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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions along the way. I've spent the last several years working with

00:00:19.840 some of the most successful top performing individuals in the world. And this podcast

00:00:23.600 is my attempt to synthesize what I've learned along the way to help you live a higher quality,

00:00:28.360 more fulfilling life. If you enjoy this podcast, you can find more information on today's episode

00:00:33.000 and other topics at peteratiyahmd.com.

00:00:41.280 Hi everybody, welcome to the fifth and final episode in the week of Tom. This is the Tour de

00:00:48.480 Force Magnum Opus course on Lipidology. As we round this out, we talk about a number of things. We

00:00:55.000 talk about LP little a, inflammation, oxidized LDL, remnants, red blood cells and cholesterol,

00:01:03.140 a biomarker called LPPLA2 that you've often probably heard about, another biomarker that

00:01:08.400 you may have not heard of called ADMA or asymmetric dimethyl arginine, and SDMA, symmetric dimethyl

00:01:14.640 arginine. And then we kind of bring it back to what is one of the more tragic stories in Tom's life,

00:01:20.280 which is a friend of his who unfortunately probably had FH, wasn't treated, and in many ways is sort of

00:01:28.120 one of those patients that still kind of haunts Tom. And I think, you know, we opened this back in

00:01:33.140 part one by talking about Tom's passion for two other things, firefighting and hockey, and how that

00:01:39.640 passion is what really got him into, or basically allowed him to apply himself to this new field once

00:01:46.760 he became obsessed. But also I think most physicians listening to this will have a similar story where

00:01:51.620 there are certain patients or there are certain personal relationships where a loss of life stays

00:01:56.720 with you for a very long period of time. And in many ways, it colors what you do over time. So I hope

00:02:02.300 you enjoy this fifth and final installment of the Lipidology Advanced course. And next week, we'll be

00:02:09.560 back to our regular scheduled programming where we're just doing, you know, one podcast a week.

00:02:14.200 So I hope you've enjoyed this and I hope you find the show notes very helpful. I can't express how

00:02:20.480 much work has gone into it. So without further delay, here is the final episode with Dr. Tom Daseberg.

00:02:28.540 This will be a nice way to dovetail niacin, statins, and PCSK9 inhibitors. What lipoprotein have we not

00:02:36.220 discussed today that would tie in a discussion of those three? Well, the astute listener realizes it's

00:02:42.260 our good friend LP little a. All right, why do I bring this up? So LP little a, there are some

00:02:47.680 people who still argue, hey, niacin makes sense because it lowers LP little a. I'm going to save

00:02:54.940 everybody on this podcast the brain damage of listening to us discuss that for the next 20

00:02:58.900 minutes and just bypass us to the more interesting question, which is why don't statins lower LP little

00:03:06.660 a? Well, first of all, we need a better understanding of LP little a clearance and

00:03:12.880 personally of the belief that it is the LDL receptor. There is a plasminogen receptor that

00:03:18.120 could clear some things and there are macrophage receptors that depending what else is going on

00:03:23.740 might internalize some LP little a and get rid of it that way, but it's the LDL receptor that clears

00:03:28.860 it. And also let's pause for one second because I realize even though we've already done an entire

00:03:34.140 podcast on what is LP little a, there's someone listening to this who hasn't heard it. You'll go

00:03:39.180 back and listen to it. I'm sure I'm going to do future podcasts where I interview the world's expert

00:03:43.620 on the topic, but Tom, can you give in two minutes a description of what LP little a is?

00:03:49.380 Yeah, it's an LDL like particle to which is adhering another apoprotein that shouldn't be there and it's

00:03:54.780 called apoprotein little a and you must pronounce it as little a. That means small case rather than

00:04:01.280 capital A. Lipoprotein capital A is apoprotein A1. That's the main apoprotein on an HDL particle.

00:04:09.820 So if you tell me you got lipoprotein A, how do I know what are you talking about? You got

00:04:14.000 HL particles? Are you talking about little a, which clearly identifies to me this potentially

00:04:20.480 pathogenic, atherogenic LDL particle. So use the correct terminology with everything.

00:04:26.300 And Peter's got that nice podcast on it. Our metrics of is that present in you or not is

00:04:33.260 most labs will run an LP little a mass, which is the weight in a deciliter of plasma of the weight

00:04:40.960 of your, all your LDL particles and everything that's in them. They're triglycerides, they're

00:04:46.080 cholesterol ester, they're phospholipids.

00:04:47.840 Meaning any lipoprotein that is carrying an apolipo little a, you weigh the entirety.

00:04:54.680 They're all of the LDL density. But you're weighing everything. You're not weighing apolittle

00:05:00.120 a. You're not measuring apolittle a per se. Yes, that has a molecular weight, but the molecular

00:05:05.440 weight of apob is way higher than the molecular weight of apolittle a, but you're measuring that

00:05:10.920 too when you do an LP little a mass.

00:05:12.740 But the molecular weight of apob is known because it's pretty much the same. Whereas the molecular

00:05:18.180 weight of apolittle a is very, very variable. So that's another reason LP little a mass becomes

00:05:22.960 a useless metric. And how do I know how many cholesterol, triglyceride, phospholipid,

00:05:28.420 10,000 other lipid moieties, other proteins are on that particle. I don't. And you have a

00:05:33.420 heterogeneous mixtures of particles that would have variable amounts of all of those constituents.

00:05:38.040 So you can see there's going to be a weakness to measuring LP little a mass. Now, if it's really

00:05:43.220 high, you've probably got too many LP little a particles. But since there's almost no more debate

00:05:48.560 that the best metric for our LDL particles is low density lipoprotein particle number, there's no

00:05:54.900 debate among those who will truly understand that HDL particle number is your best available metric on

00:06:00.800 quantifying the number. And that is a better metric than guessing that using HDL cholesterol or LDL

00:06:06.600 cholesterol. Wouldn't you rather have a really nice finite count? If LP little a particles are

00:06:13.340 dangerous, wouldn't you like to have a excellent, accurate concentration in them? Well, the only way

00:06:19.960 you can do that nowadays, NMR provides those other HDL and NMR cannot assay LP little a particles because

00:06:26.940 NMR assays lipid content of particles, not protein content. So the only way I can give you an LP little

00:06:34.580 a particle count is I have to separate all lipoproteins electrophoretically and they all you'll see

00:06:41.140 little bumps on the electrophoretogram. VLDLs congregate here, LDLs congregate here, HDLs

00:06:47.620 congregate there. And what's that little bump that is in this person, but it's not in that person? Oh,

00:06:52.160 that's LP little a because that's due to its surface charge where it migrates between the cathode and

00:06:58.260 the anode and the gel that you separate them on. So if I didn't take that LP little a hump and I

00:07:05.240 immunostain it with a antibody that binds to ApoB, I've just counted the number of particles that are

00:07:13.620 in the LP little a distribution range. I theoretically should not call that an LP little a particle count.

00:07:20.180 And I should call it LP little a ApoB. That's too much of a mouthful. It doesn't fit on a request

00:07:25.360 form. So of course it's abbreviated LP little a dash P. And to me, the downside of that is most

00:07:32.860 people think it's an NMR measurement, which it absolutely is not. Basically, if you want that

00:07:38.140 metric, and we've already announced I do work for True Health Diagnostics. I was working with a

00:07:44.120 different lab before that, the lab that actually did the development of the LP little a ApoB

00:07:49.920 assay, which True Health absorbed and got proprietary rights to when he did it. So that's it. And

00:07:57.540 believe it or not, there are people who are going to have discordance with LP little a mass, the weight

00:08:02.960 of the whole kit and caboodle versus the number of LDL particle counts in generally carly. But if you

00:08:08.700 really want to know, and also I find it useful, those at least those of you who are doing LDL P by NMR,

00:08:16.360 you have your total LDL particle count. But what does that really include? It includes LDLs that

00:08:22.700 don't have Apo little a attached, and it includes LDLs that do have Apo A attached. Now I throw a

00:08:29.040 statin at you, and we started to talk about this, that statin is not going to budge your LP little a

00:08:35.080 particle count at all. But the statin is going to dramatically lower your LDLs that don't have Apo

00:08:41.720 little a attached to it. So your LDL total particle count will get down a little bit. But

00:08:48.960 part of that is your LP little a particle count. But this shows you you are getting benefit when you

00:08:55.200 give a statin to somebody with high LP little a. Yeah, you're going to have to go after residual

00:08:59.760 risk. You know, one of the best examples I saw of this was an unusual case where a guy

00:09:03.680 had an LDL particle of 1600 ish nanomole per liter, but he had an LDL P little a of 600 nanomole

00:09:13.220 per liter. So even though it's an apples and oranges assay, directionally speaking, he's got 600

00:09:20.140 LP little a particles are nanomoles of particles per liter and a thousand non LP little a's. But when

00:09:29.060 you give him that statin, you're really only targeting the thousand. Correct. And so you'll

00:09:34.500 be surprised at the lack of response you might see because you're not getting to target those

00:09:40.060 600. No, but you'll still get your 30, 40, but your total LDL P may still be higher than you wish

00:09:45.260 it to be. And unfortunately that is LP little a particles. Then you can get into the theoretical

00:09:50.360 discussion right now that if I could get rid of them and basically the only way you can do that now

00:09:55.580 is to maybe try niacin, which is a weak lowering of a 20% or a PCSK9 inhibitor, which seems like

00:10:04.660 30 to 50%. Well, it would be an individual response, but it's in that range. So if somebody could at

00:10:11.440 least afford that drug, you can't get it covered by a third party because they don't have that

00:10:16.040 indication to help you manage LP little a patients. So, and that'll never come because could I ever

00:10:22.580 prove to anybody that the PCSK9 inhibitor because it's lowering LP little a is reducing events? No,

00:10:28.920 because they're going to turn around and say, ah, all it's event reduction is they're just getting

00:10:32.800 rid of the remnants and the LDL particles has nothing to do with lowering. And how would you

00:10:37.240 argue against that? We need a drug that only lowers APO little a or LP little a and does nothing

00:10:43.080 to LDL particles. And that drug is under investigation right now. It's an APOA synthesis inhibitor

00:10:48.080 where your liver is going to stop making the vast quantities of APOA that these people who

00:10:52.920 genetically inherit that propensity. This is courtesy ISIS. Yeah. Again, not to be confused with.

00:10:58.980 Let's hold our breath. But so until then, are there people in the lipidology world who would say,

00:11:04.700 Tom, until then, I'm going to continue to use niacin because lowering it has to work. I've been

00:11:09.760 around too long since seeing lowers this and lowers that and they don't work. So is niacin going to

00:11:16.140 have the same toxicity that I think it has in other people in LP little? I don't know.

00:11:20.920 But if you want to use that because you want to make a patient happy because you're improving some

00:11:25.980 metric, be my guess. I would not. I know many lipidologists who would not, but there are ones

00:11:31.920 and look, Sam Samikis is probably the world authority on this. Sam uses niacin in his practice too.

00:11:37.380 And I hope Peter has him on one day with a podcast. He would tell you until we get our dad on these

00:11:43.740 other drugs, I'll try and lower it a little bit. If nothing else, I'm hill hash to it. I'm

00:11:49.160 lowering APOB a little bit too. And I'm, if I don't know if it matters, but I'm raising whatever

00:11:54.740 HDL metric. By the way, although fibrates are probably our best available drug now to raise

00:12:01.000 HDL particle count, niacin, which blows away fibrates on raising HDL cholesterol, does nothing

00:12:06.820 to HDL particle counts. I didn't mention that before. Because niacin makes the HDLs bigger.

00:12:12.800 I was just about to say that could actually suggest it's worsening LDL, HDL function.

00:12:16.720 Yeah, you're right. So, but the niacin people will convince you that the big HDLs are protective,

00:12:22.500 it's laughable, and the small HDLs are harmful. Whereas the VA has real data showing it's the

00:12:27.220 opposite because the lipid poor HDLs are the ones that can accept the most lipidation. So,

00:12:33.580 you know, you're never going to have definitive answers on any of that, but yeah, there's a lot

00:12:37.200 of BS around. So, what's the best explanation for why a statin, which causes the liver to upregulate

00:12:44.280 LDL receptors, does not lower LP little a, whereas a PCSK9 inhibitor, which also net results in more

00:12:51.200 or a longer transiency of LDL receptors, seems to lower LP little a, even though that's not its

00:12:56.940 primary objective. And by the way, the data certainly tells us now that the main determinant of LP little

00:13:02.300 a mass or LP little a particle concentration is APOA production in the liver, not clearance.

00:13:07.760 So, until we can really inhibit production of APOA, who knows what you're doing. But until then,

00:13:14.420 let's see. So, how do LDL receptors clear these particles? Well, earlier, I think I mentioned that

00:13:21.940 LDL receptors looking for APOE or a section of the APOB that it can latch onto. There's a very specific

00:13:30.600 area on the APOB protein on any of the APOB particles that, because of surface charges,

00:13:36.940 will bind to a specific part of the LDL receptor. That area on APOB is called the LDL receptor binding

00:13:44.340 domain. So, if here comes an LDL particle and that domain is sticking right out, it'll stick right to

00:13:51.820 any expressed LDL receptor. But what if there's something camouflaging that APOA or that LDL receptor

00:13:59.740 binding domain on APOB, such as an interloper like APO protein little a, I could see where that would

00:14:06.660 slow the clearance of an LP little a particle, because it's not going to bind as rapidly and as

00:14:12.740 vividly to an LDL receptor. So, most of these people have way too many LDL particles. We express

00:14:19.940 whatever LDL particles we want. We try and express more with the statin. What are they going to grab

00:14:24.480 first? The LDL particles that don't have APO little a attached. And only then would they maybe

00:14:31.020 then start even grabbing APO little a particles or so. And do we all really have enough LDL receptors?

00:14:37.280 Most of us, for a variety of reasons, do not. Other things retard the clearance too. You know,

00:14:43.620 with the APO C3, I talked about other proteins that may be affecting clearance too. So, there are just

00:14:49.760 other factors at play. But right now, my guess is APOA is affecting totally efficacious binding to an

00:14:57.460 LP little a particle. It's camouflaging the LDL receptor binding domain on APOB. And therefore,

00:15:04.360 I better learn how to inhibit synthesis of it. So, Sam will obviously, hopefully we do get Sam on the

00:15:09.920 show and we'll talk about this, but that this antisense oligonucleotide is basically going after

00:15:14.300 the jugular issue, which is you inhibit the synthesis of APO little a. Yeah. And hopefully

00:15:19.460 you do that. You know, the million dollar question has always been, why do we even have APO little a to

00:15:24.920 begin with? Did it ever serve some physiologic function or is it important in any other aspect

00:15:30.920 of human life? I guess we'll know it if we eliminate it and there's some bad outcomes in that

00:15:36.140 trial. And obviously, it absolutely will be looked at for every safety aspect anybody can ever think of

00:15:43.120 right now as they're developing that drug. So, right now, I don't think there's anything they're

00:15:47.140 worried about. Sam would know more than I. But yeah, so if we can reduce that, and I don't know

00:15:53.020 that we can shut it down completely, but he can drastically lower APO little a and LP little a

00:15:57.120 levels to, you know, everybody thinks you either have it or you don't. There's a lot of people who have

00:16:03.500 what's considered a physiologic or a non-adversarial concentration of LP little a in your system. So,

00:16:11.280 you don't have to make it go to zero, you know, where risk is concerned. In fact, the only people

00:16:16.560 that are ever going to study this drug is in people like you just mentioned who have an LP

00:16:20.160 little a mass or particle count up in that 600 range or something. They're not going to take people

00:16:24.860 with borderline LP little a's and risk a clinical trial on them, just like the first statin trials

00:16:30.960 were done in sort of FH type people or so. Yeah, they're enrolling for phase three on that trial,

00:16:36.700 aren't they? And is it secondary prevention or primary prevention? I'm pretty sure it's

00:16:41.600 secondary prevention. Yeah. And remember, there is some data in the apheresis world that if you pull

00:16:47.420 out LP little a particles, there is event, they're not randomized blind to trials, because how would

00:16:52.540 you do that with apheresis? That apheresis for the non-physic, it's a dialysis where you're clearing

00:16:59.180 your blood of, you take the blood out, you get rid of the LDL particles and you give the residual

00:17:04.160 blood back. And for at least a week or two, they have less. But there's so many other things you're

00:17:10.560 clearing, the regular LDLs, all sorts of rheological things, all sorts of other hyperasmodic proteins and

00:17:17.100 things that who knows why apheresis really works. You know, I don't want to get us too far off our

00:17:23.920 main theme of lipidology, but because they're both quite recent, let's just really, really briefly

00:17:31.320 talk about two other interesting drug trials, which look at a completely different component

00:17:38.020 of the atherosclerotic mechanism pathway, which is it's the inflammatory pathway. So there was an

00:17:42.720 agonist to IL-1, I believe, or maybe it was, was it IL-1 or IL-6? Yeah, IL-1, IL-1. Yeah. And then there

00:17:47.560 was also a trial that looked at using low dose of methotrexate. Which is still ongoing. There was

00:17:52.000 some preliminary words out of that, this is looking good, but it's not been definitively released.

00:17:56.720 That's right. We won't know until the fall. So, but there is the theory this, hey, reduce

00:18:00.700 inflammation and you will certainly help vascular health in capacities. Maybe even I have nothing to

00:18:06.460 do with lipids or so. And so what's a great anti-inflammatory drug? Well, we've been using

00:18:11.560 low dose methotrexate in people with inflammatory disorders without a lot of toxicity for a long time,

00:18:17.480 rheumatoid arthritis, et cetera, et cetera. Colchicine, very powerful anti-inflammatory. There's a big

00:18:23.320 outcome trial undergoing with that. And I believe within the next year, we're going to have data on

00:18:28.420 both of those trials. So, and the problem, this IL-1 inhibitor that Peter talks about,

00:18:34.540 which has already published nice outcome data by inhibiting that, but it's a $30,000 drug.

00:18:40.880 And there was downside to it because by seriously inhibiting the inflammatory system, there was a

00:18:46.560 slight increase in cancers in some people. Your immunological system has uses in the body.

00:18:53.560 So you better be careful how much you knock it out because of course, and because of that downside,

00:18:58.680 it will never get an indication to, for me and you to use it. Again, if you're some multi-billionaire,

00:19:07.440 it's already been approved for certain type of conditions. You could use it.

00:19:12.040 Yeah. No, I think the bigger issue is really, as more and more of these drugs become available,

00:19:16.720 hopefully it leads to a more and more personalized type of intervention where,

00:19:21.240 look, if you've got somebody who's walking around with a low C-reactive protein and a low fibrinogen

00:19:25.560 and their issue is elevated LDL-P, I don't see why you'd want to use an IL-1 agonist on that,

00:19:31.980 or antagonist rather on that patient. No, not clearly not.

00:19:34.200 So yeah, it comes down to basically stratification of what's the driver? Again,

00:19:38.360 this comes back to this idea of necessary, but not sufficient, sufficient, but not necessary,

00:19:44.720 neither necessary nor sufficient. Inflammation is necessary, but not sufficient. You do need an

00:19:50.760 inflammatory response, but you can have an inflammatory response and that by itself doesn't

00:19:54.480 necessarily. No, and a certain degree of inflammation is critical for you to get rid of

00:19:59.880 certain pathologies or so. So you never want to stop the immunological system.

00:20:04.540 Yeah, look, I believe like Peter does, these are multifactorial diseases. We've spent a lot of

00:20:11.300 time on ApoBLD, but there are many other contributors that go into this. So I believe the better we can

00:20:17.700 evaluate using biomarkers, the better we can identify many of the known existing pathologies. I'm sure there's

00:20:26.560 many we don't fully understand yet. And then perhaps we can better individualize our therapeutic

00:20:31.940 suggestions to these people and know what we have to do both nutritionally and pharmacologically,

00:20:38.920 if that's necessary to normalize whatever you're trying to normalize. Yeah, it's a complex world

00:20:45.420 out there and you got to look at a lot of things. So we've already discussed many biomarkers on the

00:20:49.340 lipid front and we've alluded to some of the biomarkers on the inflammatory side, C-reactive protein,

00:20:55.900 fibrinogen. What are some other biomarkers that you find helpful as far as understanding even more

00:21:01.060 diffusely, endothelial dysfunction, or other markers of oxidized states that can give us more

00:21:07.180 of an indication and say, look, you might have two people with the same degree of dyslipidemia,

00:21:12.540 but one has a greater burden of oxidation going on than the other, which would be presumably worse.

00:21:19.280 Presumably, yes. And the problem is going to be when you even start expounding and I can throw some

00:21:23.800 markers at you that you might want to measure that would tell you there's a pro-oxidative state going

00:21:27.820 on. If your mission is to reduce atheropharmobotic events, trials that show, yeah, if we improve this

00:21:34.580 oxidative marker, that oxidative matter, people do better. They've never, ever been adjusted for

00:21:38.800 ApoB or LDL particle count. So even though you may show some nice data on them, if you really just

00:21:43.900 normalize ApoB and LDL particle counts, would it even matter? I mean, and don't tell me what common

00:21:50.080 sense suggests. And look, I'm all for it. I use oxidative markers now mostly to try and convince

00:21:55.880 people to do certain nutritional therapies rather than I got a wonderful drug for you to reduce

00:22:01.200 inflammation because right now I really don't. I know if I lower ApoB, I reduce inflammation.

00:22:06.740 So that's one, perhaps that's your first therapeutic initiative lowering ApoB by nutrition or if the

00:22:14.380 risk category is high enough a drug, fine. But if I, could I measure something that tells me you have

00:22:20.280 a pro-oxidative state? Yeah, and people do ox LDL levels in the blood, but they have no idea what

00:22:28.040 they're measuring. Remember, an LDL part, our truly oxidized LDL particle, which is the only type that a

00:22:34.300 macrophage in your arterial wall can internalize, is oxidized in the wall of the artery. And what is

00:22:39.840 oxidized? It's the phospholipids on their surface. Or maybe some freestyrols, be it a phytosterol

00:22:46.060 cholesterol. That oxidized surface lipids is what the scavenger receptor on a macrophage is going to

00:22:52.540 pull that particle into it. And then you start accumulating cholesterol and you have a sterol

00:22:57.600 laden foam cell. Bingo, you got the disease. So, but can I measure oxidized LDL in the plasma? No,

00:23:05.560 LDLs don't get oxidized in the plasma. There's too many natural antioxidants in plasma where they don't

00:23:12.240 occur. So, what you can measure in plasma is what's called minimally oxidized. All right,

00:23:18.840 there's a little bit of oxidation occurring, but it's not the phospholipids. It's some of the

00:23:25.440 proteins on the ApoB segment are being changed into aldehydes, which is what the monoclonal antibody

00:23:34.940 picks up. It picks up aldehydes on ApoB. But those aldehydes wouldn't have formed if there wasn't a

00:23:41.040 little bit of a pro-oxidative state. So, when you're measuring ox LDL, it's really ApoB,

00:23:47.400 a measure of LDL, ApoB oxidation. But where is ApoB? It's on remnants and on LDL particles.

00:23:55.600 So, just understand what you're measuring. But of all the LDL particles that are floating around,

00:24:02.000 if you get an abnormal, you're looking at maybe 5% of the total particles. Now, you might make the

00:24:09.520 case that when they do enter the artery wall, force them by the particle number, they're going

00:24:14.180 to be even further enhanced. So, maybe they got a leg up on an unoxidized LDL particle. Okay.

00:24:20.440 So, I would use that as a measure of a pro-oxidative state. And I'd try and give you

00:24:25.720 whatever nutritional things I believe might fight oxidative states or so. I'm not knowing that I got

00:24:31.420 a drug including a supplement that ensures me it can do that or not. Other than if I had to reach

00:24:39.120 for a supplement, it might be an omega-3 fatty acid, but it's another story. So, that's what

00:24:44.480 you're measuring with the ox LDL. I think there are better markers of pro-oxidative states. And look,

00:24:50.020 a lot of oxidation is the granulocytes oxidizing a variety of tissues. So, myeloperoxidize is a

00:24:57.480 granulized secreted pro-oxidative enzyme. We can measure that easily in the blood. That

00:25:02.020 would be a signal of a pro-oxidative state. And I think the best of all is as fatty acids get

00:25:10.920 oxidized, derivatives form. They're shorter chain fatty acids and they're put in a big group called

00:25:17.460 isoprostanes. And you can easily assay something called F2 isoprostanes, which have clearly been

00:25:24.580 linked to pro-oxidative states. Now, it's a urine test. It's not a serum test, but it's a small

00:25:29.260 urine sample. It's not a 24-hour urine. So, I like to do F2 isoprostanes. So, whatever you like to do,

00:25:36.520 be it ox LDL, be it myeloperoxidase, or be it the F2 isoprostanes, I can use that as useful

00:25:45.200 information and maybe even convince you that nutrition is important here. And that is the best

00:25:50.520 way to try and change them around or so. So, those are some of the pro-oxidative markers.

00:25:55.900 What I would not use as a pro-oxidative biomarker that way too many people are is lipoprotein

00:26:02.760 phospholipase A2. First of all, the data is pretty poor. Most people don't even know. The only thing

00:26:09.400 the FDA has given that approval for is as a screening test in primary prevention, never ever for anybody on

00:26:15.880 a lipid-modulating drug or on who has known coronary atherosclerosis. For the simple reason

00:26:22.900 that Mendelian randomization has shown your level of LPPLA-2 activity or mass has nothing to do with

00:26:30.400 outcomes, sort of like the HDL cholesterol story. And even more important, there have been two mega

00:26:36.940 trials where pharmaceutical industry has developed LPPLA-2 inhibitors, gave them to patients,

00:26:43.760 shut down LPPLA-2 activity, drastically reduce LPPLA-2 mass, levels plummeted, no outcome reduction

00:26:52.320 whatsoever. And LPPLA-2 is an enzyme made by the endothelium? No, it's made by macrophages. It's a

00:26:59.240 macrophage. It's just like myeloperoxides is made by granulocytes. But the MPO data are equally

00:27:04.580 unimpressive, aren't they? Well, if you want to come down to it, depends what you're using it for.

00:27:08.860 I stopped using MPO like two years ago. And I agree with you. I don't do it myself. I do the,

00:27:15.260 look, OXLDL, I do it. It's easy to do it. It's there. And it's more linked to the process that I

00:27:21.340 can see. MPO, I don't know, you could have some other vasculitis going on or something.

00:27:25.660 Yeah, my take on MPO is I found it to be unhelpful. And I agree with you that LPPLA-2,

00:27:31.040 it's one of those things you only really need to check once. Where I find it actually somewhat

00:27:34.360 helpful. And again, I could be just deluding myself is you take the patient with an elevated

00:27:38.600 LPPLA-2, and not only do you have a tongue twister, but you also have a patient that might

00:27:46.680 be a little higher risk. And I wondered if I whispered that into Peter's ear over the years.

00:27:51.080 You may have.

00:27:51.880 But anyway, I would tend to agree with him. So here's why. LPPLA-2, which is an enzyme that does

00:27:58.640 oxidize those phospholipids on an LDL when? After that LDL enters the arterial wall, is exposed to

00:28:05.960 reactive oxygen species, and some of the fatty acids on the phospholipids start oxidizing,

00:28:12.080 then LPPLA-2 activity kicks in. And it de-esterifies the fatty acids from the phospholipids. So now

00:28:20.300 you've got oxidized phospholipids floating around and a byproduct called lysolecithin, which is a pretty

00:28:26.540 pro-arthrogenic molecule. So LPPLA-2 is involved with the production of them in the arterial wall.

00:28:33.300 That's not where we're measuring LPPLA-2. But hey, if it's on the particle when it goes in the

00:28:38.980 artery wall, whose artery's wall in today's nutritional environment doesn't have reactive

00:28:44.080 oxygen species sitting there waiting to attack something. So boy, what particles entering your

00:28:51.480 artery wall are going to have the most LPPLA-2 mass on it when that's where you're going to turn on

00:28:56.220 LPPLA-2 activity. And by the way, the new assays available everywhere, they no longer measure the

00:29:01.620 mass, they measure the activity. We were the last company who finally ran out of reagents,

00:29:06.800 so we're going to activity now. So across the board, the studies show either LPPLA-2 mass or

00:29:13.120 activity are identical in predicting risk, if that's what you're using it for. But believe it or not,

00:29:18.260 the activity assay is so much easier technically to do, less costly. That's what all labs are doing

00:29:24.900 nowadays, the activity. So back to LPPLA-2 jumps on LDL. It's a little bit on HDL particles,

00:29:32.900 but most of it is on HDL particles. But HDLs are a heterogeneous species of normal size, big,

00:29:39.300 and small LDL particles. You'll find way, way more copies of LPPLA-2 on the smaller LDL.

00:29:47.920 Perhaps one of the reasons if people believe small LDLs are more atherogenic than larger sizes,

00:29:54.000 I don't know, once they're in the artery wall, which is driven pretty much by particle number,

00:29:59.020 but everybody with small LDLs has probably got too many LDL particles. So they're very prone to

00:30:03.500 oxidation when they do go in the artery wall. Not that a big LDL can't be oxidized, it could be,

00:30:08.700 but it would have less LPPLA-2 on it. But if I really wanted to know the number of copies of that

00:30:14.740 enzyme LPPLA-2, where would I find it in the blood on LPPLA particles? That's where it's all carried.

00:30:21.960 So I think Peter hinted on it in his LPPLA-2 podcast, that there's another attribute to LP

00:30:31.440 little a, other than quantifying it or weighing its mass. And that's, we do know there are people

00:30:37.340 with high LP little a who do not get out. And they may be a minority, but they're out there. Just like

00:30:41.740 not everybody with FH is going to have a heart attack. Some go through life without it. Most get

00:30:47.280 some events, but many do not. And clearly there are people without LP little a who get heart attacks

00:30:53.220 for other reasons. So if you came to me with a very high LP little a, whatever, do I just say

00:30:59.860 life's over, get your will in order, I got no drugs that can really help me with this, and you can't

00:31:05.100 afford a PCSK9 inhibitor, so I can't even experiment there. Maybe the ones who are at most risk, part of

00:31:12.140 the functionality, part of the atherogenic potential of an LP little a particle is one of the functions

00:31:20.440 perhaps of April little a is it's a garbage truck that scavenges oxidized lipid moieties, phospholipids,

00:31:28.240 sterols, and it brings them back to wherever, maybe it's macrophages that clear them and detoxify them.

00:31:35.280 So it's a, some sort of a little rescue truck, garbage truck of clearing it. But what happens

00:31:42.300 if you got way too many LP little a particles, too many LDL particles, so some of them are going

00:31:47.380 in your artery wall. Now you have an LP little a particle that's not only got a potentially pro

00:31:54.340 atherogenic apolittle a protein on it, but that thrombotic, if it is a pro thrombotic protein,

00:32:02.680 there's plenty of evidence suggesting it is. By the way, with arterial, not so much venous

00:32:07.080 thrombosis, many people have dismissed LP little a as being linked to venous thrombosis. I don't know

00:32:12.640 what the story is, but if you talk to Sam on it, he will tell you. Oh, that's interesting. So I stand

00:32:17.420 corrected because I think I was probably quoting some old data when I said that the VTE hazard ratio is

00:32:23.260 about two. Yeah, but it's just weak sort of data. So when you talk to Sam, talk to more about that.

00:32:29.020 So maybe it is, maybe it isn't. Athero, but aortic stenosis. Worry athero first.

00:32:33.680 Yeah, athero and aortic stenosis. Yeah. And part of the pathology, maybe it's just trafficking

00:32:38.020 these oxidized lipid moides into your particle, which is going to just stimulate this whole

00:32:42.700 inflammatory mess that's going on in your arterial wall. And maybe it's a pro thrombotic mess,

00:32:47.060 if that's a pro thrombotic protein too, the double whammy going in with it. So, and I think Peter

00:32:53.140 covered it nicely in his discussion there. There are these segments on APO little a called

00:32:59.060 Kringles. And there are a couple of Kringles that have a large essence of lysine amino acid

00:33:05.780 that is like fly paper for oxidized lipid moides. So they really bind to these lysine rich segments

00:33:12.760 on APO little a. So if we could start measuring oxidized phenomenon and tying it into LP little a.

00:33:21.160 Sam has written about this in his papers.

00:33:22.600 Well, and Sam has published the data showing that's who you worry about with LP little a. If

00:33:27.260 they have oxidized APO B phospholipids elevated, and Sam's got an asset for that. It's not available

00:33:32.960 widely. Yeah, that's a shame.

00:33:34.960 And he, Sam will tell you that, yes, we're measuring it on APO B particles, but the APO B

00:33:40.640 particles that carry the vast majority of these oxidized are LP little a particles. Yeah, it could

00:33:46.060 be a remnant or two or the oddball LDL particle, but mostly it's your LP. So that is, again, a double

00:33:52.620 whammy. So I think maybe in the future, we're going to be screening with whatever you want, LP little

00:33:57.260 a mass, LP little a particle count. I hopefully never LP little a cholesterol. It's like all cholesterol

00:34:03.160 metrics should be, and the only way you can assay it as a poor assay nowadays anyway, is,

00:34:08.900 all right, you do have excess LP little a, whatever in your system. Let me now do this

00:34:14.460 follow-up test. And if that's also up, let's discuss everything we can possibly do until that

00:34:20.200 miracle drug, hopefully miracle drug comes along and we got a cure for you. And maybe it'll be covered

00:34:27.320 in those people because that'll be strong because like all these new anti-sense drugs,

00:34:33.200 it's going to come with a price. Yeah. Before we leave biomarkers, anything you want to say about

00:34:38.620 asymmetric or symmetric dimethyl arginine? It's a very interesting biomarker also. Where we talked

00:34:44.300 about endothelial function, perhaps even some of the antioxidant function is this miracle molecule

00:34:50.340 every endothelial cell makes, extremely transient, makes it and it's gone. It's nitric oxide. Nitric

00:34:57.160 oxide is a powerful regulatory molecule that regulates vascular reactivity, but oxidation,

00:35:03.800 the thrombotic potential of an endothelial surface initiating a thrombus is highly dependent on nitric

00:35:11.000 oxide. So when endothelial cells make nitric oxide, which is by far the most important molecule they make,

00:35:18.740 where does that come from? Arginine, the amino acid arginine. So arginine gets converted into nitric

00:35:25.780 oxide. So last thing I want is things that are going to screw up arginine pools, which is needed

00:35:33.440 to make nitric oxide. And two proteolytic molecules we know byproducts of basically catabolism of nuclear

00:35:43.380 proteins is something, one is called symmetric and the other one is called asymmetric dimethyl

00:35:49.860 arginine. They're isoforms of one another. So if you, you know, they're mirror images of one another,

00:35:55.700 but they're actually different molecules. One directly and the other indirectly inhibits the

00:36:00.800 synthesis of arginine. So if I measured ADMA or-

00:36:05.420 Synthesis of nitric oxide, you mean?

00:36:06.820 Right. Yes.

00:36:07.420 Yeah.

00:36:07.660 Well, ultimately synthesis of arginine, which results in the synthesis of nitric oxide.

00:36:12.840 Oh, see, I always thought that SDMA inhibited the synthesis of arginine, but ADMA

00:36:18.180 inhibited NOS directly.

00:36:20.720 I should correct what I said. One inhibits the synthesis and the other enhances the

00:36:25.400 catabolism of arginine. So at the end of the day, you're going to have less-

00:36:29.260 You're going to have less nitric oxide.

00:36:30.240 And less nitric oxide. And they're both markers that we can easily measure. So, and if we measure

00:36:38.420 them and they're high, you might presume, hey, maybe that's a blood test that actually tells us

00:36:44.020 something about endothelial function. I don't think we have another that has anything close

00:36:48.680 to at least that hypothesis.

00:36:49.400 I think the nice thing about the ADMA-SDMA is it creates a biologically plausible mechanistic

00:36:56.700 explanation for why we see an association between high homocysteine and greater disease,

00:37:02.400 because homocysteine really inhibits the clearance of ADMA and SDMA. And that's very clear when you

00:37:06.960 correct it.

00:37:07.660 Which would therefore screw up nitric oxide production.

00:37:11.000 Correct.

00:37:11.020 Yeah. So it brings even oxidation into the process would disturb that process too. So

00:37:16.380 if pro-oxidated state, if hyperhomocysteine is adversarial to the vascular tree, that's one

00:37:21.860 of the pathways in which it is. So what can we do? Well, we can measure it. So who would I measure

00:37:27.880 ADA? So if you came to me and you're on your third bypass or fourth stent, I think it's a pretty safe

00:37:32.980 assumption you have screwed up endothelial function. So I don't know.

00:37:36.700 And of course, the bigger question is, what do we do about it? So one thing is, look, if they have

00:37:41.060 impaired renal function, hypertension, you know, those are things that you go after. The homocysteine,

00:37:46.420 especially in the MTHFR mutation patients, you give methylated B vitamins, which is still

00:37:51.440 controversial in sort of mainstream circles, because even though it lowers homocysteine,

00:37:56.820 some will point to that and say, well, you have no outcome data on lowering homocysteine.

00:37:59.840 No, but you have plenty of data that in people with hyperhomocysteine urea, lowering homocysteine

00:38:05.060 drastically improves their vascular outcome. So it's plausible at a certain threshold of homocysteine

00:38:10.460 that there's probably makes sense. And if you really understood the pathway of catabolism of

00:38:15.840 methionine, you'd understand this better. And remember, in that pathway is going to be the

00:38:20.660 production of a lot of neurotransmitters too. So there's a lot going on if you have the genotype

00:38:25.640 that's going to screw up methylation or the enzymes involved with that. That's another story.

00:38:31.820 But perhaps the best use of ADMA, SDMA is in the primary prevention setting where,

00:38:37.580 all right, you got a little borderline APL-B, LDLP, you're not going to do lifestyle. And do I really

00:38:44.500 want to throw you on a drug or something? If those markers are up, that tells me whatever

00:38:49.560 is going on in you, you have endothelial dysfunction. So you're down the road towards

00:38:54.820 vascular pathology. So it might be a marker to kick you in the rear to at least be super

00:39:00.300 aggressive nutritionally. Even, hey, I'm sorry, whatever nutrition we tried, you still have

00:39:06.180 abnormal endothelial function. It's time for us to, here I would rather improve these markers that

00:39:12.140 will take a drug to get them to where I want them to be. So maybe we can use it in that setting.

00:39:17.680 If you also want to tell it to me, Tom, you said, hey, if you've been through a bypass or a stent or

00:39:24.440 something, why do it? But what if I have such a patient who I've maxed out on a statinazetamide,

00:39:30.380 I've done everything else to homocysteine or insulin resistance and they're still up?

00:39:36.160 Should I lower APL-B even further with a PCS? Because I mean, you use it for what you want to use it for,

00:39:41.760 but as a marker of endothelial function. And very interesting of the two, you get both and

00:39:46.880 you also get an arginine level in the same assay. And SDMA is cleared by your kidneys. ADMA is

00:39:54.080 catabolized in the cells. So kidney function has nothing to do with ADMA. But SDMA, one of the

00:40:01.000 things that will elevate it is renal disease. And when SDMA goes into serum, it can backflux right into

00:40:07.760 the cell and decrease nitric oxide production, probably part of the pathology in people with

00:40:11.920 renal failure.

00:40:12.480 I was just about to say, the thing I like about the ADMA-SDMA stuff, even though we don't have all

00:40:16.880 this great long-term data, is it's one biochemical pathway that provides very clear evidence for two

00:40:23.920 observations that are undeniable, elevated homocysteine and renal function.

00:40:28.420 Yeah. The SDMA-O, not the ADMA.

00:40:30.860 But you get both out of the-

00:40:32.580 Yeah. You get both. It's not like you're ordering selectively. You order, you get them all three of

00:40:37.240 those markers.

00:40:37.540 And they're addressing both sides of that equation.

00:40:40.200 Yeah. So it's a very interesting little biomarker there. And hey, who doesn't want another renal

00:40:45.260 function test? Most are using creatinine. That's kind of a poor, you should be using it's like

00:40:49.060 statin-C.

00:40:50.040 Yeah, yeah, for sure.

00:40:50.680 And SDMA will be further enforcement. And mild degrees of renal impairment go ignored in this

00:40:57.880 country. And if you're even in the early, even stage two, but certainly by stage three, which

00:41:03.500 could be a clearance of 70 or something or 60, that gets ignored, even though EGFR is being reported

00:41:10.220 to people. And that's a major league risk factor that you ought to say, you're a vascular path. You're

00:41:16.220 at risk for vascular disease. I got to see what I can do to you therapeutically to lower your risk.

00:41:22.160 But it gets ignored until a creatinine clearance is 32 and you need dialysis or something, you know?

00:41:28.600 Yeah, this is one of those things I do talk about with a subset of my patients, especially these young

00:41:32.860 patients in their 40s, 50s who buy cystatin-C and creatinine and maybe even a touch of microalbumin.

00:41:41.020 And, you know, their GFR is 80. And I say, if you're 40 and your GFR is 80, there's a problem

00:41:46.580 if you want to live to be 100, because I don't know where you're going to be at 80.

00:41:50.040 Yeah. And look, if you got albumin in your urine, you got a serious

00:41:53.100 vasculopathy someplace, maybe it's just your glomerulus and you got a kidney disease, but you

00:41:58.740 probably have some other vascular disease too. So albumin is just asking something else about

00:42:03.860 something as big as a protein's escaping in your urine. You got some membrane problems that are

00:42:09.220 aligning some, either a glomerulus or a blood vessel someplace. The other ones are, and it's

00:42:15.600 interesting because Peter in his little world sees a lot of these people who are well-trained

00:42:20.220 athletes, take care of themselves. And some of them, I mean, Peter probably encouraged them

00:42:24.480 to build up muscle mass and which can influence creatinine and makes it far less usable as a

00:42:29.880 marker of renal. So statin-C has not influenced by muscle mass. So that's where it picks up some

00:42:36.760 of the imperfections, the weaknesses. We check both. Yeah. And if you do both,

00:42:41.300 which is, by the way, if you read the American, the kidney guidelines, they've actually developed

00:42:46.580 a nice equation where your clearance, and we provide this at THD, and I don't know any other

00:42:51.340 lab that does. We give you a clearance based on creatinine. We give you a clearance based on

00:42:57.360 cystatin C, and we give you the best clearance of all based on both of those parameters.

00:43:01.780 And then you segregate by African-American and non-African-American.

00:43:04.680 Because creatinine is very different in African-American. So there's a lot more to those

00:43:08.760 EGFRs if you haven't studied it lately that might be going on. And if I'm going to do a biomarker,

00:43:14.960 if there's no other restrictions, and look, that might be a third-party payer or somebody else,

00:43:19.240 I'd rather do the most informative biomarker. And that would be the dual EGFR and maybe some ADMA

00:43:27.020 or SDMA thrown in as a renal marker anyway. And that SDMA ADM marker, I really wish we could take

00:43:35.640 you through just five or six PowerPoint slides, and you'd see these pathways. And maybe I'll tweet

00:43:40.840 them in the next week or so, individual slides. Yeah, or we can just attach them here easily to

00:43:44.340 the show notes. And you'll really, it's not a high, highly, it's stare you right in the face how

00:43:50.680 they work and what they're doing. Now, we touched on something earlier that I know you wanted to come

00:43:55.020 back to, and we were deliberately short on it. But I'm trying to kind of think about how to land

00:43:59.800 this plane here. You want to go back and talk a little bit about what a remnant is? It gets so

00:44:04.980 much confusion about remnants. They're talked about like they're one homogeneous entity.

00:44:10.140 Yeah, like there is. First of all, every known lipoprotein class, including LP little A,

00:44:15.980 has remnants. All a remnant is, is a smaller part of its sister particle that's in the same

00:44:21.200 density class. So VLDLs come in multiple sizes. You got the big ones, which are only found in people

00:44:28.360 with triglyceride abnormalities. If you don't have a triglyceride disturbance, you will never have a

00:44:32.480 big VLDL particle. You'll have medium size and very often just small LDLs. But if you look at your

00:44:39.400 LDLs, there's a normal size particle, there's a big LDLs and there's small LDLs. Everybody has a

00:44:45.340 heterogeneous mixture. There's no human on the planet who has 100% exact diameter of every single

00:44:50.860 subfraction of a lipoprotein. HDLs vary widely in their density and their size and their diameters.

00:44:57.640 Even IDLs, there's a certain diameter range or density range where here's the upper limits of what

00:45:04.360 you would call an IDL. And here's the lower limits of when do you not call it an IDL? It's an LDL.

00:45:09.920 Or when does a small VLDL, I can't call it a small VLDL anymore. It's called an IDL. But wait a minute,

00:45:16.240 wouldn't an IDL be a remnant of a VLDL? If that LDL has a VLDL or IDL origin, isn't an LDL a remnant of a

00:45:24.300 IDL or maybe a VLDL? Chylomicrons, as they lose their triglycerides and phospholipids,

00:45:30.100 they become smaller chylomicrons. Chylomicron remnants, which are, for the most part, if you're

00:45:34.860 lucky, cleared by ApoE receptors somewhere. But there's chylomicron remnants floating around.

00:45:41.320 So what is the only particle I really care about? An ApoB particle that can wind up in your artery

00:45:47.440 wall, get oxidized and deliver the sterols and you oxidize them and then you got plaque.

00:45:53.820 So what forces them in? It's particle number. Now I've also explained, all right,

00:45:59.800 if that's its ApoB particle number, LDL-P is your first biomarker. ApoB is simply an LDL-P

00:46:07.200 biomarker. It's not counting VLDL particles because there are so few of them. You're certainly not

00:46:12.080 counting chylomicrons because there are even fewer of those. So ApoB is identifying to you way too many

00:46:18.240 LDL particles in this person. But there is absolutely no doubt, even though you have way,

00:46:24.460 more LDL particles than you do have VLDL particles. Because VLDL particles are two or three times

00:46:31.940 bigger than an LDL, the volume of the spear is the third power of the radius. They do carry more

00:46:37.400 cholesterol molecules per particle than an individual LDL particle. But of course, you have

00:46:43.700 so many more LDL particles than even VLDL or whatever you think a VLDL remnant is. Most of the

00:46:49.840 cholesterol getting into your artery wall is still LDL delivered. But I am not denying that VLDL

00:46:55.220 particles cannot deliver cholesterol and get oxidized when they enter the artery wall. They

00:47:01.600 can. So what has been the classic definition of a VLDL remnant? Well, they've always said, well,

00:47:09.000 do that conversion factor. We talked, divide triglycerides by five. If that's high, the VLDL

00:47:14.600 cholesterol is high. They have too many VLDL remnants. And no doubt, if we really had a VLDL

00:47:21.300 remnant test, that's true. But it would not be true in other people. So it's a poor man's perhaps

00:47:27.940 estimate of remnants. I'm trying to clarify what you're saying, right? Because I think it's a bit

00:47:32.740 confusing to the listener. You can estimate VLDL cholesterol in two ways. You can take triglyceride

00:47:38.200 and divide by five. And the higher the triglyceride level, the less accurate that becomes. You can take

00:47:43.620 non-HDL cholesterol and subtract LDL cholesterol from it. And you'll get that. You'll get an estimate

00:47:48.400 as well. Those two don't often agree, by the way. But nevertheless, you have two estimates. But that

00:47:53.520 still doesn't answer the question. Which of those go on to become pathologic remnants? Correct. So all

00:47:59.200 you're identifying there is you have increased cholesterol content in VLDL particles. And because

00:48:04.540 the ones we fear the most are remnants, we're just presuming, oh boy, there's got to be remnants.

00:48:10.000 There's got to be remnants here. So whatever therapy you're thinking of doing in this person,

00:48:15.940 you better get rid of, buy some remnant therapy too. Well, all of the FDA approved drugs that lower

00:48:22.680 APOB, whether it's statin, ezetimibe, fibrates, which are approved to lower LDL cholesterol,

00:48:29.080 even though they don't really do it that much, PCSK9, clear all APOB particles, including remnant. So

00:48:35.300 your ultimate solution. Now your first solution might be nutritional. If it's not somebody coming

00:48:40.280 off their bypass who is in the nightmare risk range classification, where I think you need a

00:48:45.260 lifestyle and pharmacology day one, you just don't have too many decades have passed, you shouldn't

00:48:51.000 be putzing around on a real short time. You know, the nutritional therapy, if I think you have remnants

00:48:57.400 is going to be I'm going to address insulin resistance in you. And so I'm being an advocate of

00:49:02.520 some degree of carbohydrate restriction and certainly a clear advocate for a lot of reasons,

00:49:09.540 apart from even APOB would be the fasting is part of your diet and too. So great. If you want to use

00:49:17.720 your VLDL cholesterol and it makes you think there's remnants and you're going to suggest the

00:49:21.820 therapy, I would tell you if you're total drug guided eye out of a drug, then that's the person you

00:49:26.400 give a fibrate to with your statin because that's what the vibrates really do well. But I can show you

00:49:32.040 data to azetamide, the statin clears as many remnants as that combination too. But I think

00:49:37.020 fibrates bring other things to the table that perhaps Zetia doesn't in people with triglyceride

00:49:41.280 rich lipoproteins. And one of them is going to be, so it's how I really think we're going to have to

00:49:47.360 identify remnants. So just even tell, there's a laboratory that produces, they separate VLDL particles

00:49:55.260 by ultracentification. The NMR people used to report total VLDLP, but they would also give you

00:50:03.260 large VLDLP plus medium VLDLP plus small VLDLP. And we used to say, well, the small VLDLP, those are

00:50:12.100 the remnants, that's the mark. Well, they don't do that anymore. They only give you the large VLDL-P

00:50:17.240 anymore. Those NMR generating labs that have the proprietary ability to release VLDL particle

00:50:25.000 data. And that's not all NMR. Is that liposcience or LabCorp now? Well, there is no more liposcience,

00:50:29.800 it's LabCorp. So you will get a large VLDLP. And it has one reason and one reason alone. It's a

00:50:36.200 lipoprotein marker of an insulin resistant state. That's it. It's not a goal of therapy. It's nothing.

00:50:41.900 There's no data that what you do to VLDLP affects outcomes, although I'd make the case that maybe

00:50:46.620 it does. But it's just an IR marker. I can measure small dense LDL cholesterol, HDL2 cholesterol,

00:50:53.380 just small LDL particle concentration. I can do an insulin level and 10 other tests that tell me

00:50:59.080 you're insulin resistant. So I don't need any VLDLP marker. I mean, they were using that as part of their

00:51:04.800 IR algorithm score. Yeah. So if you don't have that, and they use, they factor in VLDL size there,

00:51:10.620 because the big triglyceride rich VLDLs are a marker of insulin resistance. But if you're

00:51:15.060 measuring insulin levels and other insulin biomarkers, they're no better than that. I don't

00:51:21.440 know that they're any better than just measuring small LDL particle concentration, at least in a

00:51:26.340 drug naive person. So fine, it is a marker of insulin resistance. But this other lab, the Centifusion,

00:51:33.020 they tell you, ah, look at our smaller VLDL cholesterol. Those are remnants. How do they know?

00:51:39.540 All they know is that person has extra cholesterol in their small VLDL particles. But VLDLs, depending

00:51:47.000 on two things, it's ApoE content and it's ApoC3 content is going to be virtually instantly cleared.

00:51:56.040 So if your small VLDL particles are being rapidly cleared by your ApoE, ApoB100 receptors,

00:52:02.920 what do I tell you? So in other words, if you took a bunch of small VLDLs and some of them had lots

00:52:07.720 of ApoE and very little ApoC3, those aren't remnants. They're not pathological. They're not

00:52:12.420 sticking around.

00:52:12.800 They're small VLDLs. That's what they are. But are they disease-causing VLDLs?

00:52:17.280 Look, some of them probably get in, but very few compared to LDL particle number.

00:52:22.780 And very few relative to a small VLDL that would be high in ApoC3 and or low in ApoE.

00:52:29.620 They're never going to be cleared. ApoC, the main down, there's a lot of downsides to ApoC3. It's a

00:52:35.740 pro-inflammatory protein. It really enhances VLDL production in the liver, but it just retards

00:52:42.140 their clearance and it probably interferes with the hydrolysis induced by lipoprotein lipase.

00:52:47.200 So you're increasing the half-lives of all triglyceride-rich lipoproteins,

00:52:51.740 which lets CETP exchange occur longer. And what is CETP exchange doing? Bringing more cholesterol

00:52:58.540 into your VLDL particles, enhancing cholesterol enrichment. Those VLDLs are losing triglycerides

00:53:05.300 while gathering cholesterol. So these are all the pathologies that might go on if you have

00:53:10.840 delayed clearance. And C3 is going to delay the clearance through multiple reasons of these

00:53:15.280 particles. So I want a blood test that tells me the ApoC3 content of your ApoBs. LDLs that have

00:53:23.100 ApoC3 cannot be cleared. In one of the early Pravacol trials, the Pravastatin trials, the CARE trial,

00:53:30.240 they went back and they, who would high triglycerides gets coronary events? And this is Frank

00:53:35.400 Sachs up in Boston. And they've been able to measure this in sophisticated lipid labs for a long

00:53:39.780 while. If your LDL had ApoC3 on it, Pravastatin was a useless drug, didn't reduce any events.

00:53:47.180 So what? It still reduced ApoB, but it didn't reduce events? Yeah, it would clear some LDL

00:53:52.520 particles. It didn't reduce events in people that had high triglycerides. So the ApoC3,

00:54:00.220 it's not measuring triglycerides that matters. It's ApoC3. And a lot of people with ApoC3 might

00:54:06.320 only have a triglyceride of 110, 120. Wait, which trial was this?

00:54:09.620 A CARE trial, cholesterol and acute. It was a second secondary prevention trial.

00:54:15.800 Symbastatin 4S was first, and that was Swedes with super high LDL cholesterol and heart attacks.

00:54:21.580 This was done in Boston at the Brigham where they enrolled people with unremarkable,

00:54:27.780 at the time, LDL cholesterol, 130 or lower who had heart attacks. And they gave them Pravastatin and

00:54:33.740 got pretty much the same event reduction as they got in the 4S trial.

00:54:37.140 But the ones that had high trigs didn't have the reduction?

00:54:39.400 Yeah, so they went back in a post hoc analysis. And those who had high trigs,

00:54:44.220 Pravacol lowers triglycerides. Does it matter? That's one of the benefits of Pravastatin?

00:54:50.300 Well, the only people that got event reduction where Pravastatin lowered triglycerides was those

00:54:55.480 who had ApoC3-enriched LDL particles. So ApoC3 becomes your biomarker.

00:55:01.100 Is Sam's company also working on-

00:55:03.060 Yeah, and production is an anti-sense molecule that's going to stop ApoC3 production. Because

00:55:09.500 Peter, I believe you also know the Mendelian thing there is gain of function, loss of function

00:55:14.780 of ApoC3 is tied into longevity also.

00:55:17.740 Actually, I think this is, of all the major longevity genes, I do not believe, and I could

00:55:24.840 stand corrected, but I'm in the process of writing for the book now. I don't think there

00:55:30.000 is a longevity gene on cardiovascular disease that is a stronger predictor of longevity than

00:55:37.200 hypo-functioning ApoC3.

00:55:39.520 Yeah. So in very interesting, we just got, I tweeted about it, I'm sure within the last week,

00:55:45.260 a very interesting trial that if you're going to use an omega-3 fatty acid, when they compared

00:55:50.840 DHA versus EPA, DHA is the one that lowers ApoC3, not EPA. So all of these mega advocates

00:55:59.800 of EPA, I don't know, if ApoC3 is involved there, maybe you better-

00:56:05.020 Well, I got to be honest with you. I used to see myself as more of an EPA guy. And then

00:56:09.800 my focus on DHA, I think, became more something I saw in the mild cognitive impairment literature,

00:56:17.200 which was the importance of DHA in the brain. But I didn't realize this DHA-C3 relationship.

00:56:23.360 Yeah. So there, look, from my mind for years, it's been, omega-3s are not lipid drugs. Ignore

00:56:30.140 them. Don't use them to putz around with lipids because you don't know what they're doing.

00:56:34.320 That's changed now. Clearly, high-dose prescription strength EPA can be a helpful adjunctive therapy to

00:56:40.400 lower ApoB. And whether it's with remnants or whatever it's doing, it's lowering ApoB an

00:56:46.420 additional 8%, 10%. Great. And it's a pretty innocuous therapy. I always worried about those

00:56:53.760 who might not be able to convert EPA to what I believe is the necessary DHA also, especially in

00:56:58.940 the brain. But I can measure that in the plasma.

00:57:01.560 You know, I've been thinking about, I'd like to have Bill Harris on the show as well to have a

00:57:05.320 discussion about this. Because at least at the time of our recording today, I would say that the

00:57:10.120 mainstream view of EPA and DHA is that they're useless, right? That's the press today.

00:57:14.700 That's the mainstream view.

00:57:15.540 Yeah. The mainstream view is abandon all of these dumb sort of supplements. But as is often the case,

00:57:20.960 when the mainstream says something in a declarative fashion, they're usually wrong.

00:57:24.980 Especially on a nutrient, you know, where they're looking about what you're eating,

00:57:28.720 not taking pharmacologically, where you might have a real serious trial.

00:57:32.320 Yeah. They're confused by supplements versus pharmacologic grades.

00:57:35.400 Most of the trials that they would quote as omegas being useless, they're using some

00:57:39.160 miniscule, not a pharmacologic dose of these things. And they're not measuring even who's

00:57:44.360 deficient in omegas. And if you're not deficient in it, why would I even give you an omega-3

00:57:50.060 product or so? And measuring fatty acids in the blood, I would encourage you to measure red blood

00:57:56.400 cell omega-3s that are like a glycohemoglobin have a 30 or a 60, 90 day half life rather than a plasma

00:58:02.960 free fatty acid or omega, which might be, what did you eat for lunch? You know? So there's other

00:58:07.960 intricacies involved, but nonetheless, they're just all things to think about there. So in this

00:58:13.920 DHA with APOC3 is kind of interesting. Now, look, some people, if you're just going to drown them in

00:58:20.020 EPA, do convert it to DHA. So it's not an issue. But we can measure that. And I think we'd know,

00:58:26.560 oh boy, and you, you got to have some of that either eaten or supplemented, you know?

00:58:31.740 Are you pushing patients towards closer to 10% red blood cell EPA DHA level these days? Or are you?

00:58:38.480 Well, I don't see patients anymore. But if you want to ask me, yeah, that would probably,

00:58:43.260 you know, there's no, you know, Bill Harris would tell you, why not make it 14%? But we don't have

00:58:50.520 any data that would show, hey, that's harmful, but we don't have any data showing you can even make it

00:58:54.660 that high or so. Not even epistaxis and things like that? Easy bruising? So far, anything with it,

00:59:00.480 they've never turned anything from an omega-3 into coagulation disturbance. I mean, it's all data that,

00:59:07.860 hey, some Eskimos had a bloody nose one day on, and what else? They're eating EPA and DHA,

00:59:13.260 all day long. So I don't know, that would have to be tested in a clinical trial.

00:59:16.180 By the way, Tom, I just have to take issue with that as a Canadian. I think we refer to them as

00:59:20.020 Inuit now. Oh, I'm sorry. Yeah. Eskimos is an old New Jersey term.

00:59:23.880 It's super culturally insensitive. Oh my God.

00:59:25.680 I'm not going to, I'm not going to stand up for it on the show.

00:59:27.540 I'm an old Jersey, right? So you're right. I know I insulted a lot of you.

00:59:30.940 But I really do need to get Bill on the show because he's always, Bill's one of these guys who is,

00:59:36.280 and again, many of the listeners won't know who Bill Harris is, but I hope to change that.

00:59:40.060 Just, this is a guy who is as devoted to understanding the entire body of literature

00:59:46.400 and science of omega fatty acids in general, especially omega threes and sixes, way more

00:59:54.100 than me. And he was a colleague I worked for three or four years with. I love the guy we'd lunch all

01:00:00.200 the time. We go, wow. So he has taught me so much. And he is the guy who developed the red blood cell

01:00:06.980 phospholipid fatty acid assay. So he knows what he's talking about. And it gets so intriguing

01:00:13.120 because even for those of you listening, who may be taking an omega three or prescribing an omega

01:00:18.000 three, be it a supplement or be it a prescription product. What vehicle is that? It's just, is it,

01:00:25.520 are you prescribing a free omega three fatty acid? You're not. There is an FDA approved product that

01:00:31.260 the company you develop it has not brought to market yet. So you're either prescribing a sterified

01:00:36.060 omega three fatty acids, or it's a sterified to something else, or it's a sterified to glycerol

01:00:43.040 as a phospholipid, or it's a sterified to a glycerol backbone where it has three fatty acids,

01:00:48.580 but only one of us an omega three. Or are you buying a super enriched that all three fatty acids are

01:00:54.500 sterified to an omega three? You wouldn't need very small. So what is the vehicle in your favorite

01:00:59.820 supplement that's carrying the, all of that comes into the pharmacodynamics?

01:01:04.800 You know, I just realized like, I don't actually know the, cause there's only two supplements over

01:01:08.900 the counter that I fancy. One is Carlson's, the other is Nordic Naturals, just based on some of

01:01:13.300 the toxicology stuff. But I don't know the answer to the question you just asked.

01:01:17.160 And you can't get that information unless your brother works there and is privileged to that.

01:01:22.240 The companies won't even tell you what they esterify. And look, you hear about these krill products,

01:01:28.020 they're phospholipids. And that means there's one fatty acid on them. So you got to prescribe a lot

01:01:35.140 of krill pills to achieve a certain omega three way less than you would if you had a diasterified or

01:01:42.580 luckily enough, a triasterified triglyceride vehicle. I'm always, I'm always happiest when I

01:01:48.340 see my patients just eat enough salmon. Yeah. So listen, at the end of the day, that's all cool.

01:01:54.280 It's good to know. But at the end of the day, whatever way they're somehow getting omega

01:01:57.840 threes into your body, if you're normalizing the omega three index, does that even matter all that

01:02:03.560 other stuff? So it all depends. But I would implore you to follow up, please.

01:02:09.320 Yeah, I want to dig into this a little bit because it never occurred. I got to be honest

01:02:12.940 with you. I'm ashamed to admit this because I hate being the guy who makes dumb assumptions and

01:02:17.000 is too lazy to follow up. I've always assumed that the high quality EPA DHA supplements were

01:02:23.520 triacylglycerides. Almost none of them are. They're mostly monoglycerols, but it's glycerol

01:02:29.460 with two other fatty acids plus one omega three fatty acid. And what are those other fatty acids?

01:02:35.620 If nothing else, they're calories that you may or may not need or they're a harmful fatty acid

01:02:41.280 even or so, you know, who knows? We'll get to the bottom of this. And there's no pharma grade DHA

01:02:46.300 to your knowledge. No. But here's what there is. And it's already FDA approved, but the company that

01:02:53.320 developed the product is not brought to market. But I think they're going to, because this November

01:02:58.120 at the American Heart Association, you are going to get the people at risk who are on statins and

01:03:05.080 half of them are getting statins plus EPA and the other half are getting statins plus EPA placebo,

01:03:10.900 no EPA. And we're going to get outcome data. What dose of EPA? It's high. It's three, four grams.

01:03:18.120 It's the prescription strength. So are we going to see cardiovascular? All indications, and we're

01:03:24.680 all optimists, are it's going to be a positive trial. They haven't stopped it, at least for futility.

01:03:30.520 They certainly haven't stopped it for toxicity. The trial is over. They're generating the data now.

01:03:35.960 Wouldn't they have just stopped the fertility and gone away if it didn't work? So we're all expecting

01:03:40.180 that it's EPA added to the statin is going to work. Why wouldn't it? It's an EPA. It probably has

01:03:46.020 other physiologic attributes that can reduce certain inflammatory markers. And it's a nice

01:03:52.340 APOB additional lower. Now, the company that has developed free omega-3 fatty acids, so they're not

01:04:03.040 esterified to anything. That means they're very bioavailable. You just swallow it. Remember,

01:04:08.580 anytime you swallow an esterified omega-3 fatty acid, you have to secrete pancreatic enzymes to

01:04:13.780 de-esterify it because it can't be absorbed without that. Even phospholipids, krill oil has to be

01:04:19.740 de-esterified by a specific lipase coming out of your pancreas.

01:04:23.300 Right, but a free fatty acid is easy to fusion.

01:04:24.740 Free fatty acid is going to come right in. But we don't eat, you know, you might in certain foods,

01:04:29.800 but even most of the foods you eat, it's triglycerides that are delivering.

01:04:32.700 Don't free fatty acids taste horrible?

01:04:35.560 I don't know. Maybe that's why they're not there. I think most of the time they're stored

01:04:41.140 as energy and as not free fatty acids. And so they've got to be de-esterified. But anyway,

01:04:48.060 this company that has them, why didn't they? Because this is a company that manufactures a statin.

01:04:55.240 And what they were hoping was they thought the people making EPA, the FDA was going to give them

01:05:02.220 an indication based solely on additional LDL cholesterol lowering or APOB lowering that

01:05:08.120 will let you come on the market pending your outcome data because non-HDL is better, whatever.

01:05:16.080 And the FDA didn't. FDA even told them they couldn't do it. The company, which is Ameren,

01:05:20.880 actually took the FDA to court. And the Supreme Court says, no, even though you don't have an

01:05:24.900 approval for it, you can at least go share this with doctors. And that Ameren EPA product,

01:05:31.160 the SEPA has skyrocketed in sales because doctors believe this. Hey, additional data with the SEPA.

01:05:39.360 So the company that, and so you would add the SEPA to your favorite statin of choice.

01:05:45.320 And then you're taking-

01:05:46.080 Which statin do they make?

01:05:46.780 No, they don't make a statin. They make EPA. So they want you to add the SEPA to whatever statin

01:05:52.200 you're-

01:05:52.520 Oh, I thought they also made a statin.

01:05:54.080 No, they don't. So you can pick your favorite statin, but now you have, like a Zetamib,

01:05:58.900 you might add to a statin. You can now add the SEPA. If you're evidence-based, you're going to

01:06:03.720 follow that trial.

01:06:04.500 I'm going to wait until November.

01:06:05.640 Oh, I would too.

01:06:06.300 Yeah, yeah.

01:06:06.860 And not that I wouldn't be using EPA, DHA for perhaps other reasons, cognitive or whatever,

01:06:13.680 just sell membrane health. But the other company that makes a statin called Resuvastatin,

01:06:20.140 the pretty, and that would be called AstraZeneca is the one that owns this. So what they were

01:06:25.660 clearly hoping that had Ameren got an indication to add it to a statin, they would have released

01:06:31.080 a combo product called Resuvastatin, their EPA product or so. And you would have in one pill,

01:06:39.160 your statin plus your proper dose of omega-3s, and they would be free omega-3 fatty acids,

01:06:46.600 which would zoom right into your body. I got a feeling if the, and by the way, they are completing

01:06:52.200 their own big outcome trial with Resuvastatin plus the non-esterified free fatty acids.

01:06:59.160 So they'll wait for their trial too. But if this first trial works, why would theirs not even work

01:07:05.800 better? Because it's combining it with the most potent statin. So all these people who've been

01:07:11.780 bad-mouthing omega-3s with no trial data may have to change at least some of that talk come November

01:07:19.280 at the American Heart Association. It's the biggest trial going to come out of AHA this year,

01:07:24.140 at least in the lipid world. So pay strict attention. Will a month or so before, normally

01:07:29.840 they don't leak out that data because that somehow prohibits publication in prestigious journals, but

01:07:35.300 some companies do because it just means so much financially to them that it'll get published

01:07:41.700 somewhere. So I don't know, one way or another, we're going to have it in November.

01:07:45.640 Now we've danced around this idea of red blood cells for a while. They keep coming up. So

01:07:49.020 let me redirect us to another topic, which is, you've already said red blood cells per molecule

01:07:54.960 carry many, many more molecules of cholesterol than any lipoprotein does. Why don't red blood cells

01:08:02.520 cause atherosclerosis? Because they're not invading your arterial wall and not subject to oxidative

01:08:09.620 forces where a macrophage is going to ingest the red blood cell. Do they not invade the artery wall

01:08:15.940 because they can't penetrate the subendothelial space? Yeah, they're gigantic. Now listen,

01:08:19.880 can a red blood cell get into plaque? Yeah, through the vasovasorum. So could there be some

01:08:24.980 in there that are? So the vasovasorum meaning from the other side? Yeah. Well, remember artery walls

01:08:29.680 get arterial supply. They need oxygen. And even plaque has little capillaries and stuff. So are there

01:08:36.560 red blood cells in expanding plaques? Sure. So not to say they're not a tiny little part, but that's not

01:08:43.120 your primary delivery of oxidized phospholipids and sterols into the artery wall. Red blood cells

01:08:48.240 are not entering the artery wall and being oxidized, you know, like the ApoB particles are.

01:08:54.600 Yeah. So this kind of gets back to sort of the causality issue of low-density lipoproteins.

01:08:59.780 Although also red blood cells carry way more cholesterol molecules, you have bazillions

01:09:05.840 more ApoB particles than you have red blood cells also. So yes, quantity wise, they're carrying a lot

01:09:13.560 of cholesterol, but not red blood cell number wise versus LDL number. So the size of the LDL particle

01:09:19.180 obviously is what enables it to easily get into and out of. Oh yeah, not number and size, but as you

01:09:24.700 know, I've taught you this a long time ago, any VLDL or under 70 nanometers can work its way into an

01:09:31.860 endothelial gap or an arterial wall through a scavenger receptor, whatever. So not to say

01:09:37.700 remnants are an atherogen, they can't get in because remnants are way bigger than an LDL. No,

01:09:41.960 they could, but there's just more of the LDL particles. So if this is a diffusion gradient

01:09:48.220 forcing them in, there's a hell of a lot more LDL troublemakers than there are remnant troublemakers.

01:09:53.800 Not to say some big tough guy isn't a big troublemaker by himself. He is, but he's,

01:09:59.360 which would you rather have a thousand guys coming at your one guy? I take my odds that I

01:10:03.680 could beat one guy rather than a thousand guys, you know? Yeah. Yeah. You know, I, I figure it's

01:10:10.880 hard to believe we've been going at this for almost seven hours and I feel like there's at least another

01:10:15.560 hour or two we could go. But at the same time, I want to be sensitive for the listener. Normally I

01:10:21.360 say I want to be sensitive to the guest, but I know you and I can keep talking about this for another

01:10:25.780 six hours and we're going to go have dinner with Jamie Underberg tonight and just continue this

01:10:29.820 discussion. I wish I had a microphone for dinner because I have a feeling that's going to be

01:10:34.060 equally interesting. One of the things you talked about at the very outset was a really close friend

01:10:38.820 of yours who got you into hockey, took you to your first game at Madison Square Garden, got you hooked.

01:10:45.160 You were both obsessed with being firefighters. He went on to become a firefighter. You went on to

01:10:49.420 become a lipid educator. Yeah. So let me just pick up that. My absolute, you know, if you look back in

01:10:56.840 life, who are some of your absolute best friends, your high school buddies, who you really spent all

01:11:00.880 that enjoyable, the type of enjoyment you can have at that age that you never can have at another age

01:11:07.520 and you can do things. And especially when we grew up and we were in high school, 59 to 63, you could

01:11:14.260 get away with a lot of junk in those days. Whereas today, we were expelled real quickly or so with

01:11:20.980 some of the shenanigans we do. So, and look, I joked with Peter when I was telling this story,

01:11:26.460 I think he really wanted to be my best friend because my father was a fire chief in the town

01:11:30.220 of Patterson, New Jersey, where we went to high school. But even if that was true, I love firefighting.

01:11:34.740 What do I care if you love firefighters? We used to get on our bikes and ride the fires all the time

01:11:38.540 together and watch fires and stuff or drive to firehouses. So we were really tight for a million

01:11:45.320 reasons. And we just got along personality wise, but he is the guy who invited me to my first ice

01:11:49.740 hockey guy, which was certainly impacted my life and my son's life in mega ways. My son's a very

01:11:56.640 successful guy. And he would tell you, he would never be half as successful had he not played ice

01:12:00.800 hockey and developed the teamwork and the camaraderie. Speaking of a fire engine.

01:12:06.300 It is perfect timing to have a fire truck going down.

01:12:11.240 But I'm going to just keep talking about this fire truck because it's not high lipid science.

01:12:15.860 So my buddy there, he went and became, and I knew him all my life and I went and became a doctor,

01:12:20.660 but right in that same city or in a suburb of that city. So it's not like he didn't know where to find

01:12:26.220 me. But at a certain point early in our life, I knew my buddy, hey, you're a doctor now. I got this

01:12:33.440 cholesterol problem. They tell me my cholesterol is up in the blood. And, uh, you know, I was

01:12:39.100 probably at the point where we were really taking cholesterol serious and we could do something

01:12:43.220 about it. I said, oh, you got to come and see me. Come on. You know, and I was probably even the

01:12:49.100 days before I was just solely dwelling on lipoproteinology and lipidology, but I was very

01:12:54.380 aggressive with understanding cholesterol and do it and look who I evolved into. So it would have

01:12:59.400 probably been a smart choice for him to come up. It's not like I was going to charge him and he

01:13:04.100 couldn't afford me. He's a fireman in a big city. He had as good a health insurance as you could ever

01:13:09.520 get. So it's not like it would have cost him 10 cents. A lot of firemen did pick me as their doctor

01:13:15.980 because of who my father was. And they knew he was a guy who likes fire engines. We used to see him as a

01:13:20.460 kid in the firehouse. I want him to be my doctor. He knows what I do. Earl just is one of these people

01:13:26.780 who thought the farther I stay away from doctors, the better. I don't want to hear what they got to

01:13:32.080 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

01:13:39.480 fifties with a sudden acute myocardial infarction, sitting at home watching TV. He could have been

01:13:45.560 climbing a ladder at a fire. By the way, if he did die at a fire, his name would be on the Memorial

01:13:50.080 Monument up in that city. But he died at home the next day. So not that I want his name on a,

01:13:57.680 I really wish it was because he's just such a death. But there is such a needless death.

01:14:02.860 And I think across America all the time, there are many young age needless deaths occurring with a

01:14:11.240 very preventable, treatable disease that's being ignored totally because they don't go and get it

01:14:17.620 checked or they're getting bad advice based on the wrong metrics. So my buddy there is the perfect

01:14:24.420 example. But what a tragedy because had he made the right, I like this guy. He's my best buddy.

01:14:30.740 He's not going to screw me or do anything wrong. Let me go to him. He didn't. Every time I saw him,

01:14:36.400 I'd remind him, Earl, come up, come up, please come up. Yeah, yeah, Tom. Never did.

01:14:41.900 Well, in many ways, that's a reasonable and sad way to kind of end this discussion. But it also

01:14:47.200 brings it kind of back to why we why do we get so animated about this topic? Well, I think, as you

01:14:52.160 said, we think of this as, you know, one of the big three diseases that kills most people in the

01:14:57.700 civilized world once they get out of childhood. And by civilized, I really mean developed. People

01:15:02.580 know what I mean. But of the big three diseases, this is the one where I think we know the most about

01:15:07.620 it. And therefore, by extension, it's probably the one that's most delayable. Never want to say

01:15:12.400 preventable, right? We use that term. But in reality, what does that mean? It means delay.

01:15:17.200 And so if Earl died in his early 50s, maybe with the right care, he could have died in his late 60s.

01:15:23.140 You know, again, if a guy's dying in his 50s of heart disease, he's probably got really bad disease.

01:15:27.940 He needed therapy at a really young age, but he could have hung around for a while. And he's got

01:15:32.240 grandkids and children and stuff who really wish he was still here at a fire department. He was

01:15:37.260 beloved fireman. They all wish he was still on that. He'd be retired by now. But he's just one

01:15:42.900 of these people that God sends to earth that do nothing but good while they've been here through

01:15:48.160 their whole life. He had saints as parents. And it was so tragic that he left us at such a young age

01:15:56.780 and got driven to the graveyard on the back of a fire truck with a flag on a Vietnam veteran.

01:16:01.660 And so, but just so, so sad. And listen, I want to wrap this up myself. And I used to wrap up a lot

01:16:09.700 of lectures I did with this. And, you know, because I, my lectures were all high science,

01:16:15.800 no matter what group I was speaking to. So I always want guys to, you ought to come out of this

01:16:21.180 lecture that I give. And maybe with all the things, if you really sat through everything we talk about

01:16:26.300 today to say, guy's an idiot, or he's onto something. And I thought I understood this topic,

01:16:33.200 but maybe I need to understand it at a higher level. So everything is study, study, study. I

01:16:40.380 didn't learn this stuff overnight. My life has been sitting in this field.

01:16:44.700 Yeah. Well, I'll say, I'll say a couple of things. I'll say a couple of things on that. So first of all,

01:16:48.620 I obviously want to thank you for the influence you've had in me. And I, I don't know, I just feel

01:16:54.120 really lucky. I think that I got plugged into you and Alan and Ron just out of the gate to have met

01:17:00.100 the three of you so early in my interest in this topic saved me so much time because it's one thing,

01:17:07.820 I mean, no one can substitute the amount of time you have to spend obsessing over this topic and

01:17:12.000 learning it. But boy, when you can have that curriculum curated for you, you shortcut it by,

01:17:17.140 you know, three X, I'm sure. It's a gift. And I'll just extrapolate on that. Cause Peter named

01:17:22.000 three guys he can get in contact with pretty quickly and get answers. As I evolved in this

01:17:27.600 world, I had 20 guys around the world who liked me a lot because of what way I explain things,

01:17:35.140 what I could illustrate for them. So I've been blessed by, I've mentioned a few today. It would

01:17:40.800 take me another 15 minutes to list them all, but so many of the, I call them the lipid gods out there,

01:17:47.120 the people who have spent their real life in research laboratories and clinical trials and

01:17:52.100 taking care of people in the worst lipid clinics. See, and they still are available to me, but that's

01:17:59.840 who I use. I don't go on the internet and read something or make stuff up. I try and ask experts

01:18:06.000 about a lot of things. Not that you'll ever get consensus on anything, but those of us who do have

01:18:11.140 those avenues open, which many do not, but they're not afraid to still pontificate about something

01:18:17.380 that's kind of sad. Yeah. And I can't remember if I made this, this will be my final point on the

01:18:22.120 topic. And I can't remember if I made this point on a previous podcast or not. And if I did to the

01:18:26.280 listener, I apologize. You know, I started out in mathematics and engineering and really loved those

01:18:32.160 things. I excelled at those things, took great pleasure in being a first principles thinker.

01:18:38.560 So one silly story at the end of my freshman course in sort of dynamics, kinematics, like sort

01:18:45.580 of Newtonian physics, you take a final exam and you are allowed one piece of eight by 10 paper that

01:18:52.480 you can write on both sides as much as you want, whatever formula you want, because, you know,

01:18:58.660 there were just so many equations you would have to know to go in and ace one of these exams.

01:19:04.860 Now I was cocky beyond words and I was really lucky as a freshman. I used to study in this dark

01:19:13.360 part of the stacks where I met a real upperclassman guy. His first name was JP. I don't remember his

01:19:19.560 last name, but I'll never forget him. He was the only guy I'd ever met who decided to take two

01:19:24.320 engineering disciplines and finish them both in four years. So he did electrical and mechanical

01:19:28.840 engineering in four years. The price he had to pay for that was he studied every minute of every

01:19:33.980 day. But he also told me he didn't have the opportunity to learn everything because you

01:19:39.180 couldn't. If you wanted to take all of electrical and mechanical in four years, you had to accept

01:19:43.340 that there were certain things you couldn't know. So he, all of his study focused around first

01:19:47.860 principles inference. And he taught me this early. And so he saw me studying for one of my exams and I

01:19:53.640 was writing out something called the Coriolis equation, which basically explains centrifugal

01:19:58.280 forces under the condition of a changing radius. And he said, you don't need to memorize that

01:20:03.440 formula. You know how to derive it. And I was like, what are you talking about? He goes,

01:20:07.760 write out the formula for angular position and take the derivatives of it. You know, you know,

01:20:13.400 calculus. So I did. And sure enough, I was getting the same formulas to make a long story short. I go,

01:20:19.520 I, I've become so totally, totally inundated by JP's reasoning. I go into my final exam and Oh,

01:20:26.920 you have to turn in your cheat sheet at the end of the exam. And I, this is again, just,

01:20:30.680 I'm not saying this to brag about how cocky I was, but so I just have to stay. But the point is

01:20:35.280 I wanted to show the professor how well I understood this material. The only thing I

01:20:40.680 wrote on my cheat sheet in big block letters was the sum of the forces equals mass times

01:20:45.480 acceleration. Because I was like, if you know the simplest of Newton's laws, you can actually derive

01:20:52.640 everything at this level of physics. We're not talking quantum physics at this point.

01:20:56.560 And, and he, and I remember JP said, look on every question, write it out, show them how you can go

01:21:03.280 from one to the other. Cause if you make a mistake, at least they'll see what you're doing.

01:21:06.500 I ended up acing the exam and that lesson sort of stuck with me and it served me very well through

01:21:11.020 the rest of engineering and mathematics, including when it got really, really complicated that in the

01:21:16.520 end, if you truly wanted to understand something at first principles, you could derive so much.

01:21:20.580 Okay. Fast forward a few years. Now I find myself in medical school. Now I was not a pre-med.

01:21:26.720 So I'm in medical school, not as a pre-med, but as a former engineer math guy who barely squeaked into

01:21:33.040 medical school, meaning I took the MCAT having not even taken a course in biology yet. I had to take my

01:21:38.300 bio class after. And I'll tell you that first semester of med school was brutal for me because I

01:21:45.520 learned the hard way that you couldn't first principles your way through biology, at least not

01:21:52.800 at the level, at least not until you gained a certain amount of familiarity with the basics. I

01:21:58.520 couldn't walk into my histology class, look under the microscope and on first principles, know the

01:22:03.440 difference between the Golgi apparatus and the endoplasmic reticulum. You just have to know that

01:22:08.160 stuff. I couldn't go into anatomy and physiology and pathology and just first principles my way into

01:22:14.160 stuff. Eventually you can, but you have to have an enormous basis. So I sort of forgot all about

01:22:20.220 that pain. You know, you get through medical school and by the end it became, you know,

01:22:23.680 it was very enjoyable, but it wasn't until I got to the lab to NIH where my mentor told me a great

01:22:30.260 story. Now he's probably one of the most brilliant scientists I've ever known and did a PhD in biophysics

01:22:35.840 specifically for the purpose of wanting to make sure he was never in his words, intimidated by a

01:22:40.760 differential equation, despite the fact that he was an immunologist. And he told me a story,

01:22:45.800 which I need to get the details of it because I don't remember the physicist he's referring to,

01:22:49.140 but he told me the story of a physicist turned biologist who lamented once that the moment he

01:22:54.700 switched from physics to biology, he could never again take a bath in peace because as a physicist,

01:22:59.740 he could sit in the bath and wax philosophically and think about lots of things on first principles

01:23:05.860 and be very theoretical in his understanding. But as a biologist sitting in the bath, he always

01:23:11.500 realized there was one more fact he needed to remember before he could draw a conclusion.

01:23:16.160 And so he had to keep getting out of the bathtub to go and look up a certain fact. And that obviously

01:23:21.120 disrupted the beauty of taking the bath. And I think that long rambling story is a way of saying the

01:23:26.580 following. I find this subject matter to be as complicated as any I have ever tried to learn.

01:23:32.160 And unfortunately, every time I have a brilliant idea, just based on first principles, I still have

01:23:39.440 to go and check if it's grounded in the foundation of science. And sometimes it is, but many times it

01:23:46.260 is not. I come up with an idea and I'm like, this has got to be right. Oh, they're physiologically

01:23:52.360 impossible. And there's even an experiment that one day suggested this, or it's, you know, I made an

01:23:57.040 assumption, but I can clearly see that it was not the case. So I understand your frustration and I share

01:24:02.000 it. And I think, unfortunately, that is the nature of biology.

01:24:07.180 Yep. And I remain an eternal optimist. I continue to teach lipids. I think clinicians know a bit more

01:24:13.780 than we knew in 1995 when I started this journey teaching. And so that's all. If I have to do it

01:24:20.500 one at a time with people, I try and teach them what I know, and hopefully you'll do your continuing

01:24:25.320 education. And that's one of the nice things about medicine. But you got to do it. None of this comes

01:24:30.600 easy. Yeah, it does. And there's a lot of complexities in medicine nowadays. We're talking

01:24:37.000 because it's a highly pathologic state and leading cause of trouble, but there's so many other things

01:24:43.400 to, boy, take to the much higher level nowadays. You know?

01:24:48.500 Well, Tom, people, I think, will certainly by the end of this know where to find you. But on Twitter,

01:24:53.380 which is where you spend the most of your time, you're at Dr. Lipid, correct?

01:24:56.260 That's me. So, yep.

01:24:58.180 And this'll, I mean, we're generally in our brief existence as a podcast already known for probably

01:25:04.140 producing the most thorough show notes ever. I'm suspecting that this episode, which will

01:25:10.360 probably break into several parts, will have the most robust show notes that we've done. And I love,

01:25:15.540 by the way, that there's another firetruck going down. It's perfect. It's totally appropriate.

01:25:19.440 But also, if there's anything else that you think of, let's just talk about it where, you know,

01:25:25.180 offline, even we can just get to it, where there are other resources you think people ought to go

01:25:28.520 to. Again, I will steer people away from your 2000 to 2004 writings. But I think there's going to be a

01:25:36.700 number of people who listen to this who say, you know what? Look, I might've missed half of what

01:25:40.060 those guys talked about, but there's something there I want to make sure I understand better

01:25:43.660 because in the end, every doctor wants to do the best by their patient. I mean, that's just,

01:25:48.400 I believe that wholeheartedly. I get very frustrated when I hear people say that doctors

01:25:53.240 are in the pockets of pharma companies and they're just in it for the money. I mean, that's

01:25:57.600 sure there's going to be some of those people, but I haven't met those guys. You know, the doctors

01:26:01.400 that I meet, the men and women I meet who take care of patients, they all want to do the best by

01:26:05.180 their patients. And I think that those are people who are going to want to invest a little bit of

01:26:09.400 their time in understanding this problem a little better.

01:26:11.140 No, I can't say it any more than that. And as you listen to seven and a half hours,

01:26:17.480 even hopefully piecemeal market, clearly for depending on the list, there's going to be

01:26:22.080 things over your head. Even if you are a super skilled lipidologist, there's going to be some

01:26:27.340 things you said, what? Let me, you read about that or so, but it's just trying to open your mind and

01:26:32.640 understand there's a lot going on here. The field is infinitely more complex than you ever imagined.

01:26:39.120 It took me a long, and I'm a, as Mike Davison calls me, Tom's a self-taught lipidologist. I mean,

01:26:45.800 I didn't spend two years down at the National Heart, Lung, and Blood Institute, even though the

01:26:50.860 director of that NHLBI, Alan Romali, and I just authored a 70-page chapter in the TITS book of

01:26:58.600 Molecular and Clinical Biochemistry, all about lipids and apoproteins. So,

01:27:03.920 I think to be an invited author with a guy at a magnitude- Yeah, and you sent me a preprint of

01:27:08.240 that. That's a remarkable treatise. So, I mean, it's an expensive book. I don't expect you,

01:27:12.780 if you're not a lipidologist or somebody seriously into this clinician, that's what you go out and buy.

01:27:18.300 But there is a lot of information out there. So, and just be careful on what you, that's ridiculous,

01:27:25.380 or my cockamamie theory based in no clinical trials or science is what I believe. Fine,

01:27:32.000 believe it. You know, this is America here. I can't lock you up. I'm not the lipid police.

01:27:38.920 Yeah, well, on that note, Tom, thank you very much. It's hard to believe this has been seven

01:27:44.020 hours of discussion today, but it's been worth every minute to me. And I've learned a lot in

01:27:48.560 this discussion. So, that's, to me, that's always a, I mean, for selfish reasons, that's sort of my,

01:27:53.140 my primary objective is to learn as much as I can. And then along the way, if others can learn too,

01:27:57.540 that's a bonus. And without a year of my intermittent fasting and program from Peter

01:28:02.300 Atiyah, I could have never had the energy to sit here, even to use my tongue or brain. So,

01:28:09.620 thank you again, Peter. Yeah, my pleasure, Tom. Thanks.

01:28:14.520 You can find all of this information and more at peteratiyahmd.com forward slash podcast.

01:28:19.640 There you'll find the show notes, readings, and links related to this episode. You can also find

01:28:24.900 my blog and the nerd safari at peteratiyahmd.com. What's a nerd safari, you ask? Just click on the

01:28:30.900 link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my

01:28:34.920 subjectively non-lame once a week email, where I'll update you on what I've been up to, the most

01:28:39.620 interesting papers I've read, and all things related to longevity, science, performance, sleep,

01:28:44.460 et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID,

01:28:49.720 Peter Atiyah, MD. But usually Twitter is the best way to reach me to share your questions and

01:28:54.000 comments. Now for the obligatory disclaimer, this podcast is for general informational purposes

01:28:58.740 only and does not constitute the practice of medicine, nursing, or other professional healthcare

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01:29:32.900 conflicts of interest very seriously. For all of my disclosures, the companies I invest in

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The Peter Attia Drive - October 19, 2018

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

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