They're not pathological. They're not sticking out. They're small VLDLs. That's what they are, but are they disease-causing VLDLs? Right. Look, some of them probably get in, but in versus few compared to LDL particle number. So, and also, we met.

And then very few relative to a small VLDL that would be high in APO C3 and or low in APO E. It's never gonna be clear. APO C, the main down, oh, there's a lot of downsides, the APO C3, it's a pro-inflammatory protein. It really enhances VLDL production in the liver,

but it just retards their clearance. And it probably interferes with the hydrolysis induced by lipoprotein lipase. So you're increasing half-life of all triglyceride-rich lipoproteins, which let's see etp exchange occur longer. And what is etp exchange doing? Bringing more cholesterol into your VLDL particles, enhancing cholesterol enrichment. Those VLDLs are losing triglycerides of the other in cholesterol. These are all the pathologies that might go on if you have delayed clearance, and C3 is going to delay the clearance through multiple reasons of these particles.

I want to blood test the TELS Media-Apo-C-3 content of your APOBs. LDLs that have APOC3 cannot be cleared in one of the early, preavocal trials, the preavostat and trials, the care trial, they went back in a, who would high-track list rides, gets car and area events? And this is Frank Sacks up in Boston, and they've been able to measure this

and sophisticated lipid labs for a long while. If your LDL had C-APOC3 on it, preavostat and was a useless drug, didn't reduce any events. So what? It still reduced APOB, but it didn't reduce events. It would clear some LDL particles. It didn't reduce events in people

at high triglycerides. So, so, the APOC3, it's not measuring triglycerides. It matters, it's APOC3. And a lot of people with APOC3 might only have a triglyceride of 110-120. Wait, what's trial was this? A care trial, cholesterol and acute. It was a second secondary prevention trial. Symbastatin 4S was first and that was suede with super high LDL cholesterol and heart attacks.

This was done in Boston at the Brigham where they enrolled people with unremarkable at the time, Elk cholesterol, 130 or lower, who had heart attacks. And they gave him privacy and got this pretty much the same event reduction as they got in the forest trial. But the ones that had high trig didn't have the reduction. Yeah. So they went back in a post hoc analysis. And those who had high trades, a provocal lower triglycerides, does it matter? That's one of the benefits of Travis Stanton. Well, the only people that got event reduction where Travis Stanton lower triglycerides was those who had

ApoC3 enriched all the particles. And because Sam's company also working on it. Yeah, and production is anti-sense molecule. It's going to stop ApoC3 production because you Peter, I believe you also know the G Mendelian thing there is gain a function loss of function of ApoC3 is tied into longevity also. Actually, I think this is of all the major longevity genes. I do not believe and I could stand corrected, but I'm in the process of writing for the book now. I don't think there is a longevity gene on cardiovascular

disease that is a stronger predictor of longevity than hypofunctioning APOC3. Yeah, so in very interesting, I just got tweeted about it. I'm sure then the last week a very interesting trial That if you're gonna use an omega-3 fatty acid when they compared DHA versus EPA DHA is the one that lowers EpoC3 not EPA so all of these mega advocates of EPA I don't know if ApoC trees involved there involved there, maybe you better look at some of the other things.

I used to see myself as more of an EPA guy, and then my focus on DHA, I think, became more something I saw in the mild cognitive impairment literature, which was the importance of DHA and the brain, but I didn't realize this DHA C3 relationship. Yeah, so there, look, from my mind for years, it's been omega-3s are not lipid drugs, ignore them, don't use them to put around with lipids, because you don't know what they're doing. That's changed now.

Clearly, high dose prescription strength EPA can be a helpful adjunct of therapy to lower APOB, and whether it's with remnants or whatever it's doing, it's lowering APOB and whether it's with remnants or whatever it's doing, it's lowering APOB in additional 8, 10%. Great. And it's a pretty innocuous therapy. I always worried about those who might not be able to convert EPA to what I believe is

the necessary DHA also, especially in the brain. So, but I can measure that in the plasma. You know, I've been thinking about, I'd like to have Bill Harris on the show as well to have a discussion about this, because at least at the time of our recording today, I would say that the mainstream view of EPA and DHA is that they're useless, right? That's the press for today.

That's the mainstream view. Yeah, the mainstream view is abandoned in all of these dumb sort of supplements, but as is often the case, when the mainstream says something in a declarative fashion, they're usually wrong. Especially on a nutrient, you know, where they're looking about what you're eating,

not taking pharmacologically, where you might have a real trial. And they're confused by supplements versus pharmacologic. Most of the trials that they would quote is, omega's being useless, they're using some, not a pharmacologic dose of these things. And they're not measuring even whose deficient in omega's and if you're not deficient in it, why would I even give you an omega's

re-prone? And measuring fatty acids in the blood, I would encourage you to measure red blood cell omega-3s that are like a glycohemoglobin, have a 30 or a 60, 90-day half-life rather than a plasma, free fatty acid or a meg which might be what did you eat for lunch. You know, so there's other intricacies involved, but nonetheless, just all things to think about there. So in this DHA, what APOC-3 is kind of interesting. Now look, some people, if you're just gonna drown

in an EPA, do convert it to DHA. So it's not an issue, but we can measure that. And I think we know, oh boy, EPA do convert it to DHA, so it's not an issue. But we can measure that. And I think we'd know, oh boy, and you, you got to have some of that either eating or supplemented, you know. Are you pushing patients to wards closer to 10% red blood cell EPA DHA level these days? Or you? Well, I don't see patients anymore, but if you want to ask me, yeah, that would probably,

you know, there's no, you know, Bill Harris would tell you, why not make it 14%, but we don't have any data that would show, hey, that's harmful, but we don't have any data showing you can even make it that high yourself. Not even happy stacks and things like that. Easy to use. So far, anything that they've never turned anything

from an omega-3 into coagulation disturbance. I mean, it's definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good.

I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good.

I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. I'm definitely not good. Oh, sorry. Yeah. S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S.S But just this is a guy who is as devoted to understanding the entire body of literature and science of omega fatty acids in general. Fatty acids in general, especially omega trees and sixes. As you are to lipids. Oh, way more than me.

And he was a colleague I worked for three or four years with. I loved the guy we'd launched all the time. We go, wow, so he has taught me so much. And he is the guy who developed the red blood cell, phospholipid fatty acid assay. So he knows what he's talking about. And it gets so intriguing, because even for those of you listening who may be taken in omega three or prescribing

in omega three, be it a supplement or be it a prescription product, what vehicle is that? It's just, is it, are you prescribing a free omega-3 fatty acid? You're not. There is an FDA-approved product that the company would develop and it's not brought to market yet. So you're either prescribing a starified omega-3 fatty acids or it's a starified to something else or it's a starified to glycerol as a phospholipid or it's a starified to glycerol as a phospholipid, or it's a starified to a glycerobac bone, where it has three fatty acids, but only one of is an omega-3,

or are you buying a super enriched that all three fatty acids are starified to an omega-3? You would need very small amount. So what is the vehicle in your favorite supplement that's carrying the old, all of that comes into the pharmacodyne. You know,ne. I just realized, I don't actually know the, because there's only two supplements over the counter that I fancy.

One is Carlson's, the other is Nordic Naturals, just based on some of the toxicology stuff, but I don't know the answer to the question. You just have to get that information unless your brother works there and is privileged to that, the companies won't even tell you what they are starerefy and look you hear about these krill products. They're phospholipids and that means there's one fatty acid on them. So you've got to prescribe a lot of krill pills to achieve a certain omega-3. The way less than you would if you had a diasterefied or

got it luckily enough to try a star-fied triglyceride, a vehicle. I'm always happy it's when I see my patients just eat enough salmon. So listen, at the end of the day, that's all cool. It's good to know, but at the end of the day, whatever way they're somehow getting omega-3s into your body, if you're normalizing the omega-3 index, does that even matter all that other stuff?

So it all depends, but I would employ you to follow up, please. Yeah, I want to dig into this a little bit because it never occurred. I get to be honest with you, I'm ashamed to admit this because I hate being the guy who makes dumb assumptions and is too lazy to follow up. I've always assumed that the high quality EPA DHA supplements were triasol glycerides. Almost none of them are. They're mostly monoglycerols, but it's glycerol with two other fatty acids,

plus one omega-3 fatty acids. Yeah, yeah, yeah. And what are those other fatty acids? If nothing else, there are calories that you may or may not need. Or are there a harmful fatty acid even or so? Yeah, who knows? And we'll give them a bottom of this.

And there's no pharma grade DHA. Do you not? No. But here's what there is. And it's already FDA approved, but the company that developed the product is not brought to market. But I think they're going to,

because this November at the American Hot Association, you are going to get the people at risk who are on statins and half of them are getting statins plus EPA and the other half are getting statins plus EPA plus EBO, no EPA. And we're going to get outcome back. What dose of EPA? It's high, it's three, four grams. It's the prescription strength.

So are we going to see cardiovascular? All indications and we're all optimists are it's going to be a positive trial. They haven't stopped it at least for futility. They certainly haven't stopped it for toxicity. The trial is over. They're generating the data now. Wouldn't they have just stopped the fertility and gone away if it didn't work? So we're all expecting that it's EPA added to the sentence.

It's going to work. Why wouldn't it? It's an EPA, but probably has other physiologic attributes that can reduce certain inflammatory markers, hey, and it's a nice, apobel additional lower. Now, the company that has developed free omega-3 fatty acids,

so they're not a starified to anything. That means they're very bioavailable. You just swallow it. Remember, anytime you swallow in a starified omega-3 fatty acid, you have to see crepe pancreatic enzymes to de-asturify it, because it can't be absorbed without that. Even phospholipid's krill oil has to be de-asturified by a light, specific light paste coming out of the free fatty acid. The free fatty acid is going to come right in, but we don't eat it.

You know, you might in certain foods, but even most of the food you eat, it's triglycerides that are delivering. Don't free fatty acids taste horrible? I don't know, they've ever, maybe that's why they're not there. Or I think most of the time they're stored as energy and is not free fatty acids. And so they've got to be de-asturafiting. At the time, their stored is energy and is not free fatty acids. And so they got to be de-asturified. But anyway, this company that has them, why didn't they, because this is a company that

manufactures a statin. And what they were hoping was they thought the people make an EPA, the FDA was going to give them an indication based solely on additional LDL cholesterol lowering or apobel lowering that will let you come on the market pending your outcome data because non-HDL is better whatever the FDA didn't, FDA even told them they couldn't do it. The company, which is Amerin, actually took the FDA to court in the Supreme Court, says, no, even though you don't have an approval for it, you can at least go share this with doctors.

And that Amerin EPA product, Vesipa, has skyrocketed in sales, because doctors believe this, hey, additional data with the Vesipa. So, the company that, and so you would add Vespa to your favorite statin of choice and then your taking control. Which statin do they make? No, they don't make a statin, they make EPA. So they want you to add Visepa to whatever statin you're holding. Oh, why don't they also make a statin? No, they don't. So you can pick your favorite statin, but now you have a, like a Zedabab, you might add to a statin, you can now add Visepa if you're evidence-based, you're going to follow your choice. I'm going to wait till November.

I would too. And not that I wouldn't be using EPA, DHA for perhaps other reasons, cognitive or whatever, just cell membrane health. But the other company that makes a stat and called Resuvistat and the pretty, and that would be called AstraZeneca, is the one that owns this. So what they were clearly hoping that had, Amarin got an indication tattoo to a statin, they would have released a combo product called Resuvistatin, their EPA product or so.

And you would have in one pill your statin, plus your proper dose of Omega-3s, and they would be free omega-3 fatty acids, which would zoom right into your body. I got a feeling if the and by the way, they are completing their own big outcome trial with Resuva statin plus the non-asturified free fatty acids. So they'll wait for their trial too, But if this first trial works, why would there's not even work better because it's combining it with the most potent statin. So all these people who have been badmouthing omega-3s with no trial data may have to change at least some of that talk come November at the American Heart Association. It's the biggest trial going to come out of AHA this year, at least in the lipid world. So pay strict attention. We'll month or so before. Normally they don't

leak out that data because that somehow prohibits publication and prestigious journals. Some companies do because it just means so much financially to them that it'll get published somewhere. So I don't know. One way or another, we're gonna have it in November. Now, we've danced around this idea of red blood cells for where all they keep coming up. So let me redirect us to another topic, which is you've already said red blood cells per molecule carry many, many more molecules of cholesterol

than any lipoprotein does. Why don't red blood cells cause atherosclerosis? Because they're not invading your arterial wall and not subject to oxidative forces where a macrophage is going to ingest the red blood cell. Do they not invade the artery wall because they can't penetrate the subendithelial space? Yeah, they're gigantic. Now listen, can a red blood cell get into plaque? Yeah, through the veins of a serum. So, could there be some in there that are... So, the veins of a sore, meaning from the other side?

Or, remember, artery walls get the arterial supply, they need oxygen. Even plaque has little capillaries and stuff. So, are there red blood cells and expanding plaques? Sure. So, not to say they're not a tiny little part, but that's not your primary delivery of oxidized phospholipids and Starroles into the artery wall. Red blood cells are not being entering the artery wall and being oxidized, you know, like the apobiparticles are. Yeah, so this kind of gets back to sort of the causality you have bazillions more apobaparticles

than you have red blood cells. Also, so yes, quantity wise, they're carrying a lot of cholesterol, but not red blood cell number one, versus LDL number one. So the size of the LDL particle, obviously, is what enables it to easily get into and move it out of? Yeah, not number in size, but as you know, I've taught you this a long time ago, any VLDL or under 70 nanometers can work its way into

and end the DLL gap or an arterial wall through a scavenger receptor, whatever. So not to say remnants are an athergic, they can't get in because remnants are way bigger than an LDL. No, they could, but there's just more of the LDL particles. So if this is a diffusion gradient force that you'm in, there's a hell of a lot more LDL troublemakers than there are Remden troublemakers.

Not to say some big tough guy is in a big troublemaker by himself, he is, but he's, which would you rather have a thousand guys coming at you? Or one guy, I take my odds that I could beat one guy rather than a thousand guys coming at your one guy. I take my odds that I could beat one guy rather than a thousand guys, you know. Yeah, yeah. You know, I figure it's hard to believe we've been going out this for almost seven hours and I feel like there's at least another hour or two we could go but at the same time I want to be sensitive for the listener. Normally I say I want to be sensitive

to the guest but I know you and I can keep talking about this for another six hours. And we're going to go have dinner with Jamie Underberg tonight and just continue this discussion. I wish I had a microphone for dinner because I have a feeling that's going to be equally interesting. One of the things you talked about at the very outset was a really close friend of yours who got you into hockey. Took you to your first game at Madison Square Garden, got you hooked. You were both obsessed with being firefighters. He went on to become a firefighter. You went on to become a lipid educator.

Yeah, so let me just pick up that my absolute, you know, if you look back in life who are some of your absolute best friends, your high school buddies, who you really spend all that enjoyable, the type of enjoyment you can have at that age, that you never can have at another age, and you can do things, and especially when we grew up in, we were in high school 59, a 63, you could get away with a lot of junk in those days, whereas today, we were in the expel the real quickly or so with some of the shenanigans we do. So, and look, I joke with Peter when I was telling this story, I think he really wanted to be my best friend because my father was a fire chief in the town of Patterson,

New Jersey where we went to high school. But even if that was true, I love firefighting. What do I care if he loves firefighters? We used to get on our bikes and ride the fires all the time together and watch fires and stuff. Her drive the fire houses. So we were really tight for a million reasons. And we just got a long personality was, but he is the guy who invited me to my first

ice hockey guy, which was certainly impacted my life and my son's life in mega ways. My son's a very successful guy. And he would tell you, you would never be half a successful heading, not played ice hockey and develop the teamwork and the camaraderie. Speaking of a fire engine. It is perfect timing to have a fire truck going down. But I'm going to just keep talking about this fire truck because it's not high lipid science. So my buddy there, he went and became, and I knew him all my life and I went and became a doctor, but right in it, in that same city or in a suburb of that city. So it's not like he didn't know where to find me.

But at a certain point in our life, I knew my buddy, he or Dr. Nye, I got this cholesterol problem. They tell me my cholesterol's up in a blood. And I was probably at the point where we were really taking cholesterol serious and we could do something about it. Let her, you gotta come and see me, come on.

You know, I was probably even the days before I was just solely dwelling on lipoproteinology and lipidology, but I was very aggressive with understanding cholesterol and knowing look who I evolved into. So it would have probably been a smart choice for him to come up. It's not like I was gonna charge him

and he couldn't afford me. He's a fireman in a big city. He had this good of health insurance as you could ever get. So it's not like it would cost him 10 cents. A lot of firemen did pick me as their doctor because of who my father was and I knew he was a guy who likes fire engines. We used to see him as a kid in the firehouse. I want him to be my doctor. He knows what I do. Earl just is one of these people who thought the father I stay away from doctors. The better I don't want to hear what they got to tell me. I don't want to be on a medicine. I don't want to do anything.

And Earl got buried in his mid-50s with a sudden acute myocardial infarction sitting at home watching TV. He could have been climbing a ladder out of fire. But, if he did die to fire, his name would be on the memorial monument up in that city, but he died at home the next day. So, not that I want his name on it. I really wish it was because he's just such a dead, but there is such a needless death. And I think across America all the time, there are many young age needless deaths

occurring with a very preventable, treatable disease that's being ignored totally because they don't go and get it checked or they're getting bad advice based on the wrong metrics. So my buddy there is the perfect example. But what a tragedy because had he made the right, I like this guy, he's my best buddy, he's not going to screw me or do anything wrong. Let me go to him. He didn't. Every time I saw him, I'd remind him, oh, come up, come up, please come up. Yeah, yeah, Tom, never did.

Tom Well, in many ways, that's a reasonable and sad way to kind of end this discussion, but it also brings it kind of back to why we, why do we get so animated about this topic? Well, I think, as you said, we think of this as, you know, one of the big three diseases that kills most people in the civilized world. Once they get out of childhood and by civilized, I really mean develop the people know what I mean. But of the big three diseases, this is the one where I think we know the most about it and therefore by extension, it's probably the one that's most delayable.

Never want to say preventable, right? We use that term, but in reality, what does that mean? It means delay. And so if Earl died in his early 50s, maybe with the right care, he could have died in his late 60s. You know, again, if a guy's dying in his 50s of heart disease, he's probably got really bad disease. He needs a therapy at a real young age,

but he could have hung around for a while. He's got grandkids and children and stuff who really wish he was still here to fart upon me, was a beloved farm, and they always, he was still on act. He'd be retired by now, but he's just one of these people, like God sends to earth that do nothing but good while they've been here through their whole life.

He had saints as parents, and he was so tragic that he left us. It's such a young age and got driven to the graveyard on the back of a fire truck with a flag on a Vietnam veteran. So, but just so, so sad. And listen, I want to wrap this up myself. And I used to wrap up a lot of lectures I did with this. And, you know, because my lectures were all high science no matter what group I was speaking to. So I always wanted to say, you ought to come out at this lecture that I gave him, maybe with all the things, if you really sat through everything we talk about today to say, guys, an idiot, or he's on to something, and I thought I understood this topic, but maybe I need to understand it at a higher level.

So everything is study, study, study. I didn't learn this stuff overnight. My life has been simply in this field. Yeah, well, I'll say a couple things. I'll say a couple things on that. So first of all, I obviously want to thank you for the influence you've had in me. And I, I don't know, I just feel really lucky.

I think that I got plugged into you and Alan and Ron just out of the gate to have met the three of you. So early in my interest in this topic saved me so much time, because it's one thing, I mean, no one can substitute the amount of time you have to spend obsessing over this topic and learning it, but boy, when you can have that curriculum curated for you,

you shortcut it by, you know, three X, I'm sure. It's a gift and I'll just extrapolate on it because Peter named three guys, he can get in contact with pretty quickly and get answers. As I evolved in this world, I had 20 guys around the world who liked me a lot because of what I explained things, what I could illustrate for them. So I've been blessed by I've mentioned a few today. It would take me another 15 minutes to list them all, but so many of the I call them the lipid gods out there, the people who have spent their real life in research laboratories

and clinical trials and taking care of people in the worst clinic, lipid clinics, see, and they still are available to me. But that's who I use. I don't go on the internet and read something or make stuff up. I try and ask experts about a lot of things. Not that you'll ever get consensus on anything, but those of us who do have those avenues open, which many do not, but they're not afraid to still pontificate about something that's kind of sad.

Yeah, and I can't remember if I made this. This will be my final point on the topic. And I can't remember if I made this point on a previous podcast or not. And if I did, to the listener, I apologize. You know, I started out in mathematics and engineering and really loved those things. I excelled at those things. Took great pleasure in being a first principles thinker. So one silly story at the end of my freshman course in sort of dynamics kinematics,

like sort of Newtonian physics, you take a final exam and you are allowed one piece of eight by 10 paper that you can write on both sides as much as you want, whatever formula you want. Because, you know, there were just so many equations you would have to know to go in and ace one of these exams. Now I was cocky B on words and I was really lucky as a freshman. I used to study in this dark part of the stacks where I met a real upper-classman guy. His first name was JP, I don't remember his last name,

but I'll never forget him. He was the only guy I ever met who decided to take two engineering disciplines and finish him both in four years. So he did electrical and mechanical engineering but I'll never forget him. He was the only guy I'd ever met who decided to take two engineering disciplines and finish them both in four years. So he did electrical and mechanical engineering in four years. The price he had to pay for that was he studied every minute of every day, but he also told me he didn't have the opportunity to learn everything.

Because if you wanted to take all of electrical and mechanical in four years, you had to accept that there were certain things you couldn't know. So he, all of his and mechanical in four years, you had to accept that there were certain things you couldn't know. So he, all of his study focused around first principles, inference. And he taught me this early. And so he saw me studying for one of my exams, and I was writing out something called the Corialis equation, which basically explains centrifugal forces under the condition of a changing

radius. And he said, you don't need to memorize that formula. You know how to derive it. And I was like, what are you talking about? He goes right out the formula for angular position and take the derivatives of it. You know, you know calculus. So I did. And sure enough, I was getting the same formulas to make a long story short. I go, I, I've become so totally, totally inundated by JP's reasoning. I go into my final exam and oh, you have to turn in your cheat sheet at the end of the exam. And I, this is again, just, I'm not saying this to brag about how cocky I was, but so I just have to stay. But the point is, I wanted to show the professor how well I understood this material.

The only thing I wrote on my cheat sheet in big block letters was the sum of the forces equals mass times acceleration. Because I was like, if you know the simplest of Newton's laws, you can actually derive everything at this level of physics. We're not talking quantum physics at this point. And he and I remember JP said, look, on every question, write it out, show them how you can go from one to the other. Because if you make a mistake, at least they'll see what you're doing. I ended up asing the exam and that lesson sort of stuck with me, and it served me very well through the rest of engineering and mathematics, including when it got really, really complicated, that in the end, if you truly wanted to understand something at first principles, you could derive so much.

Okay, fast forward a few years now, I find myself in medical school. I was not a premed. So I'm in medical school, not as a premed, but as a former engineer math guy who barely squeaked into medical school, meaning I took the MCAT having not even taken a course in biology yet. I had to take my bio class after. And I'll tell you that first semester of med school was brutal for me because I learned the hard way that you couldn't first principles your way through biology, at least not at the level, at least not until you gained a certain amount of familiarity with the basics. I couldn't walk into my histology class, look under the microscope, and on first principles

know the difference between the Golgi apparatus and the endoplasmic reticulum. You just have to know that stuff. I couldn't go into anatomy and physiology and pathology and just first principles my way into stuff. Eventually you can, but you have to have an enormous basis. So I sort of forgot all about that pain. You get through medical school and by the end it became, you know, it was very enjoyable, but it wasn't until I got to the lab to NIH where my mentor told me a great story. Now he's probably one of the most brilliant scientists I've ever known

and did a PhD in biophysics specifically for the purpose of wanting to make sure he was never in his words intimidated by a differential equation despite the fact that he was an immunologist. And he told me a story which I need to get the details of it because I don't remember the physicist he's referring to, but he told me the story of a physicist turned biologist who lamented once that the moment he switched from physics to biology, he could never again take a bath in peace.

Because as a physicist, he could sit in the bath and wax philosophically and think about lots of things on first principles and be very theoretical in his understanding, but as a biologist sitting in the bath, he always realized there was one more fact he needed to remember before he could draw a conclusion and so he had to keep getting out of the bathtub to go and look up a certain fact. That obviously disrupted the beauty of taking the bath. I think the long rambling story is a way of saying the following, I find this subject matter to be as complicated as any I have ever tried to learn.

And unfortunately, every time I have a brilliant idea, just based on first principles, I still have to go and check if it's grounded in the foundation of science. And sometimes it is, but many times it is not. I come up with an idea and I'm like, this has gotta be right, but, oh, they're physiologically impossible and there's even an experiment that one day suggested this or it's, I made an assumption,

but I can clearly see that it was not the case. So I understand your frustration and I share it and I think unfortunately that is the nature of biology. Yep and I remain in eternal optimists. I continue to teach lipids. I think clinicians know a bit more than we do in 1995 when I started this journey teaching and so that's all if I have to do it one of the time with people I try and teach them what I know. And hopefully you'll do your continuing education. And that's one of the nice things about medicine. But you gotta do it.

None of this comes easy. Yeah, it does. And there's a lot of complexities in medicine nowadays. We're talking because it's a highly pathologic state and leading cause of trouble. But there's so many other things to, boy, take to the much higher level nowadays. Well, Tom, people, I think, will certainly by the end of this know where to find you,

but on Twitter, which is where you spend the most your time your at Dr. Lipid. Grants me. Yep. And this will, I mean, we're generally in our brief existence as a podcast already known for probably producing the most thorough show notes ever. I'm suspecting that this episode, which will probably break into several parts, will have the most robust show notes that we've done. And I love, by the way, that there's another fire truck going down. It's perfectly, it's totally appropriate. But also, if there's anything else that you think of, let's just talk about it, where offline even we can just get to it, where there are other resources you think people ought to go to. Again, I will steer people away from your 2000 to 2004 writings.

But I think there's going to be a number of people who listen to this, who say, you know what, look, I might have missed half of what those guys talked about, but there's something there I want to make sure I understand better, because in the end, every doctor wants to do the best by their patient. I mean, I believe that wholeheartedly, I get very frustrated when I hear people say that doctors are in the pockets of pharma companies,

and they are just in it for the, I mean, that's sure there's gonna be some of those people, but I haven't met those guys. The doctors that I meet, the men and women I meet who take care of patients, they all wanna do the best by their patients. And I think that those are people who are going to want to invest a little bit of their time in understanding this problem a little better. No, I can't say it anymore, Naden. As you listen to seven and a half hours, you can hopefully

piecemeal market clearly for depending on the list, it's going to be things over your head. Even if you are a super skilled lipidologist, there's gonna be some things you said, what, let me read about that or so. But it's just trying to open your mind and understand, there's a lot going on here. The field is infinitely more complex than you ever imagined.

It took me a long, and I'm a, as Mike Davidson calls me, Tom's a self-taught lipidologist. I mean, I didn't spend two years down at the National Heart Lung and Blood Institute, even though the director of that NHLBI, I Alan Romali, and I just authored a 70-page chapter in the Teets Book of Molecular and Clinical Biochemistry, all about lipids and apoprotein. So I think to be an invited author with a guide.

And you sent me a preprint of that. That's a remarkable. So I mean, it's an expensive book. I don't expect you, and if you're not a lipidologist or somebody seriously into this clinician, that's what you go out and buy. But there is a lot of information out there. So, and just be careful on what you, that's ridiculous or my cock and

Amy theory based in no clinical trials or sciences, what I believe, fine, believe it. You know, this is America here. I can't lock you up. I'm not the lipid police. Tom, thank you very much. It's hard to believe this has been seven hours of discussion today, but it's been worth every minute to me. And I've learned a lot in this discussion. So that's, to me, that's always a, I mean, for selfish reasons, that's sort of my primary objective is to learn as much as I can, and then along the way, if others can learn too, that's a bonus.

And without a year of my intermittent fasting and program from Peter at TI could have never had the energy to save you. Even to use my tongue. So, for brain. So, thank you again Peter. Yeah, my pleasure, Tom. Thanks. You can find all of this information and more at pteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safariafari at peteratia-md.com. What's a NerdSafari you ask?

Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social you can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, ATIA, MD. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only

and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition

they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and or advise, please visit peteratiamd.com-forward-slash-about. at md.com-forward-slash-about.