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

1. 0:00 – 0:04

   Intro

   1. PADr. Peter Attia0:00

      [upbeat music]

2. 0:04 – 3:08

   Episode Preview and Why Statins Don't Lower Lp(a)

   1. PADr. Peter Attia0:04

      Hey everyone, welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. Hi everybody. Welcome to the fifth and final episode in the week of Tom. This is the tour de force magnum opus course on lipidology. As we round this out, we talk about a number of things. We talk about Lp (a) , inflammation, oxidized LDL, remnants, red blood cells and cholesterol, a biomarker called Lp-PLA2 that you've often probably heard about, another biomarker that you may have not heard of called ADMA or asymmetric dimethylarginine, and SDMA, symmetric dimethylarginine. And then we kind of bring it back to what is one of the more tragic stories in Tom's life, which is a friend of his who unfortunately probably had FH, wasn't treated, and in many ways is sort of one of those patients that still kind of haunts Tom. And I think, you know, we opened this back in part one by talking about Tom's passion for two other things, firefighting and hockey, and how that passion is what really got him into or basically allowed him to apply himself to this new field once he became obsessed. But also I think most physicians listening to this will have a similar story where there are certain patients or there are certain personal relationships where a loss of life stays with you for a very long period of time, and in many ways it colors what you do over time. So I hope you enjoy this fifth and final installment of the lipidology advanced course, and next week we'll be back to our regular scheduled programming where we're just doing, you know, one podcast a week. So I hope you've enjoyed this, and I hope you find the show notes very helpful. I can't express how much work has gone into it. So without further delay, here is the final episode with Dr. Tom Dayspring. This will be a nice way to dovetail niacin, statins, and PCSK9 inhibitors. What lipoprotein have we not discussed today that would tie in a discussion of those three? Well, the astute listener realizes it's our good friend Lp (a) .

   2. TDDr. Tom Dayspring2:44

      [chuckles]

   3. PADr. Peter Attia2:44

      All right. Why do I bring this up? So Lp (a) , there are some people who still argue, "Hey, niacin makes sense because it lowers Lp (a) ." I'm going to save everybody on this podcast the brain damage of listening to us discuss that for the next twenty minutes and just bypass us to the more interesting question, which is, why don't statins lower Lp (a) ?

3. 3:08 – 12:38

   What Lp(a) Is and How It's Measured

   1. TDDr. Tom Dayspring3:08

      Well, first of all, we need a better understanding of Lp (a) clearance. I'm personally of the belief that it is the LDL receptor. There is a plasminogen receptor that could clear some things, and there are macrophage receptors that, depending what else is going on, might internalize some Lp (a) and get rid of it that way. But it's the LDL receptor that clears it. The other-

   2. PADr. Peter Attia3:30

      And also, let's pause for one second because I realize even though we've already done an entire podcast on what is Lp (a) , there's someone listening to this who hasn't heard it. You'll go back and listen to it, I'm sure. I'm going to do future podcasts where I interview the world's expert on the topic. But Tom, can you give in two minutes a description of what Lp (a) is?

   3. TDDr. Tom Dayspring3:49

      Yeah. It's an LDL-like particle to which is adhering another apoprotein that shouldn't be there, and it's called apoprotein little a, and you must pronounce it as little a. That means small case rather than capital A. Lipoprotein capital A is apoprotein A1. That's the main apoprotein on an HDL particle. So if you tell me you got lipoprotein A, how do I know, are you talking about you got HDL particles? Are you talking about little a, which clearly identifies to me this potentially pathogenic atherogenic LDL particle? So use the correct terminology with everything. And Peter's got that nice podcast on it. Our metrics of is that present in you or not is most labs will run an Lp (a) mass, which is the weight in a deciliter of plasma of the weight of your ent- all your LDL particles, everything that's in them, their triglycerides, their cholesterol ester, their phospholipids, their-

   4. PADr. Peter Attia4:48

      Meaning any lipoprotein that is carrying an apo lipo little a-

   5. TDDr. Tom Dayspring4:53

      Yeah, and-

   6. PADr. Peter Attia4:53

      You weigh the entirety

   7. TDDr. Tom Dayspring4:54

      ... they're, they're all of the LDL density.

   8. PADr. Peter Attia4:56

      Yeah.

   9. TDDr. Tom Dayspring4:56

      That's... So but you're weighing everything. You're not weighing apo little a. You're not measuring apo little a per se. Yes, that has a molecular weight, but the molecular weight of apoB is way higher than the molecular weight of apo little a, but you're measuring that too when you do an Lp (a) mass.

   10. PADr. Peter Attia5:13

       But the molecular weight of apoB is known because it's pretty much the same, whereas the molecular weight of apo little a is variable.

   11. TDDr. Tom Dayspring5:20

       It's very variable, so that's another reason Lp (a) mass becomes a useless metric. And how do I know how many cholesterol, triglyceride, phospholipid, ten thousand other lipid moieties, other proteins are on that particle? I don't. And you have heterogeneous mixtures of particles that would have variable amounts of all of those constituents. So you can see there's going to be a weakness to measuring Lp (a) mass. Now if it's really high, you've probably got too many Lp (a) particles. But since there's almost no more debate that the best metric for our LDL particles is low density lipoprotein particle number, there's no debate among those who truly understand that HDL particle number is your best met- available metric on quantifying the number, and that is a better metric than guessing that using HDL cholesterol or LDL cholesterol. Wouldn't you rather have a really nice finite count? If, if Lp (a) particles are dangerous, wouldn't you like to have a excellent, accurate concentration in them? Well, the only way you can do that nowadays, NMR provides those other HDL, and NMR cannot assay Lp (a) particles because NMR assays lipid content of particles, not protein content. So the only way I can give you an Lp (a) particle count is I have to separate all lipoproteins electrophoretically, and they all... You'll see little bumps on the electrophoretogram. VLDLs congregate here, LDLs congregate here, HDLs congregate there. And what's that little bump that is in this person but it's not in that person? Oh, that's Lp (a) because that's Due to its surface charge where it migrates between the cathode and the anode and the gel that you separate them on. So if I then take that Lp (a) hump and I immunostain it with a antibody that binds to apoB-

   12. PADr. Peter Attia7:10

       You've just counted the number of particles

   13. TDDr. Tom Dayspring7:11

       ... I've just counted the number of particles that are in the Lp (a) distribution range. I theoretically should not call that an Lp (a) particle count. I should call it Lp (a) apoB.

   14. PADr. Peter Attia7:22

       apoB.

   15. TDDr. Tom Dayspring7:22

       That's too much of a mouthful. It doesn't fit on a request form. So of course, it's abbreviated Lp (a) -P. And t- to me, the downside of that is most people think it's an NMR measurement, which it absolutely is not. Basically, if you want that metric, and we've already announced I do work for True Health Diagnostics. I was working with a different lab before that, the lab that actually did the development of the Lp (a) apoB assay, which True Health absorbed and got proprietary rights to when he did it, so that's it. And believe it or not, there are people who are gonna have discordance with Lp (a) mass, the weight of the whole kit and caboodle, versus the number of LDL particle counts in general they correlate. But if you really wanna know, and also I find it useful, those, at least those of you who are doing LDL-P by NMR, you have your total LDL particle count, but what does that really include? It includes LDLs that don't have apo (a) attached, and it includes LDLs that do have apo (a) attached. Now, I throw a statin at you, and we started to talk about this, that statin is not gonna budge your Lp (a) particle count at all. But the statin is gonna dramatically lower your LDLs that don't have apo (a) attached to it. So your LDL total particle will get down a little bit, but part of that is your Lp (a) particle count, but this shows you you are getting benefit when you give a statin to somebody with high Lp (a) .

   16. PADr. Peter Attia8:57

       Yeah, you, you-

   17. TDDr. Tom Dayspring8:58

       Which-

   18. PADr. Peter Attia8:58

       You're gonna have to go after residual risk. You know, one of the best examples I saw of this was an unusual case where a guy had an LDL particle of 1,600-ish nanomole per liter, but he had an LD- Lp (a) of 600 nanomole per liter. So even though it's an apples and oranges assay, directionally speaking, he's got 600 Lp (a) particles and-

   19. TDDr. Tom Dayspring9:22

       Or nanomoles of particles, yeah, okay

   20. PADr. Peter Attia9:23

       ... nanomole per particle per liter and 1,000 non-Lp (a) 's. But when you give him that statin, you're really only targeting the 1,000.

   21. TDDr. Tom Dayspring9:33

       Correct.

   22. PADr. Peter Attia9:34

       And so you'll be surprised at the lack of response you might see, 'cause you're not getting to target those 600-

   23. TDDr. Tom Dayspring9:40

       No, but you'll still get your 30, 40, yeah, but your-

   24. PADr. Peter Attia9:42

       Yeah, yeah

   25. TDDr. Tom Dayspring9:42

       ... total LDL-P may still be higher than you wish it to be, and-

   26. PADr. Peter Attia9:46

       Yeah

   27. TDDr. Tom Dayspring9:46

       ... unfortunately, that is Lp (a) particles. Then you can get into the theoretical discussion right now that if I could get rid of them, and basically the only way you can do that now is the maybe try niacin, which is a weak lowering of 20%, or a PCSK9 inhibitor, whi- which [laughs] to my mind-

   28. PADr. Peter Attia10:04

       Seems like 30% to 50%

   29. TDDr. Tom Dayspring10:05

       ... uh, well, it would be an individual response-

   30. PADr. Peter Attia10:07

       Yes, no, very individual
4. 12:38 – 17:22

   Therapies for Lp(a): Niacin, PCSK9 Inhibitors, and Apo(a) Synthesis Inhibitors

   1. PADr. Peter Attia12:38

      So what's the best explanation for why a statin, which causes the liver to upregulate LDL receptors, does not lower Lp (a) , whereas a PCSK9 inhibitor, which also net results in more Or a longer transiency of LDL receptors seems to lower Lp (a) , even though that's not its primary objective

   2. TDDr. Tom Dayspring12:57

      And by the way, the data certainly tells us now that the main determinant of Lp (a) mass or Lp (a) particle concentration is ApoA production in the liver, not clearance. So until we can really inhibit production of ApoA, who knows what you're doing. But until then, let's in- So how do LDL receptors clear these particles? Well, earlier I think I mentioned that LDL receptors looking for ApoE or a section of the ApoB that it can latch onto. There's a very specific area on the ApoB protein, on any of the ApoB particles that, because of surface charges, will bind to a specific part of the LDL receptor. That area on ApoB is called the LDL receptor binding domain. So if, uh, here comes an LDL particle and that domain is sticking right out, it'll stick right to any expressed LDL receptor. But what if there's something camouflaging that ApoA or that LDL receptor binding domain on ApoB, such as an interloper like apoprotein little A? I could see where that would slow the clearance of an Lp (a) particle, 'cause it's not gonna bind as rapidly and as avidly to an LDL receptor. So most of these people have way too many LDL particles. We express whatever LDL particles we want. We try and express more with the statin. What are they gonna grab first? The LDL particles that don't have apoA attached, and only then would they maybe then start even grabbing apoA particles or so, and do we all really have enough LDL receptors? Most of us, [laughs] for a variety of reasons, do not. Other things retard the clearance, too. You know, the apoC-III I talked about, g- o- other proteins that may be affecting clearance too. So there are just other factors at play. But right now my guess is ApoA is affecting totally efficacious binding to an Lp (a) particle. It's camouflaging the LDL receptor binding domain on ApoB, and therefore I better learn how to inhibit synthesis of it.

   3. PADr. Peter Attia15:07

      So Sam will obviously... Hopefully, we do get Sam on the show and we'll talk about this, but that the, this antisense oligonucleotide is basically going after the jugular issue, which is you inhibit-

   4. TDDr. Tom Dayspring15:16

      Yes

   5. PADr. Peter Attia15:16

      ... the synthesis of apoA.

   6. TDDr. Tom Dayspring15:18

      Yeah. And hopefully you do that. You know, the million-dollar question has always been why do we even have apoA to begin with? Did it ever serve some physiologic function or is it, is it important in any other aspect of human life? I guess we'll know it if we eliminate it and there's some bad outcomes in that trial, and obviously it absolutely will be looked at for every safety aspect anybody can ever think of right now as they're developing that drug. So right now I don't think there's anything they're worried about. Sam would know more than I. But yeah, so if we can reduce statin, uh, I don't know that we can shut it down completely, but he can drastically lower apoA and Lp (a) levels too. So, you know, everybody thinks you either have it or you don't. There's a lot of people who have what's considered a physiologic or a non-adversarial concentration of Lp (a) in your system, so you don't have to make it go to zero, you know, where risk is concerned. In fact, the only people that are ever gonna study this drug is in people like you just mentioned, who have an Lp (a) mass or particle count up in that 600 range or something. They're not gonna take people with borderline Lp (a) 's and risk a clinical trial on them, just like the first statin trials were done in sort of FH type people or so.

   7. PADr. Peter Attia16:34

      Yeah. They're enrolling for phase three on that trial, aren't they?

   8. TDDr. Tom Dayspring16:37

      Mm. Mm-hmm.

   9. PADr. Peter Attia16:38

      And is it secondary prevention or primary prevention?

   10. TDDr. Tom Dayspring16:40

       I'm pretty sure it's secondary prevention.

   11. PADr. Peter Attia16:43

       Yeah.

   12. TDDr. Tom Dayspring16:43

       And remember, there is some data in the apheresis world that if you pull out Lp (a) particles, there is even... They're not randomized blinded trials-

   13. PADr. Peter Attia16:52

       Yeah

   14. TDDr. Tom Dayspring16:52

       ... 'cause how would you do that with apheresis? That, apheresis, for the non-physician, you're, it's a dialysis where you're clearing your blood of... You take the blood out, you get rid of the LDL particles, and you give the r- residual blood back, [laughs] you know? So and for at least a week or two they have less... But there's so many o- other things. You're clearing the regular LDLs, all sorts of rheological things, all sorts of other hyperosmotic proteins and things that, who knows what the, why apheresis really works, you know?

   15. PADr. Peter Attia17:22

       You know,

5. 17:22 – 20:47

   Inflammation as a Target: IL-1, Methotrexate, and Colchicine

   1. PADr. Peter Attia17:22

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

   2. TDDr. Tom Dayspring17:46

      Yeah, IL-1. IL-1.

   3. PADr. Peter Attia17:46

      Yeah. And then there was also a trial that looked at using low dose of methotrexate.

   4. TDDr. Tom Dayspring17:50

      Which is still ongoing. There was, uh, some preliminary words out of that, this is looking good, but it's not been definitively released or-

   5. PADr. Peter Attia17:57

      That's right. We won't know till the fall

   6. TDDr. Tom Dayspring17:57

      ... so, but there is the theory this, hey, reduce inflammation and you will certainly help vascular health in capacities maybe even that have nothing to do with lipids or so.

   7. PADr. Peter Attia18:08

      Yeah.

   8. TDDr. Tom Dayspring18:08

      And so what's a great anti-inflammatory drug? Well, we've been using low-dose methotrexate in people with inflammatory disorders without a lot of toxicity for a long time, rheumatoid arthritis, et cetera, et cetera. Colchicine, very powerful anti-inflammatory. There's a big outcome trial undergoing with that. And I believe within the next year we're gonna have data on both of those trials. So, and the prob- the, this IL-1 inhibitor that Peter talks about, which has already published nice outcome data by inhibiting that, but it's a $30,000 drug, and there was downside to it 'cause by seriously inhibiting the inflammatory system, there was a slight increase in cancers in some people. Your immunological system has uses in the body, so you better be careful how much you knock it out. Because of cost and because of that downside, it will never get an indication to, for me and you to use it. Again, if you're, uh, some multi-billionaire-

   9. PADr. Peter Attia19:07

      Well, I mean, I think the bigger-

   10. TDDr. Tom Dayspring19:08

       Yeah, it's already, uh, been approved for certain, uh, type th- conditions. You could use it

   11. PADr. Peter Attia19:12

       Yeah, no, I think the bigger issue is really as more and more of these drugs become available, hopefully it leads to a more and more personalized type of intervention where, look, if you got somebody who's walking around with a low C-reactive protein and a low fibrinogen and their issue is elevated, you know, LDL-P, I don't see why you'd want to use an IL-1 agonist on that or antagonist rather on that patient.

   12. TDDr. Tom Dayspring19:33

       No, clearly not.

   13. PADr. Peter Attia19:34

       So yeah, it comes down to basically stratification of what's the driver? What-- Again, this comes back to this idea of necessary but not sufficient, sufficient but not necessary, neither necessary nor sufficient. Inflammation is necessary but not sufficient. You do need an inflammatory response, but you can have an inflammatory response, and that by itself doesn't necessarily-

   14. TDDr. Tom Dayspring19:55

       No, an infl- a certain degree of inflammation is critical for you to-

   15. PADr. Peter Attia19:59

       Yeah

   16. TDDr. Tom Dayspring19:59

       ... get rid of, uh, certain pathologies or so. So you, you never want to stop the immunological system. Yeah, look, I believe like Peter does, these are multifactorial diseases. We've spent a lot of time on ApoB, LDL, but the, uh, the many other contributors that go into this. So I believe the better we can evaluate using biomarkers, the better we can identify many of the known existing pathologies. I'm sure there's many we don't fully understand yet. And then perhaps we can better individualize our therapeutic suggestions to these people and know what we have to do both nutritionally and, uh, pharmacologically, if that's necessary to normalize whatever you're trying to normalize. Yeah, it's a complex world out there, and you got to look at a lot of things.

6. 20:47 – 25:56

   Oxidative Markers: oxLDL, MPO, and F2-Isoprostanes

   1. PADr. Peter Attia20:47

      So we've already discussed many biomarkers on the lipid front, and we've alluded to some of the biomarkers on the inflammatory side, C-reactive protein, fibrinogen. But what are some other biomarkers that you find helpful as far as understanding even more diffusely endothelial dysfunction or other markers of oxidized states that can give us more of an indication and say, "Look, you might have two people with the same degree of dyslipidemia, but one has a greater burden of oxidation going on than the other, which would be, uh, presumably worse"?

   2. TDDr. Tom Dayspring21:19

      Presumably, yes. And the problem is going to be when you even start expanding on that, and I can throw some markers at you that you might want to measure that would tell you there's a pro-oxidative state going on. If your mission is to reduce atherothrombotic events, trials that show, yeah, if we improve this oxidative marker, that oxidative matter, people do better. They've never ever been adjusted for ApoB or LDL particle count. So even though you may show some nice data on them, if you really just normalize ApoB and LDL particle counts, would it even matter? I mean, and don't tell me what common sense suggests. And look, I'm all for it. I use oxidative markers now mostly to try and convince people to do certain nutritional therapies rather than I got a wonderful drug for you to reduce inflammation, because right now I really don't. I know if I lower ApoB, I reduce inflammation. So that's one perhaps that's your first therapeutic initiative, lowering ApoB by nutrition, or if the risk category is high enough, a drug, fine. But if I-- How-- Could I measure something that tells me you have a pro-oxidative state? Yeah, and people do oxLDL levels in the blood, but they have no idea what they're measuring. Remember, an LDL part-- a truly oxidized LDL particle, which is the only type that a macrophage in your arterial wall can internalize, is oxidized in the wall of the artery. And what is oxidized? It's the phospholipids on their surface or maybe some free sterols, be it a phytosterol cholesterol. That oxidized surface lipids is what the scavenger receptor on a macrophage is gonna, gonna pull that particle into it, and then you, you start accumulating cholesterol, and you have a sterol-laden foam cell. Bingo, you got the disease. So but can I measure oxidized LDL in the plasma? No, LDLs don't get oxidized in the plasma. There's too many natural antioxidants in plasma where they don't occur. So what you can measure in plasma is what's called minimally oxidized. All right, there's a little bit of oxidation occurring, but it's not the phospholipids. It's some of the struct- the, uh, proteins on the ApoB segment are being changed into aldehydes, which is what the monoclonal antibody picks up. It picks up aldehydes on ApoB. But those aldehydes wouldn't have formed if there wasn't a little bit of a pro-oxidative state. So when you're measuring oxLDL, it's a, it's really ApoB, uh, a measure of LDL ApoB oxidation. But where is ApoB? It's on remnants and on LDL particles. So just understand what you're measuring. But of all the LDL particles that are floating around, if you get an abnormal ox, you're looking at maybe 5% of the total particles. Now, the-- Uh, you might make the case that when they do enter the artery wall, forced in by the particle number, they're, they're gonna be even further enhanced, so maybe they got a leg up on an unoxidized LDL particle. Okay. So like I would use that as a measure of a pro-oxidative state, and I'd try and give you whatever nutritional things I believe might fight oxidative states or so. I'm not knowing that I got a, a drug, including a supplement that ensures me it can do that or not, other than I would-- if I had to reach for a supplement, it might be an omega-3 fatty acid, but it's another story. So that's what you're measuring with the oxLDL. I think there are better mar- markers of pro-oxidative states. And look, a lot of oxidation is the granulocytes oxidizing a variety of tissues. So myeloperoxidase is a granulocyte-secreted pro-oxidative enzyme. We can measure that easily in the blood. That would be a signal of a pro-oxidative state. And I think the best of all is As fatty acids get oxidized, derivatives form. They're shorter chain fatty acids, and they're put in a big group called isoprostanes. And you can easily assay something called F2-isoprostanes, which have clearly been linked to pro-oxidative states. Now, it's a urine test. It's not a serum test, but it's a small urine sample. It's not a 24-hour urine. So I like to do F2-isoprostanes. So whatever you like to do, be it oxLDL, be it myeloperoxidase, or be it the F2-isoprostanes, I can use that as useful information and maybe even convince you that nutrition is important here, and that is the best way to try and change them around or so. So those are some of the pro-oxidative mark.

7. 25:56 – 34:36

   Lp-PLA2 and Oxidized Phospholipids on Lp(a)

   1. TDDr. Tom Dayspring25:56

      What I would not use as a pro-oxidative biomarker that way too many people are is lipoprotein phospholipase A2. First of all, the data is pretty poor. Most people don't even know the only thing the FDA has given that approval for is as a screening test in primary prevention, never ever for anybody on a lipid modulating drug or on a who has known coronary atherosclerosis for the simple reason that Mendelian randomization has shown that your level of Lp-PLA2 activity or mass has nothing to do with outcomes, sort of like the HDL cholesterol story. And even more important, there have been two mega trials where pharmaceutical industry has developed Lp-PLA2 inhibitors, gave them to patients, shut down Lp-PLA2 activity, drastically reduced Lp-PLA2 mass, levels plummeted, no outcome reduction whatsoever.

   2. PADr. Peter Attia26:53

      And Lp-PLA2 is an enzyme made by the endothelium?

   3. TDDr. Tom Dayspring26:57

      No, it's made by macrophages. It's a macro-

   4. PADr. Peter Attia26:59

      It's macrophage-secreting

   5. TDDr. Tom Dayspring27:00

      ... just like myeloperoxidase is made by granulocytes.

   6. PADr. Peter Attia27:02

      But the, but the, the MPO data are equally unimpressive, aren't they?

   7. TDDr. Tom Dayspring27:06

      Well, if you want to come down to, depends what you're using it for. If you-

   8. PADr. Peter Attia27:09

      I, I stopped using MPO-

   9. TDDr. Tom Dayspring27:10

      Yeah

   10. PADr. Peter Attia27:10

       ... like two years ago. I-

   11. TDDr. Tom Dayspring27:11

       So look-

   12. PADr. Peter Attia27:12

       And I, and I agree with you. I think I would only-

   13. TDDr. Tom Dayspring27:14

       I don't do it myself. I do the, uh... Look, oxLDL I do and it's e- easy to do.

   14. PADr. Peter Attia27:18

       Yeah.

   15. TDDr. Tom Dayspring27:18

       It, it's there, and it's more linked to the process that I can see. MPO, uh, I don't know. You could have some other vasculitis going on or something.

   16. PADr. Peter Attia27:25

       Yeah. My take on MPO is I found it to be unhelpful, and I agree with you that Lp-PLA2, it's one of those things you only really need to check once. Where I find it actually somewhat helpful, and again, I could be just deluding myself, is you take the patient with an elevated Lp little a who has an elevated Lp-PLA2, and not only do you have a tongue twister, but you also have a patient that might be a little higher risk.

   17. TDDr. Tom Dayspring27:48

       And I wondered if I whispered that into Peter's ear over the years or so. [laughs]

   18. PADr. Peter Attia27:51

       Oh, you may have. You, you may have.

   19. TDDr. Tom Dayspring27:52

       But anyway, I, I would tend to agree with him, so here's why. Lp-PLA2, which is an enzyme that does oxidize those phospholipids on an LDL when? After that LDL enters the arterial wall, is exposed to reactive oxygen species, and some of the fatty acids on the phospholipids start oxidizing, then Lp-PLA2 activity kicks in, and it de-esterifies the fatty acids from the phospholipids, so now you got oxidized phospholipids floating around and a byproduct called lysolesithin, which is a pretty pro-atherogenic molecule. So Lp-PLA2 is involved with the production of them in the arterial wall. Well, that's not where we're measuring Lp-PLA2. But, hey, if it's on the particle when it goes in the artery wall, whose wa- whose artery's wall in today's nutritional environment doesn't have reactive oxygen species sitting there waiting to attack something? So, uh, boy, what particles entering your artery wall are gonna have the most Lp-PLA2 mass on it when that's where you're gonna turn on Lp-PLA2 activity? And by the way, the new assays available everywhere, they no longer measure the mass, they measure the activity. We're the last company who finally ran out of reagents, so we're going to activity now. So across the board, the studies show either Lp-PLA2 mass or activity are identical in predicting risk if that's what you're using it for. But believe it or not, the activity assay is so much easier technically to do, less costly. That's what all labs are doing nowadays, the activity. So back to L- Lp-PLA2 jumps on LDL. It's a little bit on HDL particles, but most of it is on HDL particles. But HDLs are a heterogeneous species of normal size, big and small LDL particles. You'll find way, way more copies of Lp-PLA2 on the smaller LDL. Perhaps one of the reasons if people believe small LDLs are more atherogenic than larger sizes, I don't know, once they're in the artery wall, which is driven pretty much by particle number, but everybody with small LDLs has probably got too many LDL particles, so they're very prone to oxidation when they do go in the artery wall. Not that a big LDL can't be oxidized. It could be, but it would have less Lp-PLA2 on it. But if I really wanted to know the number of copies of that pr- uh, enzyme, Lp-PLA2, where would I find it in the blood? On Lp little a particles. W- That's where it's all carried. So I think Peter hinted on it in his Lp, uh, PLA2 podcast that there's another attribute to Lp little a other than quantifying it or weighing its mass, and that's we do know there are people with high Lp little a who do not get out, and they may be a minority, but they're out there. Just like not everybody with FH is gonna have a heart attack, some go through life without it. Most get some events, but many do not. And, uh, clearly there are people without Lp little a who get heart attacks for other reasons. So if you came to me with a very high Lp little a whatever, do I just say, "Life's over. Get your will in order. Uh, I got no drugs that, uh, can really help me with this, and you can't afford a PCSK9 inhibitor, so I can't even experiment there"? Maybe the ones who are at most risk, part of the functionality, part of the atherogenic potential of an Lp little a particle is one of the functions perhaps of apoA is it's a garbage truck that scavenges oxidized lipid moieties, phospholipids, sterols, and it brings them back to wherever. Maybe it's macrophages that clear them and detoxify them. So it's a some sort of a little rescue truck, garbage truck of clearing it. But what happens if you got way too many Lp little a particles, too many LDL particles, so some of them are going in your artery wall? Now you have an Lp little a particle that's not only got a potentially proatherogenic apo little a protein on it, but that thrombotic, if it is a prothrombotic protein, there's plenty of evidence suggesting it is. By the way, with arterial, not so much venous thrombosis, many people have dismissed Lp little a as being linked to venous thrombosis. I don't know the source. But if you talk to Sam on it, he will tell you it's not-

   20. PADr. Peter Attia32:15

       Oh, that's interesting.

   21. TDDr. Tom Dayspring32:16

       It's not, uh-

   22. PADr. Peter Attia32:16

       So I, I, I stand corrected because I think I was probably quoting some old data when I said that the VTE hazard ratio is about two.

   23. TDDr. Tom Dayspring32:24

       Yeah, but it's just weak sort of data. So wh- when you talk to Sam, talk to more about that. So maybe it is, maybe it isn't, but-

   24. PADr. Peter Attia32:30

       Athero, but aortic stenosis

   25. TDDr. Tom Dayspring32:32

       ... worry athero first.

   26. PADr. Peter Attia32:33

       Yeah.

   27. TDDr. Tom Dayspring32:33

       Yeah, and aortic stenosis.

   28. PADr. Peter Attia32:35

       Athero and aortic stenosis.

   29. TDDr. Tom Dayspring32:35

       Yeah. And part of the pathology maybe is just trafficking these oxidized lipid moieties into your particle, which is gonna just stimulate this whole inflammatory mess that's going on in your arterial wall, and maybe it's a prothrombotic mess if that's a prothrombotic protein too, the double whammy going in with it. So and I think Peter covered it nicely in his discussion there. There are these segments on apo little a called kringles, and there are a couple of kringles that have a large essence of lysine amino acid that is, uh, like flypaper for oxidized lipid moieties, so they really bind to these lysine-rich segments on apo little a. So if we could start measuring oxidized phenomenon and tying it into Lp little a-

   30. PADr. Peter Attia33:21

       Now, Sam, Sam has written about this in his papers.
8. 34:36 – 44:01

   ADMA, SDMA, Homocysteine, and Kidney Function

   1. PADr. Peter Attia34:36

      Before we leave biomarkers, anything you want to say about asymmetric or symmetric dimethylarginine?

   2. TDDr. Tom Dayspring34:41

      It's a very interesting biomarker also. Where we talked about endothelial function, perhaps even some of the antioxidant function is this miracle molecule every endothelial cell makes extremely transiently makes and it's gone. It's nitric oxide. Nitric oxide is a powerful regulatory molecule that regulates vascular reactivity by oxidation. The thrombotic potential of an endothelial surface initiating a thrombus is highly dependent on nitric oxide. So and when endothelial cells make nit- nitric oxide, which is by far the most important molecule they make, where does that come from? Arginine, the amino acid arginine. So arginine gets converted into nitric oxide. So last thing I want is things that are gonna screw up arginine pools, which is needed to make nitric oxide. And two, uh, proteolytic molecules we know, uh, byproducts of basically catabolism of nuclear proteins is something one is called symmetric and the other one is called asymmetric dimethylarginine. They're isoforms of one another. So if you, you know, they're mirror images of one another, but they're actually different molecules. One directly and the other indirectly inhibits the synthesis of arginine. So if I measured ADMA or-

   3. PADr. Peter Attia36:05

      The synthesis of nitric oxide, you mean?

   4. TDDr. Tom Dayspring36:06

      Right. Yes.

   5. PADr. Peter Attia36:07

      Yeah.

   6. TDDr. Tom Dayspring36:07

      Well, ultimately, synthesis of arginine, which results in the synthesis of nitric oxide.

   7. PADr. Peter Attia36:12

      Oh, see, I always thought that SDMA inhibited the synthesis of arginine, but ADMA inhibited-

   8. TDDr. Tom Dayspring36:19

      Well-

   9. PADr. Peter Attia36:19

      ... NOS directly.

   10. TDDr. Tom Dayspring36:20

       I should correct what I said. One inhibits the synthesis and the other, uh, enhances the catabolism of arginine. So at the end of the day, you're gonna have less arginine-

   11. PADr. Peter Attia36:29

       You're gonna have less nitric oxide

   12. TDDr. Tom Dayspring36:30

       ... and less, uh, nitric oxide. And they're both, uh, uh, markers that we can, uh, easily measure. So and if we measure them and they're high, you might presume Hey, maybe that's a blood test that actually tells us something about endothelial function. I don't think we have another that has anything close to at least that hypothesis

   13. PADr. Peter Attia36:49

       I think, I think the nice thing about the ADMA, SDMA is it, it, it creates a, a biologically plausible mechanistic explanation for why we see an association between high homocysteine and greater disease, because homocysteine really inhibits the clearance of ADMA and SDMA, and that's very clear when you correct it

   14. TDDr. Tom Dayspring37:07

       Which would therefore screw up nitric oxide production.

   15. PADr. Peter Attia37:10

       Correct.

   16. TDDr. Tom Dayspring37:11

       Yeah, so it brings even oxidation into the process would disturb that process too. So if a pro-oxidative state, if hyperhomocysteinemia is adversarial to the vasculature, that's one of the pathways in which it is. So, uh, what can we do? Well, we can measure it. So who would I measure ADA? So if you came to me and you're on your third bypass or fourth stent, I think it's a pretty safe assumption you have screwed up endothelial function, so I don't... Do I need to mention that?

   17. PADr. Peter Attia37:37

       And of course, the bigger question is, what do we do about it? So one thing is, look, if they have impaired renal function, hypertension, you know, those are things that you go after. The homocysteine, especially in the MTHFR mutation patients, you give methylated B vitamins, which is still controversial in sort of mainstream circles, because even though it lowers homocysteine, some will point to that and say, "Well, you have no outcome data on lowering homocysteine."

   18. TDDr. Tom Dayspring38:00

       No, but you have plenty of data that in people with hyperhomocysteinuria, lowering homocysteine drastically improves their vascular outcome. So it's plausible at a certain threshold-

   19. PADr. Peter Attia38:09

       Yeah

   20. TDDr. Tom Dayspring38:09

       ... of homocysteine that there's probably makes sense, and if you really understood the pathway of catabolism of methionine, you'd understand this better. And remember, in that pathway is gonna be the production of a lot of neurotransmitters too. So there's a lot going on if you have the genotype that's gonna screw up methylation or the enzymes involved with that. That's another story. But perhaps the best use of ADMA, SDMA is in the primary prevention setting where, all right, you got a little borderline ApoB, LDL-P, you're not gonna do lifestyle. Do I really want to throw you on a drug or something? If those markers are up, that tells me whatever is going on in you, you have endothelial dysfunction, so you're down the road towards vascular pathology. So it might be a marker to kick you in the rear to at least be super aggressive nutritionally. Even, "Hey, I'm sorry. Of whatever nutrition we tried, you still have abnormal endothelial function. It's time for us to... Here I would rather improve these markers that will take a drug to get them to where I want them to be." So maybe we can use it in that setting. If you also want to tell it to me, uh, "Tom, you said, hey, if you've been through a bypass or a stent or something, why do it? But what if I have such a patient who I've maxed out on a statin and ezetimibe, I've done everything I else to homocysteine or insulin resistance and they're still up? Should I lower ApoB even further with a PCS?" 'Cause, um, I- I mean, you use it for what you want to use it for, but as a marker of endothelial function. And very interesting, of the two, you get both, and y- you also get an arginine level in the same assay. And SDMA is cleared by your kidneys. ADMA is catabolized in the cells, so kidney function has nothing to do with ADMA. But SDMA, one of the things that'll elevate it is renal disease. And when SDMA goes into serum, it can back flux right into the cell and decrease nitric oxide production, probably part of the pathology in people with renal failure.

   21. PADr. Peter Attia40:12

       I was just about to say, the thing I like about the ADMA, SDMA stuff, even though we don't have all this great long-term data, is it's one biochemical pathway that provides very clear evidence for two observations that are undeniable, elevated homocysteine-

   22. TDDr. Tom Dayspring40:27

       And renal function

   23. PADr. Peter Attia40:27

       ... and renal function.

   24. TDDr. Tom Dayspring40:28

       Yeah. The SDMA, not the ADMA.

   25. PADr. Peter Attia40:30

       But, but you get both out of the... But the, the-

   26. TDDr. Tom Dayspring40:33

       Yeah. You, you get both.

   27. PADr. Peter Attia40:34

       Yeah.

   28. TDDr. Tom Dayspring40:34

       It's not like you're ordering them selectively. You order, you get them all three of those markers.

   29. PADr. Peter Attia40:37

       And, uh, but they're, they're, and they're addressing both sides of that equation.

   30. TDDr. Tom Dayspring40:40

       Yeah. So it's a very interesting little biomarker there. And hey, who, who doesn't want another renal function test? Most are using creatinine. That's kind of a poor. You should be using cystatin, uh-
9. 44:01 – 47:29

   What Remnants Really Are

   1. PADr. Peter Attia44:01

      You want to go back and talk a little bit about what a remnant is? It gets so much confusion about remnants. They're talked about like they're one homogeneous entity.

   2. TDDr. Tom Dayspring44:10

      Yeah. Like there is a... First of all, every known lipoprotein class, including Lp (a) , has remnants. All a remnant is, is a smaller part of its sister particle that's in the same density class. So VLDLs come in multiple sizes. You got the big ones, which are only found in people with triglyceride abnormalities. If you don't have a triglyceride disturbance, you will never have a big VLDL particle. You'll have medium size and very often just small LDLs. But if you look at your A- LDLs, there's a normal size particle, there's big LDLs, and there's small LDLs. Everybody has a heterogeneous mixture. There's no human on the planet who has one hundred percent exact diameter of every single subfraction of a lipo. HDLs vary widely in their density and their size and their diameters. Even IDLs, there's a certain diameter range or density range where here's the upper limits of what you would call an IDL, and here's the lower limits of when do you not call it an IDL, it's an LDL. Or when does a small VLDL, I can't call it a small VLDL anymore, it's called an IDL. But wait a minute, 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 IDL or maybe a VLDL? Chylomicrons, as they lose their triglycerides and phospholipids, they become smaller chylomicrons, chylomicron remnants, which are, for the most part, if you're lucky, cleared by ApoE receptors somewhere. But there's chylomicron remnants floating around. So what is the only particle I really care about? A part-- an ApoB particle that can wind up in your artery wall, get oxidized, and deliver the sterols, and you can oxidize them, and then you got plaque. So what forces them in? It's particle number. Now, I've also explained, all right, if that's a, its ApoB particle number, LDL-P is your first biomarker. ApoB is simply an LDL-P biomarker. It's-- You're not counting VLDL particles because there are so few of them. You're certainly not counting chylomicrons because there are even fewer of those. So ApoB is identifying to you way too many LDL particles in this person. But there is absolutely no doubt, even though you have way, way more LDL particles than you do have VLDL particles, because VLDL particles are two or three times bigger than an LDL, the volume of the sphere is the third power of the radius, they do carry more cholesterol molecules per particle than an individual LDL particle. But of course, you have so many more LDL particles than even VLDL or whatever you think a VLDL remnant is. Most of the cholesterol getting into your artery wall is still LDL delivered. But I am not denying that VLDL particles cannot deliver cholesterol and get oxidized when they are into the artery wall. They can. So what has been the classic definition of a VLDL remnant? Well, they've always said, well, do that conversion factor we talked. Divide triglycerides by five. If that's high, the VLDL cholesterol is high. Those are-- They have too many VLDL remnants. And no doubt, if we really had a VLDL remnant test, that's true. But it would not be true in other people. So, uh, it's a poor man's perhaps estimate of re- remnants.

10. 47:29 – 56:23

    ApoC-III and Its Role in Remnant Pathology

    1. PADr. Peter Attia47:29

       I, I'm trying to clarify what you're saying, right? And what-- Because I think it's a bit confusing to the listener. You can estimate VLDL cholesterol in two ways. You can take triglyceride and divide by five, and the higher the triglyceride level, the less accurate that becomes. You can take non-HDL cholesterol and subtract LDL cholesterol from it, and you'll get that-- you'll get an estimate as well. Those two don't often agree, by the way, but nevertheless, you have two estimates. But that still doesn't answer the question.

    2. TDDr. Tom Dayspring47:55

       Right.

    3. PADr. Peter Attia47:55

       Which of those go on to become pathologic remnants?

    4. TDDr. Tom Dayspring47:58

       Correct. So all you're identifying there is you have increased cholesterol content in VLDL particles, and because the ones we fear the most are remnants, we're just presuming, "Oh, boy, there's got to be remnants."

    5. PADr. Peter Attia48:10

       Higher of one leads to higher of another.

    6. TDDr. Tom Dayspring48:10

       "There's got to be remnants here." So whatever therapy you're thinking of doing in this person, you better get rid of probably some remnant therapy too. Well, all of the FDA-approved drugs that lower ApoB, uh, whether it's statin, ezetimibe, fibrates, which are approved to lower LDL cholesterol, even though they don't really do it that much, PCSK9, clear all ApoB particles, including remnants. So your ultimate solution... Now, your first solution might be nutritional if it's not somebody coming off their bypass or is in the nightmare risk range classification where I think you need a lifestyle and pharmacology day one. You just don't have the-- Too many decades have passed. You shouldn't be putzing around. But in a real short time, you know the nutritional therapy, if I think you have remnants, is gonna be I'm gonna address insulin resistance in you. And so I, being an advocate of l- some degree of l- carbohydrate restriction and, uh, certainly a clear advocate for a lot of reasons, apart from even ApoB, would be the fasting as part of your, your diet and, and too. So great, if you want to use your VLDL cholesterol and it makes you think there's remnants and you're gonna suggest a therapy, I would tell you if you're total drug guided, I have a drug, then that's the person you give a fibrate to with your statin because that's where-- what the fibrates really do well. But I can show you data, ezetimibe, the statin clears as many remnants as that combination too, but I think fibrates bring other things to the table that perhaps zetia doesn't in people with triglyceride-rich lipoproteins. And one of them is gonna be... So it's how I really think we're gonna have to identify remnants. So just even tell-- There's a laboratory that produces... They separate VLDL particles by ultracentrifugation. The NMR people used to report total VLDL-P, but they would also give you large VLDL-P plus medium VLDL-P plus small VLDL-P. And we used to say, "Well, the small VLDL-P, those are the remnants. That's the mark." Well, they don't do that anymore. They only give you the large VLDL-P anymore. Those NMR generating labs that have the proprietary ability to release VLDL particle data, and that's not all NMR labs.

    7. PADr. Peter Attia50:26

       Is that, is that LipoScience or LabCorp now?

    8. TDDr. Tom Dayspring50:28

       Well, there is no more LipoScience. It's LabCorp.

    9. PADr. Peter Attia50:30

       It's LabCorp now.

    10. TDDr. Tom Dayspring50:30

        So you will get a large VLDL-P, and it has one reason and one reason alone. It's a lipoprotein marker of an insulin-resistant state. That's it. It's not a goal of therapy. It's nothing. There's no data that of what you do to VLDL-P affects outcomes, although I'd make the case that maybe it does. But it's just an IR marker. I can measure small dense LDL cholesterol, HDL2 cholesterol, s- just small LDL particle concentration. I can do an insulin level and 10 other tests that tell me you're insulin resistant, so I don't need any VLDL-P marker.

    11. PADr. Peter Attia51:03

        Yeah. I mean, they were using that as part of their IR-

    12. TDDr. Tom Dayspring51:05

        Yeah

    13. PADr. Peter Attia51:05

        ... algorithm score.

    14. TDDr. Tom Dayspring51:06

        So if you don't have that, and they use, they factor in VLDL size here, 'cause the big triglyceride-rich VLDLs are a marker of insulin resistance. But if you're measuring insulin levels and other insulin biomarkers, they're no better than that. I don't know that they're any better than just measuring small LDL particle concentration, at least in a drug-naive person. So, uh, fine, it is a marker of insulin resistance. But this other lab, the Centrifusion, they tell you, "Ah, look at our smaller VLDL cholesterol. Those are remnants." How do they know? All they know is that person has extra cholesterol in their small VLDL particles. But VLDLs, dependent on two things, its ApoE content and its apoC-III content, is gonna be virtually instantly cleared. So if your V- small VLDL particles are being rapidly cleared by your ApoE, ApoB 100 receptors, what do I care?

    15. PADr. Peter Attia52:03

        So in other words, if you took a bunch of small VLDLs and some of them had lots of ApoE and very little apoC-III, those aren't remnants. They're not pathological. They're not sticking around.

    16. TDDr. Tom Dayspring52:12

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

    17. PADr. Peter Attia52:16

        Right.

    18. TDDr. Tom Dayspring52:17

        Uh, look, some of them probably get in, but-

    19. PADr. Peter Attia52:19

        Versus

    20. TDDr. Tom Dayspring52:19

        ... very few-

    21. PADr. Peter Attia52:20

        Yeah, yeah, yeah

    22. TDDr. Tom Dayspring52:20

        ... compared to LDL particle number. So, and also remember-

    23. PADr. Peter Attia52:24

        And, and very few relative to a small VLDL that would be high in apoC-III-

    24. TDDr. Tom Dayspring52:28

        Yeah

    25. PADr. Peter Attia52:29

        ... and/or low in ApoE

    26. TDDr. Tom Dayspring52:29

        Which is, is never gonna be cleared. ApoC, the main down... Well, and there's a lot of downsides to apoC-III. It's a pro-inflammatory protein. It really enhances VLDL production in the liver, but it just retards their clearance, and it probably interferes with the hydrolysis induced by lipoprotein lipase. So you're increasing the half-lifes of all triglyceride-rich lipoproteins, which lets CETP exchange occur longer. And what is CETP exchange doing? Bringing more cholesterol into your VLDL particles, enhancing cholesterol enrichment. They're, those VLDLs are losing triglycerides but gathering cholesterol. So these are all the pathologies that might go on if you have delayed clearance, and C3 is gonna delay the clearance through multiple reasons of these particles. So I want a blood test that tells me the apoC-III content of your ApoBs. LDLs that have apoC-III cannot be cleared. In one of the early Pravachol trials, the pravastatin trials, the CARE trial, they went back and they... Who with high triglycerides gets coronary events? And this is Frank Sacks up in Boston, and they've, they've been able to measure this in sophisticated lipid labs for a long while. If your LDL had C- apoC-III on it, pravastatin was a useless drug. Didn't reduce any events. So what?

    27. PADr. Peter Attia53:48

        It still reduced ApoB, but it didn't reduce events?

    28. TDDr. Tom Dayspring53:51

        Yeah, yeah. It would clear some LDL particles. It didn't reduce events in people who had high triglycerides. So, uh, so the apoC-III, it's not measuring triglycerides that matters, it's apoC-III. And a lot of people with apoC-III might only have a triglyceride of 110, 120.

    29. PADr. Peter Attia54:08

        Wait, which trial was this?

    30. TDDr. Tom Dayspring54:09

        A CARE trial. Cholesterol and acute... It was a second secondary prevention trial. Simvastatin 4S was first, and that was Swedes with super high LDL cholesterol and heart attacks. This was done in Boston at the Brigham, where they enrolled people with unremarkable, at the time, LDL cholesterol 130 or lower, who had heart attacks, and they gave them pravastatin and got this, pretty much the same event reduction as they got in the 4S trial.
11. 56:23 – 1:07:45

    Omega-3s: EPA vs. DHA, Red Blood Cell Levels, and Formulations

    1. TDDr. Tom Dayspring56:23

       Yeah. So there, uh... Look, from my mind, for years it's been Omega-3s are not lipid drugs. Ignore them. Don't use them to putz around with lipids, 'cause you don't know what they're doing. Uh, that's changed now. Clearly, high-dose prescription-strength EPA can be a helpful adjunctive therapy to lower apoB. And whether it's with remnants or whatever it's doing, it's lowering apoB an additional 8, 10%. Great, and it's a pretty innocuous therapy. I always worried about those who might not be able to convert EPA to what I believe is the necessary DHA also, especially in the brain. So, uh, but I can measure that in the plasma.

    2. PADr. Peter Attia57:01

       You know, I've been thinking about, I'd like to have Bill Harris on the show as well to have a discussion about this, because-

    3. TDDr. Tom Dayspring57:06

       You really should

    4. PADr. Peter Attia57:06

       ... at, at least at the time of our recording today, I would say that the mainstream view of EPA and DHA is that they're useless, right? That's the press for today.

    5. TDDr. Tom Dayspring57:14

       That's the mainstream view.

    6. PADr. Peter Attia57:15

       Yeah, the mainstream view is abandon all of these dumb sort of supplements. But, uh, as is often the case, when the mainstream says something in a declarative fashion, they're usually wrong.

    7. TDDr. Tom Dayspring57:25

       Especially on a nutrient, you know, where they're looking about what you're eating, not taking pharmacologically, where you might have a real serious trial.

    8. PADr. Peter Attia57:31

       So they, uh, they... Yeah, they're confused by supplements versus pharmacologic grades.

    9. TDDr. Tom Dayspring57:35

       Yeah. Uh, most of the trials that they would quote as omegas being useless, they're using some minis- not a pharmacologic dose of these things. And they're not measuring even who's deficient in omegas. And if you're not deficient in it, why would I even give you an omega-3 prod or so? And measuring fatty acids in the blood, I would encourage you to measure red blood cell Omega-3s that are like a glycohemoglobin, have a 30 or a 60, 90-day half-life, rather than a plasma free fatty acid omega, which might be what did you eat for lunch.

    10. PADr. Peter Attia58:06

        Yeah, yeah.

    11. TDDr. Tom Dayspring58:06

        You know? So there's other intricacies involved. But nonetheless, they're just all things to think about there. So, and this DHA with apoC3 is kind of interesting. Now look, some people, if you're just gonna drown them in EPA, do convert it to DHA, so it's not an issue. You... But we can measure that, and I think we'd know. Oh boy, and you, you got to have some of that either eaten or supplemented, you know?

    12. PADr. Peter Attia58:32

        Are you pushing patients towards closer to 10% red blood cell EPA, DHA level these days, or are you...?

    13. TDDr. Tom Dayspring58:38

        Well, I don't see patients anymore, but if you want to ask me, yeah, that would probably... You know, there's no... Y- you know, Bill Harris would tell you, "Why not make it 14%?" But we don't have any data that would show, hey, that's harmful, but we don't have any data showing you can even make it that high or so. So-

    14. PADr. Peter Attia58:55

        Not even epistaxis and things like that? Easy bruising?

    15. TDDr. Tom Dayspring58:59

        I, uh... S- so far anything with it, they've never turned anything from an Omega-3 into a coagulation disturbance.

    16. PADr. Peter Attia59:06

        Got it.

    17. TDDr. Tom Dayspring59:06

        I mean-

    18. PADr. Peter Attia59:06

        Well, I definitely have to-

    19. TDDr. Tom Dayspring59:07

        ... it's old data that, hey, some Eskimos had a bloody nose one day on and what else? They're eating EPA and DHA all day long. So I don't know. That would have to be tested in a clinical trial.

    20. PADr. Peter Attia59:16

        By the way, Tom, I just have to take issue with that as a Canadian. I think we refer to them as Inuit now.

    21. TDDr. Tom Dayspring59:20

        Oh, I'm sorry. Yeah.

    22. PADr. Peter Attia59:21

        [laughs] I'm sorry.

    23. TDDr. Tom Dayspring59:22

        Eskimos is an old New Jersey term.

    24. PADr. Peter Attia59:23

        It's super culturally insensitive.

    25. TDDr. Tom Dayspring59:25

        Oh, my God.

    26. PADr. Peter Attia59:25

        And I'm not gonna, I'm not gonna stand for it on this show.

    27. TDDr. Tom Dayspring59:27

        I'm an old Jerseyite, so you're right.

    28. PADr. Peter Attia59:29

        Okay.

    29. TDDr. Tom Dayspring59:29

        I know I insulted a lot of you.

    30. PADr. Peter Attia59:31

        But, but I really do need to get Bill on the show because he's always... He... Bi- Bill's one of these guys who is... And again, many of the listeners won't know who Bill Harris is, but I, I hope to change that. Just this is a guy who is as devoted to understanding the entire body of literature and science of omega fatty acids in general-
12. 1:07:45 – 1:10:26

    Why Red Blood Cells Don't Cause Atherosclerosis

    1. PADr. Peter Attia1:07:45

       Now, we've danced around this idea of red blood cells for a while. They keep coming up. So let me redirect us to another topic, which is you've already said red blood cells per molecule carry many, many more molecules of cholesterol than any lipoprotein does.

    2. TDDr. Tom Dayspring1:08:00

       Right.

    3. PADr. Peter Attia1:08:01

       Why don't red blood cells cause atherosclerosis?

    4. TDDr. Tom Dayspring1:08:05

       Because they're not invading your arterial wall and not subject to oxidative forces, uh, where a macrophage is gonna ingest the red blood cell.

    5. PADr. Peter Attia1:08:13

       Do they not invade the artery wall because they can't penetrate the subendothelial space?

    6. TDDr. Tom Dayspring1:08:18

       Yeah, they're gigantic. Now listen, can a red blood cell get into plaque? Yeah, through the vasa vasorum. So could there be some in there that are... [laughs] Yeah.

    7. PADr. Peter Attia1:08:26

       So the vasa vasorum, meaning from the other side?

    8. TDDr. Tom Dayspring1:08:28

       Yeah. Well, remember, artery walls get arterial supply. They need oxygen.

    9. PADr. Peter Attia1:08:32

       Mm-hmm.

    10. TDDr. Tom Dayspring1:08:32

        Even plaque has little capillaries and stuff. So are there red blood cells in, uh, expanding plaques? Sure. So not to say they're not a tiny little part, but that's not your primary delivery of oxidized phospholipids and sterols into the artery wall. Red blood cells are not being, entering the artery wall and being oxidized, [laughs] you know? Like, uh, the ApoB particles are.

    11. PADr. Peter Attia1:08:54

        Yeah, so this kind of gets back to sort of the causality issue of-

    12. TDDr. Tom Dayspring1:08:58

        And-

    13. PADr. Peter Attia1:08:58

        ... of low-density lipoproteins

    14. TDDr. Tom Dayspring1:08:59

        ... although also red blood cells carry way more cholesterol molecules, you have bazillions more ApoB particles than you have red blood cells also. So yes, quantity-wise, they're carrying a lot of cholesterol, but not red blood cell number-wise-

    15. PADr. Peter Attia1:09:16

        Yeah, yeah

    16. TDDr. Tom Dayspring1:09:16

        ... versus LDL number-wise.

    17. PADr. Peter Attia1:09:17

        So the size of the LDL particle obviously is what enables it to easily get into and, and out of-

    18. TDDr. Tom Dayspring1:09:23

        Oh, yeah, nu- number and size, but as you know, I've taught you this a long time ago, any VLDL or, uh, under 70 nanometers can work its way into an endothelial gap or an arterial wall through a scavenger receptor, whatever. So not to say remnants are an atherogen, they can't get in 'cause remnants are way bigger than an LDL. No, they could. But there's just more of the LDL particles. So if this is a d- a diffusion gradient for sitting in, then there's a hell of a lot more LDL troublemakers than there are remnant troublemakers. Not to say some big tough guy isn't a big troublemaker by himself. He is, but he's... Which would you rather have, 1,000 guys coming at you or one guy? I'd take my odds that I could beat one guy rather than 1,000 guys, you know?

    19. PADr. Peter Attia1:10:06

        Yeah, yeah. You know, I, I figure it's hard to believe we've been going at this for almost seven hours, and I feel like there's at least another hour or two we could go, but at the same time, I want to be sensitive to the listener. Normally, I say I want to be sensitive to the guest, but I know you and I-

    20. TDDr. Tom Dayspring1:10:24

        Yeah, you know-

    21. PADr. Peter Attia1:10:24

        ... could keep talking about this for another-

    22. TDDr. Tom Dayspring1:10:25

        There's no limit

    23. PADr. Peter Attia1:10:25

        ... six hours.

    24. TDDr. Tom Dayspring1:10:26

        Right.

13. 1:10:26 – 1:16:44

    Remembering Earl: A Friend Lost to Untreated Cholesterol

    1. PADr. Peter Attia1:10:26

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

    2. TDDr. Tom Dayspring1:10:52

       Yeah, so let me just pick up that, my abso- you know, if you look back in life, who are some of your absolute best friends? Your high school buddies who you really spent all that enjoyable, the type of enjoyment you can have at that age that you never can have at another age, and you can do things, and especially when we grew up, and we were in high school '59 to '63. You could get away with a lot of junk in [laughs] those days, whereas today, uh, we would've been expelled real quickly or so with some of the shenanigans we'd do, so. And look, I, I joked with Peter when I was telling this story. I, I think he really wanted to be my best friend 'cause my father was a fire chief in the town of Paterson, New Jersey, where we went to high school. But even if that was true, I love firefighting. What do I care if he loved firefighters? We used to get on our bikes and ride to fires all the time together, and, uh, watch fires and stuff or drive to firehouses. So we were really tight for a million reasons, and we just got along personality-wise, but he's the guy who invited me to my first ice hockey guy, which was certainly impacted my life and my son's life in mega ways. My son's a very successful guy, and he would tell you he'd never be half as successful had he not played ice hockey and developed the teamwork and the camaraderie. Speaking of a fire engine. [laughs]

    3. PADr. Peter Attia1:12:07

       Uh, it, it is perfect timing to have a fire truck going down, uh-

    4. TDDr. Tom Dayspring1:12:11

       But I'm gonna just keep talking-

    5. PADr. Peter Attia1:12:12

       Yeah, yeah

    6. TDDr. Tom Dayspring1:12:12

       ... over this fire truck 'cause it's not high lipid science. So my buddy there, he went and became... And I knew him all my life, and I went and became a doctor, but right in, in that same city or in a suburb of that city, so it's not like he didn't know where to find me. But at a certain point early in our life, I knew my buddy, "Hey, uh, you're a doctor now. I got the, this cholesterol problem. They tell me my cholesterol's up in the blood." And, uh, you know, that was probably at the point where we were really taking cholesterol serious, and we could do something about it. "You know, you gotta come and see me. Come on." Uh, you know, and it was probably even the days before I was just solely dwelling on l- lipoproteinology and lipidology, but I, I was very aggressive with understanding cholesterol and knowing look who I evolved into, so it would've probably been a smart choice for him to come up. It's not like I was gonna charge him and he couldn't afford me. He's a fireman in a big city. He had the, as good a health insurance as you could ever get, so it's not like it would've cost him 10 cents. A lot of firemen did pick me as their doctor because of who my father was, and they knew he was a guy who likes fire engines, the way you used to see him as a kid in the firehouse. So I want him to be my doctor. He knows what I do. Earl just is one of these people who thought the farther I stay away from doctors, the better. I don't wanna hear what they got to tell me. I don't wanna be on a medicine. I don't wanna do anything. And Earl got buried in his mid-50s with a sudden acute myocardial infarction sitting at home watching TV. He could've been climbing a ladder at a fire. By the way, if he did die at a fire, his name would be on the memorial monument up in that city, but he died at home the next day. So Not that I want his name on a... I really wish it was, 'cause he's just such a de- but there is such a needless death, and I think across America all the time, there are many young age needless deaths occurring with a very preventable, treatable disease that's being ignored totally 'cause they don't go and get it checked or they're getting bad advice based on the wrong metrics. So my buddy there is the perfect example. But what a tragedy, 'cause had he made the right, "Eh, I like this guy. He's my best buddy. He's not gonna screw me or do anything wrong. Let me go to him." He didn't. Every time I saw him, I'd remind him, "Earl, come up, come up, please come up." "Yeah, yeah, Tom." Never did.

    7. PADr. Peter Attia1:14:42

       Well, in many ways that's a reasonable and sad way to kind of end this discussion, but it also brings it kind of back to why we, why do we get so animated about this topic? Well, I think as you said, we think of this as, you know, one of the big three diseases that kills most people in the civilized world once they get out of childhood, and by civilized I really mean developed. People know what I mean. But of the big three diseases, this is the one where I think we know the most about it, and therefore by extension, it's probably the one that's most delayable. Never want to say preventable, right? We use that term, but in reality-

    8. TDDr. Tom Dayspring1:15:14

       Correct

    9. PADr. Peter Attia1:15:14

       ... what does that mean? It means delay. And, and so if Earl died in his early 50s, maybe with the right care, he could have died in his late 60s. You know, again, if a guy's dying in his 50s of heart disease, he's probably got really bad disease.

    10. TDDr. Tom Dayspring1:15:27

        Yeah, he needed therapy at a real young age.

    11. PADr. Peter Attia1:15:29

        Yeah.

    12. TDDr. Tom Dayspring1:15:30

        But he could've hung around for a while, and he's got grandkids and children and stuff who really wish he was still here. The fire department, he was a beloved fireman. They all wish he was still on ac- He'd be retired by now, but he's just one of these people that God sends to earth that do nothing but good while they've been here through their whole life. He had saints as parents, and he, it was so tragic that he left us at s- at such a young age and got driven to the graveyard on the back of a fire truck with a flag on, a Vietnam veteran. And so, uh, but just so, so sad. And listen, I, I want to wrap this up myself, and I used to wrap up a lot of lectures I did with this and, y- you know, 'cause I, my lectures were all high science no matter what group I was speaking to. So I always warned guys, "You ought to come out of this lecture that I give," and maybe with all the things, if you really sat through everything we talk about today to say, "Guy's an idiot," or, "He's onto something and I thought I understood this topic, but maybe I need to understand it at a higher level." So everything is study, study, study. I didn't learn this stuff overnight. My life has been spent in this field.

14. 1:16:44 – 1:29:43

    Closing Reflections on Learning, First Principles, and Biology

    1. PADr. Peter Attia1:16:44

       Yeah. Well, I'll s- I'll say a couple things. I'll say a couple things on that. So first of all, I, I obviously want to thank you for the influence you've had in, in me, and, and I, I don't know, I just feel really lucky. I think that I got plugged into you and Alan and Ron just out of the gate to have met the three of you so early in my interest in this topic saved me so much time because it's one thing... I mean, no one can substitute the amount of time you have to spend obsessing over this topic and learning it, but boy, when you can have that curriculum curated for you, you shortcut it by, you know, three X, I'm sure.

    2. TDDr. Tom Dayspring1:17:19

       It's a gift, and I'll just extrapolate on that 'cause Peter named three guys he can get in contact with pretty quickly and get answers. As I evolved in this world, I had 20 guys around the world who liked me a lot because of what, the way I explained things, what I could illustrate for them. So I've been blessed by, I've mentioned a few today. It would take me another 15 minutes to list them all, but so many of the, I call them the lipid gods out there, the people who have spent their real life in research laboratories and clinical trials and taking care of people in the worst clinic, lipid clinic scene. And, uh, they still are available to me, but that's who I use. I don't go on the internet and read something or make stuff up. I try and ask experts about a lot of things. Not that you'll ever get consensus on anything, but those of us who do have those avenues open, which many do not, but they're not afraid to still pontificate about something, and it's kind of sad.

    3. PADr. Peter Attia1:18:19

       Yeah, and I can't remember if I made this... This'll be my final point on the topic, and I can't remember if I made this point on a previous podcast or not, and if I did to the listener, I apologize. You know, I started out in mathematics and engineering and really loved those things. I excelled at those things, took great pleasure in being a first principles thinker. So one silly story, at the end of my freshman course in sort of dynamics, kinematics, like sort of Newtonian physics, you take a final exam, and you are allowed one piece of eight by 10 paper that you can write on both sides as much as you want, whatever formula you want, because, you know, there were just so many equations you would have to know to go in and, and ace one of these exams. Now, I was cocky beyond words, and I was really lucky as a freshman. I used to study in this dark part of the stacks where I met a real upperclassman guy. His first name was JP. I don't remember his last name, but I'll never forget him. He was the only guy I'd ever met who decided to take two engineering disciplines and finish them both in four years. So he did electrical and mechanical engineering in four years. The price he had to pay for that was he studied every minute of every day, but he also told me he didn't have the opportunity to learn everything, 'cause you couldn't. If you wanted to take all of electrical and mechanical in four years, you had to accept that there were certain things you couldn't know. So he, all of his study focused around first principles inference, and he taught me this early. And so he saw me studying for one of my exams, and I was writing out something called the Coriolis equation, which basically explains centrifugal forces under the condition of a changing radius. And he said, "You don't need to memorize that formula. You know how to derive it." And I was like, "What? What are you talking about?" He goes, "Write out the formula for angular position and take the derivatives of it." You know, you know calculus. So I did, and sure enough, I was getting the same formulas. To make a long story short, I go-- I, I've become totally, totally inundated by JP's reasoning. I go into my final exam and, oh, you have to turn in your cheat sheet at the end of the exam. And I-- this is again, just, I'm not saying this to brag about how cocky I was, but so I just have to state.

    4. TDDr. Tom Dayspring1:20:33

       Oh, heavens.

    5. PADr. Peter Attia1:20:34

       But the point is, I wanted to show the professor how well I understood this material. The only thing I wrote on my cheat sheet in big block letters was the sum of the forces equals mass times acceleration. Because I was like, if you know the simplest of Newton's laws, you can actually derive everything at this level of physics. We're not talking quantum physics at this point. And, and he-- and I remember JP said, "Look, on every question, write it out, show them how you can go from one to the other, because if you make a mistake, at least they'll see what you're doing." I ended up acing the exam, and that lesson sort of stuck with me, and it served me very well through the rest of engineering and mathematics, including when it got really, really complicated, that in the end, if you truly wanted to understand something at first principles, you could derive so much. Okay. Fast-forward a few years, now I find myself in medical school. Now, I was not a pre-med, so I'm in medical school not as a pre-med, but as a former engineer math guy who barely squeaked into medical school, meaning I took the MCAT having not even taken a course in biology yet. I had to take my bio class after. And I'll tell you, that first semester of med school was brutal for me because I learned the hard way that you couldn't first principles your way through biology, at least not at the level-- at, at least not until you'd gained a certain amount of familiarity with the basics. I couldn't walk into my histology class, look under the microscope, and on first principles know the difference between the Golgi apparatus and the endoplasmic reticulum. You just have to know that stuff. I couldn't go into anatomy and physiology and pathology and just first principles my way into stuff. Eventually, you can, but you have to have an enormous basis. So I, I sort of forgot all about that pain. You know, you get through medical school, and by the end it became-- you know, it was very enjoyable, but it wasn't until I got to the lab, to NIH, where my mentor told me a great story. Now, he's probably one of the most brilliant scientists I've ever known and did a PhD in biophysics specifically for the purpose of wanting to make sure he was never, in his words, intimidated by a differential equation, despite the fact that he was an immunologist. And he told me a story, which I, I need to get the details of it because I don't remember the physicist he's referring to, but he told me the story of a physicist turned biologist who lamented once that the moment he switched from physics to biology, he could never again take a bath in peace. Because as a physicist, he could sit in the bath and wax philosophically and think about lots of things on first principles and be very theoretical in his understanding. But as a biologist sitting in the bath, he always realized there was one more fact he needed to remember before he could draw a conclusion, and so he had to keep getting out of the bathtub to go and look up a certain fact, and that obviously disrupted the beauty of taking the bath. And I think that long, rambling story is a way of saying the following: I find this subject matter to be as complicated as any I have ever tried to learn. And unfortunately, every time I have a brilliant idea just based on first principles, I still have to go and check if it's grounded in the foundation of science. And sometimes it is, but many times it is not. I come up with an idea and I'm like, "This has got to be right," blah, blah, blah. Oh, they're-- it's physiologically impossible, and there's even an experiment that one day suggested this or it's, you know, I, I made an assumption, but I can clearly see that it was not the case. So I understand your frustration and I share it, and I think unfortunately that is the nature of biology.

    6. TDDr. Tom Dayspring1:24:07

       Yep, and I remain an eternal optimist. I continue to teach lipids. I think clinicians know a bit more than we knew [chuckles] in 1995 when I started this journey teaching. And so that's all. If I have to do it one at a time with people, I try and teach them what I know, and hopefully you'll do your continuing education. And that's, uh, one of the nice things about medicine, yeah. But you got to do it. None of this comes easy. Yeah, yeah, it does-- And there's a lot of complexities in, uh, medicine nowadays. We're talking because it's a highly pathologic state and leading cause of trouble, but there's so many other things to, boy, take to the, uh, much higher level nowadays, you know?

    7. PADr. Peter Attia1:24:48

       Well, Tom, people, I think, will certainly by the end of this know where to find you. But, uh, on Twitter, which is where you spend the most of your time, you're @doctarlippin, correct?

    8. TDDr. Tom Dayspring1:24:56

       That's me.

    9. PADr. Peter Attia1:24:57

       Yeah.

    10. TDDr. Tom Dayspring1:24:57

        So, yep.

    11. PADr. Peter Attia1:24:58

        And this'll-- I mean, we're generally in our brief existence as a podcast already known for probably producing the most thorough show notes ever. I'm suspecting that this, this episode, which will probably break into several parts, will have the most robust show notes, um, that we've done. And I love, by the way, that there's another firetruck going down. It's, it's perfect.

    12. TDDr. Tom Dayspring1:25:18

        [laughs] Great way to end.

    13. PADr. Peter Attia1:25:18

        It's, like, totally appropriate.

    14. TDDr. Tom Dayspring1:25:20

        Yeah.

    15. PADr. Peter Attia1:25:20

        But also, if there's anything else that you think of j- let's just talk about it where, you know, offline even we can just get to it. Where there are other resources you think people ought to go to. Again, I, I will-- we'll steer people away from your 2000 to 2004 writings.

    16. TDDr. Tom Dayspring1:25:34

        Yeah. [laughs]

    17. PADr. Peter Attia1:25:35

        [laughs] But I think there's gonna be a number of people who listen to this who say, "You know what? Look, I might have missed half of what those guys talked about, but there's something there I want to make sure I understand better." Because in the end-

    18. TDDr. Tom Dayspring1:25:45

        Yeah

    19. PADr. Peter Attia1:25:45

        ... every doctor wants to do the best by their patient. I mean, that's just, I, I-

    20. TDDr. Tom Dayspring1:25:48

        Yeah

    21. PADr. Peter Attia1:25:48

        ... believe that wholeheartedly.

    22. TDDr. Tom Dayspring1:25:50

        Yeah, yeah.

    23. PADr. Peter Attia1:25:50

        I, I get very frustrated when I hear people say that doctors are in the f- pockets of pharma companies, and they're just in it for the m- I mean, that's-- sure there's gonna be some of those people, but I haven't met those guys, you know? The doctors that I meet, the, the men and women I meet who take care of patients, they all want to do the best by their patients. And I think that those are people who are gonna wanna invest a little bit of their time in understanding this problem a little better.

    24. TDDr. Tom Dayspring1:26:11

        No, I can't say it any more nad and, uh- As you listen to these seven and a half hours, even hopefully piecemeal marker, clearly for depending on the list, there's going to be things over your head. Even if you are a super skilled lipidologist, there's going to be some things you said, "What? Let me you read about that or so." But it's just trying to open your mind and understand there's a lot going on here. The field is infinitely more complex than you ever imagined. It took me a long... And I'm a, as Mike Davidson calls me, Tom's a self-taught lipidologist. I mean, I didn't spend two years down at the National Heart, Lung, and Blood Institute, even though the director of that NHLBI, Alan Romali, and I just authored a 70-page chapter in the Teach Book of Molecular and Clinical Biochemistry, all about lipids and apoproteins. So I think to be an invited author with a guy of that magnitude-

    25. PADr. Peter Attia1:27:07

        Yeah, and you've sent me a preprint of that. That's a remarkable treatise.

    26. TDDr. Tom Dayspring1:27:10

        So I mean, it's an expensive book. I don't expect you, if you're not a lipidologist or somebody seriously into this clinician, that's what you go out and buy. But there is a lot of information out there. So just be careful on what you, that's ridiculous or my cockamamie theory based in no clinical trials or science is what I believe. Fine, believe it. This is America here. [laughs] I can't lock you up. I'm not the lipid police.

    27. PADr. Peter Attia1:27:39

        Yeah, well, on that note, Tom, thank you very much. It's hard to believe this has been seven hours of discussion today, but it's been worth every minute to me. And I've learned a lot in this discussion. So to me, that's always a, I mean, for selfish reasons, that's sort of my primary objective is to learn as much as I can. And then along the way, if others can learn too, that's a bonus.

    28. TDDr. Tom Dayspring1:27:58

        And without a year of my intermittent fasting and program from Peter Attia, I could have never had the energy to sit here all day long, even to use my tongue or brain. So thank you again, Peter.

    29. PADr. Peter Attia1:28:10

        Yeah, my pleasure, Tom. Thanks. You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peterattiamd.com. What's a Nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit peterattiamd.com/about.

Episode duration: 1:29:46