#334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, cholesterol, brain health, and more | Tom Dayspring, M.D.

27:59Of course, we would understand why hyperglycemia is problematic for microscopic vessels, but it's kind of these larger vessels that seem to have a negative response to hyperinsulinemia. It almost comes back to this idea of what's going on with uric acid and homocysteine. Are these things somehow inflammatory to the endothelium and therefore render the endothelium even more susceptible to a given concentration of lipoproteins. Again, it might be a moot point because I think when it comes to AACVD, the goal is probably to address everything and therefore we might be sort of having more of an academic debate on this.

28:40I think the other point that is probably worth mentioning to people when we talk about causality and biology is distinguishing between things that necessary and things that are sufficient. And obviously, once in a while, you find something in biology that is both necessary and sufficient. But many times, it's neither, and it can still be causal. So I'll use the example of smoking. So is there any doubt that smoking causes lung cancer? There's no doubt in anyone's mind, anybody who doubts that probably shouldn't be having a discussion at this point. So smoking is causally related to lung cancer.

29:17But is it necessary for lung cancer? No. Only about 85 % of people with lung cancer are smokers. 15 % have never smoked. Is it sufficient for generating lung cancer? No, it's not because there are many smokers who don't go on to develop lung cancer. So in that sense, you can have something that is very causal, meaning it's about a thousand times increasing the risk of lung cancer, but it's neither necessary nor sufficient. This will be relevant when we pivot to our next topic, which is APOB. It'll be interesting to talk about APOB through the lens of necessity and sufficiency. So before we do that, maybe give folks the little explanation on what APOB is and maybe why we shouldn't think of it as synonymous with, say, LDL cholesterol.

30:07Yes, well, APOB is the ball game nowadays. It's not widely tested like it should be, but anyway, cholesterol's got to get in your artery wall to cause this disease atherosclerosis. We know cholesterol as an organic molecule that is in the lipid classification. There are many other lipids, but the definition of a lipid is it's a molecule that's not soluble and water. And the dilemma is our delivery system of everything in the human body is a water solution called plasma. So how in the world are lipids trafficked in plasma? That's basically a physical chemistry and possibility. You know, you've heard me say this many times to patients, evolution had to develop a lipid transportation vehicle.

30:53So these hydrophobic lipids could be traffic in aqueous plasma. And the solution was very simple because proteins are soluble in water. So if one just combines a collection of lipids to a protein carrier, lipids can go where the human body wants them to go in plasma. The things that traffic lipids in our body are protein and rapolipids. The proteins are called apoprotines. Once they bind to lipids, They're called apolipoproteins and the whole macromolecule, once it's fully developed, it's called the lipoprotein. So lipids go nowhere in the human body unless they're a passenger inside of a lipoprotein.

31:36Now there are many proteins that can associate with these lipid collections, but there's two. We're going to put it at the top of the list. There are structural apoproteins. These proteins provide structure stability and water solubility to the lipids. There are two basically categories of lipoprotein families in our body. We're talking about the APOB family right now. So APOB happens to be the largest of all the APO proteins that the liver and even the intestine can produce. By the way, no other cells in the human body produce APOB. It's the liver and the small intestine. Very high molecular weight.

32:17So particles that are enrapt with APOB, and of course they're full of thousands of molecules of triglycerides or colostraw, phospholipids and other lipid moieties. The APOB family, we have other ways of classifying them and that's in the centerfuge. So the APOB family consists of what everybody has probably heard, low density lipoproteins, the LDL, very low density lipoproteins, the VLDLs, which are triglyceride carrying particles, I'm going to mention for completeness intermediate density lipoproteins, they're very transient characters in between VLDLs and LDLs. They're not a consequence other than some very rare lipid disorder.

33:05So that's the APOB family, but the really good thing in what makes APOB so valuable is there is one molecule of APOB per APOB containing lipoprotein. And this is great because it's a very easy assay for labs to do. It's an immunosay well standardized. So we can have on our patients, hey, go get an APOB concentration. And when we get that number back, we know we are actually counting the number of APOB containing lipoproteins. And that's so critical because the particle that can leave plasma Antony artery wall and start off this atherogenic process are the apobie family. The other family of lipoproteins are our high density lipoproteins, our HDLs.

33:55Their structural protein is apoprotein A1 except there's from one to five copies of APOA1 per HDL particle. So that doesn't become a useful biomarker to get an HDL particle concentration. And the HDLs, And until you get into the sub -discussions of them, per se, you're not atherogenic. So don't worry about them too much. It's the APOB particles. And to just complete this discussion on the importance of APOB, what makes an APOB particle decide to leave plasma and crash the artery wall rather than go back to a receptor in the liver that can bind it and pull it out of plasma in a process called clearance?

34:37Because of all your apob particles are being cleared in a liver, there would be none to invade your artery wall. So what forces them into the artery wall, and depending on other factors, there are threshold concentrations above which the odds are good, apob particles are crashing your artery wall. And because, unless you have horrific other risk factors, that's why Ather's grossest takes decades to develop. But because it takes a long time for these tiny apob particles to keep crashing the artery wall and maybe later we can discuss what happens to an apob particle once it's in the artery wall.

35:14But step one is crashing the artery wall, traversing the end of the allele barrier, the one cell lining that's on every artery in our body and going in. So it's particle number and the best and easiest way in the most tested way to get an accurate Atherogenic particle number is to measure apo B. You'll hear even statements say apo B is causal. You hear LDL cholesterol is causal because of its very long plasma residence time compared to the short plasma residence time of VLDLs. About 95 % of our apo B particles are LDLs and LDL -P, another way of checking a particle number, is really what drives total APOB.

36:01Not that the VLDOs are not important, they can be. But it's the LDOs that are doing most of the cholesterol dumping in the artery wall. So APOB really gives us a good handle on LDO particle concentration. So, and yes, APOB bringing that starrals into the artery wall is causal, but it's really the starrals that do the dirty work once the APOB is in the artery. So you can separate APOB from cholesterol. So I don't care whether people say cholesterol is caused, the lower APOB is cholesterol, because you can't separate the two in physiologic circumstances. So let's maybe go a little bit further into that process just so folks understand it.

36:40So let's for the purpose of this discussion, assume that it is indeed the most common APOB bearing particle. It's a low density lipoprotein. So an LDL molecule carrying its load of cholesterol, maybe a little bit of triglyceride to boot, makes its way from the lumen of the artery through the endothelial barrier between a couple of cells into a potential space called the subendothelial space. What set of factors increase or decrease the probability that it is there long enough for its cholesterol package to begin the process of oxidation? Do we have any sense of this idea of retention? Yes, and so we subject to new data coming in because this is under a long time and continuing investigation.

37:31One little minor correction, you called LDL molecule. It's a macro molecule. Yeah, thank you for working on that. And I'm stickler for terms as you know. So once the APOB particle traverses that endothelium, and that can happen even if you have a normal endothelium, it certainly can happen easily if you have a disease endothelium. And probably worth noting, Tom, that's almost assuredly where things like smoking and high blood pressure Make your odds worse. Those are things that are damaging the endothelium making that barrier More permeable, which is simply a probabilistic game. This is all probabilistic.

38:08What increases the odds of an APOB getting in? More particles. That's higher APOB. More porous endothelium. That's what happens with smoking. That's what happens with high blood pressure. That's in my view probably what happens with things like high -home assistant, high insulin, or renal insufficiency, higher -acastas, all of those things. So anyway, yeah, it's all about the probability of making the gradient such that the APOB is going where it's not supposed to go. Yeah, you mentioned at ADMA before. That's basically a regulator of nitric oxide, probably the most crucial molecule that an endotelium produces to defend the integrity of the artery or so.

38:48And once that's out of whack, the endotelium is not functioning like it should. There are receptors that can get expressed there that can pull these particles in. But okay, the APOB particle is in the all of the artery, the intimal layer there. One of my jokes is usually it's like once a fly its fly paper if there is such a thing anymore. It's stuck. Then what happens to it. So when an APOB particle enters the artery wall, it has a high affinity to bind to collective tissue molecules called proteoglycans, syndectins, there's a whole subfamily of them. And now you have that APOB particle that is just stuck there.

39:29Now look, the number of LDL particles floating around your plasma, we're sort of talking like APOB, you can count the number of particles. And now, well, actually, there are quadrillions and quintillions of these particles. And that's how many are crashing your artery, wall two. So there's a lot of them in there. And they're all right next to each other bound to these proteoglycans. So it's now believed the next step that happens. What's on the surface of all these APOB containing particles. It's phospholipids. The cholesterol and triglycerides are inside these particles. There's a little bit of unauthorified cholesterol on the surface, but these phospholipids are very susceptible to two things.

40:14One is ultimately going to be oxidation, which is a big, big role in atherogenesis. But the first is there are enzymes called mutations that somehow realign the phospholipids that are on the surface of these particles. And when distinct phospholipids are put next to each other, these particles have a high affinity to stick to one another. And that's called LDL or APOB Particle Aggregation. And that is believed to be the first step. So what you ultimately have is a lot, a lot of these APOB particles in a big mass of cholesterol and all the other lipids that are inside that particle. And that's where the oxidation starts to occur because sterols get exposed, the phospholipids, many of which have double bonds are highly susceptible to oxidation.

41:07So now you have this clump of gookie cholesterol and phospholipids which are oxidized. Well, oxidation is a major signal to the immune system. The immune system is going all over the body and when things get oxidized that means it's on fire It's often an infection or some other pathology and here come the white blood cells to put out the fire so once you get this Aggregated mass of oxidized Whatever you want to call it it's way beyond cholesterol white blood cells start traversing that endothelium the monocytes and they come in and they transform into to macrophages, which express receptors that can start ingesting all these aggregated apoby particles.

41:57And the next step, and this was seen by the Great Russian, I think, in 1913, a niche corth, when they overfit rabbits pure cholesterol and they developed atherosclerosis, something rabbits normally don't get. You drown them with that type of cholesterol. And under the microscope, he saw all these things that there was some long German name. I wish I had it for its basically cells that are full of claslippids. So this was what we now call the foam cell, which is just a lot of cholesterol in the interior of these macrophages. And under the microscope, they look very foamy. So that's how they got their name foam cells.

42:38And as you can imagine, all these masses over the decades we've talked about, now you have plaque. But as this plaque is being formed, that immune system is still trying to put out the darn fire. So what the next thing the immune system does is once the magnifies have eaten it and sort of organized it into a pool of cholesterol, is smooth muscle cells are recruited from the external surface of the arterial wall. They migrate and they start covering this guk, this mass of cholesterol and other lipids. And now you really have a distinct plaque where you have a cap on it. And the cap is simply smooth muscle cells originally.

43:21But these smooth muscle cells transform into more complex cells that can start some creating calcium. And that gives this cap plaque a fibrous integrity. And what is the purpose of that? To prevent what Peter and I talked about early on. You don't want this plaque to rupture. It's like putting a heavy mound of dirt on a volcano, I guess. It's less likely to rupture if you can cover it. Ultimately, the type of cytokines and chemokines that are being produced by these white blood cells, some of them have bone forming ability. And that's why much later in the disease, calcium starts to get deposited in this cap And that's maybe somewhat fortunate because being radio opaque, that enables the type of imaging studies we have now to say, oh my goodness, there's calcium in your artery wall, which there's only one cause and that's atherosclerosis.

44:16So those are the several steps maybe you want to lose the data on further Peter, but none of this happens like you overeat a lot of cholesterol tonight. And then boy, next week you're going to have a heart attack. It takes decades. That's a great explanation. Maybe I'll just summarize it a little bit. So we've already talked about how we get into this process where you have the APOB carrying lipoprotein. Let's again, just simplify it and call it the LDL in this situation, although as we'll talk about, I'm sure they can also be an LP little A. It enters that subendithelial space and its presence alone makes it susceptible to have its contents oxidized.

44:53cholesterol is a rich target for oxidation. And as that happens, we once again have this example of the immune system, which is out there basically surveying, constantly looking for things that are bad, usually in the form of monocytes, and they're sensing, they're seeing a chemical signal for that oxidation. And as they enter that space, they become this other type of cell, they metamorphize into something called a macrophage. And the The job of the macrophage is to literally consume to phagocytose to eat the thing that it is concerned with, and it begins to eat that oxidized cholesterol that produces the foam cell.

45:34I want to pause there for a second and talk about how way down the line, when we ultimately have that calcification, as you said, that's actually quite visible. At calcium scan is exactly looking for that phenomenon. on. But I often get asked the question, Peter, is there anything I can do today to know if there is any damage to my endothelium? Are there any foam cells in me? Are there any fatty streaks? And then of course, the next thing we kind of talk about is a CT angiogram, which in its first phase, when it's run without contrast, which it usually is, you have the opportunity to potentially see calcifications.

46:16And then once the contrast is injected, you get a higher resolution image that shows more anatomic detail of the Lumen. But in my experience, Tom, you have to have a reasonable amount of soft plaque, non -calcified soft plaque to show that suggesting that there's probably still quite a bit of damage that could occur before you would see anything on a CTA. And of course, I realize there are Some people listening to this saying, well, what about newer tests clearly that are using a fat attenuation index to look at the changes in the character of the fatty tissue in and around the adventisha and to see if that is in and of itself predictive of damage.

47:00So I'll just kind of let you take that in whatever way you see fit outside of research -based tools such as intravascular ultrasound, do we have tools to really understand these early stages of disease? If a person says, look, I don't want to get treatment now, but I don't want to wait until I actually have calcium. Is there a middle ground? Not definitively, but there's two things. Certainly, there are these advanced imaging techniques, and that's one where they're analyzing certain characteristics of the watery wall. I think still not ready for primetime play yet. And, certainly because of its cause, it's nothing the average person's gonna run down and get tomorrow.

47:42So, we go back to then, hey, these macrophages that are sending out these signals recruiting more and more white cells to get in there and help me. It's like a fire department calling for a second, and third, fourth alarm, we need more immune operators on the system. Is are there immune markers we can perhaps measure in the blood? And that's basically what we're doing right now. So obviously these would be different types of inflammatory markers and they're looking at other type of biomarkers that might signal this type of pathology going on. This is the ones that are readily available to most people.

48:19and these are wrist markers because by themselves they're not causal and they have other ideologies or other causes that might explain and why they're high. The first and the one with the most evidence is the C -reactive protein test. That was used for years to help dying host rheumatic fever, which obviously had a lot of inflammation. Down the road, Paul Rittker was the guy who did this. He discovered, well, the type of inflammation that goes on in the artery wall was incredibly subtle at first. So you're not going to see a C -reactive protein of 22 or a sedimentation rate of 55 in the blood test, the old -time markers of inflammation.

49:00He says, can we analyze C -reactive protein at here to four? trivial, not even looked at levels. So they started looking at extremely low c -reactive protein levels and low in behold, he's shown it's beyond the bait now that yes, they call the test high sensitivity but it's actually the same damn assay that checks for CRP if you have rheumatoid arthritis but the high sensitivity has a different reference range that they relate to atherosclerosis and obviously much lower than you would have with some rheumatic disease. So subtle elevations of this serious protein, the rule is, hey, above two, you're at worry above four, you've got some serious inflammation in your body going on.

49:44It's not necessarily cardiovascular, but could you be in an early stage of some other inflammatory disease? Sure, that's why it's not specific. But you know, we look at levels even less than two is a signal to us to start worrying. So that's the first inflammatory marker. I just haven't been that impressed with HSCRP's specificity. There are too many people I have seen who have a normal HSCRP and I actually define normal as less than one. So I'm not even talking about the actual assay cutoff of two. So these are people that walk around within HSCRP of 0 .8. And yet you actually do a calcium score on them and you find they've got a calcium score of 10.

50:24Which again, this is not a person who's gonna die anytime soon, but they've already progressed to a calcium score of 10. This is a person who might be in their 40s. So, this is a person who's actually on the path towards premature atherosclerosis. So, I just think that inflammatory markers are probably not specific enough, or in the case that I just gave even sensitive enough, at low, low levels of this disease, in particular because I think that this disease has multiple paths. Even though we're not gonna talk about it today another topic we love talking about is Alzheimer's disease and brain health.

51:02And how there are different paths that patients will take to get Alzheimer's disease. Some patients come at it through almost a genetically pre -programmed path. Others come at it from much more of a vascular disease path and yet others come at it from a more metabolic and an inflammatory path and there are at least one paths And then I almost wonder if there are similar paths towards atherosclerosis. And there are some people who are arriving at it. It's almost genetically programmed in them. And then there are others who are showing up through this very lipid based path. And yet there are others for whom inflammation is the dominant path.

51:38And maybe those are the people where the HSCRP shows up very early in the process. Again, I'm completely making this up as an analog to what we see more commonly in the path to dementia. But I guess what I'm saying in a long -londed way is I find myself rather unconvinced that we have great tools to measure the phenotype of early atherosclerosis. That's so true and the specificity, as you said, I can name two or three other inflammatory markers that would have the same weakness. You could have a fatty liver in their elevated or subtle infectious disease somewhere. So they're not specific. You could say, and Ritker would tell you in the scenario you describe where we got coronary calcium is there already, but their CRP is perfect.

52:25Maybe that's a stable plaque that's not going to rupture or sell. You can get into those type of debates. Maybe they had a CRP blip five years earlier when that plaque was still being oxidized. Yeah, I understand that for sure. So I think the only way we can use these inflammatory markers is, hey, If Apo B is high, LP little A, two major risk factors, and these inflammatory markers coexist with them, I worry about you perhaps a little more, but that doesn't mean if Apo B is high, or LP little A is high, and your inflammatory markers are perfect that we dismiss you as, ah -ha, you're the one who's not going to get that grosses, because that's not a game you wanna play.

53:08So that is the weakness of those type of markers. I don't have any other markers that I can tell you to check on inflammation other than there are 10 other subtle rarely tested inflammatory cytokines and chemokines that can be measured. Same. Hey, if your APOB is whatever in your home of cystine is high, we worry a little bit more about you. We have to maybe attack that because it's modifiable. So I'm not sure what the other markers would be outside of you. Wait long enough. you're going to get some imaging thing that's positive. Or do we just start respecting APOB? And that's basically where the lipid world is going.

53:46And that's where this new concept primordial prevention has come into play. And the old days it used to be primary or secondary prevention. Hey, you've had a heart attack. Thank God you've survived. We're going to try and prevent the third heart attack, secondary prevention. Or once imaging came along, then we can say, oh, how your CTA or your CAC is positive. To me, that secondary prevention right there, I wouldn't call that primary prevention. So what is primary prevention? You have a high APOB, you have high blood pressure, but we're not talking about that aspect and what we would do with that today.

54:23And therefore what is primordial prevention? People with physiologic parameters in the lipid and lipoprotein spear. So we still gonna check them because we think at a certain age or depending what else goes on in that person's life, they will enter that primary prevention. And then once that is, if that's defined as escalation of APOB, then you're going to get into the decision of what sort of therapeutics we want to offer this person, whose APOB is just slightly high. We don't want to be able to be as in the 80 if they're 90 % high, Because I think if there was a way of getting into those people and looking for this pre -imaging atherosclerosis, we might find it.

55:07And some we would not. There are no doubt there are some people who, just as you said, not every smoker that's lung cancer, there are people with high APOB who live long and healthy lives. But I don't know what else is going on in their artery wall. And I have no way of measuring that to assure them, aha, you're the exception to the APOB rule. Well, there's a lot you said there that I think is a great place to go next, but maybe just to finish a little bit of housekeeping, we've now both brought up LP Little A at least twice. So I think we've done many podcasts on this, but what would be the three minute explanation for the person who either needs a refresher or maybe who is new to this and hasn't heard of what LP Little A is yet?

55:48Why should they care about it? We've defined an LDL particle as a collection of cholesterol, a little bit of triglycerides wrapped by one peptide called apolipoprotein B. In some people who have the genetic machinery, their liver makes another protein called apoprotein small case A. The guy who discovered it, thought he discovered a new antigen A was the signal for antigen, so that's where the little A came about. Again, capital A is the apoprotein A that is on an HDL particle, so are distinctions between small APOA and capital A. All right. So if your genes tell your liver protein, mac and apparatus to produce this APOA, within the liver it binds to the APOB that's on a primordial LDL particle.

56:40It's being produced in the liver. So now some of your LDL's APO -little -A binds to it and the liver just secretes them into your plasma. So that's what an LP little A particle is. It's a low -density lipoprotein that is carrying another protein that should never be on an LDL particle. That apoprotein little A has some characteristics that make it extremely atherogenic, much of it ties into the oxidation that we mentioned before. So if that particle enters your artery wall, whatever oxidative forces are a player going to get much worse, which is not good as far as after a genesis is concerned.

57:22So if you have these LP little A particles and it's not a concentration gradient that drives them into your artery wall, that's sort of an inflamed particle carrying some oxidized phospholipage that can be pulled in by receptors that are still not defined, but it can easily get into your artery wall. So it's like, hey, we got a little fire in somebody these backyard and somebody brings a can of gasoline and throws it on the existing fire. So the atheroscotic process occurs much more rapidly earlier in life. It's bad news. Now the good news perhaps is 80 % of people don't inherit the gene that makes you produce the sapoprotein little A.

58:03But 20 % do. Now it's people are 20 % no big deal. We'll get 20 % of the world population. I should not talk billions of people who have what's now recognized to be the number one lipid lipoprotein disorder associated with atherosclerosis. So my goodness, and this is why there's an alcohol for let's everybody get that checked once in your life early on because you either have it or you don't. And if you do have it, then we can start looking at ways to perhaps modify some of the bad news risk that's going to occur with that process. right now we can't get rid of the apolidol A particle that's perhaps coming there are drugs under investigation to do that All we can do if we discover this LP little A is look with a magnifying glass at every other risk factor or risk marker you have and do what we can to control those So LP little A is a bad news LDL type particle it's not atherogenic because of the the amount of cholesterol it's carrying.

59:06It's what I call a minor LDL particle, but particle for particle it's 7 to 8 times more atherogenic than an LDL particle. So even now you have way, way, way more LDL particles when average person might have an LDL -P of 1200 nanomoles. So you might have an LP little A of 100 nanomoles. And you would say, oh, that's some minor particle, yes, but if it's eight times more after a genic than an LDL, it's a bad -news particle. Not everybody's a criminal in our country, but it doesn't take a lot of criminals to cause a lot of havoc. So it's a terribly dangerous, inherited type of lipoprotein. That's a great analogy to think about it.

59:49You don't need a lot of something that has high virulence and potency to cause a lot of difficulty. Let's pivot for a minute to talk a little bit about something you also touched on briefly, which was that when we're young, we have what's referred to as a physiologic level of APOB or LDL cholesterol. So the concentration of LDL cholesterol in a child is low. The concentration of APOB is low. We don't see this very often because we're not used to checking these things in kids, but occasionally you'll even notice it as a parent if your kid gets sort of with an LDL cholesterol of 30 milligrams per desoleter and an HDL cholesterol of 25 milligrams per desoleter.

1:00:36I mean, they're very, very low levels of this. Why does this change as we age? Why is it that aging seems to be associated with a monotonic increase in lipoproteins? And this is absent something that we could even get to later if we have time, which is what happens during menopause for women, which is more abrupt. but just talk to me about ages 10 to 50. Why does everybody seem to go the wrong way? Well, a lot of, of course, is the multitude of things we subject our bodies to, if you want to encompass that with the environment or lifestyle, if you quote, unquote, whatever, and you can throw probably whatever you want into that category of things that might cause your body to, as apob goes up, it's almost all related to your liver is losing the ability to clear these particles out of plasma.

1:01:30It's not like you're overproducing 10 tons of them. It can happen, but that's rarely a contributor to the high apob levels. So scientifically, we have to zero in on what regulates clearance of these particles. And the simplest thing is to say, well, the only way these APOB particles get cleared as our liver produces something called an LDL receptor, which migrates to the surface of the liver cell that interacts with the blood flow, the plasma, and these LDL receptors are engineers to recognize any APOB peptide that floats by it. So if an LDL particle containing APOB floats by an LDL receptor, it will get grabbed, and and then it gets internalized into the LDL receptor and it gets catabolized.

1:02:18And then the liver can take whatever cholesterol, triglycerides fatty acids, blah, blah, blah, is in that molecule and use it for other purposes, or somehow get rid of it in the biliary system if the liver doesn't need it. So it's gonna come down to what are these factors that I called, hey, environmental lifestyle, that affects what we call LDL receptor expression. And it's a lot of things, one of the things you mentioned before, or insulin resistance would affect that. Numerous components of the diet express, are you regulating LDL receptors or not? How much cholesterol your liver is being told it needs to put in the next VLDO particle or more importantly, the HDO particle going out.

1:03:01So, lipid balance in the liver is regulated by a bunch of things called nuclear transcription factors. They actually sense, hey, the liver needs some lipids or the liver's got too much lipids and we got to get rid of it. Those nuclear transcription factors migrate into the nucleus and the nucleolus of ourselves and they bind to specific parts of the DNA and tell our genes produce this protein, produce that protein, this enzyme, that enzyme, this receptor, that receptor that can go out and help restore sterile homeostasis to this human body. So probably every adversarial thing you've been told in your life not to do, gain weight, donate, this donate, that are all affecting these nuclear transcription factors that are going to regulate clearance of these APOB particles.

1:03:54And it's a long list of things that can probably do that. It is interesting that on average, more of the things that we do that are, quote unquote, less healthy, whether it be gain weight, be to a certain way, tends to result in decreased hepatic clearance. So on that topic, one of the questions you and I get asked all the time is, look, hey, doc, I buy your thesis that ApoB is bad. I buy your thesis that minus too high. I buy your thesis that I should probably lower it. I'd really like to start with my diet before I turn to pharmacology. Typically, there's two things I tell patients here. the first is, I think, your two best levers nutritionally to reduce ApoB are lowering triglycerides and lowering saturated fat intake.

1:04:44Now, of course, this assumes that you have high enough triglycerides that lowering them further will indeed lower ApoB, and it, of course, assumes you're eating a high enough amount of saturated fat that reducing it significantly will lower ApoB. So let's assume from them at the those things are true. We're talking to a patient, Tom, who's APOB is 100 milligrams per desoleter. You and I have just, I don't want to say red, I'm the riot act, but we've given him the education that says, look, you'd be a heck of a lot better off if you were at 60 milligrams per desoleter. His triglycerides are sitting at about 162 milligrams per desoleter.

1:05:20And when we query his diet, we realize it's pretty high in saturated fat. He's probably getting, call it, I don't know, 40 or 50 % of his calories from fat and he's probably getting 50, 60 grams per day of saturated fat alone. So in other words, he seems like a really ideal candidate if he's willing to switch more of his fat calories to mono unsaturated and polyunsaturated or even just reduce fat altogether. And he's willing to take the dietary steps to reduce total calories and maybe even carbohydrates specifically to kind of bring down his triglycerides. So So without getting into how he's going to do that, can you explain why lowering triglycerides and lowering saturated fat intake, those two things could bring this guy from 100 down to 60?

1:06:06Sure. The saturated fat is a little easier to explain. We have plenty of studies that show excess saturated fat, those nuclear transcription factors that are regulating lipid balance in the liver, and the liver is the master controller of lipid homeostasis in the body. It works hand in hand with the intestine, but the liver is sort of the brains of the operation. In many, many people exposure to saturated fat, the nuclear transcription factors realize, oh my God, fatty acid toxicity is going to cartoonist liver. We have to take our defensive mechanisms on that. First thing they do is say, my God, we don't want more lipids being pulled into the liver by these LDL receptors.

1:06:48So the nuclear transcription factors go into your DNA and say, stop making these LDL receptors, stop sending out the signal that will be translated into an LDL receptor. So of course, if you eat saturated fat and your liver stops expressing LDL receptors, your APOB is going to go through the roof. What is the APOB particle carrying cholesterol and above the threshold concentration that's going in the artery wall? Typically, if that person does follow your advice and restricts the saturated fat, they will go back to some more increase in their LDL receptor expression. Saturators that in some people too also turn on the enzymes that induce cholesterol synthesis.

1:07:30Now if the liver starts overproducing cholesterol, then the lipid pool is out of whack. The same nuclear transcription factors go in and say, stop making LDL receptors. because we don't want to pull it more cholesterol into this liver that's over synthesizing cholesterol. It's another whole story, as you know, Peter, why we don't necessarily tell people you have to restrict cholesterol in your diet. We're talking about saturated fat here. And the absorption of starols in your gut has nothing to do with the absorption of fatty acids in your gut, totally different mechanisms that pull them in. The triglyceride story gets much more interesting.

1:08:05And maybe much more important because it's so epidemic in this world now. We know triglycerides is a poor man's biomarker of insulin resistance. Two things I wanted to say with your measuring triglycerides in the blood, personally I believe the only things you need to measure in the blood are APOB and triglycerides. There are basically two categories of hyper triglyceridemia. One is it above 500 ,000. If it is, you have some crazy genetic disorder that is involved with your high triglyceride. And most of those are not associated with atherosclerosis. But nonetheless, they are associated with pancreatitis and other pathologies, so you would want to lower it.

1:08:48What's called a very high triglyceride level. But the average doc, who's out there doing lipid levels is going to see a triglyceride maybe between 130 and 160, 180. Say everyone's allowed, you'll see a 300, 400, but they're less common. That almost is always insulin resistance as the ideology of that through many factors. So once you have too many triglycerides and where are those triglycerides being made in your liver. Other cells don't produce triglycerides, other than an adipocyte, but if your liver is overproducing triglycerides, the liver says, oh my god, I gotta get these out of here, because if the liver retains triglycerides, you know it's gonna get fatty liver, not a wise thing the liver wants to do.

1:09:36So the liver then package them into the triglyceride containing lipoprotein, the very low density lipoprotein. Why do we even make VLDL's? What purpose do they serve? Even if you have a physiologic VLDL concentration, it must be doing something once the liver makes it and secretes it. And that is very similar to the big chylamycron particle that comes out of your intestine. These are the triglyceride carrying vehicles that are bringing fatty acids in the form of triglycerides to the tissues that need to grab the triglycerides, convert them to fatty acids and oxidize those fatty acids to make ATP.

1:10:17They would be our muscle cells. The heart being a very important muscle that you want to keep beating. It's a big consumer of triglycerides. The muscles, the big column microns, the big VLDLs coming out of the liver, they go into beds that express the triglycerides that's all they can, Xionolipoprotein lipase, muscular beds, or adipocyte beds. The triglycerides are hydrolyzed to fatty acids. They enter those muscular beds and then they can be oxidized for ATP. In an adipocyte, the fatty acids are pulled in, reconverted to triglycerides and stored for future energy needs. So that's what VLDLs do.

1:10:57But if you have way more triglycerides in your liver because you're insulin resistant into your liver's overproducing them, the liver makes very big VLDL particles. Earlier on, I talked about, hey, there are certainly NMR signatures of insulin resistance, the big VLDL is one. A normal person with physiologic triglyceride never makes big VLDL particles. There's no need for them. That person makes smaller VLDL particles that carry just enough traits to be sufficient for energy needs of the muscle. But in an insulin resistant person with high triglycerides, here come these big particles out. Now insulin resistance is not only associated with too much triglycerides, there's another apoprotein that is made in excess and it's called apoprotein C3.

1:11:46So the VLDLs coming out of the liver are now carrying something they shouldn't carry very much of, apoc3. Make a long story short, it retards the catabolism of these triglyceride -rich VLDLs. So it blocks their attachment to lipoprotein lipase. So the plasma -residence time of a VLDL or columnicron, which should be extremely short, is now prolonged. What is the consequence of letting these triglyceride -rich VLDLs float around longer than they should? Number one, if you measure triglycerides in the blood, it's going to be higher than it would in the early would be. And that's why if you look at a certain triglyceride level, you might suspect this is happening.

1:12:29But here's the continuing bad news. When these triglyceride -rich VLDLs are floating around in plasma, they bump into the much, much, much more numerous LDL and HDL particles. And what happens? We carry a lipid transfer protein that actually locks LDLs and HDLs into VLDLs or LDLs into HDLs. It's called cholesterol estertransfer protein, CETP. It really should be called CETTP, cholesterol estertraglyceride transfer protein. Because what happens is when these two particles, my joke is they're mating because they're now connected with this little canal. They exchange one molecule of triglycerides for one molecule of cholesterol.

1:13:18In essence, the VLDL's and chylamicrons become triglyceride poorer but more cholesterol rich, whereas the LDL and the HDL become cholesterol poorer and triglyceride rich. Any doctor who does a lot of lipid profiles knows, yeah, you're right Tom, I notice every time triglycerides goes LDL cholesterol doesn't necessarily goes up, but almost assuredly HDL cholesterol goes down. And that's because HDLs, which should really carry almost no triglyceride molecules, have now sucked in a lot of Triggs, but they've given up cholesterol. If we were measuring HDL triglyceride levels, we would see it's very high.

1:14:01But we just see the HDL cholesterol is low. The last step, what happens to any triglyceride -rich particle, there are lightpaces ready to dissolve it. Endothelial lightpacin hepatical -lightpace attack triglyceride -rich HDLs. By extracting and hydrolyzing the trigs, the HDL particles become so small they break apart. APOA1 goes down to the kidney where it can be catabolized into amino acids and excrete it. Hence, explaining why diabetics people with high trends have such low HDL particle counts in low HDL cholesterol. But basically here's what happens to the LDL now. The LDL ascending cholesterol in exchange for triglycerides to the VLDL or the chylo.

1:14:46So the little LDL particle much smaller than those monsters becomes triglyceride -riching cholesterol poor. So what is the fate of that type of LDL? If we can only measure LDL triglycerides, it would be by far the best lipid metric we could ever measure. So, Tom, it seems like the reason APOB is going up in a high triglyceride environment is because you need more LDLs to carry the same amount of cholesterol ester because so much of their carrying capacity is going towards also managing the transport of triglycerides. And therefore, while LDL cholesterol might remain constant, it's being spread out over more particles, therefore APOB, which is the marker of particle concentration is going up.

1:15:43And of course, that's the metric that matters. This, of course, is the classic example of where we see discordance between LDL cholesterol and APOB particle concentration. So we were talking about the triglyceride rich LDL particle. And what happens is the light paste, is mostly a paddock light paste, takes the trig cell, and then the LDL particle becomes very small. So you have a small LDL particle which and the most per particle can't carry many cholesterol molecules. But the major reason apob goes up is an LDL that is small. The apob assumes a different confirmation on the surface of the LDL, and it is no longer recognized by the LDL receptor.

1:16:28So you have markedly delayed clearance of the small LDL. So yes, whether your LDL cholesterol goes up or not, The cholesterol is spread among more LDL particles because they can't be cleared anymore. So that is why lifestyle can work very good. Anything that lowers tricks can interrupt this pathologic lapalysis or catabolism of these APOB particles. If we could make those small LDLs disappear and they would assume they're more circular shape, they can form to the LDL receptor more. So, this is why if you look at the APO -B or even the LDL particle count in diabetics, it's through the roof or in people with high triglycerides due to mostly decreased clearance, so the LDL -P goes up.

1:17:19But what's driving the total LDL -P? It's the small LDL -P. They would have some large LDL still floating around. There's never going to be anybody who has 100 % small or 100 % big, but the predominant species when triglycerides goes above a certain threshold is the cholesterol poor smaller leels that have decreased clearance. So apob goes up. When apob goes up where do these small particles go? That's an apob particle. It crashes the artery wall with relative ease. So that's the basic explanation there. The other thing I should tie into this at what level of triglycerides can this occur? The silly guidelines have put hey and triglyceride of 150 above is where it's high risk, and that's what the average practitioner or patient believes, because that's what the labs report on the lipid profile.

1:18:09This transformation, it starts to delay the laparlysis of these particles, occurs somewhere at a triglyceride 100 or above. You don't have to have a trig of 150. That's the 75th percentile of a population triglyceride distribution. Oh, God. We don't want for any other lipid metric to hit the 75th percentile. So I'm not sure why they still do that other than perhaps they didn't have enough to tell people what to do about it But you when I know when we look at it at the lipid panel We're a little nervous when tricks start to go much above 80 never mind 100 to 120 I often use myself an example I've been a lifelong very insulin -resistant guy always had a pretty decent LDL cholesterol my trig was always in the 102, 105 range, which I dismissed as being normal.

1:19:03But of course, once in a mark came around, I said, oh my god, look at your LDL particle concentration. Look at the number of small LDLs. And this is why triglycerides cannot be unlinked from APO B2, because the real pathology of high trig, it's just creating too many cholesterol -carrying particles that can invade the artery wall. It's not triglycerides in the artery wall that are generating atherosclerosis. It's the delivery of cholesterol. But as tricks go up, you have a lot more apob cholesterol -carrying particles, even though each particle is carrying lesser numbers of cholesterol than before, there's just many more of those LDL particles that are crashing your artery wall.

1:19:47When we do come up with a way to lower triglycerides nutritionally, or even if we wanted to use a drug. Virtually every single one of our lipid modulating drugs is FDA approved to lower triglycerides. You can't look at it and say, oh I've lower your trig from point x to x minus whatever. You have to lower APOB to see event reduction with trig. Now most of the time when you lower trig with proper therapies like stoward drugs you will see a drop in APOB. But there There have been several trials that dramatically lower triglycerides with the fibrates that did not reduce mace, because although they dramatically lower triglycerides, they're not the greatest apobelowing drugs in the world.

1:20:32So, respect triglycerides at much lower levels than you've never been taught, but your goal of therapy, be it lifestyle or drug, is did I normalize apob? day. I think that's a very important point, which is it's always worth taking a shot at modifying your nutrition to fix ApoB, but don't forget the goal. The goal is lowering ApoB. We have these two proxies that are quite helpful triglycerides. If they're high, great, great way to approach, usually in most people, caloric reduction is the key of doing that. And therefore, you have a person who's eating a lot of saturated fat, a lot of carbohydrates, low -quality carbohydrates, sugars, hypercaloric, that person can actually do a lot of APOB reduction with nutrition.

1:21:21Conversely, when you see a person whose trig's are 50 milligrams per desoleter who's not mainlining saturated fat and eating in relatively normal amounts, I typically advise those people against draconian fat reduction, which admittedly will indeed lower cholesterol, but often comes at the consequence of something else nutritionally. And so we tend to steer clear of that and save that for people who have an obvious reduction. I think this point, by the way, about the conformational change in the relationship between the LDL receptor on the liver and the LDL particle is a very interesting one. And of course, it begs the question, Tom, do we believe that LDL particle size should be of concern given that you just acknowledged that these smaller cholesterol depleted LDL may linger longer?

1:22:17Or can we largely ignore that if we have a good handle on APOB? In other words, is all of the risk of everything you just discussed captured in the APOB marker? Yes, but if you were doing everything you say nutritionally or pharmacologically to do it, you would see a transformation of those small LDLs. You wouldn't find them anymore and you'd have a normally sized and APOB composed particle. But what I should introduce into this discussion is the nonsense going out here at these big LDLs often called fluffy buffy are cardio protective. But guess what happens on a big LDL? The APOB gets distorted on the big LDL too.

1:23:00And those particles are far less compliant to the LDL receptor. So one of the reasons people with FH have such, because they all have very big particles. And their high APOBs do do defective LDL receptors, but it's also due to defective attachment to LDL receptors because the APOB is no longer in the proper confirmation. And the last thing I'm always going to sneak in on this triglyceride topic, I did mention it's the chylose in the VLDL's that carry shrigs. They're the big triglyceride carrying particles. Yes, they screw up the HDL's and LDL's by sending shrigs over there. But normally those particles should deliver the shrigs to the muscle cells where they loose trigs and then they get smaller the chylose and VLDLs.

1:23:47Smaller chylose and VLDLs are called remnant VLDLs or chylose. But when they shrink, the main reason they get clear from the body is they carry multiple copies of apoliper protein E. And apolipus is the apolipotin on VLDLs and chylose that binds to a very specific hepatic receptor in the LDL receptor family called LRP. LDL receptor -related protein. But when APOB is on big VLDLs in chylamarkrons, it's contorted. It doesn't bind to the LRP. But once the chylos in VLDL shrink down, the APOB assumes a confirmation in that that's why their plasma resonance time is so short. So APOE mediated and each of those particles carry several copies of APOE.

1:24:38But in some resistance where the VLDLs and Kilos can't get rid of their tregs, then these people have what is called increased remnants. Now, there are nowhere near the particle number of remnants doesn't even come close to an LDL particle number, but it's up the way more than it should be. And particle for particle remnants carry five to six to seven times more cholesterol per particle than an APOB LDL particle. So if you let these remnants float around, they get pulled into the end of the helium. They're a very inflammatory particle in part because of the apoc3 on them. They get internalized easily into the artery wall, which is another reason people with high trig have so much atherosclerosis.

1:25:23It's not only because they have too many LDL particles. They got too many remnants and if they're losing HDLs, if HDLs perform a cardio protective function by extracting cholesterol out of you, they no longer have enough HDLs to do that. That's why you and I get very nervous when we start to see trig exceeding 100 because we assume some of these pathological pathways are at play. A couple of very important points there, Tom. The first is, yeah, it's true that the remnants just like the LP little a's are captured in the APOB concentration. But it's almost like you have three populations for lack of a better term, really four populations that are buried within APOB.

1:26:09You have the majority of them which are LDLs. You have VLDLs, your garden variety VLDLs. You have your LP little A's if you have too many of those. And then you might have too many remnant VLDLs. And of these four, it's that remnant VLDL and L .P. Little A that pack more of a punch than their counterparts, the regular garden variety VLDL and the LDL. And so this is where I think APOB by itself can be a bit misleading. In other words, you could have two people that both have an APOB concentration that's identical. But if one of them has it in the context of basically it's all LDL cholesterol and some VLDL, yeah, they're okay.

1:26:55And then the other person might actually have a disproportionately high LP little A and or remnant Concentration and you won't know that unless you're doing some of this additional analysis. Is that a fair rationale for saying why we want to look at everything? Yes, so you measure LP little A that's easy and you see it's not a major contributed APO B But it's a terribly ethnic particle. So we get nervous with it with the VLDL particles measuring APOB tells you nothing about the number of VLDL's half, because although they can be particle for particle more atherogenic, there's not very many of them.

1:27:33So what's a poor doc to do? Here's my little pearl. So there's another metric people should look at. It's called non -HDL cholesterol. Think of what that means. That's the cholesterol that's not in your HDL particles. In essence, it's your APOB cholesterol. So how would I know if your APOB cholesterol is up? I can't look at APOB, but if I did that calculation, non -HDL cholesterol, if your APOB is looking good, but non -HDL cholesterol is still a little high, I'm suspecting you got some of them remnant via the old particles floating around. Now it's not 100 % true, but it's about the only thing you can do.

1:28:15There are no accurate remnant tests that are available to the run of the mill doctor. So, look at non -HDL cholesterol and by the way for the listeners, that's a freebie on the lipid profile. It's basically total cholesterol minus HDL cholesterol. So that means it's the cholesterol that is in your VLDLs and LDLs. So if your LDL cholesterol, APOB is looking good, But your VLD cholesterol is still high. That would drive non -HDL cholesterol to be higher than it should. And that's why Peter and I also have very aggressive goals for non -HDL cholesterol also. We don't always discuss it with the patient, but we would if it was still elevated within the face of a normal April B.

1:28:59All right. Let's talk about HDLs. the most confusing of the lot. Now, we've already done dedicated podcasts on this topic. We've spoken at length about this. So we're not going to be able to obviously cover this in too much detail and we'll point people back towards the previous podcasts where I've done this. But you've already alluded to the fact that HDLs can be protective. This has led many people to refer to HDL as the so -called good cholesterol. and if your quote unquote good cholesterol is high, you don't need to worry about anything. I'm not going to ask you to debunk that because the tone of my question already suggests that that's nonsensical.

1:29:42So let's have a modest but brief discussion on how HDLs work and why is it that when they're functioning, they can be quite protective. But at the same time, maybe say a word about why, unfortunately, we can't figure this out or discern this from blood tests. Yup, and it's so important and it's so unknown out there in a real world and in the layman's world it's probably not known at all because they keep reading these idiotic missiles and newspapers and magazines that boy check your good cholesterol and even if it's high you don't have to worry about your bad cholesterol LDL. It's so sad. Even sadder that some providers still believe this and tell their patients that.

1:30:24So, basically what we say very quickly to any patients is, as we're teaching them about lipoproteins and what they do and what they carry, we get to a point where we say we're not going to talk about HDLs anymore. Now, don't get me wrong. HDL particles are incredibly important to both your cardiovascular system and probably many other tissues in your body. And that means HDLs perform a lot of functions that, especially with the heart, may be very cardio protective. We also know that some people have the type of HDLs that don't perform those cardio protective functions. They actually perform bad functions to the artery wall plaque in the heart.

1:31:07So the important thing is you can understand, boy, what HDLs do? Let's call that HDL functionality and to make a long story short, whether your HDLs are doing no cardio protective functions or they're doing bad things to your vasculature. Whatever they're doing has zero relationship to their cholesterol cargo, meaning your HDL cholesterol level in the blood. There are people with low HDL cholesterol, often a signal for high cardiovascular risk, but not everybody. And there are people with very high HDL cholesterol been told they're protected and we know they They are not a group of them get to ethyrscherotic disease, a group of them have been described with breast cancer, dementia.

1:31:54So obviously you can't look at an HDL cholesterol in an individual patient and make extravelations on what the HDLs are doing in that person. The reason HDLs have these either miraculous or disastrous properties comes down not to their lipid content, certainly not their cholesterol content, but two things. Their protein content over 150 proteins have been found to be associated with various HDL particles, and they perform an immense number of likely very necessary actions that need to go on in certain tissues where things may be going wrong. We also know that the coat of an HDL apart from its proteins is virtually all phospholipid So the exact phospholipid concentration of an HDL surface has tremendous amount to what to do.

1:32:50Can an HDL do wonderful things or bad things? Those phospholipids really determine what an HDL can bind to in various tissues. Now of course we can't measure HDL phospholipid content. There are hundreds of phospholipids. You would get a lipidome coming back that you couldn't even pronounce after the phospholipids or at least the fatty acids that are in those phospholipids. And same with the protein. If there's 150 of my guaranteed average doctor, might be familiar with about 10 of those proteins and not with the rest of them. So I don't know how to determine a patient's HDL functionality. Clearly the people having adverse effects with high HDL cholesterol have dysfunctional HDLs probably related to that proteome or their phospholipid content and vice versa.

1:33:41So what we tell a person right now is in the year 2024, we didn't always believe this. This bad cholesterol had an origin that everybody believed way back when framing him Mr. 50 earlier observational trials. Nobody ever adjusted for APLB in those trials. It wasn't even available when they were doing it. So, we now know that the people with low HDL cholesterol who do get ather sclerosis always have high APOB. And why? Why do those people have low HDL cholesterol? I've already told you it's the trig that knocked the HDL. And the trig may not be 400. The trig may only be 130, which are being ignored.

1:34:20And what is high in them, APOB? So the proper treatment of low HDL cholesterol in the person you believe has cardiovascular risk is just like trig's lower APOB. lower non -HDL cholesterol if you can't get an APO B. If somebody has a high HDL cholesterol, I don't know what blood tests to tell you. I would always check an APO B. We do that and 100 % of people. And if it was high, we would treat APO B regardless of an HDL cholesterol level. But I can't look at a man or a woman and say, oh my God, you're the one with high HDL C who might wind up with dementia or some cancer or some... I don't know.

1:34:55So we'll track those other diseases with other modalities that we have at our Beckincore. I don't know what to tell you about your cardiovascular health if you have high HDLC, but I can guarantee you it is not a declaration of cardiac immortality. So it's HDL functionality. And you recall we had a nice email exchange about a friend of mine who I've known for many years. He's always had a very high HDL cholesterol and a very low LDL cholesterol. in fact, his HDL has routinely been above 100 milligrams per deciliter, and his LDL cholesterol has always been below 100 milligrams per deciliter. So this is a guy that by anybody's metric looks like he's in tip top shape.

1:35:35But I did suggest to him at one point, it would be reasonable to at least do a calcium score because I've seen these case studies of individuals with high HDLC low LDLC who still end up having athrosgroices, and it can be quite aggressive because it could be that that high HDL cholesterol is actually a marker of dysfunctional HDL that are having a difficult time clearing it to make a long story short. He ended up having quite a high calcium score. And so now he's on very aggressive treatment to take any residual risk out of that ApoB. So he's on double therapy now and he walks around with an ApoB in the 20 to 30 range.

1:36:10And hopefully that's going to be sufficient to retard this. But again, always a great story. I remember you sharing that case with me and I, why did you do a CAC? Because you've heard me spout enough, you learned your lesson. I don't use HDLC to make any decision. Yeah, I distinctly remember reading a case study 10 years ago about a woman who looked just like that and ended up having very advanced atherosclerosis. Let's pivot and talk about the brain a little bit. This is an area where your own knowledge has grown rapidly. Tom, this is clearly an area of immense curiosity for you for me because cholesterol plays an important role in the brain.

1:36:52I think to put it mildly. And people have many questions about the role of cholesterol, lowering therapy and brain health. So let's just start with a basic question, which is what role does cholesterol play in the brain? And what do we know about the different pools of cholesterol? We have cholesterol outside of the central nervous system. Cholesterol inside the central nervous system. Can they move back and forth? Can lipoproteins go back and forth? Is LDL taking cholesterol into the brain and back? Tell us about how that whole system works. So important. I'm glad we're going to chat about this a little bit.

1:37:24It's obviously so complex. Really, I almost give you credit. You're the guy who got me interested in lipids in the brain probably 15 years ago when you introduced me to Richard Isaacson at the Cornell dementia clinic. And he was very interested in lipids because he just knew lipids are part of what's going on in the brain And I bet I learned more about lipids and you were good buddies and I got dragged pulled into that circle I like how you said dragged initially. I mean, I mean, I mean pulled pulled slowly. Yes Now you're a strong guy Peter you You've promoted me to study a lot of things that maybe I wouldn't have over the trip into and I would have ever met a Richard Isaacson had it not been for you, but thank God you did.

1:38:05And so we've been trying to learn about brain and lipids so often. The last thing I'll say, you did that great podcast with Dan Raider on HDL's. And it's a podcast everybody should listen to. At the end, you sort of turned to Dan, you said, where are we going with lipids, Dan? We've solved the APO B. We're learning a lot now about HDL. And Dan said it's lipids and the brain is the next frontier. And why has that not been studied very much until now? Because you can't stick a needle, you have to go into it, it gets cerebral spinal fluid to analyze what's going on in the brain. And most people are amenable to a venipunctional neural bone, not a spinal tap.

1:38:45So here's what's going on. Collestral is almost certainly the most important molecule in the brain. The brain is by far the most cholesterol carrying organ in the body. the brain actually makes more cholesterol than any other organ per se, way more than the liver even. So if I gave you a dumb question, I got this body here and I want to find out where all the cholesterol is, where should I go? Open this skull and take out the brain. That's where you're going to find the most cholesterol. Wow, so obviously cholesterol is crucial to the brain. And that's because the brain is made up of a lot of cells, All of which have important functions, especially those neurons that shoot off all the action potentials that make our body function and everything.

1:39:30And what's on the surface of a neuron, free cholesterol and phospholipids? So evolution, I guess figured out a long time ago that the brain needs cholesterol. So we're not going to make the brain dependent on cholesterol that's floating around the plasma or what's in your liver or your intestine. And we're going to let the brain make all the cholesterol it needs. So we're going to really drive the enzymes that synthesize cholesterol in the brain. So the brain needs cholesterol to make a long story short. Every cholesterol molecule that's in the brain got there by denovo synthesis in the brain.

1:40:08Not a single molecule of cholesterol was delivered from the periphery, meaning that floating around our plasma leaves the plasma and enters the brain. Now, by the way, where is all the cholesterol in our plasma? I've already told you, it's got to be inside of a lipoprotein floating in plasma. That's where we measure cholesterol. That's where we measure lipids in the plasma. But I can assure you there is no cholesterol carrying particle in the plasma, be it a VLDL and HDL or an LDL that crosses the blood brain barrier and says, okay, brain, here's your cholesterol for today. Doesn't happen. There is a rapid turnover of cholesterol in the periphery.

1:40:50Cells make it, they get rid of what they don't need. It's brought back to the liver for the liver to decide what to do with it. The turnover time for cholesterol in the plasma is two to three days. So if a cholesterol molecule is synthesized in the brain, what is its half -life? Five years. Now half -life is a half -life is a given number. the total brain residents time of that cholesterol molecule, you multiply that by seven. So, some cholesterol molecules last up to 30 years once they're synthesized in the brain. And that's why cholesterol synthesis in the brain starts in utero. Early on, mom's supply in the little fetal brain with a lot of cholesterol, but very rapidly, second, third trimester, those brain cells start making their own cholesterol.

1:41:40Once a child is born, there's a lot of cholesterol synthesis going on by virtually every cell that exists in the brain. There's only like three of them. But at a certain point, somewhere between the ages of five and ten, the brain has made all the cholesterol it needs. So then only two cells continue to make cholesterol. So, lesson number two, what are the cells in the brain that we're in this conversation with? Nauron's I'd mentioned. In Uniro and in childhood, Nauron's produced a lot of cholesterol. But at a certain age, the Nauron's got more work to do. They don't want to make cholesterol. Why?

1:42:19Because every cholesterol molecule requires 27 molecules of ATP to produce. So, super energy -driven process. Neurons need ATP for a lot of other functions. Those electrical charges they make. All right. So what are the other two cells in the brain? Oligode -dendrocytes make the most cholesterol. And where does the cholesterol they make become? Myelin, which coats every nerve, ending every axon and dendrite in your body. Those oligodendrocytes are big -time cholesterol producers. But they make all their cholesterol go to myelin. They don't send any cholesterol over to neurons. So what is the other cell in its astrocytes in infancy and childhood in utero?

1:43:06Aligatendusites, astrocytes, and neurons are making cholesterol at disnote tomorrow. Once the neuron stops making it, astrocytes are the sole maker of cholesterol that supplies the neurons. But how would an astrocyte synthesize cholesterol and send it over to the neurons? Aha! The brain has to have a lipoprotein system just like the periphery does. Now, between astrocytes and neurons, basically it's brain -interstitial fluid, sort of a loose connective tissue. It's called the matricone. So if astrocytes synthesize cholesterol, they obviously have to package it inside of a brain -lipoprotein, See, create that lipoprotein which swims through the mattressome and goes over, and guess what the neuron expresses, LDL receptors, LDL receptor -related protein, or something called the scavenger receptor, all of which combine to the type of lipoprotein that an astrosite produces.

1:44:07So the protein also has a lipoprotein delivery system, but here's the difference. What is the main structural protein in the periphery? Apobere or ApoA1? What is the main structural protein in the brain? ApoE. So when an astrocyte mix in the olipoprotein, it's an apoE containing olipoprotein. And by the way, they're smaller, much smaller than the particles that we find in the periphery. If we put them in a centrifuge, they have the density of a high density hypoprotein that floats around the periphery. So they're often called brain HDLs but don't confuse brain HDLs with peripheral HDLs because most of the brain HDLs have apoe is their structural protein in the periphery they have apoe 1.

1:44:57Here's where the story gets a little more complicated as always. What is the smallest apoprotein the body can make? It's actually apoprotein A1 which is why NHL needs four or five of them. So if APOA1 can dissociate from an HDL, and we do have free HDL in the plasma, that's measurable, it is small enough that it can cross the blood -brain barrier. And once it joins the blood -brain barrier, what is the small APOA1 looking for? NHL buoyancy particle. So it joins with the APOE particles. So the brain lipo proteins are all apoe, or they're all apoe plus apoe1. And you can have multiple copies of each of those on those particles.

1:45:44So now, as long as they apoe1, by the way, which can bind to an LDL receptor or the scavenger receptor, same with the apoe, the neuron can grab them and either internalize them or and lipidate them and the neuron gets its cholesterol and the neurons happy. And then the de -lippidated particles can go right back and fill up the astro site again. So that's brain cholesterol transformation. But Peter, I know you check apoe genotype on your patients. And you do worry when certain apoe genotypes come back, especially those carrying the E4 allele. Because we know that's associated with AD and we have enough knowledge to know that God those brain apoproteins, the brain HDL's carrying apoi -4, or guess what?

1:46:31This functional HDL's, just like we've discussed, you can have this functional HDL's in the plasma. So if your brain makes apoi -4 instead of apoi -3 or apoi -2, you are not going to have the best brain HDL particles. And not only do brain HDL particles carry cholesterol back and forth, If amyloid or tau is being produced in a neuron, they can grab it and transfer it over to microglia, which are brain immune cells, which can get it and take it down and get rid of it in the brain lymphatics. So your apoe genotype certainly affects our violyos and chylos in the plasma. That's a lecture for another day because that's not that common.

1:47:17But in the brain, the apoe 4, you only have apoe containing lipoprotein, so you don't want to have it. I just want to make sure people aren't confused on that point. So definitely people listening to us are familiar with the apoe 4 gene. but just to reiterate, you're gonna have two copies of these genes just as you do for every gene. This is a gene that exists in three is reforms. So none of these are considered mutations, meaning there are three types that occur in nature, the E2, the E3, and the E4 isoform. So you have six combinations of these and therefore three of these combinations include at least one copy of an E4.

1:47:59So there's the two four, the 3, 4, and the 4, 4. So we know epidemiologically that there's a clear increase in the risk of Alzheimer's disease as you move from 2, 4 to 3, 4 to 4, 4. And I just want to make sure people understand that we're kind of going back and forth between the gene and the protein. If you have an E4 gene or a E3 gene or a 2, or whichever combinations you have, you still make an apoe protein. What is different is what the protein looks like in response to the gene. And what's very interesting is, if my memory serves me correctly, I believe it's only a single amino acid substitution between each of these.

1:48:45In other words, one amino acid difference between the one made by the three isoform and the who have the APOE4 gene have an APOE4 protein that wraps their brain -lipoproteins that gives it less affinity for doing this job of transferring cholesterol from astrocytes to neurons. So this is a very important explanation of why it is that people with an APOE4 gene are at an increased risk. This is not to say it is a causative gene. It's not a deterministic gene. It's not a gene that if you have a copy or two copies of the apoi for gene, you're going to get Alzheimer's disease. This just explains why there's a greater susceptibility and why an individual who has one or two apoi for genes needs to work that much harder on all of the other variables that factor into AD.

1:49:43And again, to your point, why does this not really play as much of a role in the periphery? We could save that for another day, but it sort of does in the edge cases. And that's why we see a higher incidence of AACVD and ApoE4 carriers. You did already allude to it, but only the astute listener will remember it when you talked about the ApoE and the conformational change of lipoprotein. I'm not going to go back to it because I want to stay on the brain. But anyway, I just wanted to interject that point so people knew the relationship between the genotype and the phenotype of the structural protein.

1:50:15Very, but even that single amino acid change just affects the shape of the protein, so it no longer binds where it should, and it screws up its so -called functionality of the particle. One amino acid in a peptide, you wouldn't think, but it's true. Now, there's one other part for the brain lipid story, and it's gets deeper. And remember, in the brain we're on our infancy, so much of what I'm going to tell you now is not carved in stone and in the discussion, But it's how we understand it in September, October, November of 2024. So it's the cholesterol story in them. We know if the brain can't get rid of cholesterol, that is associated with one of the characteristics of people with dementia or Alzheimer's disease.

1:51:01So there comes a point where too much cholesterol in the brain can be bad news. But we also know, and I'll discuss it in a moment, but because cholesterol synthesis is so crucial to the brain, you would never want to restrict cholesterol synthesis to a severe degree. That wouldn't just suggest that you would say, yeah, that doesn't sound too bright. So let's get into cholesterol homeostasis in the brain. Now the neuron is an interesting little cell there because it gets its cholesterol in adulthood from these apoeicontaining particles. cells. But if the neuron wound up with too much cholesterol, just like too much cholesterol in any peripheral cell, the liver is lipotoxic, it by itself would kill the cell.

1:51:46So the neuron is the one cell in the brain that was given an enzyme that it can transform cholesterol molecule into a metabolite that's called an oxy -starol. We have another name for oxy -starols and if we'll make you scratch your head, yeah, they're bile acids. The liver, by the way, can change cholesterol to an oxysterol, which being sends it right down the bile acid synthesis pathway, and the liver dumps it in the bile, and we excrete it fecly. So if the neuron can change cholesterol to an oxysterol, is it possible for that oxysterol to leave the neuron and enter the plasma?

1:52:31And that minute that's a lipid lipids can't pass through that blood brain barrier. So the neuron makes these oxysterols that's basically a sterile with extra oxygen molecules attached. So the neuron makes something called 24 -S hydroxy cholesterol. For those of you who've listened to our first podcast, you know cholesterol at one end has a hydroxy group. That's what It makes it somewhat water soluble, but the other end of the cholesterol molecule has no hydroxyureitol lipids. But if we could step another hydroxy group on the tail of the cholesterol molecule, it has a hydroxy group at both ends.

1:53:11It actually becomes a rare hydrophilic lipid. It's a lipid that's kid soluble in water, and it has no trouble passing through the blood -brain barrier. Once it enters the blood -brain barrier, it's in plasma, and it either rapidly binds to albumin or to any lipoprotein that's passing by. And both the albumin or the lipoprotein brings that oxysteril to the liver which converts it to a bile acid and excrets it. So the brain can actually get rid of steriles and have fortuitous way by sending it down to the liver which makes a bile salt from it. So 24s hydroxylase is the enzyme only neurons have. People think if we measure 24 S hydroxycholestrol in the bloodstream and it's high, we know the brain is trying to get rid of cholesterol and it's a marker of brain cholesterol health because you really should have trivial amounts of that in the bloodstream and it is with mass spectrometry easily measurable.

1:54:12All right, but let's get back to the astrocyte and the neuron making cholesterol. Our cells, Peter has talked about this many times. There's a bunch of original steps that go to a linear molecule called squalene, and then it starts to form a cyclic molecule that are called sterols. And the ultimate sterol is cholesterol. But there's many steps of the sterol. One sterol becomes another one becomes another one becomes another one. The penultimate next to last sterols that ultimately will transform into cholesterol are either lethosterol or desmosterol. As it turns out, and it's lucky for us, lethosterol is the major pathway of peripheral cell cholesterol synthesis.

1:54:59When your liver makes cholesterol it goes through the lethosterol pathway. Same with most of the cells in your body. Who uses the desmosterol pathway? Why did evolution give us two cholesterol synthesis pathways? Because cholesterol is essential for human life. God forbid you had some genetic defect where you knocked out one synthesis pathway, you've still got another, so you're still survivable. So the, there's a monstral pathway, although it could be used by any cell is primarily used by the brain astrocytes, also in the periphery by the steroidogenic tissue. So very interesting. So in your brain, Can we measure serum Desmosterol?

1:55:42Would it reflect what's going on in the brain? Actually, we know it does because people have done the studies where they've done spinal taps analyze CSF Desmosterol and it correlates incredibly well with serum Desmosterol. So serum Desmosterol is a biomarker reflective of the Desmosterol synthesis pathway by the way for the nerds that's called the block pathway The lethoscural pathways called the candach rustle pathway. Astrocytes predominantly use the block to desnostro pathway. And in adults, astrocytes are the supplier of cholesterol to the neurons. If for some reason the astrocyte fails in the neuron in an emergency how to make cholesterol, it actually uses the lethoscural candach rustle pathway.

1:56:32But in adults, that pathways for the most part, not at play. It's inactive. So again, that's why we don't measure the testosterone telling us anything going on in the brain because it's all coming from peripheral cells. It would be a minuscule amount that might be brain. All right. So why am I telling you all of this? My speculation has been that the reason that the place we see Desmastral in the periphery in the steroidal tissue is that that's the tissue that has the highest demand for cholesterol production, maybe suggesting that the Dismostral pathway is more suited to a high demand pathway, vis -a -vis the astrocytes and the steroidal tissue.

1:57:13Again, we're so far in the nerdy stuff on this now that's just a speculative comment. Listen, it's the ATT brain that thinks of stuff like that's why I love that I've known you for 15 years because many of the things you tell me, I got to go look up and say, God, that sound logical. Let me check out their any truth to it. I think you're absolutely right with that statement. So before I get more into that, anybody who's ever prescribed the stat into people knows there's a very small amount. And it's even in the packaging search that comes back and tell Doc, since you started this, I'm not right.

1:57:49I'm not thinking right. I'm not calculating right, my brain is in a fog, and we use the word brain fog. Again, an extreme minority of people given statins have that we had no clue what caused that. Invariably would stop the statin, try another one, it usually occurred, or if it didn't find, but if not, then we'd have to figure out other ways to lower LDL cholesterol, which was not easy years ago. But anyway, my hypothesis nowadays is these small number of people get brain fog. I wish I had this monstros levels on them. Could some people be very sensitive to the effects of a statin? We know in the periphery hyper synthesizers of cholesterol respond incredibly well.

1:58:32Or should me over synthesizers do, hyper synthesizers do not. So who knows, but that being said, now here comes the next part of that epidemiologic study where they correlated low -dismostral with serum -dismostral. People who had low serum -dismostral had a much higher incidence of cognitive impairment in Alzheimer's disease, which would lead simply to the hypothesis that serum -dismostral is a usable biomarker to say is somebody at risk for Alzheimer's disease. And this goes back to when I met Richard Isaacson with Peter. We started throwing these hypotheses around and we've watched that ever since.

1:59:17Where would it come into play? Until recently, statins were our only game in town. So if we write a stat, and especially if you used it at higher dose, if Desmastro was dropping low and we use an arbitrary cutoff point to 20th percentile, would that be maybe you don't want inhibit cholesterol synthesis in the brain to that degree, might we want to attack APOB with another agent? All hypothetical reasons I'm putting on the table here right now. And I think right now we look at that, especially in who? Who are the people that we know are likely prone to dimension cognitive impairment? To eat four carriers, people maybe with strong family histories, people that have other identifiable traits that make us think they're prone to AD.

2:00:04We would watch this mosterole incredibly closely in that population. So now the last thing I'll tell you, if the astrocyte is not making cholesterol because of its being over suppressed by a statin, the neuron would be getting less cholesterol. The neuron would convert none of that cholesterol to 24 -S hydroxy cholesterol because it's trying to conserve of every cholesterol molecule again. So I think if you were somebody who could measure 24 -S hydroxycholestrol in the serum, you would not see it in somebody who had cholesterol synthesis suppression in the brain. This all has to be worked out in future clinical trials, but there are looking at this in some clinical trials right now.

2:00:47So one day will be a lot smarter on this. Right now, if you want, you could measure does a master all it perhaps use that as a cautionary marker. Number one, if they're not on a drug and it's low, they haven't done an ApoE4 genotype. You might look at it. But if it is somebody who has a propensity does master all you have to use a stat and maybe you want to watch that. The good news is, and I think it's why our mantra is if we have to use a stat and we start with low dose statins, we have very little use for the high dose statin in the year 2024 because none of The other APOE lowering drugs be a benpidolic acid, a zeta mime, certainly PCSK9 inhibitors get into the brain and suppress cholesterol synthesis.

2:01:32So we have many ways of lowering APOE if we were a little fearful of low -dismostral in a patient prone to A -D or so. So that's about as much as we want to get into probably with brain lipids right now. Understand APOE is a big player up there and there are different types of the APOE protein. But understand cholesterol homeostasis has a lot to do with what is in the peripheral cells we can look at markers of synthesis. The markers of cholesterol absorption that we use big time when evaluating peripheral cholesterol homeostasis obviously is not at play in the brain. The brain is not absorbing cholesterol from your gut.

2:02:10Before we leave that time, what is our hypothesis around the hydrophobicity of various statins? and do we think that certain statins are more likely to cross the blood brain barrier or there are certain statins that should be ignored in patients with marginal desmosterol? Great question. In the thoughts of changed on this too, because early on, if you go back, probably maybe even listen to the podcast you and I did in 2018, I believe, we were talking about hydrophilic and lipophilic statins and the lipophilic ones can pass right through the barrier a little easier than the hydrophilic one, which need receptors to pull their men.

2:02:51But subsequent analyses has shown all statins get into the brain ultimately. Once you have a steady state, statin level in the blood, they all will get into your brain and they all have the ability to suppress cholesterol synthesis in the brain. Now the last thing I want to say about statins before everybody says, oh my god, I'm stopping my statinum are I can't get a desmosceral level. Oh, they're available if you look for them. But in general, if you analyze all of the statin data, the many trials be they observational or randomized control, there is no signal whatsoever that in a population, statins worsen or cause cognitive impairment or Alzheimer's disease.

2:03:34There's a few studies that even suggest perhaps some lowering. Maybe that's through atherosclerotic cerebral vascular disease, who knows? But don't worry that statins in the overwhelming vast majority people are not hurting the brain. But I think we've introduced perhaps a biomarker that you might know a little more certainty if you have the right to statin in somebody's subject to dementia. Yeah, we actually covered this at length in one of the previous AMAs and I went through every meta -analysis on this topic. It's important for people to understand that at least at the time, and I don't think this has changed.

2:04:10There has not been any statin trial where the primary outcome was dementia. The primary trial is always cardiovascular disease, but there have been more than a dozen such trials where the secondary outcomes are dementia. It's worth noting that in every one of those trials, regardless of statin used, there has either been no change in the risk of dementia or a reduction in the risk of dementia. Now it's interesting, these studies were almost all done in the setting of trying to determine if lipophilic versus hydrophilic statins were more or less or better, and the answer always emerged it didn't seem to matter, which of course makes sense if you understand now that they probably all cross the blood brain barrier.

2:04:58So, the question remains, will there ever be a study done that tests this question specifically as the primary outcome? In other words, where the study is powered to ask the question, does the use of a statin increase, decrease, or have no effect on the risk of Alzheimer's disease and dementia? Or will we instead be forced to rely on these secondary outcomes, which are always subject to some potential misinterpretation? Again, I take much more comfort it in knowing that they are all either neutral or favorable that would certainly be better than the opposite. But again, that remains a bit of an unknown.

2:05:37And you might be right, Tom. It might be that on average, it's having no effect on the brain. On average, it's having a beneficial effect through the vascular system. But then there might be edge cases that are not to be in captured in large clinical trials based on hundreds of thousands of people. And it might in fact be those patients in whom a little extra knowledge goes a long way vis -a -vis cholesterol synthesis in the brain. And the final point I'll make here is what a privilege it is to be practicing medicine in 2024 when we don't have only statins, but we have azetamide, we have bempidoic acid, We have short -acting PCSK9 inhibitors.

2:06:23We now have long -acting PCSK9 inhibitors. We have ASOs around the corner. There really is no need for a patient to ever endure a side effect of lipid lowering medication. Today we can lower everybody's lipids without side effects and that's only going to become more and more true in the next decade. Couldn't argue with anything you said there. It's brilliant what you said. And also, this is not a reason not to use statins. We're not evaluating populations. We treat people one at a time. So in somebody we're worried about dementia, we have a biomarker that's probably usable. And if God, you can't take the statins so what?

2:07:03We can get your apobie gold pretty easily with the other things that we know are not affecting the brain. What Peter said wouldn't it be nice to have a randomized blind trial to answer this question? And while statins are generic, I don't know of any form of company that's going to spend a billion dollars to prove or disprove what statins do to cognitive functions of the brain. So it's not going to happen. So if it's not, we can use in individual patients, these oddball biomarkers that is what I think is part of medicine 3 .0 where we maybe use a little smarter knowledge to try and do a better job.

2:07:40The last thing I'm going to repeat are as hard this enough to, maybe I bad mouth high dose stands. We don't use them. We're not treating your cucarnary syndrome patients where maybe you want to be high dose stand for X amount of time. You can get most of the APO B lowering with a statin with the baby dose. This has been proven in trial after trial. Most of the LDL receptor up regulation occurs with the lowest dose that inhibits cholesterol synthesis. you start doubling, tripling quadrupling, you might get another six, seven percent, not the original 30 percent lowering or so. So in today's world, why do you ever have to double, triple, or quadruple the dose of a statin?

2:08:21When we have all these other additive drugs that you take a baby statin, my acronym for a low -dose statin, and you combine it with a ZETA, my BEMPODOIC ACERR, like PCSK9 in Iberter, you've got a military machine that can destroy APO B. So that should be the thought processes about attacking APO B nowadays. We have so many options which we didn't have in the heyday. I always say one last thing because I'm old enough to remember, where did all this hydrophilic, lipophilic stuff come from? The first two competitive statins on the market were Symba statin, which was Merck's most potent statin, more potent and then their lovestatin' or mevacore.

2:09:02So everybody jumped on Zilcore or Simvestatin' but Bristol Myersquit made pravastatin' hydrophilic. And there was a lot of thought looking at other biomarkers that the, and even catabolism that the hydrophilic statins were safe for the new others, was there a little more brain fog with mevacore, Zilcore than there was with pravacol? And it totally people said that. I never saw it. Trial it looked at that. But that's where it all came from. Farma competitiveness, hydrophilic versus a philic statin. Well, Tom, my final question, I guess, really comes down to what are you most looking forward to in the next three to five years?

2:09:42I have an answer for what I'm most excited about, but I'm obviously more interested in hearing what you're most excited about in the entire field of cardiovascular medicine. Is it something on the drug side? Is it something on the diagnostic side? Is something else? What has you most excited? Well, most excited is I hope I'm still here in five years and now I hope I'm still capable of having these discussions with you. Peter's working hard to make that half of with me. So I high five among that. But if I do make it that long, look, I think we've got APOB solved right now. They're looking at even other types of PCSK9s coming down the pipe a little more potent on LDLC than the current ones.

2:10:18There's an oral PCS -K9 that they're working on. Would you rather swallow a pill and take an inch, but you're still just chasing APOB. And we can pretty much with rare exception get that to gold now. So I'd be more excited about for the people with the rare genetic disorders that are driving their lipids and lipoproteins out of whack. There are drugs coming at attack, other APO proteins that are there. But again, that's going to be a minority of patients on that. And diagnostically, I would hope I can't ever see it coming, but I couldn't see a lot of things coming that there might be some usable HDL functionality tests, which would make us a little smarter, perhaps, on giving a patient some insight to their HDL markers or so.

2:11:04Would there be other types of earlier markers? I don't know that we're going to get an earlier imaging marker than a CTA right now without being invasive or maybe optimal tomography and stuff is showing us stuff within the vessel wall. So who knows what imaging is going to bring to the table, but that probably won't be in widespread use when it first comes out. Would there be other inflammatory markers we have now? Fine, you can use them, you can look at them. I hope I didn't say it before, but does everybody understand that whatever inflammatory marker you're looking at, that is not the goal of therapy.

2:11:40Apo B is the goal of therapy. The thought being, if you make Apo B low enough, the atheroscotic process in the artery wall would dry up, scar up, and there'd be no more information in the artery wall. But there are other things going on, as Peter alluded to. So there are other biomarkers coming that certain amino acid biomarkers are being looked at or so that might give us other types of insight, looks at the arterial wall pathology that might be going on. I would love to see some of these synthesis and cholesterol markers, perhaps even LDL and H triglyceride levels, the latter two are just simple assays being made available to the general public.

2:12:21And I would like to see more widespread availability of the sterile biomarkers. And you need some education on how to use them, but that would be all great. And the last two things, I guess about two weeks ago, the NLA published their first statement on APOB and we've given you a lot of info why we use it but you want to get down into the weeds, that's a statement to read. And they do mention as good as it is, it can't happen tomorrow. No guideline is going to tell you to make APOB for the simple reason is the overwhelming majorities of practitioners really don't know what APOB is. Including those in the cardiology community for goodness sake.

2:13:02You can't get a guideline declaring everybody, stop doing lipid Profiles just get APO B because nobody would know what you're talking about. Sadly today the NLA put out a secondary expert person statement on LP little A and they get into the same thing. Yeah, everybody should get an LP little A once in your life, but right now in 2024 there are several drugs coming to lower it We have no idea whether they're going to reduce mace or not. So stay tuned. We're going to get to read out on one next year. What if it failed? Then LP Little A just becomes a risk marker like CRP or something. It's not a goal of therapy.

2:13:41So stay tuned for that But they also get into it a lot of labs. They're not doing the right type of LP little A testing I was shocked to hear because it's kind of a cheap test But apparently there are third -party payers given doctors grief for ordering it for God's sakes And again, the overwhelming majority of PCPs and a heck of a lot of cardiologists have no idea what LP Little A is. What good does it tell you to go get a test that in your shop and your doctor's office he goes, who doubts? Nothing, don't worry about it. So I'm hoping for better education among doctors in the lipid world. God knows Peter, you've done your part.

2:14:19And I just always like to pat you on the back. Last year Peter was made an honorary lifetime member of the NLA and I would suggest you go to their website and see who else has ever achieved that title. It's the giants of the field who invented a certain of you or that type of serious analysis. Why did Peter give it? Peter has probably brought more lipid education to more people than any of those gigantic thought leaders ever did. So I fight my buddy for doing these type of things and giving lipid its due presence on his missus, his Instagrams and his podcast for sure. So like always Peter, we're gonna know a lot more.

2:15:04Some of the stuff we said today is probably gonna sound like idiocy and for ten years. But I think I love it's gonna be right if I look back at my life And I'd prognosticate about a lot of stuff. I've been a lot more right than wrong So I'll have my own back. It was a huge honor last year to receive that award from the NLA and no small part of all that's obviously due to your mentorship and the mentorship of others. So thank you very much and thank you obviously for your continued education. Both for me personally and also for everybody listening, you're an absolutely tireless educator. your zeal for teaching your generosity of knowledge is really unparalleled.

2:15:44And you and I joke all the time about that first time we met way back in Reno, total chance, coincidence. And certainly one of the more fortuitous things that's happened to us both. So thank you again. I think this was a great discussion. I know that at times it got a bit technical, but I would encourage people to maybe go back and listen to this again, really go through the show notes on this one. All the stuff we talked about, you'll find summarized there and links to other things. studies if you want to be able to go into some of the details. So thank you once again Tom, for everything you've taught me and obviously everything you've taught the listeners.

2:16:16Vice -darsen my dear friend. Thank you for listening to this week's episode of the drive. Head over to peteratia -md .com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter all with the handle Peter Atia MD. You can also leave us, review on Apple podcasts or whatever podcast player you use. 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. No doctor -patient relationship is formed.

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