The Peter Attia Drive - #334 - Cardiovascular disease, the number one killer： development, biomarkers, apoB, cholesterol, brain health, and more

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

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00:01:04.220 My guest this week is Tom Dayspring. This may be a familiar name to you, as Tom has been a guest on

00:01:11.060 a podcast several times already. Tom is a fellow of both the American College of Physicians and the

00:01:15.640 National Lipid Association, and he is certified in internal medicine and clinical lipidology.

00:01:19.820 He was the recipient of the 2011 National Lipid Association President's Award for Services to

00:01:25.780 Clinical Lipidology and the 2023 Foundation of NLA Clinician Educator Award. Boy, have I known Tom for

00:01:32.420 a while. Tom and I met back in 2011. At the time, I had a budding interest in cardiovascular disease

00:01:39.180 and lipids. Tom took me under his wing and has been one of the more important mentors I have had in

00:01:45.120 the field of clinical lipidology. In this episode with Tom, we talk about the foundations of atherosclerosis,

00:01:52.080 why it is the number one killer in the U.S. and abroad, both for males and females, and how the

00:01:58.080 disease works from a pathologic perspective. We talk about the various risk factors for cardiovascular

00:02:02.380 disease and the role of insulin resistance and chronic kidney disease, which are two things that

00:02:06.940 don't get talked about quite as much as high blood pressure, smoking, and lipids. We then do a bit of a

00:02:12.460 dive into cholesterol and lipoproteins, discussing the role of ApoB, the development of atherosclerosis,

00:02:17.920 and also talking about other particles that make up ApoB, so LDL, VLDL, IDL, in addition to HDL and

00:02:24.860 their associations on cardiovascular risk. Talk about testing the various biomarkers as well as the

00:02:30.380 impact of nutrition, particularly saturated fat and fat consumption on lipid levels. We then talk about

00:02:36.620 the impact of cholesterol in the brain, where cholesterol in the brain comes from, how it's

00:02:42.840 synthesized there, how that differs from the periphery, and the role of pharmacology in that.

00:02:48.440 So without further delay, I hope you enjoy my conversation with Tom Dayspring.

00:02:57.360 Hey Tom, thank you so much for joining me. It's actually probably been a while since we've done an

00:03:03.340 actual podcast together, though of course we speak so frequently that it almost feels a little strange

00:03:09.420 to be talking in this way, but anyway, thank you for joining us.

00:03:12.960 No, it's a thrill to be back on the podcast series. It has been a while, and there's always stuff to

00:03:18.300 talk about in lipids, as you and I know too well.

00:03:21.980 So Tom, we're obviously going to talk about CARS today, because that's, no, I'm just kidding.

00:03:27.820 Everybody knows what we're here to talk about. We're here to talk about ASCVD,

00:03:30.940 cardiovascular disease. I think in part, I'd like to do this because there aren't many people who

00:03:36.600 probably heard our first podcast series together. I think that was a five, seven part series,

00:03:43.920 something of that effect. I still obviously get many notes from people who are just discovering

00:03:48.300 that or who listened to it way back. But I also think if I could be critical of that discussion,

00:03:52.800 as much as you and I enjoyed speaking for what I think amounted to eight or nine hours,

00:03:56.720 it's a little bit intimidating for someone who's trying to understand this topic. And so the two

00:04:04.680 things I would like to accomplish today would be to sort of bring a little bit of brevity to what

00:04:10.100 we discussed then. And of course, also to update people on all the things that have changed since

00:04:15.800 then, because that's sort of the beauty of this field is that a lot has changed in the probably

00:04:20.840 six years since that discussion. But maybe we should at least start by letting you define for

00:04:28.940 people what is meant by atherosclerotic cardiovascular disease. That's a very specific

00:04:34.420 type of a vascular disease. And that means arteries throughout your body acquire a pathology. And that

00:04:42.680 pathology is simply the deposition of cholesterol in the artery wall. I always joke, there's like

00:04:48.840 one sine qua non for atherosclerosis. And that says, do you have cholesterol in your artery wall or do

00:04:54.480 you not? If you don't, you don't have atherosclerotic heart disease. And of course, we have many, many

00:05:00.660 arteries in our body, and some are much more afflicted than others. And the ones of most concern are

00:05:07.200 typically the smaller ones that are supplying our heart and our brain, because those are sort of

00:05:13.200 essential organs that need a profuse blood flow with all the nutrients and oxygen in the blood.

00:05:19.720 So small arteries, if pathology is afflicting the artery wall, can cause trouble before the big

00:05:26.160 arteries. You can get atherosclerosis in your big abdominal aorta, but that takes an awful long time

00:05:31.980 before it's going to get to the point where you have an aneurysm and explodes. But the coronary disease

00:05:38.260 of the cerebral arteries, because their lumen is so small, and the lumen of a coronary artery is like

00:05:44.980 the dot of a pencil. So it doesn't take much to affect the blood flow that's going through it. And over

00:05:51.080 time, this deposition of cholesterol has two things that can happen. It can build up, and the artery lumen

00:05:58.740 starts to narrow, narrow, which would interrupt the blood flow. But all too often, probably more often,

00:06:05.620 is the deposition of cholesterol in the artery wall. And those collections are called plaque.

00:06:11.580 That plaque can become very inflamed and rupture or erode. And that sets off the coagulation system

00:06:18.640 in the arteries, which rapidly cause narrowing or obstruction of the coronary artery. So atherosclerosis

00:06:26.140 is the deposition of cholesterol in the artery wall. As you know, and we'll get into it likely in some

00:06:32.440 parts is, well, how did that happen? The artery is not oversynthesizing cholesterol. My joke is it's

00:06:38.780 a dump job. Somebody brought cholesterol into that artery wall. I just want to reiterate a few things

00:06:44.960 you said there, which is probably the role I'm going to try to play today is play the interpreter

00:06:49.000 sometimes. So we talked about how, you know, obviously we have arteries in all shapes and sizes.

00:06:54.900 Largest artery in the body, of course, the aorta coming off the heart, running up in an arch to supply

00:07:00.780 the vessels of the head and then down into the abdomen where every artery of the body arises.

00:07:05.940 And as you point out, it's not that the arteries of the heart are uniquely susceptible to this

00:07:12.580 process you just described as atherosclerosis. It's just that two things are conspiring against us.

00:07:19.000 The first is that they are very small arteries and therefore it does not take a significant

00:07:24.680 amount of obstruction or occlusion to create ischemia, which is just the technical term for

00:07:31.800 when oxygen is no longer able to perfuse the tissue. And then of course, at the risk of stating the

00:07:38.200 obvious, the second fundamental problem is it happens to afflict an artery that is, let's call it

00:07:44.240 specifically sensitive to the demands of oxygen. I remember explaining this to my daughter when she was

00:07:51.400 in grade school and I came in to do a little dissection for her seventh grade class. And I

00:07:57.020 explained that part of the reason we don't have butt attacks and we have heart attacks is that the

00:08:01.800 glute muscles are not quite as sensitive to oxygen and there are many forms of collateralization. And

00:08:07.520 of course, saying that to a group of seventh graders or fifth graders or whatever turned out to be

00:08:12.440 maybe not the best judgment because that was all they remembered for the rest of the class was butt

00:08:16.100 attacks. So head or brain and heart have this issue where tiny blood vessels, not a lot of

00:08:23.400 collateralization, catastrophic things happen. And I also want to highlight the other point you made,

00:08:28.940 which was, look, this can happen in two ways. One tends to be catastrophic and one maybe not as

00:08:36.220 frequently catastrophic. The gradual occlusion of the arteries is probably what more often leads people

00:08:43.740 to complain of chest pain under demand. You know, gosh, I was climbing the stairs or I was at the

00:08:50.420 gym and I just felt a tightness in my chest and under normal circumstances, I don't feel it or maybe

00:08:55.740 I do feel it, but then I take a nitroglycin and everything grows away. We'll talk about why all of

00:08:59.940 that's happening. But it's that really frightening scenario where a person in a moment has a complete

00:09:06.900 occlusion of a coronary artery when a plaque ruptures. And as you explained it, the clotting system

00:09:13.580 of the body responds in the way that it should respond when damage occurs. If you, for example,

00:09:20.000 cut your skin, but it turns out to be absolutely the worst thing the body could have done. And in an

00:09:26.280 ironic way, the body kills itself. This clotting response is what creates a sudden occlusion. And

00:09:32.540 if that occurs in the wrong part of the anatomy of the heart, that person will be dead within a matter

00:09:38.160 of minutes if an intervention is not performed. So with all that said, anything you would add to

00:09:42.980 that, Tom, as far as just setting the stage for what we're about to talk about?

00:09:45.700 No, you explain things very well from my physiologic or pathologic explanations to really drive home

00:09:53.920 why those two vascular beds are so important. Brain and the heart can't go very long without the nutrients.

00:10:00.860 That was a great point, too, that the obstructive part of coronary artery disease or even carotid

00:10:07.560 disease, extracranial disease, the bigger arteries that are bringing blood to the brain,

00:10:12.720 they're pretty asymptomatic until studies have shown that the arteries have to be almost 75,

00:10:18.560 80% occluded before those organs are deprived of the nutrients they need. So you can go a long time

00:10:26.320 building an expansion of an artery that's going to occlude your artery without knowing it or so.

00:10:31.860 And I don't know whether that's good or bad, but ultimately, if you at least report chest pain,

00:10:37.820 you will get diagnosed in time to do something about it. It's not like you said, a plaque rupture,

00:10:43.540 you got four minutes for somebody to dial 911 and hopefully somebody can CPR you till you can get

00:10:50.860 and take a clot buster. Yeah. So let's talk a little bit about the pathophysiology of this.

00:10:57.240 Before we get into what the non-modifiable and modifiable risks are, because we have two categories

00:11:04.180 of risk, let's just talk a little bit about the timeline of events. Of course, I'm spoon-feeding you

00:11:11.360 an answer here that I know is a very important teaching point. But when we think about atherosclerosis

00:11:16.960 being the leading cause of death, which it is, I guess we should have stated that at the outset,

00:11:21.440 this is the leading cause of death in the United States. It's the leading cause of death globally.

00:11:26.480 It's the leading cause of death in men, and it's the leading cause of death in women.

00:11:30.780 So it's hard to really imagine anybody listening to this who shouldn't be concerned by it.

00:11:35.900 I suppose if you're a squirrel, you can probably skip this podcast. So given that it's the leading

00:11:41.400 cause of death, it doesn't exactly show up as the leading cause of death in people

00:11:46.140 too young. It's not like we're watching teenagers, 20-year-olds, 30-year-olds, or many 40-year-olds,

00:11:52.580 although there are some tragically, who die of this disease. This is largely viewed as a disease

00:11:57.340 of the elderly. Does that give us any insight into the time horizon of this disease or the pathophysiology?

00:12:05.420 I think it clearly does. So if the deposition of cholesterol is the problem, if you ran to your

00:12:12.160 doctor tomorrow and got your cholesterol checked and it's very high, you don't have to rush out to

00:12:16.740 see a cardiologist to check your arteries that day because it takes a long, long time for this

00:12:23.820 cholesterol deposition to occur. We're talking about very small molecules here, and even the way that

00:12:31.400 it's being deposited in your artery wall are very, very tiny dump trucks. They don't each carry

00:12:36.740 four pounds of cholesterol. So if carriers of cholesterol are invading the artery wall,

00:12:42.460 it takes decades for this plaque to finally get to a point where it's noticeable on some diagnostic

00:12:48.760 image. Certainly, it would take even longer for symptoms to occur and everything. So it's a slow-so

00:12:55.880 process. But we know this is occurring basically from childhood on. There are pediatric studies,

00:13:03.140 P-Day, Bugaloosa Heart Study, where young children have died of this or that, and they get autopsied

00:13:09.680 and they have fatty streaks in their aorta at ages four, five, seven, and eight. We know from autopsy

00:13:15.660 studies of military personnel who unfortunately get killed in their job that these young men, many of

00:13:23.160 them robust in great shape, have subclinical atherosclerosis, but none of them are dropping dead of heart

00:13:29.640 attacks while they're serving in the military with rare exception. So it takes a long, long time.

00:13:37.260 So that's the point. Ultimately, yes, you will pay the price, and most of the heart attacks are men

00:13:42.700 after 40, women after 40. But we are recognizing now the real opportunity is to sort of diagnose who

00:13:50.740 might be having cholesterol deposition at a much younger age when we can just arrest it with various

00:13:57.160 modalities. Yeah, I've told this story before, but it probably bears repeating. In medical school,

00:14:02.620 so now this is almost 30 years ago, the pathology professor, this is first year of medical school,

00:14:08.460 said, what is the most common presenting sign of myocardial infarction? This was true at the time.

00:14:15.780 I don't think it's still true today, but it's close. And everybody, of course, every medical student

00:14:19.900 put up their hand and went through the litany of symptoms that you might have, chest pain, shortness of

00:14:24.300 breath, left shoulder pain, nausea, etc. And he said, no, it's actually sudden death. The last thing I

00:14:28.880 read suggested slightly fewer than 50% of people's first MI will be a fatal one. Do you happen to know

00:14:34.940 the most recent stats on that, Tom? No, but it's still quite high. It's very high. Yeah, it's just not

00:14:40.920 more than 50%. The majority do survive and get to us, but it's got to be close to 40% that just don't

00:14:48.540 have that opportunity. Yeah, which is staggering. And to think that only 25, 30 years ago, that number was

00:14:53.820 north of 50%. The other statistic that I've shared before, but again, it always bears repeating, is

00:15:00.200 that if you take all of the men who are going to suffer a major adverse cardiac event, so heart attack,

00:15:07.680 inclusive of stroke, cardiac death, etc. You take that whole group of men, and that's a pretty big

00:15:12.420 number. 50% of them will experience their first event before the age of 65. And 33% of women in the

00:15:22.180 same boat will experience their first event before the age of 65. Now, the older I get, the younger 65

00:15:28.040 feels. So there was a day when 65 seemed, those are old people. I don't think of 65-year-olds as old

00:15:34.480 people anymore. I'll tell you that much. And therefore, to think that 50% of men and a third

00:15:39.980 of women who are going to ultimately suffer a cardiac event will suffer their first one, which could

00:15:45.260 potentially be their only one if it's fatal prior to that age, also I think puts in perspective

00:15:50.680 the temporality of this condition. So we've just established that this is a disease that begins

00:15:55.300 at birth. This is largely established through autopsy studies where children, teenagers, people

00:16:01.120 in their 20s die for other reasons, car accidents, homicides, war. And in the process of doing an

00:16:07.840 autopsy, we begin to see the early stages of atherosclerosis. I think it's quite conclusive that

00:16:15.100 this is a disease process that might be inevitable to our species if we live long enough. And what

00:16:20.840 might separate the people who never get it or the people who die from something else at old age

00:16:25.540 versus the people who do simply has to do with the rate of the accelerator and the rate of the

00:16:30.440 brake application vis-a-vis these modifiable and non-modifiable risks, which I guess we should

00:16:36.120 talk about now.

00:16:36.760 One addendum to that is just to show you how early this can start. There are fetal autopsy

00:16:43.260 studies in mothers who have familial hypercholesterolemia. And when they look at the

00:16:48.700 little fetus's heart, they actually see the beginning of plaque development in that instance. So it occurs

00:16:54.880 early. And this is why pediatric guidelines have now at least encouraged lipid testing in the

00:17:01.920 pediatric age group, probably age eight or nine. You don't wait till you're 40 or 50 like you just

00:17:08.220 implied because, yes, we can still help that patient, but we're moving into what's called

00:17:13.680 primordial prevention. Discover the risk factors early and whatever ones you can modify earlier

00:17:21.440 rather than later is the time to do it.

00:17:24.320 Yeah. Thank you for making that point. And I was actually not aware of the fetal studies in FH.

00:17:29.060 We're going to obviously come back and talk about FH or familial hypercholesterolemia,

00:17:33.740 as it is sadly not as uncommon as one would wish. So let's talk about the risk factors here. There

00:17:39.520 are a solid seven or eight really, really well understood risk factors. Many of these are

00:17:45.100 modifiable, but some are not. So take them in any order you like, Tom.

00:17:49.560 Yeah. And the one thing we've been trying to exemplify later is the difference between risk factors

00:17:55.560 and risk modifiers, risk markers. Risk factors have pretty much been shown to be causal of the

00:18:03.220 disease through the ways you do that, Mendelian trials, a ton of randomized trials and even

00:18:10.120 observational trials. Whereas the risk markers are not causal per se, not to say they're not

00:18:17.080 important and we should attempt to modify them all. So there is that little bit of distinction.

00:18:21.680 So let's start off with the risk factors, things that are no doubt about it. Let's not argue about

00:18:27.700 these. And age is one. Now we can't modify that, so fine and dandy. But the things we can,

00:18:35.740 smoking, of course, is really at the top of the list and that can be modified with the patient's

00:18:42.520 cooperation. Lipid disorders are certainly in the causal risk factors and high blood pressure.

00:18:49.140 You can say things like diabetes and everything, but they bring basically the hypertension and the

00:18:55.280 lipid disorders to the table. So the risk markers would be a long list of other things. And there

00:19:01.820 are ones that are biomarkers, others are not, like coronary calcium, CTA. If you see that you have

00:19:08.780 atherosclerosis, there's certainly a risk marker. But homocysteine, omega-3 issues, vitamin D,

00:19:16.940 a lot of the bioinflammatory markers that we can look at that would be, if you have risk factors

00:19:23.140 and you have these risk markers on top of them, the worse gets worse. It's like a Chinese menu. The

00:19:27.980 more things on there, it's going to be more expensive at the end of the day. Of course,

00:19:33.020 my world is lipidology. That's what I focus on. But I know in your practice, you're super aggressive

00:19:39.100 with blood pressure management. It doesn't seem like there's too many smokers in your practice,

00:19:44.120 which is good. Maybe they don't want Peter as their doctor if they're puffing away. You can take

00:19:49.920 it from there with that little introduction. Yeah. I like that distinction of looking at the

00:19:55.160 causal and the non-causal as you could almost have a two by two causal versus associative and

00:20:01.200 modifiable versus not. So I would say two of the most important non-modifiable or really three

00:20:08.020 would be obviously age, one particular gene that we don't yet have the ability to fully modify its

00:20:14.780 phenotype, which is Lp little a that we'll talk about. And then of course, there are other very

00:20:19.820 strong lines of family history that aren't necessarily transmitted through lipids the way

00:20:26.280 the FH gene or sets of genes are. In other words, there seem to be other polygenic causes here

00:20:32.160 that run very strongly in families. I would argue that I have some of these genes, Tom.

00:20:37.080 As you know, my family history is riddled with cardiovascular disease, and yet it doesn't come

00:20:41.680 in the flavor of profound dyslipidemia. All right. I have a normal Lp little a. I never actually had a

00:20:47.540 very elevated ApoB. And in fact, when I had that first calcium score at the age of 35 that already

00:20:53.900 showed the presence of calcium, it was in the context of an LDL cholesterol at about the 50th

00:20:59.180 percentile. It was about an average Joe as you could be. And yet there was clearly something

00:21:04.600 else going on. I wasn't insulin resistant. I wasn't a smoker. I had none of the risk factors,

00:21:10.900 normotensive. There was something else going on. We could probably spend a minute on talking about why

00:21:16.100 I've had zero evolution of that disease over the past 16 years, which also speaks to the nature of

00:21:23.000 interrupting causal pathways. And now on the causal side, I don't think there would be any dispute for

00:21:29.140 any reasonable person on the causality of ApoB, hypertension. Let's talk about two other things

00:21:34.940 though, specifically. Let's talk about insulin resistance per se and chronic renal failure.

00:21:42.600 Do we have strong enough evidence on the causality of these, which are clearly highly associated with

00:21:49.340 the condition? Or how do you think about that? Well, the chronic kidney disease is a super major

00:21:54.380 risk factor for there. But probably primarily through virtually everybody with chronic renal

00:22:00.260 failure has lipid disturbances, high ApoB, which you just mentioned, and they have a high degree of

00:22:06.760 serious hypertension. So you've got two really causal things that are basically present in everybody with

00:22:14.200 CKD. So is that the only reason CKD is doing it? I suspect that when your kidney is not getting

00:22:22.200 rid of a lot of things, there are other things floating around that are irritating your arteries

00:22:26.660 for sure. One other thing I might add there, Tom, is when we do see people with even compromised

00:22:33.540 kidney function, we generally see homocysteine go through the roof. And while it might be a bit of

00:22:38.820 a stretch, as you recall, we used to spend some time looking at markers. I don't even want to get

00:22:44.060 into it because it's such a mouthful, but you'll recall the days of asymmetric and symmetric

00:22:48.240 dimethyl arginine. And we would see these things skyrocket in people with high homocysteine

00:22:55.420 because homocysteine impaired their clearance. And of course, there's at least reasonable mechanistic

00:23:01.360 data to suggest that high amounts of symmetric and asymmetric dimethyl arginine impaired the enzyme

00:23:08.000 nitric oxide synthase, which produces nitric oxide, which leads to vasodilatation. So to put that entire

00:23:14.180 path together, there's a very clear link between kidneys that don't work fully, high homocysteine,

00:23:21.200 and then the buildup of amino acids that prevent the body from making a vasodilator.

00:23:28.400 I don't know that the causality of that has been clearly established in humans, but it would serve

00:23:34.120 as at least one additional plausible mechanism for why renal insufficiency could be leading to an

00:23:42.100 increase in vascular disease. Yes. That's sort of what I said. Hey, there's other things floating

00:23:46.560 around when you have CKD, homocysteine, which certainly be one you can throw uric acid into

00:23:52.500 that equation probably also, and other metabolites, ceramides, and things that are beyond what we want

00:23:59.580 to discuss today. So multifactorial CKD as far as atherosclerosis. Yeah. And then let's talk a

00:24:09.200 little bit about hyperinsulinemia and insulin resistance. Again, let's try to disentangle

00:24:13.600 what's obvious, which is, as you pointed out already, that condition tends to traffic

00:24:18.420 hand in hand with hyperlipidemia and hypertension, which are clearly and independently established as

00:24:25.240 causal. What do you make specifically of hyperinsulinemia and hyperglucosemia as independent

00:24:33.340 risk factors beyond the lipid and hypertensive components?

00:24:37.740 I sort of don't accept that. And it goes back to this incredible study in the 90s by Steve Garvey,

00:24:45.220 when NMRs came to the table, nuclear magnetic resonance analysis of lipoproteins. And there

00:24:52.560 are distinct lipoprotein signatures associated with insulin resistance. They can go back and listen to our

00:24:59.060 original podcast. But basically, if you look at certain characteristics of the low-density lipoprotein,

00:25:06.180 the very low-density lipoprotein, and the high-density lipoprotein, you will see distinct

00:25:11.960 patterns that appear in insulin-resistant people. You would have bigger VLDLs because they're

00:25:18.220 triglyceride carriers. You would have smaller LDLs because the triglycerides convert big LDLs into small.

00:25:25.460 Likewise, you would not have big HDLs because triglycerides enhance HDL catabolism, making

00:25:32.440 the HDL small. So if you look at all those distinct, and they're easily measurable by NMR,

00:25:39.240 if you have those patterns, and this was corroborated doing insulin clamp studies.

00:25:45.380 So if we saw these type of lipoprotein signatures and we looked at the insulin clamp studies,

00:25:50.160 they're all insulin resistance. And the interesting thing was these signals occur

00:25:55.600 before postprandial insulin goes up, certainly before fasting insulin goes up, decades before

00:26:02.980 glucose goes up. So I think it's just impossible to separate insulin resistance and lipoprotein

00:26:10.580 abnormalities. Those type of lipoproteins that I just discussed are the ones that are delivering

00:26:16.180 cholesterol to your artery wall. So we also know not everybody who has atherosclerosis has

00:26:23.060 insulin resistance. So there are people out there who believe, boy, if you don't have insulin

00:26:27.820 resistance, you cannot get atherosclerosis. That's silly, but it's still promulgated out there.

00:26:33.920 So I don't know. I look, and maybe it's my little sphere of lipidology. I look at everything as

00:26:39.240 related to lipids maybe too much. But there is that very early on, before at least insulin levels start

00:26:45.580 to go up. Now, we even know before insulin levels goes up, there are other cellular mechanisms that

00:26:51.420 are going on in insulin resistant people. So I don't know. They're together. I don't know what purpose it

00:26:58.200 serves to, hey, whether you call insulin resistant causal or non-causal, it's a very serious abnormality

00:27:05.500 to be taken incredibly serious. I think I tend to lean towards some independent causality there. And I

00:27:13.200 point to some of the diabetic research where they look at studies where you take two different

00:27:18.760 approaches to maintaining euglycemia. So as you know, Tom, there are obviously pharmacologic aids

00:27:25.100 that can do that without the use of exogenous insulin and with the use of exogenous insulin.

00:27:31.000 So in other words, you could have two different ways to bring glucose down, one by increasing insulin

00:27:36.200 sensitization and one by actually just giving more insulin. And interestingly, when you parse apart

00:27:43.660 the results of these studies, you see something interesting, which is that there appears to be

00:27:48.560 some vascular damage that is mediated by just the hyperinsulinemia alone, even in the presence

00:27:56.600 of normal glycemia. Of course, we would understand why hyperglycemia is problematic for microscopic vessels,

00:28:05.020 but it's kind of these larger vessels that seem to have a negative response to hyperinsulinemia.

00:28:10.820 It almost comes back to this idea of what's going on with uric acid and homocysteine. Are these things

00:28:16.880 somehow inflammatory to the endothelium and therefore render the endothelium even more susceptible

00:28:23.740 to a given concentration of lipoproteins? Again, it might be a moot point because I think when it comes to

00:28:30.900 ASCVD, the goal is probably to address everything and therefore we might be sort of having more of an

00:28:38.380 academic debate on this. I think the other point that is probably worth mentioning to people when

00:28:44.460 we talk about causality in biology is distinguishing between things that are necessary and things that

00:28:49.340 are sufficient. And obviously, once in a while, you find something in biology that is both necessary

00:28:54.900 and sufficient, but many times it's neither and it can still be causal. So I'll use the example of

00:29:00.940 smoking. So is there any doubt that smoking causes lung cancer? There's no doubt in anyone's mind.

00:29:09.760 Anybody who doubts that probably shouldn't be having a discussion at this point. So smoking is causally

00:29:15.700 related to lung cancer. But is it necessary for lung cancer? No. Only about 85% of people with lung

00:29:23.800 cancer are smokers. 15% have never smoked. Is it sufficient for generating lung cancer? No, it's not.

00:29:32.540 Because there are many smokers who don't go on to develop lung cancer. So in that sense, you can have

00:29:38.000 something that is very causal, meaning it's about a thousand times increasing the risk of lung cancer,

00:29:43.940 but it's neither necessary nor sufficient. This will be relevant when we pivot to our next topic,

00:29:50.100 which is ApoB. It'll be interesting to talk about ApoB through the lens of necessity and sufficiency.

00:29:56.460 So before we do that, maybe give folks the little explanation on what ApoB is and maybe why we

00:30:03.820 shouldn't think of it as synonymous with, say, LDL cholesterol. Yes, well, ApoB is the ballgame

00:30:10.280 nowadays. It's not widely tested like it should be. But anyway, cholesterol has got to get in your

00:30:16.520 artery wall to cause this disease, atherosclerosis. We know cholesterol is an organic molecule that is

00:30:22.900 in the lipid classification. There are many other lipids, but the definition of a lipid is it's a

00:30:29.480 molecule that's not soluble in water. And the dilemma is our delivery system of everything in the human body

00:30:36.600 is a water solution called plasma. So how in the world are lipids trafficked in plasma? That's basically

00:30:43.800 a physical chemistry impossibility. You know, you've heard me say this many times to patients,

00:30:49.800 evolution had to develop a lipid transportation vehicle. So these hydrophobic lipids could be

00:30:56.760 trafficked in aqueous plasma. And the solution was very simple because proteins are soluble in water.

00:31:03.680 So if one just combines a collection of lipids to a protein carrier, lipids can go wherever the human

00:31:12.200 body wants them to go in plasma. The things that traffic lipids in our body are protein and wrap

00:31:18.160 lipids. The proteins are called apoproteins. Once they bind to lipids, they're called apolipoproteins.

00:31:24.880 And the whole macromolecule, once it's fully developed, is called the lipoprotein.

00:31:29.720 So lipids go nowhere in the human body unless they're a passenger inside of a lipoprotein.

00:31:36.220 Now, there are many proteins that can associate with these lipid collections, but there's two

00:31:40.720 we're going to put at the top of the list. They're the structural apoproteins. These proteins provide

00:31:46.760 structure, stability, and water solubility to the lipids. There are two basically categories of

00:31:54.600 lipoprotein families in our body. We're talking about the ApoB family right now.

00:32:01.100 So ApoB happens to be the largest of all the apoproteins that the liver and even the intestine

00:32:08.120 can produce. By the way, no other cells in the human body produce ApoB. It's the liver and the

00:32:14.080 small intestine. Very high molecular weight. So particles that are wrapped with ApoB, and of course,

00:32:21.700 they're full of thousands of molecules of triglycerides or cholesterol, phospholipids,

00:32:28.080 and other lipid moieties. The ApoB family, we have other ways of classifying them, and that's in

00:32:35.600 the centrifuge. So the ApoB family consists of what everybody has probably heard, low-density

00:32:41.700 lipoproteins, the LDL, very low-density lipoproteins, the VLDLs, which are our triglyceride-carrying

00:32:50.240 particles. IDLs, I'm going to mention them for completeness, intermediate-density lipoproteins.

00:32:56.180 They're very transient characters in between VLDLs and LDLs. They're not a consequence other than

00:33:02.400 some very rare lipid disorder. So that's the ApoB family. But the really good thing and what

00:33:09.180 makes ApoB so valuable is there is one molecule of ApoB per ApoB-containing lipoprotein.

00:33:17.060 And this is great because it's a very easy assay for labs to do. It's an immunoassay,

00:33:23.500 well-standardized. So we can have on our patients, hey, go get an ApoB concentration.

00:33:30.240 And when we get that number back, we know we are actually counting the number of ApoB-containing

00:33:36.420 lipoproteins. And that's so critical because the particle that can leave plasma, enter the artery

00:33:43.780 wall, and start off this atherogenic process are the ApoB family. The other family of lipoproteins

00:33:51.300 are our high-density lipoproteins, our HDLs. Their structural protein is apoprotein A1, except

00:33:59.320 there's from one to five copies of ApoA1 per HDL particle. So that doesn't become a useful biomarker

00:34:06.220 to get an HDL particle concentration. And the HDLs, until you get into the sub-discussions of

00:34:14.640 them per se, are not atherogenic. So we don't worry about them too much. It's the ApoB particles.

00:34:21.020 And to just complete this discussion on the importance of ApoB, what makes an ApoB particle

00:34:27.000 decide to leave plasma and crash the artery wall, rather than go back to a receptor in the liver that

00:34:33.420 can bind it and pull it out of plasma in a process called clearance. Because if all your ApoB particles

00:34:39.340 are being cleared in the liver, there would be none to invade your artery wall. So what forces them

00:34:44.700 into the artery wall, and depending on other factors, there are threshold concentrations above

00:34:50.740 which the odds are good ApoB particles are crashing your artery wall. And because, unless you have

00:34:57.440 horrific other risk factors, that's why atherosclerosis takes decades to develop. Because it takes a long

00:35:04.040 time for these tiny ApoB particles to keep crashing the artery wall. And maybe later we can discuss what

00:35:11.340 happens to an ApoB particle once it's in the artery wall. But step one is crashing the artery wall,

00:35:17.420 traversing the endothelial barrier, the one cell lining that's on every artery in our body,

00:35:22.880 and going in. So it's particle number. And the best and easiest way and the most tested way to get an

00:35:30.260 accurate atherogenic particle number is to measure ApoB. You'll hear even statements say ApoB is

00:35:37.620 causal. You'll hear LDL cholesterol is causal. Because of its very long plasma residence time

00:35:44.200 compared to the short plasma residence time of VLDLs, about 95% of our ApoB particles are LDLs.

00:35:52.880 Hence, LDL-P, another way of checking particle number, is really what drives total ApoB. Not that

00:36:02.340 the VLDLs are not important. They can be. But it's the LDLs that are doing most of the cholesterol

00:36:08.700 dumping in the artery wall. So ApoB really gives us a good handle on LDL particle concentration.

00:36:15.980 So, and yes, ApoB bringing that sterols into the artery wall is causal, but it's really the

00:36:20.980 sterols that do the dirty work once the ApoB is annealed. So you can't separate ApoB from

00:36:26.580 cholesterol. So I don't care whether people say cholesterol is causal or ApoB is cholesterol,

00:36:31.900 because you can't separate the two in physiologic circumstances.

00:36:36.480 So let's maybe go a little bit further into that process just so folks understand it. So let's,

00:36:41.440 for the purpose of this discussion, assume that it is indeed the most common ApoB-bearing particle.

00:36:46.740 It's a low-density lipoprotein. So an LDL molecule carrying its load of cholesterol,

00:36:54.980 maybe a little bit of triglyceride to boot, makes its way from the lumen of the artery

00:37:00.140 through the endothelial barrier between a couple of cells into a potential space called the

00:37:06.760 subendothelial space. What set of factors increase or decrease the probability that it

00:37:11.980 is there long enough for its cholesterol package to begin the process of oxidation? Do we have

00:37:20.400 any sense of this idea of retention? Yes. And it's always subject to new data coming in because

00:37:27.740 this is under a long time and continuing investigation. One little minor correction,

00:37:33.440 you called LDL a molecule. It's a macromolecule. Yeah, thank you for correcting me.

00:37:37.560 Stickler for terms, as you know. So once the ApoB particle traverses that endothelium,

00:37:44.660 and that can happen even if you have a normal endothelium, and it certainly can happen easily

00:37:49.080 if you have a diseased endothelium. And probably worth noting, Tom, that's

00:37:53.680 almost assuredly where things like smoking and high blood pressure make your odds worse. Those are

00:37:59.340 things that are damaging the endothelium, making that barrier more permeable, which is simply a

00:38:05.820 probabilistic game. This is all probabilistic. What increases the odds of an ApoB getting in?

00:38:11.280 More particles. That's higher ApoB. More porous endothelium. That's what happens with smoking.

00:38:18.220 That's what happens with high blood pressure. That's, in my view, probably what happens with

00:38:23.080 things like high homocysteine, high insulin, or renal insufficiency, high uric acid, all of those

00:38:28.060 things. So anyway, yeah, it's all about the probability of making the gradient such that the

00:38:33.020 ApoB is going where it's not supposed to go. Yeah, you mentioned at ADMA before, that's basically

00:38:38.520 a regulator of nitric oxide, probably the most crucial molecule that an endothelium produces

00:38:44.500 to defend the integrity of the artery or so. And once that's out of whack, the endothelium is not

00:38:51.560 functioning like it should. There are receptors that can get expressed there that can pull these

00:38:56.700 particles in. But okay, the ApoB particle is in the wall of the artery, the intimal layer there.

00:39:03.820 One of my jokes is usually it's like, once a fly hits flypaper, if there is such a thing anymore,

00:39:10.040 it's stuck. Then what happens to it? So when an ApoB particle enters the artery wall, it has a high

00:39:17.060 affinity to bind to collective tissue molecules called proteoglycans, syndectins, there's a whole

00:39:23.460 subfamily of them. And now you have that ApoB particle that is just stuck there. Now, look, the

00:39:30.440 number of LDL particles floating around your plasma, we're sort of talking like ApoB, you can count the

00:39:36.980 number of particles. And now, well, there actually are quadrillions and quintillions of these particles.

00:39:43.080 And that's how many are crashing your artery wall too. So there's a lot of them in there. And they're all

00:39:48.340 right next to each other bound to these proteoglycans. So it's now believed the next step that happens,

00:39:55.380 what's on the surface of all these ApoB-containing particles? It's phospholipids. The cholesterol and

00:40:02.180 triglycerides are inside these particles. There's a little bit of unasterified cholesterol on the surface.

00:40:09.580 But these phospholipids are very susceptible to two things. One is ultimately going to be oxidation,

00:40:17.280 which is a big, big role in atherogenesis. But the first is there are enzymes called mutases that

00:40:24.540 somehow realign the phospholipids that are on the surface of these particles. And when distinct

00:40:31.240 phospholipids are put next to each other, these particles have a high affinity to stick to one another.

00:40:37.960 And that's called LDL or ApoB particle aggregation. And that is believed to be the first step.

00:40:45.240 So what you ultimately have is a lot, zillions of these ApoB particles in a big mass of cholesterol

00:40:54.060 and all the other lipids that are inside that particle. And that's where the oxidation starts

00:40:59.480 to occur because sterols get exposed. The phospholipids, many of which have double bonds,

00:41:04.980 are highly susceptible to oxidation. So now you have this clump of gooky cholesterol and phospholipids,

00:41:14.760 which are oxidized. Well, oxidation is a major signal to the immune system. The immune system is

00:41:22.820 going all over the body. And when things get oxidized, that means it's on fire. It's often an

00:41:27.500 infection or some other pathology. And here come the white blood cells to put out the fire.

00:41:32.640 So once you get this aggregated mass of oxidized, whatever you want to call it, it's way beyond

00:41:41.020 cholesterol, white blood cells start traversing that endothelium, the monocytes. And they come in

00:41:48.220 and they transform into macrophages, which express receptors that can start ingesting all these

00:41:54.780 aggregated ApoB particles. And the next step, and this was seen by the great Russian, I think in 1913,

00:42:02.380 a Nitschkoff, when they overfit rabbits, pure cholesterol, and they developed atherosclerosis,

00:42:09.920 something rabbits normally don't get. You drown them with that type of cholesterol. And under the

00:42:15.460 microscope, he saw all these things that there was some long German name. I wish I had it for it's

00:42:21.380 basically cells that are full of cholesterol lipids. So this was what we now call the foam

00:42:26.560 cell, which is just a lot of cholesterol in the interior of these macrophages. And under the

00:42:33.420 microscope, they look very foamy. So that's how they got their name, foam cells. And as you can

00:42:39.300 imagine, all these masses over the decades we've talked about, now you have plaque. But as this plaque

00:42:46.920 is being formed, that immune system is still trying to put out the darn fire. So what the

00:42:52.420 next thing the immune system does is once the macrophages have eaten it and sort of organized

00:42:57.780 it into a pool of cholesterol, is smooth muscle cells are recruited from the external surface of

00:43:04.940 the arterial wall. They migrate and they start covering this gook, this mass of cholesterol and

00:43:12.000 other lipids. And now you really have a distinct plaque where you have a cap on it. And the cap is

00:43:18.080 simply smooth muscle cells originally. But these smooth muscle cells transform into more complex

00:43:24.600 cells that can start secreting calcium. And that gives this cap plaque a fibrous integrity.

00:43:32.120 And what is the purpose of that? To prevent what Peter and I talked about early on, you don't want

00:43:37.240 this plaque to rupture. It's like putting a heavy mounded dirt on a volcano, I guess. It's less

00:43:43.700 likely to rupture if you can cover it. Ultimately, the type of cytokines and chemokines that are being

00:43:51.260 produced by these white blood cells, some of them have bone forming ability. And that's why much later

00:43:57.740 in the disease, calcium starts to get deposited in this cap plaque. And that's maybe somewhat fortunate

00:44:05.380 because being radio opaque, that enables the type of imaging studies we have now to say,

00:44:11.120 oh my goodness, there's calcium in your artery wall, which there's only one cause, and that's

00:44:15.340 atherosclerosis. So those are the several steps maybe you want to elucidate them on further, Peter.

00:44:21.080 But none of this happens like you overeat a lot of cholesterol tonight. And boy, next week,

00:44:26.440 you're going to have a heart attack. It takes decades.

00:44:30.040 That's a great explanation. Maybe I'll just summarize it a little bit. So we already talked about how we get

00:44:34.360 into this process where you have the ApoB carrying lipoprotein. Let's again, just simplify it and call

00:44:40.340 it the LDL in this situation. Although, as we'll talk about, I'm sure they can also be an LP little

00:44:45.260 a. It enters that subendothelial space and its presence alone makes it susceptible to have its

00:44:52.320 contents oxidized. Cholesterol is a rich target for oxidation. And as that happens, we once again

00:44:59.320 have this example of the immune system, which is out there basically surveying, constantly looking

00:45:05.700 for things that are bad, usually in the form of monocytes. And they're sensing, they're seeing a

00:45:11.620 chemical signal for that oxidation. And as they enter that space, they become this other type of

00:45:17.820 cell. They metamorphize into something called a macrophage. And the job of the macrophage is to

00:45:24.000 literally consume, to phagocytose, to eat the thing that it is concerned with. And when it begins to

00:45:30.260 eat that oxidized cholesterol, that produces the foam cell. I want to pause there for a second and

00:45:36.760 talk about how way down the line, when we ultimately have that calcification, as you said, that's actually

00:45:43.520 quite visible. A calcium scan is exactly looking for that phenomenon. But I often get asked the

00:45:50.480 question, Peter, is there anything I can do today to know if there is any damage to my endothelium?

00:45:58.940 Are there any foam cells in me? Are there any fatty streaks? And then of course, the next thing we kind

00:46:05.560 of talk about is a CT angiogram, which in its first phase, when it's run without contrast, which it

00:46:11.880 usually is, you have the opportunity to potentially see calcifications. And then once the contrast is

00:46:17.820 injected, you get a higher resolution image that shows more anatomic detail of the lumen.

00:46:24.580 But in my experience, Tom, you have to have a reasonable amount of soft plaque, non-calcified

00:46:31.140 soft plaque to show that, suggesting that there's probably still quite a bit of damage that could

00:46:37.540 occur before you would see anything on a CTA. And of course, I realize there are some people listening

00:46:41.900 to this saying, well, what about newer tests clearly that are using a fat attenuation index

00:46:48.620 to look at the changes in the character of the fatty tissue in and around the adventitia and to see if

00:46:57.880 that is in and of itself predictive of damage. So I'll just kind of let you take that in whatever way

00:47:02.040 you see fit. Outside of research-based tools, such as intravascular ultrasound, do we have tools to

00:47:12.040 really understand these early stages of disease? If a person says, look, I don't want to get treatment

00:47:17.560 now, but I don't want to wait until I actually have calcium. Is there a middle ground?

00:47:23.180 Not definitively, but there's two things. Certainly there are these advanced imaging techniques,

00:47:28.720 and that's one where they're analyzing certain characteristics of the artery wall. I think

00:47:33.240 still not ready for primetime play yet. And certainly because of its course, it's nothing

00:47:39.060 the average person is going to run down and get tomorrow or so. So we go back to then, hey,

00:47:44.780 these macrophages that are sending out these signals, recruiting more and more white cells to

00:47:49.800 get in there and help me. It's like a fire department calling for a second, third, fourth alarm.

00:47:54.520 We need more immune operators on the system. Are there immune markers we can perhaps measure in

00:48:02.200 the blood? And that's basically what we're doing right now. So obviously these would be different

00:48:07.760 types of inflammatory markers, and they're looking at other type of biomarkers that might signal this

00:48:14.520 type of pathology going on. These are the ones that are readily available to most people. And these are

00:48:20.940 risk markers because by themselves, they're not causal and they have other etiologies or other

00:48:25.680 causes that might explain and why they're high. The first and the one with the most evidence is the

00:48:31.780 C-reactive protein test. That was used for years to help diagnose rheumatic fever, which obviously had

00:48:38.280 a lot of inflammation. Down the road, Paul Richter was the guy who did this. He discovered, well,

00:48:44.360 the type of inflammation that goes on in the artery wall is incredibly subtle at first. So you're not

00:48:50.280 going to see a C-reactive protein of 22 or a sedimentation rate of 55 in the blood test, the

00:48:57.720 old time markers of inflammation. He says, can we analyze C-reactive protein at heretofore trivial,

00:49:05.080 not even looked at levels? So they started looking at extremely low C-reactive protein levels.

00:49:12.680 And lo and behold, he's shown it's beyond debate now that yes, they call the test high sensitivity,

00:49:18.920 but it's actually the same damn assay that checks for CRP if you have rheumatoid arthritis.

00:49:23.880 But the high sensitivity has a different reference range that they relate to atherosclerosis and

00:49:29.440 obviously much lower than you would have with some rheumatic disease. So subtle elevations of this

00:49:35.420 C-reactive protein, the rule is, hey, above two, you're at worry. Above four, you've got some serious

00:49:42.200 inflammation in your body going on. It's not necessarily cardiovascular, but could you be

00:49:48.660 in an early stage of some other inflammatory disease? Sure. That's why it's not specific.

00:49:53.560 But you know, we look at levels even less than two as a signal to us to start worrying. So that's

00:49:59.160 the first inflammatory marker.

00:50:01.160 I just haven't been that impressed with HSCRP's specificity. There are too many people I have seen

00:50:08.340 who have a normal HSCRP, and I actually define normal as less than one. So I'm not even talking

00:50:14.440 about the actual assay cutoff of two. So these are people that walk around with an HSCRP of 0.8,

00:50:20.400 and yet you actually do a calcium score on them and you find they've got a calcium score of 10,

00:50:25.300 which again, this is not a person who's going to die anytime soon, but they've already progressed

00:50:30.500 to a calcium score of 10. This is a person who might be in their 40s. So this is a person who's

00:50:35.720 actually on the path towards premature atherosclerosis. So I just think that inflammatory

00:50:41.620 markers are probably not specific enough, or in the case that I just gave, even sensitive enough

00:50:49.280 at low, low levels of this disease, in particular, because I think that this disease has multiple

00:50:55.040 paths. Even though we're not going to talk about it today, another topic we love talking about is

00:50:59.760 Alzheimer's disease and brain health, and how there are different paths that patients will take

00:51:05.060 to get Alzheimer's disease. Some patients come at it through almost a genetically pre-programmed path.

00:51:11.660 Others come at it from much more of a vascular disease path, and yet others come at it from a

00:51:16.720 more metabolic and an inflammatory path. And there are all these different paths. And I almost wonder if

00:51:21.040 there are similar paths towards atherosclerosis. And there are some people who are arriving at it,

00:51:27.760 it's almost genetically programmed in them. And then there are others who are showing up

00:51:32.100 through this very lipid-based path. And yet there are others for whom inflammation is the dominant

00:51:37.720 path. And maybe those are the people where the HSCRP shows up very early in the process. Again,

00:51:43.180 I'm completely making this up as an analog to what we see more commonly in the paths to dementia.

00:51:49.920 But I guess what I'm saying in a long-winded way is I find myself rather unconvinced that we have

00:51:55.160 great tools to measure the phenotype of early atherosclerosis.

00:52:01.860 That's so true. And it's the specificity, as you said, I can name two or other three other

00:52:07.120 inflammatory markers that would have the same weakness. You could have a fatty liver and they're

00:52:11.440 elevated or so, or subtle infectious disease somewhere. So they're not specific. And you could

00:52:17.760 say, and Ritker would tell you in the scenario you described, where we've got coronary calcium is there

00:52:23.480 already, but their CRP is perfect. Maybe that's a stable plaque that's not going to rupture herself.

00:52:29.560 You can get into those type of debates.

00:52:32.160 Maybe they had a CRP blip five years earlier when that plaque was still being oxidized. Yeah,

00:52:38.480 I understand that for sure.

00:52:39.840 So I think the only way we can use these inflammatory markers is,

00:52:44.020 hey, if ApoB is high, LP little a, two major risk factors, and these inflammatory markers coexist with

00:52:52.320 them, I worry about you perhaps a little more. But that doesn't mean if ApoB is high or LP little

00:52:58.140 a is high and your inflammatory markers are perfect that we dismiss you as, aha, you're the one who's

00:53:03.340 not going to get atherosclerosis because that's not a game you want to play. So that is the weakness

00:53:09.260 of those type of markers. I don't have any other markers that I can tell you to check on inflammation

00:53:15.340 other than there are 10 other subtle, rarely tested inflammatory cytokines and chemokines that

00:53:21.440 can be measured. Same, hey, if your ApoB is whatever and your homocysteine is high, we worry a little

00:53:27.560 bit more about you. We have to maybe attack that because it's modifiable. So I'm not sure what the

00:53:33.600 other markers would be outside of you wait long enough, you're going to get some imaging thing that's

00:53:39.240 positive. Or do we just start respecting ApoB? And that's basically where the lipid world is going

00:53:46.560 and that's where this new concept primordial prevention has come into play. In the old days,

00:53:53.180 it used to be primary or secondary prevention. Hey, you've had a heart attack. Thank God you've

00:53:57.820 survived. We're going to try and prevent the third heart attack, secondary prevention. Or once imaging

00:54:03.020 came along, then we can say, aha, your CTA or your CAC is positive. To me, that's secondary prevention

00:54:10.560 right there. I wouldn't call that primary prevention. So what is primary prevention? You have

00:54:16.680 a high ApoB, you have high blood pressure, but we're not talking about that aspect and what we would do

00:54:22.240 with that today. And therefore, what is primordial prevention? People with physiologic parameters in

00:54:29.320 the lipid and lipoprotein sphere. So we still going to check them because we think at a certain age or

00:54:36.320 depending what else goes on in that person's life, they will enter that primary prevention. And then

00:54:42.320 once that is, if that's defined as escalation of ApoB, then you're going to get into the decision of

00:54:48.200 what sort of therapeutics might we want to offer this person whose ApoB is just slightly high.

00:54:54.760 We don't wait till the ApoB is in the 80th or 90th percentile, because I think if there was a way of

00:55:00.760 getting into those people and looking for this pre-imaging atherosclerosis, we might find it.

00:55:07.360 In some, we would not. There are no doubt there are some people who, just as you said, not every smoker

00:55:13.700 gets lung cancer. There are people with high ApoB who live long and healthy lives, but I don't know

00:55:19.640 what else is going on in their artery wall. And I have no way of measuring that to assure them,

00:55:24.680 aha, you're the exception to the ApoB rule. Well, there's a lot you said there that I think

00:55:29.340 is a great place to go next, but maybe just to finish a little bit of housekeeping, we've now both

00:55:34.280 brought up LP little a at least twice. So I think we've done many podcasts on this, but what would be

00:55:42.260 the three-minute explanation for the person who either needs a refresher or maybe who is new to

00:55:46.600 this and hasn't heard of what LP little a is yet, and why should they care about it?

00:55:50.240 We've defined an LDL particle as a collection of cholesterol, a little bit of triglycerides

00:55:55.440 wrapped by one peptide called apolipoprotein B. In some people who have the genetic machinery,

00:56:02.980 their liver makes another protein called apoprotein small case A. The guy who discovered it thought he

00:56:10.080 discovered a new antigen, A was the signal for antigen, so that's where the little a came about.

00:56:16.820 Again, capital A is the apoprotein A that is on an HDL particle, so there are distinctions between

00:56:24.240 small ApoA and capital A. All right, so if your genes tell your liver protein matching apparatus to

00:56:32.740 produce this ApoA, within the liver, it binds to the ApoB that's on a primordial LDL particle that's being

00:56:41.280 produced in the liver. So now some of your LDLs, apolittle a binds to it, and the liver just secretes them

00:56:49.100 into your plasma. So that's what an LP little a particle is. It's a low-density lipoprotein that is

00:56:56.200 carrying another protein that should never be on an LDL particle. That apoprotein little a has some

00:57:03.000 characteristics that make it extremely atherogenic. Much of it ties into the oxidation that we

00:57:09.840 mentioned before. So if that particle enters your artery wall, whatever oxidative forces are at play

00:57:16.120 are going to get much worse, which is not good as far as atherogenesis is concerned. So if you have

00:57:23.960 these LP little a particles, and it's not a concentration gradient that drives them into

00:57:29.200 your artery wall, that's sort of an inflamed particle carrying some oxidized phospholipage

00:57:35.100 that can be pulled in by receptors that are still not defined, but it can easily get into your artery

00:57:40.560 wall. So it's like, hey, we got a little fire in somebody's backyard, and somebody brings a can of

00:57:46.220 gasoline and throws it on the existing fire. So the atherosclerotic process occurs much more rapidly

00:57:52.640 earlier in life. It's bad news. Now, the good news perhaps is 80% of people don't inherit the gene

00:58:00.300 that makes you produce the sapoprotein little a, but 20% do. Now, people are, 20%, no big deal.

00:58:07.540 Look at 20% of the world population. You're talking billions of people who have what's now recognized to

00:58:14.660 be the number one lipid lipoprotein disorder associated with atherosclerosis. So my goodness,

00:58:22.820 and this is why there's an hour call for it. Let's everybody get that checked once in your life early

00:58:28.000 on, because you either have it or you don't. And if you do have it, then we can start looking at ways

00:58:33.720 to perhaps modify some of the bad news risk that's going to occur with that process.

00:58:38.360 Right now, we can't get rid of the apolittle a particle. That's perhaps coming. There are drugs

00:58:43.900 under investigation to do that. All we can do if we discover this LP little a is look with a

00:58:50.240 magnifying glass at every other risk factor or risk marker you have and do what we can to control

00:58:56.620 those. So LP little a is a bad news, LDL type particle. It's not atherogenic because of the amount

00:59:05.340 of cholesterol it's carrying. It's what I call a minor LDL particle. But particle for particle,

00:59:12.300 it's seven to eight times more atherogenic than an LDL particle. So even now you have way, way,

00:59:18.460 way more LDL particles. An average person might have an LDL-P of 1,200 nanomoles. So you might have an

00:59:27.140 LP little a of 100 nanomoles. And you would say, oh, that's a minor particle. Yes, but if it's eight

00:59:33.320 times more atherogenic than an LDL, it's a bad news particle. Not everybody's a criminal in our

00:59:39.260 country, but it doesn't take a lot of criminals to cause a lot of havoc. So it's a terribly dangerous,

00:59:45.160 inherited type of lipoprotein. That's a great analogy to think about it. You don't need a lot

00:59:50.500 of something that has high virulence and potency to cause a lot of difficulty. Let's pivot for a minute

00:59:55.920 to talk a little bit about something you also touched on briefly, which was that when we're young,

01:00:00.860 we have what's referred to as a physiologic level of ApoB or LDL cholesterol. So the concentration

01:00:09.780 of LDL cholesterol in a child is low. The concentration of ApoB is low. We don't see

01:00:16.520 this very often because we're not used to checking these things in kids, but occasionally you'll even

01:00:21.520 notice it as a parent. If your kid gets sort of a comprehensive blood test, their total cholesterol

01:00:26.300 might be 60 milligrams per deciliter with an LDL cholesterol of 30 milligrams per deciliter and an

01:00:33.380 HDL cholesterol of 25 milligrams per deciliter. I mean, they're very, very low levels of this.

01:00:39.440 Why does this change as we age? Why is it that aging seems to be associated with a monotonic increase

01:00:47.600 in lipoproteins? And this is absent something that we could even get to later if we have time,

01:00:53.360 which is what happens during menopause for women, which is more abrupt, but just talk to me about

01:00:58.380 ages 10 to 50. Why does everybody seem to go the wrong way? Well, a lot of, of course, is the

01:01:05.560 multitude of things we subject our bodies to. If you want to encompass that with the environment

01:01:11.540 or a lifestyle, you quote unquote, whatever, and you can throw probably whatever you want into that

01:01:17.500 category of things that might cause your body to, as ApoB goes up, it's almost all related to your

01:01:25.980 liver is losing the ability to clear these particles out of plasma. It's not like you're overproducing 10

01:01:32.340 tons of them. It can happen, but that's rarely a contributor to the high ApoB levels. So scientifically,

01:01:38.780 we have to zero in on what regulates clearance of these particles. And the simplest thing is to say,

01:01:46.600 well, the only way these ApoB particles get cleared is our liver produces something called an LDL

01:01:51.720 receptor, which migrates to the surface of the liver cell that interacts with the blood flow,

01:01:58.220 the plasma. And these LDL receptors are engineers to recognize any ApoB peptide that floats by it.

01:02:06.320 So if an LDL particle containing ApoB floats by an LDL receptor, it will get grabbed and then it gets

01:02:13.840 internalized into the LDL receptor and it gets catabolized. And then the liver can take whatever

01:02:19.720 cholesterol, triglycerides, fatty acids, blah, blah, blah, is in that molecule and use it for other

01:02:24.860 purposes or somehow get rid of it in the biliary system if the liver doesn't need it. So it's going

01:02:31.340 to come down to what are these factors that I called, hey, environmental or lifestyle that

01:02:36.060 affects what we call LDL receptor expression. And it's a lot of things. One of the things you

01:02:42.120 mentioned before, insulin resistance would affect that. Numerous components of the diet express

01:02:47.780 are you regulating LDL receptors or not, how much cholesterol your liver is being told it needs to put in

01:02:55.480 the next VLDL particle or more importantly, the HDL particle going out. So lipid balance in the liver

01:03:03.320 is regulated by a bunch of things called nuclear transcription factors. They actually sense, hey,

01:03:09.720 the liver needs some lipids or the liver's got too much lipids and we got to get rid of it.

01:03:14.200 Those nuclear transcription factors migrate into the nucleus and the nucleolus of our cells,

01:03:20.840 and they bind to specific parts of the DNA and tell our genes, produce this protein, produce that

01:03:29.320 protein, this enzyme, that enzyme, this receptor, that receptor that can go out and help restore

01:03:35.260 sterile homeostasis to this human body. So probably every adversarial thing you've been told in your life

01:03:42.860 not to do, gain weight, don't eat this, don't eat that, are all affecting these nuclear transcription

01:03:49.640 factors that are going to regulate clearance of these ApoB particles. And it's a long list of

01:03:55.920 things that can probably do that. It is interesting that on average, more of the things that we do that

01:04:02.580 are quote unquote less healthy, whether it be gain weight, eat a certain way, tends to result in

01:04:09.360 decreased hepatic clearance. So on that topic, one of the questions you and I get asked all the time

01:04:16.680 is, look, hey doc, I buy your thesis that ApoB is bad. I buy your thesis that mine is too high and I

01:04:22.460 buy your thesis that I should probably lower it. I'd really like to start with my diet before I turn

01:04:28.840 to pharmacology. Typically there's two things I tell patients here. The first is I think your two best

01:04:34.640 levers nutritionally to reduce ApoB are lowering triglycerides and lowering saturated fat intake.

01:04:44.040 Now, of course, this assumes that you have high enough triglycerides that lowering them further

01:04:49.800 will indeed lower ApoB. And it of course assumes you're eating a high enough amount of saturated fat

01:04:55.340 that reducing it significantly will lower ApoB. So let's assume for a moment that those things are

01:05:00.560 true. We're talking to a patient, Tom, whose ApoB is 100 milligrams per deciliter. You and I have just,

01:05:06.680 I don't want to say read him the riot act, but we've given him the education that says, look,

01:05:10.960 you'd be a heck of a lot better off if you were at 60 milligrams per deciliter. His triglycerides are

01:05:16.160 sitting at about 162 milligrams per deciliter. And when we query his diet, we realize it's pretty

01:05:23.560 high in saturated fat. He's probably getting, call it, I don't know, 40 or 50% of his calories from

01:05:29.180 fat. And he's probably getting 50, 60 grams per day of saturated fat alone. So in other words,

01:05:34.900 he seems like a really ideal candidate if he's willing to switch more of his fat calories to

01:05:40.720 monounsaturated and polyunsaturated, or even just reduce fat altogether. And he's willing to take the

01:05:45.840 dietary steps to reduce total calories and maybe even carbohydrates specifically to kind of bring

01:05:52.140 down his triglycerides. So without getting into how he's going to do that, can you explain why

01:05:57.820 lowering triglycerides and lowering saturated fat intake? Those two things could bring this guy from

01:06:04.640 100 down to 60. Sure. The saturated fat is a little easier to explain. We have plenty of studies that

01:06:12.680 show excess saturated fat, those nuclear transcription factors that are regulating lipid balance in the

01:06:19.120 liver. And the liver is the master controller of lipid homeostasis in the body. It works hand in

01:06:24.480 hand with the intestine, but the liver is sort of the brains of the operation. In many, many people,

01:06:30.780 exposure to saturated fat, the nuclear transcription factors realize, oh my God, fatty acid toxicity is

01:06:36.940 going to occur to this liver. We have to take our defensive mechanisms on that. First thing they do is

01:06:43.000 say, my God, we don't want more lipids being pulled into the liver by these LDL receptors. So the nuclear

01:06:49.780 transcription factors go into your DNA and say, stop making these LDL receptors. Stop sending out

01:06:56.560 the signal that will be translated into an LDL receptor. So of course, if you eat saturated fat

01:07:02.600 and your liver stops expressing LDL receptors, your ApoB is going to go through the roof. What is the

01:07:08.260 ApoB particle carrying cholesterol? And above the threshold concentration, it's going in the artery wall.

01:07:14.720 Typically, if that person does follow your advice and restricts the saturated fat,

01:07:18.960 they will go back to some more increase in their LDL receptor expression.

01:07:24.340 Saturative fat in some people too also turn on the enzymes that induce cholesterol synthesis.

01:07:30.220 Now, if the liver starts overproducing cholesterol, then the lipid pool is out of whack. The same

01:07:35.440 nuclear transcription factors go in and say, stop making LDL receptors. We don't want to pull in more

01:07:40.600 cholesterol into this liver that's oversynthesizing cholesterol. It's another whole story,

01:07:46.160 as you know, Peter, why we don't necessarily tell people you have to restrict cholesterol in your

01:07:50.460 diet. We're talking about saturated fat here. And the absorption of sterols in your gut has nothing

01:07:56.720 to do with the absorption of fatty acids in your gut. Totally different mechanisms that pull them in.

01:08:02.020 The triglyceride story gets much more interesting and maybe much more important because it's so

01:08:08.380 epidemic in the world now. We know triglycerides is a poor man's biomarker of insulin resistance.

01:08:16.960 Two things I wanted to say, if you're measuring triglycerides in the blood, personally, I believe

01:08:22.160 the only things you need to measure in the blood are ApoB and triglycerides. There are basically two

01:08:27.440 categories of hypertriglyceridemia. One is it above 500, 1,000. If it is, you have some crazy genetic

01:08:36.040 disorder that is involved with your high triglyceride. And most of those are not

01:08:40.920 associated with atherosclerosis. But nonetheless, they are associated with pancreatitis and other

01:08:46.220 pathologies. So you would want to lower what's called a very high triglyceride level. But the

01:08:52.140 average doc who's out there doing lipid levels is going to see a triglyceride maybe between 130 and

01:09:00.380 160, 180. So every once in a while, you'll see a 300, 400, but they're less common. That almost is

01:09:07.080 always insulin resistance as the etiology of that through many factors. So once you have too many

01:09:14.020 triglycerides, and where are those triglycerides being made? In your liver. Other cells don't produce

01:09:21.020 triglycerides other than an adipocyte. But if your liver is overproducing triglycerides, the liver says,

01:09:28.880 oh my God, I got to get these out of here. Because if the liver retain triglycerides, you know it's

01:09:32.740 going to get fatty liver. Not a wise thing the liver wants to do. So the liver then packages them

01:09:38.780 into the triglyceride containing lipoprotein, the very low density lipoprotein. Why do we even make

01:09:46.880 VLDLs? What purpose do they serve? Even if you have a physiologic VLDL concentration, it must be doing

01:09:54.260 something once the liver makes it and secretes it. And that is very similar to the big chylomicron

01:10:00.480 particle that comes out of your intestine. These are the triglyceride carrying vehicles that are bringing

01:10:06.320 fatty acids in the form of triglycerides to the tissues that need to grab the triglycerides, convert

01:10:13.260 them to fatty acids, and oxidize those fatty acids to make ATP. They would be our muscle cells. The heart

01:10:20.080 being a very important muscle that you want to keep beating. It's a big consumer of triglycerides.

01:10:26.700 The muscles, the big chylomicrons, the big VLDLs coming out of the liver, they go into beds that

01:10:33.460 express the triglyceride dissolving enzyme lipoprotein lipase, muscular beds or adipocyte beds.

01:10:40.860 The triglycerides are hydrolyzed to fatty acids. They enter those muscular beds and then they can be

01:10:45.780 oxidized for ATP. And in adipocyte, the fatty acids are pulled in, reconverted to triglycerides

01:10:52.220 and stored for future energy needs. So that's what VLDLs do. But if you have way more triglycerides

01:11:00.460 in your liver because you're insulin-resistant and your liver is overproducing them, the liver makes

01:11:06.640 very big VLDL particles. Earlier on, I talked about, hey, there are certainly NMR signatures of

01:11:13.260 insulin resistance. The big VLDL is one. A normal person with physiologic triglyceride never makes

01:11:19.660 big VLDL particles. There's no need for them. That person makes smaller VLDL particles that carry

01:11:25.780 just enough trigs to be sufficient for energy needs of the muscle. But in an insulin-resistant person

01:11:32.000 with high triglycerides, here come these big particles out. Now, insulin resistance is not only

01:11:38.520 associated with too much triglycerides. There's another apoprotein that is made in excess and it's

01:11:44.120 called apoprotein C3. So the VLDLs coming out of the liver are now carrying something they shouldn't

01:11:51.100 carry very much of, apoc3. Make a long story short, it retards the catabolism of these triglyceride-rich

01:11:59.260 VLDLs. So it blocks their attachment to lipoprotein lipase. So the plasma residence time of a VLDL or

01:12:08.740 chylomicron, which should be extremely short, is now prolonged. What is the consequence of letting

01:12:14.940 these triglyceride-rich VLDLs float around longer than they should? Number one, if you measure

01:12:19.980 triglycerides in the blood, it's going to be higher than it ordinarily would be. And that's why

01:12:24.660 if you look at a certain triglyceride level, you might suspect this is happening. But here's the

01:12:30.400 continuing bad news. When these triglyceride-rich VLDLs are floating around in plasma,

01:12:36.600 they bump into the much, much, much more numerous LDL and HDL particles. And what happens? We carry a

01:12:45.540 lipid transfer protein that actually locks LDLs and HDLs into VLDLs or LDLs into HDLs.

01:12:53.920 It's called cholesterol ester transfer protein, CETP. It really should be called CETTP,

01:13:01.720 cholesterol ester triglyceride transfer protein. Because what happens is when these two particles,

01:13:08.360 my joke is they're mating because they're now connected with this little canal,

01:13:13.020 they exchange one molecule of triglycerides for one molecule of cholesterol. In essence,

01:13:19.120 the VLDLs and chylomicrons become triglyceride poorer but more cholesterol rich, whereas the LDL

01:13:27.160 and the HDL become cholesterol poorer and triglyceride rich. Any doctor who does a lot of

01:13:33.840 lipid profiles knows, yeah, you're right, Tom. I notice every time triglycerides goes up, LDL cholesterol

01:13:39.860 doesn't necessarily go up. But almost assuredly, HDL cholesterol goes down. And that's because HDLs,

01:13:47.740 which should really carry almost no triglyceride molecules, have now sucked in a lot of trigs,

01:13:54.820 but they've given up cholesterol. If we were measuring HDL triglyceride levels, we would see

01:13:59.920 it's very high. But we just see the HDL cholesterol is low. The last step, what happens to any triglyceride

01:14:07.140 rich particle? There are lipases ready to dissolve it. Endothelial lipase and hepatic lipase attack

01:14:14.220 triglyceride rich HDLs. By extracting and hydrolyzing the trigs, the HDL particles become so small,

01:14:21.860 they break apart. ApoA1 goes down to the kidney where it can be catabolized into amino acids and

01:14:27.740 excrete it. Hence explaining why diabetics, people with high trigs have such low HDL particle counts and

01:14:34.880 low HDL cholesterol. But basically, here's what happens to the LDL now. The LDL is sending

01:14:41.540 cholesterol in exchange for triglycerides to the VLDL or the chylo. So the little LDL particle,

01:14:48.600 much smaller than those monsters, becomes triglyceride rich and cholesterol poor.

01:14:54.620 So what is the fate of that type of LDL? If we could only measure LDL triglycerides,

01:15:00.000 it would be by far the best lipid metric we could ever measure.

01:15:04.360 So Tom, it seems like the reason ApoB is going up in a high triglyceride environment

01:15:12.940 is because you need more LDLs to carry the same amount of cholesterol ester because so much of

01:15:22.920 their carrying capacity is going towards also managing the transport of triglycerides. And

01:15:31.080 therefore, while LDL cholesterol might remain constant, it's being spread out over more particles.

01:15:38.780 Therefore, ApoB, which is the marker of particle concentration, is going up. And of course,

01:15:44.200 that's the metric that matters. This, of course, is the classic example of where we see discordance

01:15:50.140 between LDL cholesterol and ApoB particle concentration.

01:15:53.380 So we were talking about the triglyceride rich LDL particle. And what happens is the lipase is mostly

01:16:01.500 hepatic lipase takes the trigs out and then the LDL particle becomes very small. So you have a small

01:16:09.900 LDL particle, which per particle can't carry many cholesterol molecules. But the major reason ApoB goes

01:16:17.680 up is an LDL that is small. The ApoB assumes a different confirmation on the surface of the LDL

01:16:25.020 and it is no longer recognized by the LDL receptor. So you have markedly delayed clearance of the small

01:16:32.000 LDL. So yes, whether your LDL cholesterol goes up or not, the cholesterol is spread among more LDL

01:16:40.600 particles because they can't be cleared anymore. So that is why lifestyle can work very good.

01:16:46.920 Anything that lowers trigs can interrupt this pathologic lipolysis or catabolism of these ApoB

01:16:54.060 particles. If we could make those small LDLs disappear and they would assume they're more

01:16:59.780 circular shape, they conform to the LDL receptor more. So this is why if you look at the ApoB or even the

01:17:08.340 LDL particle count in diabetics, it's through the roof or in people with high triglycerides,

01:17:13.920 due to mostly decreased clearance, so the LDL goes up. But what's driving the total LDL? It's the small

01:17:23.040 LDL. They would have some large LDL still floating around. There's never going to be anybody who has

01:17:28.860 100% small or 100% big. But the predominant species when triglycerides goes above a certain

01:17:35.360 threshold is the cholesterol-poor small LDLs that have decreased clearance. So ApoB goes up. When ApoB

01:17:43.700 goes up, where do these small particles go? It's an ApoB particle. It crashes the artery wall with

01:17:48.980 relative ease. So that's the basic explanation there. The other thing I should tie into this,

01:17:55.000 at what level of triglycerides can this occur? The silly guidelines have put, hey, a triglyceride of

01:18:01.080 150 above is where it's high risk. And that's what the average practitioner or patient believes

01:18:06.240 because that's what the labs report on the lipid profile. This transformation that starts to delay

01:18:12.000 the lipolysis of these particles occurs somewhere at a triglyceride 100 or above. You don't have to

01:18:19.860 have a trig of 150. That's the 75th percentile of a population triglyceride distribution. My God,

01:18:26.940 we don't wait for any other lipid metric to hit the 75th percentile. So I'm not sure why they still do

01:18:33.440 that other than perhaps they didn't have enough to tell people what to do about it. But you and I know

01:18:39.520 when we look at it at the lipid panel, we're a little nervous when tricks start to go much above

01:18:44.720 80, nevermind 100 to 120. I often use myself an example. I've been a lifelong, very insulin-resistant

01:18:53.020 guy. Always had a pretty decent LDL cholesterol. My trig was always in the 102, 105 range, which I

01:19:01.380 dismissed as being normal. But of course, once NMR came around, I saw, oh my God, look at your LDL

01:19:08.100 particle concentration. Look at the number of small LDLs. And this is why triglycerides cannot be

01:19:15.000 unlinked from ApoB2 because the real pathology of high trigs, it's just creating too many cholesterol

01:19:22.020 carrying particles that can invade the artery wall. It's not triglycerides in the artery wall that are

01:19:27.500 generating atherosclerosis. It's the delivery of cholesterol. But as trigs go up, you have a lot

01:19:33.440 more ApoB cholesterol carrying particles. Even though each particle is carrying lesser numbers of

01:19:40.320 cholesterol than before, there's just many more of those LDL particles that are crashing your artery

01:19:46.640 wall. When we do come up with a way to lower triglycerides nutritionally, or even if we wanted

01:19:52.500 to use a drug, virtually every single one of our lipid-modulating drugs is FDA-approved to lower

01:19:59.060 triglycerides. You can't look at it and say, oh, I've lowered your trigs from 0.X to X minus whatever.

01:20:06.400 You have to lower ApoB to see event reduction with trigs. Now, most of the time when you lower

01:20:12.780 trigs with proper therapies, lifestyle or drugs, you will see a drop in ApoB. But there have been

01:20:18.600 several trials that dramatically lowered triglycerides with the fibrates that did not reduce MACE

01:20:24.420 because although they dramatically lowered triglycerides, they're not the greatest ApoB-lowering

01:20:30.400 drugs in the world. So, respect triglycerides at much lower levels than you've ever been taught.

01:20:37.120 But your goal of therapy, be it lifestyle or drug, is did I normalize ApoB?

01:20:42.560 I think that's a very important point, which is it's always worth taking a shot at modifying your

01:20:48.380 nutrition to fix ApoB, but don't forget the goal. The goal is lowering ApoB. We have these two

01:20:55.620 proxies that are quite helpful. Triglycerides, if they're high, great, great way to approach.

01:21:03.560 Usually, in most people, caloric reduction is the key of doing that. And therefore, if you have a

01:21:08.600 person who's eating a lot of saturated fat, a lot of carbohydrates, low-quality carbohydrates,

01:21:13.940 sugars, hypercaloric, that person can actually do a lot of ApoB reduction with nutrition.

01:21:20.780 And conversely, when you see a person whose trigs are 50 milligrams per deciliter, who's not

01:21:26.460 mainlining saturated fat and eating in relatively normal amounts, I typically advise those people

01:21:32.300 against draconian fat reduction, which admittedly will indeed lower cholesterol, but often comes at

01:21:40.240 the consequence of something else nutritionally. And so, we tend to steer clear of that and save that

01:21:45.360 for people who have an obvious reduction. I think this point, by the way, about the conformational

01:21:50.360 change in the relationship between the LDL receptor on the liver and the LDL particle is a very

01:21:56.540 interesting one. Of course, it begs the question, Tom, do we believe that LDL particle size should be of

01:22:07.060 concern, given that you just acknowledged that these smaller cholesterol-depleted LDL may linger longer,

01:22:16.740 or can we largely ignore that if we have a good handle on ApoB? In other words, is all of the risk

01:22:24.140 of everything you just discussed captured in the ApoB marker?

01:22:29.800 Yes, but if you were doing everything you say nutritionally or pharmacologically to do it,

01:22:35.060 you would see a transformation of those small LDLs. You wouldn't find them anymore, and you'd have

01:22:40.600 a normally sized and ApoB-composed particle. But what I should introduce into this discussion is

01:22:47.200 the nonsense going out there that these big LDLs, often called fluffy-buffy, are cardioprotective.

01:22:54.540 But guess what happens on a big LDL? The ApoB gets distorted on the big LDL, too, and those particles

01:23:01.500 are far less compliant to the LDL receptor. It's one of the reasons people with FH have such,

01:23:07.420 because they all have very big particles. And their high ApoB is due to defective LDL receptors,

01:23:14.700 but it's also due to defective attachment to LDL receptors, because the ApoB is no longer in the

01:23:21.060 proper conformation. And the last thing I'm always going to sneak in on this triglyceride topic,

01:23:26.260 I did mention it's the chylos and the VLDLs that carry trigs. They're the big triglyceride-carrying

01:23:32.480 particles. Yes, they screw up the HDLs and LDLs by sending trigs over there, but normally those

01:23:39.500 particles should deliver the trigs to the muscle cells where they lose trigs, and then they get

01:23:45.300 smaller, the chylos and VLDLs. Smaller chylos and VLDLs are called remnant VLDLs or chylos.

01:23:52.300 But when they shrink, the main reason they get cleared from the body is they carry multiple copies

01:23:59.600 of apolipoprotein E. And ApoE is the apoprotein on VLDLs and chylos that binds to a very specific

01:24:08.780 hepatic receptor in the LDL receptor family called LRP, LDL receptor-related protein.

01:24:16.760 But when ApoB is on big VLDLs and chylomicrons, it's contorted. It doesn't bind to the LRP.

01:24:23.000 But once the chylos and VLDLs shrink down, the ApoB assumes a conformation, and that's why their

01:24:29.620 plasma residence time is so short. It's all ApoE-mediated. And each of those particles carry

01:24:35.560 several copies of ApoE. But in some resistance where the VLDLs and chylos can't get rid of their

01:24:43.240 trigs, then these people have what is called increased remnants. Now, they're nowhere near the

01:24:50.900 particle number of remnants. It doesn't even come close to an LDL particle number, but it's up way

01:24:57.460 more than it should be. And particle for particle, remnants carry five to six to seven times more

01:25:04.480 cholesterol per particle than an ApoB LDL particle. So if you let these remnants float around, they get

01:25:11.020 pulled into the endothelium. They're a very inflammatory particle in part because of the ApoC3 on

01:25:16.800 they get internalized easily into the artery wall, which is another reason people with high

01:25:21.860 trigs have so much atherosclerosis. It's not only because they have too many LDL particles,

01:25:27.300 they got too many remnants. And if they're losing HDLs, if HDLs perform a cardioprotective function by

01:25:34.460 extracting cholesterol, they no longer have enough HDLs to do that. That's why you and I get very

01:25:41.480 nervous when we start to see trigs exceeding 100 because we assume some of these pathological

01:25:47.620 pathways are at play. A couple of very important points there, Tom. The first is, yeah, it's true

01:25:54.120 that the remnants, just like the LP little As, are captured in the ApoB concentration, but it's almost

01:26:01.600 like you have three populations, for lack of a better term, really four populations that are buried

01:26:08.300 within ApoB. You have the majority of them, which are LDLs. You have VLDLs, your garden variety VLDLs.

01:26:16.040 You have your LP little As, if you have too many of those. And then you might have too many remnant

01:26:21.620 VLDLs. And of these four, it's that remnant VLDL and the LP little A that pack more of a punch

01:26:30.300 than their counterparts, the regular garden variety VLDL and the LDL. And so this is where I think ApoB

01:26:37.780 by itself can be a bit misleading. In other words, you could have two people that both have an ApoB

01:26:44.180 concentration that's identical. But if one of them has it in the context of basically it's all LDL

01:26:51.500 cholesterol and some VLDL, yeah, they're okay. And then the other person might actually have a

01:26:58.400 disproportionately high LP little A and or remnant concentration. And you won't know that unless

01:27:04.340 you're doing some of this additional analysis. Is that a fair rationale for saying why we want to

01:27:09.380 look at everything?

01:27:10.740 Yes. So you measure LP little A, that's easy. And you see, it's not a major contributor to ApoB,

01:27:16.860 but it's a terribly atherogenic particle. So we get nervous with it. With the VLDL particles,

01:27:23.620 measuring ApoB tells you nothing about the number of VLDLs have. Because although they can be

01:27:28.340 particle for particle more atherogenic, there's not very many of them. So what's a poor doctor do?

01:27:34.900 Here's my little pearl. So there's another metric people should look at. It's called non-HDL

01:27:43.060 cholesterol. Think of what that means. That's the cholesterol that's not in your HDL particles.

01:27:48.460 In essence, it's your ApoB cholesterol. So how would I know if your ApoB cholesterol is up?

01:27:55.100 I can't look at ApoB. But if I did that calculation, non-HDL cholesterol, if your ApoB is looking good,

01:28:04.080 but non-HDL cholesterol is still a little high, I'm suspecting you got some of them remnant VLDL

01:28:10.260 particles floating around. Now, it's not 100% true, but it's about the only thing you can do. There are

01:28:16.220 no accurate remnant tests that are available to the run-of-the-mill doctor. So look at non-HDL

01:28:23.060 cholesterol. And by the way, for the listeners, that's a freebie on the lipid profile. It's

01:28:28.160 basically total cholesterol minus HDL cholesterol. So that means it's the cholesterol that is in your

01:28:35.040 VLDLs and LDLs. So if your LDL cholesterol, ApoB is looking good, but your VLDL cholesterol is still

01:28:42.540 high, that would drive non-HDL cholesterol to be higher than it should. And that's why Peter and I

01:28:48.740 also have very aggressive goals for non-HDL cholesterol also. We don't always discuss

01:28:54.420 it with the patient, but we would if it was still elevated within the face of a normal ApoB.

01:29:00.080 All right. Let's talk about HDLs, the most confusing of the lot. Now, we've already done

01:29:09.400 dedicated podcasts on this topic. We've spoken at length about this. So we're not going to be able

01:29:15.840 to obviously cover this in too much detail and we'll point people back towards the previous podcast

01:29:20.140 where I've done this, but you've already alluded to the fact that HDLs can be protective. This has

01:29:26.200 led many people to refer to HDL as the so-called good cholesterol. And if your quote unquote good

01:29:32.740 cholesterol is high, eh, you don't need to worry about anything. I'm not going to ask you to debunk

01:29:38.000 that because the tone of my question already suggests that that's nonsensical.

01:29:41.620 So let's have a modest but brief discussion on how HDLs work and why is it that when they're

01:29:49.700 functioning, they can be quite protective, but at the same time, maybe say a word about why

01:29:54.740 unfortunately we can't figure this out or discern this from blood tests.

01:29:59.820 Yep. And it's so important and it's so unknown out there in the real world. And in the layman's

01:30:05.200 world, it's probably not known at all because they keep reading these idiotic missives in newspapers

01:30:09.960 or magazines that, boy, check your good cholesterol. And even if it's high, you don't have to worry

01:30:16.300 about your bad cholesterol, LDL. It's so sad. Even sadder that some providers still believe this and

01:30:23.400 tell their patients that. So basically what we say very quickly to any patients is as we're teaching

01:30:30.200 them about lipoproteins and what they do and what they carry, we get to a point where we say we're not

01:30:35.260 going to talk about HDLs anymore. Now, don't get me wrong. HDL particles are incredibly important to

01:30:41.760 both your cardiovascular system and probably many other tissues in your body. And that means HDLs

01:30:48.780 perform a lot of functions that, especially with the heart, may be very cardioprotective.

01:30:55.680 We also know that some people have the type of HDLs that don't perform those cardioprotective

01:31:01.180 functions. They actually perform bad functions to the artery wall and plaque and the heart. So

01:31:07.880 the important thing is you can understand, boy, what HDLs do, let's call that HDL functionality.

01:31:15.440 And to make a long story short, whether your HDLs are doing those cardioprotective functions or

01:31:20.740 they're doing bad things to your vasculature, whatever they're doing has zero relationship to

01:31:27.640 their cholesterol cargo, meaning your HDL cholesterol level in the blood. There are people with low HDL

01:31:34.340 cholesterol, often a signal for a high cardiovascular risk, but not everybody. And there are people with

01:31:41.660 very high HDL cholesterol have been told they're protected, and we know they are not. A group of

01:31:47.600 them gets atherosclerotic disease. A group of them have been described with breast cancer, dementia.

01:31:53.320 So obviously, you can't look at an HDL cholesterol in an individual patient and make extrapolations

01:32:00.680 on what the heck the HDLs are doing in that person. The reason HDLs have these either miraculous or

01:32:08.920 disastrous properties comes down not to their lipid content, certainly not their cholesterol content,

01:32:15.400 but to two things. Their protein content, over 150 proteins have been found to be associated with

01:32:24.020 various HDL particles, and they perform an immense number of likely very necessary actions that need

01:32:32.160 to go on in certain tissues where things may be going wrong. We also know that the coat of an HDL,

01:32:38.900 apart from its proteins, is virtually all phospholipids. So the exact phospholipid concentration of an HDL

01:32:46.740 surface has tremendous amount to what to do. Can an HDL do wonderful things or bad things? Those

01:32:54.280 phospholipids really determine what an HDL can bind to in various tissues. Now, of course, we can't measure

01:33:01.960 HDL phospholipid content. There are hundreds of phospholipids. You would get a lipid dome coming back that

01:33:08.280 you couldn't even pronounce half of the phospholipids or at least the fatty acids that are in those

01:33:13.040 phospholipids. And same with the protein. If there's 150 of them, I guarantee the average doctor

01:33:18.620 might be familiar with about 10 of those proteins and not with the rest of them.

01:33:23.440 So I don't know how to determine a patient's HDL functionality. Clearly, the people having adverse

01:33:30.700 effects with high HDL cholesterol have dysfunctional HDLs probably related to that proteome

01:33:37.060 or their phospholipid content and vice versa. So what we tell a person right now is, in the year

01:33:45.020 2024, we didn't always believe this. This bad cholesterol had an origin that everybody believed

01:33:51.160 way back when. Framingham, Mr. Fit, the earlier observational trials, nobody ever adjusted for

01:33:57.960 APLD in those trials. It wasn't even available when they were doing it. So we now know that the people

01:34:03.740 with low HDL cholesterol who do get atherosclerosis always have high APL-B. And why? Why do those

01:34:10.800 people have low HDL cholesterol? I've already told you it's the trigs that knock the HDL. And the

01:34:15.860 trigs may not be 400. The trigs may only be 130, which are being ignored. And what is high in them?

01:34:21.700 APL-B. So the proper treatment of low HDL cholesterol in the person you believe has cardiovascular risk is

01:34:28.560 just like trigs, lower APL-B, lower non-HDL cholesterol if you can't get an APL-B.

01:34:34.680 If somebody has a high HDL cholesterol, I don't know what blood tests to tell you. I would always

01:34:39.160 check an APL-B. We do that in 100% of people. And if it was high, we would treat APL-B regardless of

01:34:45.260 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

01:34:50.640 high HDLC who might wind up with dementia or some cancer or something. I don't know. So we'll track those

01:34:57.420 other diseases with other modalities that we have at our beck and call. I don't know what to tell you

01:35:02.660 about your cardiovascular health if you have high HDLC, but I can guarantee you it is not a

01:35:07.140 declaration of cardiac immortality. So it's HDL functionality. And you recall we had a nice

01:35:13.340 email exchange about a friend of mine who I've known for many years. He's always had a very high

01:35:18.240 HDL cholesterol and a very low LDL cholesterol. In fact, his HDL has routinely been above 100 milligrams

01:35:24.980 per deciliter and his LDL cholesterol has always been below 100 milligrams per deciliter. So this

01:35:30.760 is a guy that by anybody's metric looks like he's in tip-top shape. But I did suggest to him at one

01:35:37.360 point, it would be reasonable to at least do a calcium score because I've seen these case studies

01:35:43.920 of individuals with high HDLC, low LDLC who still end up having atherosclerosis. And it can be quite

01:35:49.400 aggressive because it could be that that high HDL cholesterol is actually a marker of dysfunctional

01:35:54.720 HDL that are having a difficult time clearing it. To make a long story short, he ended up having

01:35:58.360 quite a high calcium score. And so now he's on very aggressive treatment to take any residual risk

01:36:03.660 out of that ApoB. So he's on double therapy now, and he walks around with an ApoB in the 20 to 30

01:36:09.460 range. And hopefully that's going to be sufficient to retard this. But again, always a great story.

01:36:14.200 I remember you sharing that case with me and I, my God, why the heck did you do a CAC?

01:36:19.620 See, because you've heard me spout enough, you learned your lesson. I don't use HDLC to make

01:36:25.900 any decision. Yeah. I distinctly remember reading a case study 10 years ago about a woman who looked

01:36:31.100 just like that and ended up having very advanced atherosclerosis. Let's pivot and talk about the

01:36:38.440 brain a little bit. This is an area where your own knowledge has grown rapidly, Tom. This is clearly

01:36:45.840 an area of immense curiosity for you, for me, because cholesterol plays an important role in

01:36:51.880 the brain, I think, to put it mildly. And people have many questions about the role of cholesterol

01:36:57.420 lowering therapy and brain health. So let's just start with a basic question, which is what role

01:37:02.800 does cholesterol play in the brain? And what do we know about the different pools of cholesterol?

01:37:08.340 We have cholesterol outside of the central nervous system, cholesterol inside the central nervous

01:37:12.960 system. Can they move back and forth? Can lipoproteins go back and forth? Is LDL taking

01:37:18.040 cholesterol into the brain and back? Tell us about how that whole system works.

01:37:21.540 So important. I'm glad we're going to chat about this a little bit. And it's obviously so complex.

01:37:26.880 Really, I'll almost give you credit. You're the guy who got me interested in lipids in the brain

01:37:31.300 probably 15 years ago when you introduced me to Richard Isaacson at the Cornell Dementia Clinic.

01:37:37.220 And he was very interested in lipids because he just knew lipids are part of what's going on in the

01:37:42.440 brain. And I better learn more about lipids. And you were good buddies. And I got pulled into that

01:37:47.220 circle.

01:37:47.780 I like how you said dragged initially. I mean, pulled slowly. Yes.

01:37:53.640 Well, you're a strong guy, Peter. You've motivated me to study a lot of things that

01:37:58.780 maybe I wouldn't have tripped into. And I would have ever met a Richard Isaacson had it not been

01:38:03.360 for you. But thank God you did. And so we've been trying to learn about brain and the lipids

01:38:08.520 so often. The last thing I'll say, you did that great podcast with Dan Rader on HDLs. And it's a

01:38:15.540 podcast everybody should listen to. At the end, you sort of turned to Dan. You said, where are we

01:38:20.480 going with lipids, Dan? We've solved the ApoB. We're learning a lot now about HDL. And Dan said,

01:38:26.300 it's lipids in the brain is the next frontier. And why has that not been studied very much until now?

01:38:32.280 Because you can't stick a needle. You have to go into the cerebral spinal fluid to analyze what's

01:38:38.880 going on in the brain. And most people are amenable to a venipuncture in their elbow,

01:38:43.360 not a spinal tap. So here's what's going on. Cholesterol is almost certainly the most important

01:38:49.900 molecule in the brain. The brain is by far the most cholesterol-carrying organ in the body.

01:38:56.100 The brain actually makes more cholesterol than any other organ per se, way more than the liver even.

01:39:03.220 So if I gave you a dumb question, I got this body here and I want to find out where all the

01:39:07.940 cholesterol is, where should I go? Open his skull and take out the brain. That's where you're going

01:39:12.400 to find the most cholesterol. Wow. So obviously cholesterol is crucial to the brain. And that's

01:39:18.480 because the brain is made up of a lot of cells, all of which have important functions, especially

01:39:23.520 those neurons that shoot off all the action potentials that make our body function and

01:39:29.380 everything. And what's on the surface of a neuron? Free cholesterol and phospholipids.

01:39:35.600 So evolution, I guess, figured out a long time ago that the brain needs cholesterol. So we're not going

01:39:42.240 to make the brain dependent on cholesterol that's floating around the plasma or what's in your liver or

01:39:47.840 your intestine. We're going to let the brain make all the cholesterol it needs. So we're going to

01:39:54.040 really drive the enzymes that synthesize cholesterol in the brain. So the brain needs cholesterol. To make

01:40:01.720 a long story short, every cholesterol molecule that's in the brain got there by de novo synthesis in the

01:40:07.680 brain. Not a single molecule of cholesterol was delivered from the periphery, meaning that floating

01:40:14.040 around our plasma leaves the plasma and enters the brain. Now, by the way, where is all the

01:40:20.140 cholesterol in our plasma? I've already told you it's got to be inside of a lipoprotein floating in

01:40:25.500 plasma. That's where we measure cholesterol. That's where we measure lipids in the plasma. But I can assure

01:40:31.700 you there is no cholesterol carrying particle in the plasma, be it a VLDL, an HDL, or an LDL, that crosses

01:40:40.000 the blood-brain barrier and says, okay, brain, here's your cholesterol for today. Doesn't happen.

01:40:46.720 There is a rapid turnover of cholesterol in the periphery. Cells make it. They get rid of what they

01:40:52.380 don't need. It's brought back to the liver for the liver to decide what to do with it. The turnover

01:40:58.020 time for cholesterol in the plasma is two to three days. So if a cholesterol molecule is synthesized in

01:41:04.680 the brain, what is its half-life? Five years. Now, half-life, if a half-life is a given number,

01:41:12.060 the total brain residence time of that cholesterol molecule is you multiply that by seven. So some

01:41:18.280 cholesterol molecules last up to 30 years once they're synthesized in the brain. And that's why

01:41:24.640 cholesterol synthesis in the brain starts in utero. Early on, mom's supplying the little fetal brain

01:41:32.740 with a lot of cholesterol. But very rapidly, second, third trimester, those brain cells start

01:41:38.720 making their own cholesterol. Once a child is born, there's a lot of cholesterol synthesis going on by

01:41:46.560 virtually every cell that exists in the brain. There's only like three of them. But at a certain

01:41:51.620 point, somewhere between the ages of five and 10, the brain has made all the cholesterol it needs.

01:41:56.940 So then only two cells continue to make cholesterol. So lesson number two, what are the cells in the

01:42:04.140 brain that we're in this conversation with? Neurons I've mentioned. In utero and in childhood,

01:42:10.700 neurons produce a lot of cholesterol. But at a certain age, the neurons got more work to do.

01:42:16.920 They don't want to make cholesterol. Why? Because every cholesterol molecule requires 27 molecules of

01:42:23.600 ATP to produce. It's a super energy-driven process. Neurons need ATP for a lot of other functions,

01:42:31.180 those electrical charges they make. All right. So what are the other two cells in the brain?

01:42:38.060 Oligodendrocytes make the most cholesterol. And where does the cholesterol they make become?

01:42:43.320 Myelin, which coats every nerve ending, every axon and dendrite in your body.

01:42:48.360 Those oligodendrocytes are big-time cholesterol producers. But they make all their cholesterol go

01:42:55.160 to myelin. They don't send any cholesterol over to neurons. So what is the other cell? And it's

01:43:01.340 astrocytes. In infancy and childhood and utero, oligodendrocytes, astrocytes, and neurons are

01:43:08.300 making cholesterol. Let us know tomorrow. Once the neuron stops making it, astrocytes are the

01:43:14.740 soul maker of cholesterol that supplies the neurons. But how would an astrocyte synthesize

01:43:21.400 cholesterol and send it over to the neurons? Aha! The brain has to have a lipoprotein system,

01:43:27.740 just like the periphery does. Now, between astrocytes and neurons, basically it's brain

01:43:35.060 interstitial fluid, sort of a loose connective tissue. It's called the matrosome.

01:43:40.460 So if astrocytes synthesize cholesterol, they obviously have to package it inside of a brain

01:43:46.800 lipoprotein, secrete that lipoprotein, which swims through the matrosome and goes over.

01:43:53.020 And guess what the neuron expresses? LDL receptors, LDL receptor-related protein,

01:43:59.600 or something called the scavenger receptor, all of which can bind to the type of lipoprotein that an

01:44:05.880 astrocyte produces. So the brain also has a lipoprotein delivery system, but here's the

01:44:12.400 difference. What is the main structural protein in the periphery? ApoB or ApoA1? What is the main

01:44:19.800 structural protein in the brain? ApoE. So when an astrocyte makes a lipoprotein, it's an ApoE

01:44:27.520 containing lipoprotein. And by the way, they're smaller, much smaller than the particles that we find

01:44:33.480 in the periphery. If we put them in a centrifuge, they have the density of a high-density lipoprotein

01:44:41.040 that floats around the periphery. So they're often called brain HDLs, but don't confuse brain HDLs

01:44:48.160 with peripheral HDLs, because most of the brain HDLs have ApoE as their structural protein. In the

01:44:55.200 periphery, they have ApoA1. Here's where the story gets a little more complicated, as always.

01:45:01.420 What is the smallest ApoA1 protein the body can make? It's actually ApoA1, which is why an HDL needs

01:45:08.440 four or five of them. So if ApoA1 can dissociate from an HDL, and we do have free HDL in the plasma,

01:45:16.680 that's measurable, it is small enough that it can cross the blood-brain barrier. And once it joins

01:45:23.240 the blood-brain barrier, what is the small ApoA1 looking for? An HDL buoyancy particle.

01:45:30.600 So it joins with the ApoE particles. So the brain lipoproteins are all ApoE, or they're all ApoE plus

01:45:39.600 ApoA1. And you can have multiple copies of each of those on those particles. So now, as long as the

01:45:46.540 ApoA1, by the way, which can bind to an LDL receptor or the scavenger receptor, same with the ApoE,

01:45:53.560 the neuron can grab them and either internalize them or delipidate them, and the neuron gets its

01:45:59.740 cholesterol, and the neuron's happy. And then the delipidated particles can go right back and fill

01:46:05.360 up at the astrocyte again. So that's brain cholesterol transformation. But Peter, I know

01:46:11.220 you check ApoE genotype on your patients, and you do worry when certain ApoE genotypes come back,

01:46:18.400 especially those carrying the E4 allele. Because we know that's associated with AD,

01:46:23.940 and we have enough knowledge to know that, God, those brain apoproteins, the brain HDLs carrying

01:46:29.720 ApoE4 are, guess what, dysfunctional HDLs. Just like we've discussed, you can have dysfunctional HDLs

01:46:36.180 in the plasma. So if your brain makes ApoE4 instead of ApoE3 or ApoE2, you are not going to have the best

01:46:45.300 brain HDL particles. And not only do brain HDL particles carry cholesterol back and forth,

01:46:52.440 if amyloid or tau is being produced in a neuron, they can grab it and transfer it over to microglia,

01:47:01.040 which are brain immune cells, which can get it and take it down and get rid of it in the brain

01:47:05.520 lymphatics. So your ApoE genotype certainly affects our VLDLs and chylos in the plasma.

01:47:14.040 That's a lecture for another day, because that's not that common. But in the brain, the ApoE4,

01:47:19.880 you only have ApoE containing lipoproteins, so you don't want to have it.

01:47:24.660 I just want to make sure people aren't confused on that point. So definitely people listening to us

01:47:29.160 are familiar with the ApoE4 gene. But just to reiterate, you're going to have two copies of

01:47:34.920 these genes, just as you do for every gene. This is a gene that exists in three isoforms. So none of

01:47:41.820 these are considered mutations, meaning there are three types that occur in nature, the E2,

01:47:47.160 the E3, and the E4 isoform. So you have six combinations of these, and therefore three of

01:47:55.040 these combinations include at least one copy of an E4. So there's the 2-4, the 3-4, and the 4-4.

01:48:02.820 So we know epidemiologically that there's a clear increase in the risk of Alzheimer's disease

01:48:09.060 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

01:48:17.200 of going back and forth between the gene and the protein. If you have an E4 gene or a E3,

01:48:25.020 gene or a 2 or whichever combinations you have, you still make an ApoE protein. What is different

01:48:32.240 is what the protein looks like in response to the gene. And what's very interesting is,

01:48:39.200 if my memory serves me correctly, I believe it's only a single amino acid substitution between each

01:48:44.680 of these. In other words, one amino acid difference between the one made by the 3-isoform and the 4-isoform

01:48:52.220 results in what you just said, which is individuals who have the ApoE4 gene have an ApoE4 protein that

01:49:01.180 wraps their brain lipoproteins that gives it less affinity for doing this job of transferring

01:49:09.620 cholesterol from astrocytes to neurons. So this is a very important explanation of why it is that people

01:49:18.040 with an ApoE4 gene are at an increased risk. This is not to say it is a causative gene. It's not a

01:49:25.080 deterministic gene. It's not a gene that if you have a copy or two copies of the ApoE4 gene, you're

01:49:29.820 going to get Alzheimer's disease. This just explains why there's a greater susceptibility and why an

01:49:34.440 individual who has one or two ApoE4 genes needs to work that much harder on all of the other variables

01:49:42.040 that factor into AD. And again, to your point, why does this not really play as much of a role in the

01:49:48.440 periphery? We could save that for another day, but it sort of does in the edge cases. And that's why we

01:49:54.500 see a higher incidence of ASCVD and ApoE4 carriers. You did already allude to it, but only the astute

01:50:01.820 listener will remember it when you talked about the ApoE and the conformational change of lipoprotein.

01:50:06.400 I'm not going to go back to it because I want to stay on the brain. But anyway, I just wanted to

01:50:09.860 interject that point so people knew the relationship between the genotype and the phenotype of the

01:50:14.180 structural protein. Very much. And even that single amino acid change just affects the shape of the

01:50:21.260 protein. So it no longer binds where it should, and it screws up its so-called functionality of

01:50:27.580 the particle. One amino acid in a peptide, you wouldn't think, but it's true. Now there's one other

01:50:33.260 part of the brain lipid story, and it gets deeper. And remember, in the brain, we're on our infancy.

01:50:38.700 So much of what I'm going to tell you now is not carved in stone in the discussion,

01:50:43.240 but it's how we understand it in September, October, November of 2024. So it's the cholesterol

01:50:51.120 story. We know if the brain can't get rid of cholesterol, that is associated to one of the

01:50:58.060 characteristics of people with dementia or Alzheimer's disease. So there comes a point where

01:51:03.260 too much cholesterol in the brain can be bad news. But we also know, and I'll discuss it in a moment,

01:51:09.460 but because cholesterol synthesis is so crucial to the brain, you would never want to restrict

01:51:15.120 cholesterol synthesis to a severe degree. That wouldn't, or just suggesting that you would say,

01:51:21.360 yeah, that doesn't sound too bright. So let's get into cholesterol homeostasis in the brain.

01:51:26.740 Now, the neuron is an interesting little cell there because it gets its cholesterol in adulthood from

01:51:33.380 these ApoE-containing particles. But if the neuron wound up with too much cholesterol,

01:51:39.980 just like too much cholesterol in any peripheral cell, the liver is lipotoxic. It by itself would

01:51:45.300 kill the cell. So the neuron is the one cell in the brain that was given an enzyme that it can

01:51:51.560 transform cholesterol molecule into a metabolite that's called an oxysterol. We have another name

01:52:00.420 for oxysterols, and this will make you scratch your head. Yeah, they're bile acids. The liver, by the

01:52:06.320 way, can change cholesterol to an oxysterol, which means sends it right down the bile acid synthesis

01:52:11.900 pathway, and the liver dumps it in the bile and we excrete it fecally. So if the neuron can change

01:52:18.320 cholesterol to an oxysterol, is it possible for that oxysterol to leave the neuron and enter the

01:52:25.980 plasma? And that would be a way of the central nervous system to get rid of cholesterol. Now,

01:52:31.360 wait a minute. That's a lipid. Lipids can't pass through that blood-brain barrier. So the neuron makes

01:52:38.120 these oxysterols. That's basically a sterol with extra oxygen molecules attached. So the neuron makes

01:52:46.620 something called 24S hydroxycholesterol. For those of you who've listened to our first podcast, you know

01:52:53.980 cholesterol at one end has a hydroxy group. That's what makes it somewhat water-soluble. But the other

01:53:00.020 end of the cholesterol molecule has no hydroxy. It's all lipids. But if we could stick another hydroxy

01:53:06.500 group on the tail of the cholesterol molecule, it has a hydroxy group at both ends. It actually becomes a

01:53:12.860 rare hydrophilic lipid. It's a lipid that's soluble in water. And it has no trouble passing through the

01:53:20.360 blood-brain barrier. Once it enters the blood-brain barrier, it's in plasma. And it either rapidly binds

01:53:26.820 to albumin or to any lipoprotein that's passing by. And both the albumin or the lipoprotein brings that

01:53:34.140 oxysterol to the liver, which converts it to a bile acid and excretes it. So the brain can actually

01:53:40.620 get rid of sterols in a fortuitous way by sending it down to the liver, which makes a bile salt from it.

01:53:47.740 So 24S hydroxylase is the enzyme only neurons have. People think if we measure 24S hydroxycholesterol in

01:53:56.740 the bloodstream, and it's high, we know the brain's trying to get rid of cholesterol. And it's a marker of brain

01:54:03.440 cholesterol health, because you really should have trivial amounts of that in the bloodstream. And it is with

01:54:09.620 mass spectrometry, easily measurable. All right. But let's get back to the astrocyte and the neuron

01:54:16.120 making cholesterol. Our cells, Peter has talked about this many times. There's a bunch of original

01:54:23.620 steps that go to a linear molecule called squalene, and then it starts to form a cyclic molecule that

01:54:29.720 are called sterols. And the ultimate sterol is cholesterol. But there's many steps of the sterol.

01:54:36.900 One sterol becomes another one, becomes another one, becomes another one. The penultimate next-to-last

01:54:42.380 sterols that ultimately will transform into cholesterol are either lithosterol or desmosterol.

01:54:50.500 As it turns out, and it's lucky for us, lithosterol is the major pathway of peripheral cell cholesterol

01:54:58.120 synthesis. When your liver makes cholesterol, it goes through the lithosterol pathway. Same with

01:55:03.340 most of the cells in your body. Who uses the desmosterol pathway? Why did evolution give us

01:55:09.980 two cholesterol synthesis pathways? Because cholesterol is essential for human life. God

01:55:15.380 forbid you had some genetic defect where you knocked out one synthesis pathway, you've still

01:55:19.740 got another. So you're still survivable. So the desmosterol pathway, although it could be used by any

01:55:27.540 cell, it's primarily used by the brain astrocytes, also in the periphery by the steroidogenic tissue.

01:55:35.400 So very interesting. So in your brain, can we measure serum desmosterol? Would it reflect what's going

01:55:43.360 on in the brain? Actually, we know it does, because people have done the studies where they've done spinal

01:55:49.000 taps, analyzed, CSF desmosterol, and it correlates incredibly well with serum desmosterol. So serum

01:55:57.500 desmosterol is a biomarker reflective of the desmosterol synthesis pathway. By the way, for the nerds,

01:56:05.640 that's called the block pathway. The lithosterol pathway is called the canned Dutch russel pathway.

01:56:11.640 Astrocytes predominantly use the blocked desmosterol pathway. And in adults, astrocytes are the supplier

01:56:20.400 of cholesterol to the neurons. If for some reason the astrocyte fails and the neuron in an emergency

01:56:27.700 how to make cholesterol, it actually uses the lithosterol canned Dutch russel pathway. But in adults, that

01:56:33.740 pathway is for the most part not at play. It's inactive. So again, that's why we don't measure

01:56:39.060 lithosterol. Lithosterol is telling us anything going on in the brain because it's all coming

01:56:43.460 from peripheral cells. It would be a minuscule amount that might be brain. All right. So why am

01:56:49.360 I telling you all of this? My speculation has been that the reason that the place we see desmosterol

01:56:55.560 in the periphery, in the steroidal tissue, is that that's the tissue that has the highest demand

01:57:02.280 for cholesterol production, maybe suggesting that the desmosterol pathway is more suited to a high

01:57:09.820 demand pathway vis-a-vis the astrocytes and the steroidal tissue. Again, we're so far in the nerdy

01:57:16.360 stuff on this now that it's just a speculative comment. Listen, it's the AT a brain that thinks

01:57:22.000 of stuff like that. That's why I love that I've known you for 15 years because many of the things you

01:57:27.800 tell me, I got to go look up and say, God, that sounded logical. Let me check if there are any

01:57:32.000 truth to it. And I think you're absolutely right with that statement. So before I get more into that,

01:57:38.140 anybody who's ever prescribed a statin to people knows there's a very small amount,

01:57:43.760 and it's even in the package insert that comes back and tell, Doc, since you started this,

01:57:48.220 I'm not right. I'm not thinking right. I'm not calculating right. My brain is in a fog.

01:57:54.080 And we use the word brain fog. Again, an extreme minority of people given statins have that. We

01:58:00.220 had no clue what caused that. Invariably, it would stop the statin, try another one. It usually

01:58:05.860 occurred. If it didn't, fine. But if not, then we'd have to figure out other ways to lower LDL

01:58:11.880 cholesterol, which was not easy years ago. But anyway, my hypothesis nowadays is these small

01:58:18.380 number of people who get brain fog, I wish I had desmostrol levels on them. Could some people be

01:58:23.720 very sensitive to the effects of a statin? We know in the periphery, hypersynthesizers of

01:58:29.740 cholesterol respond incredibly well. Or excuse me, oversynthesizers do, hyposynthesizers do not.

01:58:37.400 So who knows? But that being said, now here comes the next part of that epidemiologic study where they

01:58:44.140 correlated low desmostrol with serum desmostrol. People who had low serum desmostrol had a much higher

01:58:51.500 incidence of cognitive impairment in Alzheimer's disease, which would lead simply to the hypothesis

01:58:58.580 that serum desmostrol is a usable biomarker to, say, is somebody at risk for Alzheimer's disease.

01:59:08.620 And this goes back to when I met Richard Isaacson with Peter. We started throwing these hypotheses

01:59:14.180 around, and we've watched that ever since. Where would it come into play? Until recently,

01:59:20.520 statins were our only game in town. So if we write a statin, especially if used it at a higher dose,

01:59:26.400 if desmostrol was dropping low, and we use an arbitrary cutoff point, the 20th percentile,

01:59:33.120 would that be maybe you don't want to inhibit cholesterol synthesis in the brain to that degree?

01:59:38.380 Might we want to attack Apo B with another agent? All hypothetical reasons I'm putting on the table

01:59:44.920 here right now. And I think right now we look at that, especially in who? Who are the people that

01:59:50.760 we know are likely prone to dimension cognitive impairment? The E4 carriers, people maybe with

01:59:57.200 strong family histories, people that have other identifiable traits that make us think they're prone

02:00:03.040 to AD. We would watch desmostrol incredibly closely in that population. So now the last thing I'll tell

02:00:11.460 you, if the astrocyte is not making cholesterol because of its being oversuppressed by a statin,

02:00:17.840 the neuron would be getting less cholesterol. The neuron would convert none of that cholesterol to 24-S

02:00:24.780 hydroxycholesterol because it's trying to conserve every cholesterol molecule it can. So I think if you

02:00:30.600 were somebody who could measure 24-S hydroxycholesterol in the serum, you would not see it in somebody who

02:00:36.980 had cholesterol synthesis suppression in the brain. This all has to be worked out in future clinical

02:00:42.840 trials, but there are looking at this in some clinical trials right now. So one day we'll be a lot

02:00:48.820 smarter on this. Right now, if you want, you could measure desmostrol and perhaps use that as a

02:00:54.940 cautionary marker. Number one, if they're not on a drug and it's low, if you haven't done an ApoE4,

02:01:00.600 genotype, you might look at it. But if it is somebody who has a propensity to desmostrol and

02:01:06.160 you have to use a statin, maybe you want to watch that. The good news is, and I think it's why our

02:01:12.140 mantra is, if we have to use a statin, we start with low-dose statins. We have very little use for

02:01:17.800 the high-dose statin in the year 2024 because none of the other ApoB-lowering drugs, be it bempidoic acid,

02:01:26.000 azetamide, certainly PCSK9 inhibitors, get into the brain and suppress cholesterol synthesis.

02:01:32.200 So we have many ways of lowering ApoB if we were a little fearful of low-desmostrol

02:01:37.080 in a patient prone to AD or so. So that's about as much as we want to get into probably with brain

02:01:44.380 lipids right now. Understand ApoE is a big player up there and there are different types of the ApoE

02:01:49.860 protein. But understand cholesterol homeostasis has a lot to do with what is in the peripheral

02:01:55.360 cells. We can look at markers of synthesis. The markers of cholesterol absorption that we use big

02:02:01.540 time when evaluating peripheral cholesterol homeostasis obviously is not at play in the

02:02:07.640 brain. The brain is not absorbing cholesterol from your gut.

02:02:10.540 Before we leave that, Tom, what is our hypothesis around the hydrophobicity of various statins? And

02:02:20.880 do we think that certain statins are more likely to cross the blood-brain barrier? Are there certain

02:02:26.800 statins that should be ignored in patients with marginal desmostrol?

02:02:31.880 Great question. And the thoughts have changed on this too. Because early on, if you go back,

02:02:36.420 probably maybe even listen to the podcast you and I did in 2018, I believe, we were talking about

02:02:42.040 hydrophilic and lipophilic statins. And the lipophilic ones can pass right through the barrier

02:02:47.260 a little easier than the hydrophilic one, which need receptors to pull them in. But subsequent

02:02:52.340 analyses has shown all statins get into the brain. Ultimately, once you have a steady state statin level

02:02:58.940 in the blood, they all will get into your brain. And they all have the ability to suppress

02:03:04.060 cholesterol synthesis in the brain. Now, the last thing I want to say about statins before everybody

02:03:09.220 says, oh my God, I'm stopping my statin anymore. I can't get a desmostrol level. Well, they're

02:03:14.320 available if you look for them. But in general, if you analyze all of the statin data, the many trials,

02:03:21.020 be they observational or randomized control, there is no signal whatsoever that in a population

02:03:28.400 statins worsen or cause cognitive impairment of Alzheimer's disease. There's a few studies that

02:03:35.320 even suggest perhaps some lowering. Maybe that's through atherosclerotic cerebrovascular disease.

02:03:40.880 Who knows? But don't worry that statins in the overwhelming vast majority of people are not

02:03:47.100 hurting the brain. But I think we've introduced perhaps a biomarker that you might know with a

02:03:52.820 little more certainty if you have to write a statin in somebody subject to dementia.

02:03:58.200 Yeah. We actually covered this at length in one of the previous AMAs. And I went through every

02:04:04.660 meta-analysis on this topic. It's important for people to understand that at least at the time,

02:04:09.280 and I don't think this has changed, there has not been any statin trial where the primary outcome

02:04:15.300 was dementia. The primary trial is always cardiovascular disease, but there have been

02:04:21.280 more than a dozen such trials where the secondary outcomes are dementia. It's worth noting that in

02:04:27.540 every one of those trials, regardless of statin used, there has either been no change in the risk

02:04:34.880 of dementia or a reduction in the risk of dementia. Now, it's interesting. These studies were almost all

02:04:41.740 done in the setting of trying to determine if lipophilic versus hydrophilic statins were more,

02:04:48.600 less, or better. And the answer always emerged, it didn't seem to matter, which of course makes sense

02:04:54.680 if you understand now that they probably all crossed the blood-brain barrier. So the question remains,

02:05:00.520 will there ever be a study done that tests this question specifically as the primary outcome? In other

02:05:06.620 words, where the study is powered to ask the question, does the use of a statin increase, decrease,

02:05:13.700 or have no effect on the risk of Alzheimer's disease and dementia? Or will we instead be forced

02:05:19.260 to rely on these secondary outcomes, which are always subject to some potential misinterpretation?

02:05:26.780 Again, I take much more comfort in knowing that they are all either neutral or favorable. That would

02:05:32.680 certainly be better than the opposite. But again, that remains a bit of an unknown. And you might be right,

02:05:38.880 Tom, it might be that on average, it's having no effect on the brain. On average, it's having a

02:05:46.300 beneficial effect through the vascular system. But then there might be edge cases that are not being

02:05:52.500 captured in large clinical trials based on hundreds of thousands of people. And it might in fact be those

02:06:00.600 patients in whom a little extra knowledge goes a long way vis-a-vis cholesterol synthesis in the brain.

02:06:07.800 And the final point I'll make here is what a privilege it is to be practicing medicine in 2024

02:06:14.280 when we don't have only statins, but we have ezetimibe, we have benpedoic acid, we have

02:06:21.380 short-acting PCSK9 inhibitors, we now have long-acting PCSK9 inhibitors, we have ASOs around the corner.

02:06:29.820 There really is no need for a patient to ever endure a side effect of lipid-lowering medication

02:06:36.180 today. We can lower everybody's lipids without side effects. And that's only going to become

02:06:41.360 more and more true in the next decade.

02:06:42.660 I couldn't argue with anything you said there. It's brilliant what you said. And also,

02:06:46.760 this is not a reason not to use statins. We're not evaluating populations. We treat people one at a

02:06:53.900 time. So in somebody we're worried about dementia, we have a biomarker that's probably usable.

02:06:59.380 And if, God, you can't take the statins, so what? We can get your ApoB goal pretty easily with the

02:07:06.060 other things that we know are not affecting the brain. What Peter said, wouldn't it be nice to

02:07:11.280 have a randomized blinded trial to answer this question? All statins are generic. I don't know

02:07:17.140 of any pharma company that's going to spend a billion dollars to prove or disprove what statins do to

02:07:22.440 cognitive functions of the brain. So it's not going to happen. So if it's not, we can use in individual

02:07:29.060 patients these oddball biomarkers that is what I think is part of medicine 3.0, where we maybe use

02:07:36.800 a little smarter knowledge to try and do a better job. The last thing I'm going to, and Peter has

02:07:42.880 harped this enough to, maybe I badmouth high-dose statins. We don't use them. We're not treating acute

02:07:48.600 coronary syndrome patients where maybe you want to be on a high-dose statin for X amount of time.

02:07:54.440 You can get most of the ApoB lowering with a statin with the baby dose. This has been proven in trial

02:08:00.560 after trial. Most of the LDL receptor upregulation occurs with the lowest dose that inhibits cholesterol

02:08:07.440 synthesis. You start doubling, tripling, quadrupling, you might get another 6%, 7%, not the original 30%

02:08:14.340 lowering or so. So in today's world, why do you ever have to double, triple, or quadruple the dose

02:08:20.300 of a statin? When we have all these other additive drugs that you take a baby statin, my acronym for a

02:08:28.180 low-dose statin, and you combine it with azetamide, bempedoic acid, or PCSK9 inhibitor, you've got a

02:08:35.320 military machine that can destroy ApoB. So that should be the thought processes about attacking ApoB

02:08:42.000 nowadays. We have so many options, which we didn't have in the heyday. I always say one last

02:08:47.940 thing because I'm old enough to remember, where did all this hydrophilic, lipophilic stuff come from?

02:08:53.080 The first two competitive statins on the market were simvastatin, which was Merck's most potent

02:08:59.220 statin, more potent than their lovastatin or mevacor. So everybody jumped on zilcor or simvastatin,

02:09:04.920 but Bristol-Myers squid made pravastatin, hydrophilic. And there was a lot of thought

02:09:11.480 looking at other biomarkers that the, and even catabolism, that the hydrophilic statins were

02:09:17.900 safer than the others. Was there a little more brain fog with mevacor, zilcor than there was

02:09:23.820 with pravacor? Anecdotally, people said that. I never saw a trial that looked at that. But that's

02:09:30.480 where it all came from, pharma competitiveness, hydrophilic versus a lipophilic statin.

02:09:36.100 Well, Tom, my final question, I guess, really comes down to what are you most looking forward

02:09:39.800 to in the next three to five years? I have an answer for what I'm most excited about,

02:09:44.420 but I'm obviously more interested in hearing what you're most excited about in the entire

02:09:48.120 field of cardiovascular medicine. Is it something on the drug side? Is it something on the diagnostic

02:09:52.740 side? Is it something else? What has you most excited?

02:09:55.840 Well, most excited is I hope I'm still here in five years and I hope I'm still capable of having

02:10:00.780 these discussions with you. Peter's working hard to make that happen with me. So I high five him on

02:10:06.300 that. But if I do make it that long, look, I think we've got ApoB solved right now. They're looking at

02:10:12.300 even other types of PCSK9s coming down the pipe, a little more potent on LDLC than the current ones.

02:10:18.440 There's an oral PCSK9 that they're working on. Would you rather swallow a pill and take an inch?

02:10:23.940 But you're still just chasing ApoB. And we can pretty much, with rare exception, get that to

02:10:29.100 goal now. So I'd be more excited about for the people with the rare genetic disorders that are

02:10:35.040 driving their lipids and lipoproteins out of whack. There are drugs coming that attack other

02:10:40.620 apoproteins that are there. But again, that's going to be a minority of patients on that.

02:10:46.480 Diagnostically, I would hope, I can't ever see it coming, but I couldn't see a lot of things coming,

02:10:52.100 that there might be some usable HDL functionality tests, which would make us a little smarter,

02:10:58.260 perhaps, on giving a patient some insight to their HDL markers or so. Would there be other types of

02:11:06.140 earlier markers? I don't know that we're going to get an earlier imaging marker than a CTA right now

02:11:12.760 without being invasive. Or maybe optimal tomography and stuff is showing us stuff within the vessel wall.

02:11:19.020 So who knows what imaging is going to bring to the table, but that probably won't be in widespread

02:11:24.540 use when it first comes out. Or would there be other inflammatory markers we have now? Fine,

02:11:31.820 you can use them, you can look at them. I didn't say it before, but does everybody understand that

02:11:37.360 whatever inflammatory marker you're looking at, that is not the goal of therapy. ApoB is the goal

02:11:42.380 of therapy. The thought being, if you make ApoB low enough, the atherosclerotic process in the artery

02:11:48.540 wall would dry up, scar up, and there'd be no more inflammation in the artery wall. But there are other

02:11:53.880 things going on, as Peter alluded to. So there are other biomarkers coming that certain amino acid

02:11:59.540 biomarkers are being looked at or so that might give us other types of insight, looks at the arterial

02:12:05.860 wall pathology that might be going on. I would love to see some of these synthesis and cholesterol

02:12:12.440 markers, perhaps even LDL and H triglyceride levels. The latter two are just simple assays

02:12:19.040 being made available to the general public. And I would like to see more widespread availability of

02:12:24.660 the sterile biomarkers. And you need some education on how to use them, but that would be all great.

02:12:30.940 And the last two things, I guess about two weeks ago, the NLA published their first statement on

02:12:36.940 ApoB. And we've given you a lot of info why we use it, but you want to get down into the weeds.

02:12:43.000 That's a statement to read. And they do mention as good as it is, it can't happen tomorrow. No guideline

02:12:50.480 is going to tell you to make ApoB for the simple reason is the overwhelming majorities of practitioners

02:12:56.180 really don't know what ApoB is, including those in the cardiology community, for goodness sake.

02:13:02.280 You can't get a guideline declaring everybody stop doing lipid profiles, just get ApoB because nobody

02:13:07.680 would know what you're talking about. Sadly, today, the NLA put out a secondary expert person

02:13:14.960 statement on LP little a, and they get into the same thing. Yeah, everybody should get an LP little a

02:13:21.500 once in your life. But right now in 2024, there are several drugs coming to lower it. We have no

02:13:27.800 idea whether they're going to reduce MACE or not. So stay tuned. We're going to get the readout on one

02:13:33.640 next year. What if it failed? Then LP little a just becomes a risk marker like CRP or something.

02:13:40.320 It's not a goal of therapy. So stay tuned for that. But they also get into it. A lot of labs,

02:13:46.380 they're not doing the right type of LP little a testing. I was shocked to hear it because it's kind

02:13:50.640 of a cheap test, but apparently there are third party payers giving doctors grief for ordering it

02:13:55.940 for God's sakes. And again, the overwhelming majority of PCPs and a heck of a lot of cardiologists

02:14:03.640 have no idea what LP little a is. What good does it tell you to go get it tested and you show up in

02:14:09.680 your doctor's office and goes, who that's nothing? Don't worry about it. So I'm hoping for better

02:14:15.060 education among doctors in the lipid world. God knows, Peter, you've done your part.

02:14:19.940 And I just always like to pat you on the back. Last year, Peter was made an honorary lifetime member

02:14:27.100 of the NLA. And I would suggest you go to their website and see who else has ever achieved that

02:14:33.080 title. It's the giants of the field who invented the centrifuge or that type of serious analyses.

02:14:41.060 Why did Peter give it? Peter has probably brought more lipid education to more people than any of

02:14:47.440 those gigantic thought leaders ever did. So I high five my buddy for doing these types of things

02:14:53.360 and giving lipid its due presence on his missives, his Instagrams and his podcast for sure.

02:15:01.820 So like always, Peter, we're going to know a lot more. Some of the stuff we said today is probably

02:15:06.760 going to sound like idiocy in five or 10 years. But I think a lot of it's going to be right.

02:15:11.600 If I look back at my life and I prognosticate about a lot of stuff, I've been a lot more right

02:15:17.480 than wrong. So I'll pat my own back. It was a huge honor last year to receive

02:15:22.240 that award from the NLA and in no small part at all, that's obviously due to your mentorship

02:15:27.260 and the mentorship of others. So thank you very much. And thank you obviously for your continued

02:15:31.640 education, both for me personally and also for everybody listening. You're an absolutely tireless

02:15:38.260 educator. Your zeal for teaching, your generosity of knowledge is really unparalleled. And you and

02:15:44.680 I joke all the time about that first time we met way back in Reno, total chance coincidence and

02:15:50.180 certainly one of the more fortuitous things that's happened to us both. So thank you again. I think this

02:15:55.020 was a great discussion. I know that at times it got a bit technical, but I would encourage people to

02:15:59.980 maybe go back and listen to this again, really go through the show notes on this one. All the stuff

02:16:04.700 we talked about, you'll find summarized there and links to other studies if you want to be able to

02:16:10.440 go into some of the details. So thank you once again, Tom, for everything you've taught me and

02:16:14.060 obviously everything you've taught the listeners. Vice versa, my dear friend. Thank you for listening

02:16:19.520 to this week's episode of The Drive. Head over to peteratiyamd.com forward slash show notes.

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The Peter Attia Drive - February 03, 2025

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

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