The Peter Attia Drive - October 31, 2022

#229 ‒ Understanding cardiovascular disease risk, cholesterol, and apoB

Episode Stats

Length

1 hour and 18 minutes

Words per minute

156.12349

Word count

12,289

Sentence count

710

Harmful content

Misogyny

6

sentences flagged

Hate speech

6

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Summary

Summaries generated with gmurro/bart-large-finetuned-filtered-spotify-podcast-summ .

In this episode, we re-visit a topic covered in depth in previous episodes: Atherosclerotic cardiovascular disease. Why is it so important to care about this topic? And what are the tools we have to mitigate it?

Transcript

Transcript generated with Whisper (turbo).

Misogyny classifications generated with MilaNLProc/bert-base-uncased-ear-misogyny .

Hate speech classifications generated with facebook/roberta-hate-speech-dynabench-r4-target .

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

00:00:15.500 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.820 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:24.780 wellness, full stop. And we've assembled a great team of analysts to make this happen.

00:00:28.900 If you enjoy this podcast, we've created a membership program that brings you far more

00:00:33.320 in-depth content. If you want to take your knowledge of the space to the next level at

00:00:37.340 the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. Welcome to another special episode of the drive. As the podcast is now over

00:00:54.920 four years old, we realize we've covered certain topics in a variety of ways across multiple

00:00:59.000 episodes. We realize, of course, at times it can be hard to piece together this information,

00:01:02.960 and it's also difficult for new listeners to be able to go back and keep track of information

00:01:07.880 that's been covered in great depth in previous episodes. As a result, we wanted to release

00:01:12.140 another episode that is kind of a compilation of clips from previous episodes. We did this before,

00:01:16.580 and it was a huge success. So for this one, we want to focus on atherosclerotic cardiovascular

00:01:22.000 disease, ASCVD, cholesterol, and ApoB. This episode includes clips on why it is so important

00:01:28.400 to care about ASCVD, the role of cholesterol in ASCVD, and why I don't think anyone should refer to

00:01:34.180 cholesterol as good or bad. And finally, we look at why ApoB is an important metric to track when

00:01:39.320 looking at your lipids. We put these clips in the order of what we think is the best way to listen

00:01:44.220 to them from top to bottom, and also provide some commentary in between clips to give you a little

00:01:49.300 bit of context. Our hope is that not only will you understand this topic better, but you will also be

00:01:55.740 able to identify some past episodes you may want to go back to and listen more deeply. Final thing

00:02:00.660 is that some of these clips are taken from AMAs, so if you're not a subscriber, we hope this gives

00:02:04.940 you a little bit of a sneak peek of what's covered in those episodes. This is still a fairly new concept.

00:02:09.800 We've only done this once before. We got great feedback on that, which is why we're doing it again.

00:02:13.540 So if you continue to like this, please tell us, and if you don't, tell us why.

00:02:17.380 So without further delay, I hope you enjoy this special episode of The Drive.

00:02:25.960 What we thought would be important is just answering the first question, which is why

00:02:29.660 should someone care about this? It's such a complex topic. Why is it important for people

00:02:36.400 to put the time in to really think through and understand it?

00:02:39.340 It really starts with the ubiquity of this disease and its assault on human longevity. People have

00:02:47.140 probably heard me say this before, but atherosclerosis is really the only inevitable disease of our

00:02:52.440 species. Cancer, while prevalent with aging and dementia, while prevalent with aging, do not appear

00:02:58.540 inevitable the way atherosclerosis does. So not everybody dies from atherosclerosis, but I think,

00:03:05.300 to my knowledge, everybody dies with it, assuming they live long enough. So you have a condition

00:03:11.300 that, as I said, is inevitable, is ubiquitous. Also, I think based on what you're going to hear

00:03:18.060 me talk about today, we know a lot about this condition, and we really have tools to mitigate it.

00:03:25.120 To me, that's the reason you want to really understand this. The impact is huge, and the tools

00:03:32.300 that we have are also huge. So again, we talk about longevity. Longevity has two parts, health

00:03:38.940 span, lifespan. The lifespan part comes down to delaying the onset of chronic disease, of which

00:03:43.840 this is the most common chronic disease. So you can think of a couple of different paths to get there,

00:03:50.460 but really the two biggest risk factors, I am putting smoking aside for a moment, which is

00:03:55.760 a very straightforward behavioral risk factor. In terms of less clear behavioral risk factors,

00:04:01.940 the two biggest are clearly hypertension, high blood pressure, and lipid abnormalities. And that's the

00:04:07.200 one we're going to focus on here. So atherosclerotic cardiovascular disease, we'll just abbreviate

00:04:11.800 ASCVD for short, is really what we're here to talk about. As we get started on this topic, Peter,

00:04:18.040 I think we have people who listen to this podcast of all ages, young, old, everywhere in between.

00:04:23.860 And I think it's a common thought for people under 30, 40, even some people under 50,

00:04:31.080 where they're just like, this is something that only affects old people. I'll think about this 0.89

00:04:35.460 when I'm older, but right now it doesn't really affect me. How would you answer the question in

00:04:40.260 its basic form of, isn't this just a disease of old age? And why should those people who think that

00:04:45.420 not just shut off the podcast at this point and instead continue to listen and continue to put in

00:04:50.240 the effort? Probably have told this story before. And if not, or if folks haven't heard it,

00:04:56.700 I think it's worth hearing again, right? I remember in sort of my first year pathology

00:05:00.040 lecture in medical school, the pathologist said, what's the most common presentation for a first

00:05:05.980 heart attack? So if a person is having their first heart attack, what is the most common thing that

00:05:11.020 they will present with? That's the terminology we use in medicine. And of course, the hands shot up,

00:05:15.600 chest pain being the obvious. Nope, that's not it. Nausea. Nope, that's not it. Left arm pain. No,

00:05:21.820 that's not it. And it was a trick question. Of course, the answer was sudden death. The answer

00:05:26.480 was that over 50% of people's first heart attack is fatal. Now, the good news is today, that number

00:05:34.120 is a little bit less. It's probably slightly below 50%, but that's still a staggering number. Now,

00:05:40.160 another way to think about this is through the lens of understanding the age distribution of people

00:05:47.600 who have their first major adverse cardiac effect. So that is a heart attack, stroke, or sudden death

00:05:53.780 due to one of those. If you don't mind, Nick, pull up figure one. This graph shows the age distribution

00:06:00.820 for both male and female in the United States in terms of these incidents. I think the easiest graph

00:06:09.740 for me to look at here is the one on the right, total annual events. And what you can focus on is the

00:06:20.840 first two bars. That is the bars that are for people up to the age of 65. So if you look at the male

00:06:30.180 bars, which are the darker bars, you can see that the sum total of those two bars, slightly below 25%,

00:06:37.060 slightly above 25%. The implication of that is over 50% of men who are going to have a cardiac event in

00:06:45.960 their life will have it before the age of 65. And for women, you do the same exercise. You can see 0.99

00:06:53.660 that it's one third of women. So it's clear that there's a shift in time and that women, while subject 1.00

00:07:01.040 to the exact same burden of disease, seem to experience it about a decade later, still fully

00:07:06.900 one third of women are going to have their first cardiac event, which is going to be heart attack,

00:07:11.260 stroke, or death as a result of those things before the age of 65. And a little over 50% of men will be

00:07:17.840 in that camp. So as we're going to talk about in this episode, that's not the whole story. It's even

00:07:23.800 more compelling to care about this when you're young, when you understand how long it takes for this

00:07:28.880 disease to take hold and the implications therefore for prevention. The most sobering thing for me,

00:07:34.080 when you look at this is it's not even the 50% under 65. It's almost the, especially for males,

00:07:40.660 the almost 25% under 54. And especially when we get to what we get to later, which is for that to

00:07:47.960 happen to someone who's 45, 50, it doesn't mean it started two years earlier. Right. And so I think

00:07:54.000 it's pretty crazy when you see these type of stats laid out, how it creates that shift in your mind

00:08:00.680 around why you should care about this. What we need to do is first almost step back and look at

00:08:13.000 what exactly is ASCVD. I think people have to understand what it is to then really understand

00:08:21.240 how it comes about, how to think about prevention. So what do you think the best way to walk people

00:08:27.120 through in a relatively simple form, what this disease is? I'll explain it at a high level now.

00:08:33.840 And I think we should go through it in some detail in a moment. But the pricey on this would be that

00:08:38.720 ASCVD is a disease state characterized by the deposition or the buildup of cholesterol more clearly

00:08:45.160 or more rigorously sterols, which include cholesterol and phytosterol in the artery

00:08:50.700 wall. It initially starts as something called a fatty streak, which I'll explain in a little bit

00:08:55.320 more detail later. And then it later consolidates into things called plaques. And these can ultimately

00:09:01.320 lead to a reduction in blood flow. And of course, it's this reduction in blood flow that leads to

00:09:06.960 what's called ischemia. Ischemia is the reduction in blood flow and therefore the resulting tissue

00:09:14.260 damage that occurs to the heart is what results in a heart attack, which can be fatal depending on the

00:09:19.620 amount of the cardiac tissue that is impeded from appropriate amount of oxygenation. To have this

00:09:26.360 disease, you don't have to be obese. You don't have to have high blood pressure or things of that

00:09:30.400 nature. It's really a question of the cholesterol in your blood. That's really what defines the disease.

00:09:36.220 So the essential condition of atherosclerosis is the presence of cholesterol in the artery wall,

00:09:41.060 which by the way, is not necessarily related to the measure of cholesterol in circulation,

00:09:45.760 which we will talk about in great length. And although these often coexist, patients with

00:09:50.800 cholesterol in their arteries do not necessarily have to have co-aggravating factors such as high

00:09:57.280 blood pressure, diabetes, obesity, family history, smoking, all these things that exacerbate it.

00:10:02.900 You mentioned cholesterol a few times, and obviously it's a topic that's been talked about on

00:10:07.120 more podcasts than I can even count or recall right now. But for this conversation, can you define

00:10:13.540 cholesterol just in its simplest form so everyone's aware of exactly what we're talking about as we're

00:10:19.060 going to get into kind of the more nitty gritty? Cholesterol is an organic molecule that resides in

00:10:24.760 the lipid family. So we typically characterize these molecules by their solubility in water,

00:10:31.200 and this is a not soluble in water molecule. So it is a hydrophobic molecule. And I think the easiest

00:10:39.080 way to sort of picture those things is to think about oils. So if you took an oil like olive oil

00:10:44.520 and you poured some of it into a cup of water, you would immediately see what it means to have a

00:10:51.060 hydrophobic substance in contact with something which is the ultimate hydrophilic substance, water,

00:10:56.700 right? So they repel each other. Now, of course, cholesterol is about one of the most important

00:11:02.060 molecules in the body. To be clear, if we didn't have the ability to make cholesterol, we would cease

00:11:08.880 to exist. In fact, you couldn't be born without the ability to do this. There are rare genetic

00:11:14.120 conditions that impair the ability to make cholesterol, and these are uniformly fatal. Why do we need

00:11:20.260 cholesterol? There are broadly two things that cholesterol is essential for. The first is that

00:11:27.060 they contribute heavily to the cell membrane of virtually every cell in the body. So cells are

00:11:34.860 actually kind of fluid things, spherical things. And what allows them to have that fluidity and what

00:11:42.200 allows them to have membrane channels that allow things in and out of them is the cholesterol layer

00:11:47.940 that forms the membrane. And secondly, cholesterol is an essential substrate for the production of some

00:11:54.340 of the most important hormones in the body, cortisol, estrogen, testosterone. It's also essential for the

00:11:59.460 creation of bile acids, which are necessary to be able to digest food. So the mantra that I like to say

00:12:05.020 is no cholesterol, no life, period. You should put that on a bumper sticker on your car. Just roll around

00:12:10.780 Texas with that guy. No, I think that's great. Why don't we look at and discuss, Peter, how does

00:12:17.380 AS CBD come about? So before I jump to the figures, I want to make one other point that I should have

00:12:23.320 made a moment ago, and that is the necessity of the body to make cholesterol. So I think most people,

00:12:31.180 when they think of cholesterol, will probably first think of what it is that's floating around in their

00:12:35.680 bloodstream, but will very quickly turn to cholesterol within food. Because it turns out that when you eat

00:12:41.580 certain foods, you can also eat cholesterol. So everybody knows, for example, eating eggs

00:12:46.220 means eating cholesterol. And a natural question is, what is the relationship between the food that I eat

00:12:53.800 that contains cholesterol and cholesterol you're measuring in my bloodstream? And the short answer is

00:12:57.500 very little. And the reason for that is the cholesterol that we eat is in a form that the fancy term

00:13:04.600 for it is called esterified. So it has a chemical bond that swings between an intermediary oxygen and

00:13:12.080 then another side chain. From just a straight mechanical problem, that is too large for the

00:13:18.840 receptors in our gut to absorb. So most of the cholesterol that we eat is in fact excreted out of

00:13:26.400 our backside. We don't bring it into our body. And therefore, most of the cholesterol that we are going to

00:13:33.280 talk about today is actually cholesterol that we have made. And it's transported between cells

00:13:40.160 through these things called lipoproteins. One of the things I remembered from pathology A,

00:13:50.340 so it's the first of the three major classes you take in pathology, was something that the professor

00:13:55.720 said, which is he said, no doctor has more experience with what it is to have heart attacks than pathologists

00:14:06.960 because 50% of the people who have a heart attack die on their first heart attack. So he said,

00:14:15.900 I'm seeing 50% of the people who have a heart attack and their first presentation is death.

00:14:23.300 So I kind of remembered that. And it's a very sobering fact to think that half the time. And

00:14:29.100 again, I don't think that's true today, but I think 25 years ago, that was the case. The numbers are

00:14:32.940 probably a bit better today. It might be a third of first events are fatal, but nevertheless, it was

00:14:39.160 sobering. So you have this sort of weird factoid that's again, off in the recesses of my brain

00:14:44.260 somewhere. And then you hand me this textbook and it actually made sense with what he said,

00:14:51.480 because in addition to going through in great detail, the pathological staging of atherosclerosis,

00:14:58.480 it was littered with autopsy sections of coronary arteries of people who had died for other reasons.

00:15:06.200 And notably they were quite young. So here's a 26 year old male victim of a gunshot wound. Here's a

00:15:11.740 27 year old female who died in a motor vehicle accident. Here's a so-and-so-and-so-and-so. 0.99

00:15:17.760 And when you look at their coronary arteries, you realize they already have atherosclerosis.

00:15:24.540 They already have oxidized ApoB bearing particles engulfed by macrophages and thickened intima. And

00:15:35.120 while they may not have calcification in their arteries yet, or the types of plaque that would

00:15:40.540 rupture within the ensuing weeks or days or months, they nevertheless had atherosclerosis and they were

00:15:46.700 in their twenties and in their thirties. So all of a sudden, what this professor said 20 some odd

00:15:53.420 years earlier made sense, which is this was now an explanation. This was a bridge to explain what

00:15:59.920 otherwise seemed hard to understand. Atherosclerosis, it's a disease in the tissue and

00:16:06.240 almost everything that lipid people talk about is in plasma. And if we don't understand the natural

00:16:13.180 history of the disease, how can we construct a strategy to prevent it? And although much of my

00:16:21.220 work has been on ApoB, the more important part I think has been on understanding how the natural

00:16:30.340 history of atherosclerosis should direct our prevention strategy. What that leads to is that

00:16:39.440 every major guideline in the world bases their selection of subjects for statin prevention

00:16:47.740 prevention on the 10-year risk of disease. And that was a huge step forward in 1980 and 1990. But it

00:16:58.900 totally, or not totally, but it very fundamentally makes prevention of premature disease almost

00:17:08.460 impossible. When you plug in the numbers to calculate somebody's risk for any of the risk algorithms,

00:17:17.280 the American College of Cardiology, 2019 AHA, Multisociety, you plug in numbers that belong to

00:17:25.360 that particular patient. And what comes out is what you think is the risk for that particular patient.

00:17:34.400 It actually isn't. But what drives that calculation is the age and the sex of that patient. Things like

00:17:44.860 cholesterol, blood pressure, they contribute minimally to the actual calculation of 10-year risk.

00:17:53.920 So what that means is if you're 35, well, there is even a risk calculator for you. But if you get to 40,

00:18:00.780 almost everybody's risk is low at age 40. And it is until you get to about 55, 60, that risk gets you

00:18:09.740 over the threshold for the American Prevention Guideline treatment. So prevention really starts

00:18:17.380 at 55 to 60. But half, almost half of all infarcts and strokes occur before the age of 60.

00:18:28.840 So how can that be? What Starry and his colleagues established was for the first three decades or so

00:18:37.160 of life, the disease begins, gets a foothold in the artery. But it's only in the fourth decade that

00:18:44.560 you start to develop the lesions that can actually precipitate a clinical event. But risk is low,

00:18:52.260 and yet the event rate is high. How can that possibly be? Well, the answer is stunningly obvious.

00:18:58.840 Which we've published. There are a ton more people under 60 than over 60. So the rate of events is

00:19:08.280 low, but the absolute number of events is high. That's problem number one. Problem number two is, say you

00:19:19.800 get to 60 and you didn't have an event. Well, the disease was developing and extending during your

00:19:26.820 30s, 40s, and 50s. So by the time we start to try and prevent an event, the disease is well-advanced

00:19:36.420 in the arteries. That, to me, are the two fatal flaws in the 10-year risk approach. And we published

00:19:45.000 a paper pointing this out in JAMA Cardiology a few years ago. Borg Nordiskart and his colleagues have

00:19:51.620 done exactly the same thing with the European guidelines. You can't beat these numbers.

00:19:58.100 So rather than what Steri taught me, and it took some years before we could develop the methodology,

00:20:07.800 of course risk is a good concept. Of course it is. But we should be selecting people also based on

00:20:15.540 causes. I can measure your ApoB pretty precisely. I could measure your non-HDL cholesterol a little

00:20:24.700 less precisely, but pretty well. And I know it's yours. When I calculate the risk, if I said, okay,

00:20:32.620 Peter, you're my patient. You're a healthy guy. I calculate your risk is 4.1%. Now, what does that

00:20:42.380 number mean? Is that your risk? Nope. It means that out of 100 people at 4.1%, 4.1% of them will

00:20:52.000 have an infarct. But we know that within that category, there's a tremendous variance in real

00:20:59.180 risk. Not everybody's at 4.1%. Some are higher, some are lower, some are dead on. So if I had two risk

00:21:09.360 algorithms, the philosopher, A.J. Ayer, the English, the logical positive, he was actually

00:21:16.460 darn good on probability. There's a real challenge predicting singular events. I'm either going to

00:21:24.700 have an infarct in the next year or I'm not. It's not really a probability. So I either am or I'm not.

00:21:31.560 If one algorithm said I had a 10% risk and another one said I had a 15% or 20%, whether I have an

00:21:39.360 infarct or not, both of them were right because they said there was sort of a chance you could

00:21:45.380 and there was a far larger chance you wouldn't. When we say people should be treated with a risk

00:21:53.020 above 7.5%, that means 92.5% of the time, nothing will happen. Well, that's not a great incentive,

00:22:01.360 I think, for helping people understand what's truly going to happen. So the way we can deal with

00:22:07.480 this and what we've done is develop what's called a causal benefit model. We measure it, non-HDL or APOB,

00:22:14.140 and we can project the risk over 20 or 30 years. If you're 30 years old, the period of time you should

00:22:23.260 care about is up to age at least to 60. And so if you were in a group, let's say, and let's say I make

00:22:31.860 you 35 again, and I say your chances of having an infarct or a stroke before you're 65 are 30%,

00:22:40.380 now that's a number you can deal with. That's a number that has meaning. And we could also

00:22:46.680 calculate how much the risk can be reduced by starting at age 35, or how much you lose by

00:22:53.720 starting at age 45, or how much more you lose by starting at age 55.

00:22:59.680 This next set of clips is a deeper dive into cholesterol, the limitations of the standard

00:23:09.920 cholesterol blood panel, and an important segment on why I think no one should ever

00:23:13.800 refer to cholesterol as good or bad.

00:23:21.340 So I recently posted something on social media about my frustration with the way that the press,

00:23:26.960 and frankly, even sometimes the medical establishment, writes about cholesterol,

00:23:30.500 referring to good cholesterol and bad cholesterol. Now, if you've ever listened to me on podcasts,

00:23:35.700 you understand that I talk about this in great detail. But a number of the comments suggested that

00:23:40.920 there are a lot of people that are kind of new to this discussion. They haven't necessarily

00:23:44.220 followed me. They certainly haven't heard the, I don't know, literally 25 hours worth of content on

00:23:50.880 cholesterol over the last four years on my podcast. And they were kind of looking for a little bit of,

00:23:55.700 call it the TLDR version of cholesterol. And I thought this would be a great excuse to do it.

00:24:00.980 So if you want to understand why I wail on people when they say bad cholesterol and good cholesterol,

00:24:06.920 you have to really understand what cholesterol is and why that type of imprecise language is

00:24:12.980 unhelpful, to put it mildly. Okay, so let's take a step back. What is cholesterol?

00:24:17.780 So cholesterol is a lipid. It is synthesized by every cell in our body. That means every cell in

00:24:26.700 our body makes cholesterol. Okay, so why do we make this stuff? Well, this stuff is super important

00:24:32.260 where every cell in our body wouldn't make it. It's essential for the creation of a cell. So a cell,

00:24:40.700 when you look at a picture of a cell in a book or online or something, they look like two-dimensional

00:24:45.340 structures, right? They're sort of these flat things. But really, that's not what cells look

00:24:48.300 like. That's kind of a cut open cell projected onto 2D. The reality of the cells are three-dimensional

00:24:53.180 and they are fluid. They have to be able to be more than just perfectly open spheres.

00:25:01.520 So what gives them that fluidity is their membranes. And it's the cholesterol within the

00:25:06.220 membrane that provides that fluidity. It's also what allows transporters to go across the surface of 0.80

00:25:13.340 cells. These transporters are what allow various things like glucose, ions, hormones, etc. to traverse

00:25:19.160 cell membranes. So it's important to understand that if we didn't have cholesterol, we wouldn't

00:25:24.300 have cells. If we didn't have cells, I wouldn't be making this video and you wouldn't be here to

00:25:29.020 watch this video. No cholesterol equals no life. Full stop. There are things that are almost equally

00:25:36.620 essential for life that go beyond that. Cholesterol is the precursor to some of the most important

00:25:42.040 hormones in our body, which ranges from things like vitamin D to cortisol, to estrogen, to

00:25:47.320 testosterone, progesterone, etc. It's also essential for bile acids. We wouldn't be able to digest most

00:25:53.400 of our food without bile acids, especially fatty foods. So the list goes on and on as to why cholesterol

00:25:58.940 is essential. So why does the story not end there? Why are we having this discussion? Well, when it comes

00:26:06.020 to something as essential as cholesterol, not every cell in the body is capable of making enough

00:26:12.380 cholesterol to meet its individual needs. So the body has to be able to traffic cholesterol. So there

00:26:20.000 are certain cells that tend to be net exporters of cholesterol, the liver, for example. As a general

00:26:25.140 rule, the liver makes more cholesterol than it needs, whereas there are parts of the body that need

00:26:30.900 more cholesterol than they are typically capable of making, especially during periods of high stress.

00:26:35.100 So those parts of the body need to receive cholesterol. And this poses a little bit of a

00:26:40.160 problem because the main channel that we like to use in the body to transport things back and forth

00:26:46.600 is, of course, the circulatory system. It is not the only system. We have a lymphatic system,

00:26:51.060 but the circulatory system is the system that we tend to use most to transport things like this.

00:26:57.820 Now, there are lots of things we transport in the circulatory system, and we do without any difficulty.

00:27:02.580 We transport glucose without any difficulty. We transport electrolytes without any difficulty.

00:27:09.460 We transport lactate without any difficulty. Why? Because all of those things that I just stated are

00:27:14.100 water-soluble. And of course, the circulatory system is made up of plasma and proteins. That's

00:27:19.800 what your blood is, the plasma being basically the water of the cell. And so things that are water-soluble,

00:27:25.240 like all of the proteins, hemoglobin, and things like that, things that I already stated,

00:27:28.920 glucose, electrolytes, they are soluble in water, and therefore they transport easily.

00:27:33.960 But as I said at the very outset, cholesterol is a lipid. And if you remember a little bit from a

00:27:40.180 chemistry class, you'll know that a lipid is not water-soluble. It is hydrophobic as opposed to what

00:27:45.640 we say is hydrophilic. So things that are hydrophobic can't move in water. Just as you would dump

00:27:52.280 olive oil into a glass of water, you would quickly realize how much they repel each other.

00:27:58.920 So we have this totally essential thing that we have to move around the circulatory system. Otherwise,

00:28:06.340 we would die. And we can't do it directly because the medium through which we need to

00:28:11.980 transport it repels the thing we're trying to transport. Aha, there's a solution. We need to

00:28:19.400 create a vehicle that we can transport this in. And that vehicle is called a lipoprotein.

00:28:26.840 And as its name suggests, lipo and protein, it's part lipid, part protein. And it's engineered in

00:28:34.880 a way that the lipid part is on the inside. The protein part is on the outside. Protein is water

00:28:40.380 soluble. So now you create this spherical molecule, which on the inside, you can package the cargo that

00:28:49.280 is hydrophobic, repels water. And on the outside, you have a coating that is hydrophilic, that is

00:28:56.460 attractive to water, and moves effortlessly through the water. And that's how we transport cholesterol.

00:29:04.000 Now, broadly speaking, these lipoproteins traffic in two types of families. A family that is defined by

00:29:12.920 ApoB, which is a lipoprotein that wraps around it, or an apolipoprotein that wraps around the

00:29:20.260 spherical larger lipoprotein. And ApoA, there's an ApoA family, there's an ApoB family. Technically,

00:29:27.140 there's two ApoB families. There's an ApoB 100 and an ApoB 48. I'm going to ignore the ApoB 48 right

00:29:34.640 now. That just exists on chylomicrons. And we could do another class on that at another day. But for now,

00:29:40.360 we're going to focus on ApoB 100, which defines the lineage of lipoproteins that are terms you've

00:29:48.160 probably heard of, VLDL, IDL, LDL, LP little a. And the ApoA lipoproteins define a totally different

00:29:55.560 class of these called HDLs. So what do those names mean anyway? VLDL, IDL, LDL, HDL. They all refer to

00:30:04.380 another feature of the lipoproteins that is distinct from the ApoLipoprotein that wraps around them,

00:30:10.360 which is their density. So if you think about the high school experiment where you take various

00:30:16.820 different substances and you put them into water, you might notice that you can separate how they

00:30:23.540 would float. Now, water is kind of a bad example of how that works because things are typically

00:30:28.980 binary behaving in water, either they're sink or they're going to float. But I think that gives you 0.99

00:30:33.360 a conceptual understanding of the difference in density. Density is mass over volume. And a higher

00:30:41.080 density object relative to a lower density object will sink versus float. So if you take all of those

00:30:48.760 lipoproteins that I mentioned, all of the ApoB ones, all of the ApoA ones, and you put them in a certain

00:30:54.440 type of gel in the lab, you can see a separation of them based on their density. And the highest density

00:31:01.420 ones of those, we just call the high density lipoproteins, the HDLs. You have more than one

00:31:08.120 ApoA on an HDL and you have different subclasses of HDLs. HDLs are really complicated and we don't

00:31:13.980 even come close to understanding all the ins and outs of them, which by the way is why I get really

00:31:18.880 annoyed when people say having a high good cholesterol is good. Again, what they really

00:31:23.740 mean to be saying is having a high HDL cholesterol is good. And while it's true that on average,

00:31:31.200 higher HDL cholesterol is associated with and traffics with metabolic health in a way that

00:31:39.000 low HDL cholesterol tends to traffic with bad metabolic health, you can absolutely not tell by

00:31:45.760 looking at an individual based on how high their HDL cholesterol is, if they're in good shape or not.

00:31:51.380 Because that single snapshot of how much cholesterol is in the HDL tells you nothing about the

00:31:57.740 functionality of the HDL and it's the functionality of the HDL that matters. I'm not going to talk any

00:32:02.800 more about that because I have an entire podcast coming out on HDL biology where we'll go into that

00:32:08.020 in great detail. But it should be stated that efforts to raise HDL cholesterol pharmacologically

00:32:15.120 have by and large, mostly not exclusively, but mostly failed in improving outcomes.

00:32:21.360 Okay. So over on the LDL ApoB side, the most abundant ApoB 100 or ApoB for short lipoprotein is

00:32:29.880 the low density lipoprotein. That's the one that gets called bad cholesterol. And again, on the ApoA

00:32:36.780 side, we have HDL, which gets called good cholesterol. So a couple of things I want to say on this.

00:32:41.840 One, if you're talking LDL, you are referring to the low density lipoprotein. If you say HDL,

00:32:49.180 you are referring to the high density lipoprotein. But if someone says, what is your HDL? What is your

00:32:56.160 LDL? They're asking for a laboratory metric. They are asking incorrectly. There is no laboratory metric

00:33:02.780 called LDL or HDL. There is HDL cholesterol, LDL cholesterol, abbreviated LDL-C and HDL-C.

00:33:12.440 There is LDL-P and HDL-P, which is the particle number of LDL, which can be counted via electrophoresis

00:33:19.700 or NMR. Of course, my preferred way to count the number of these particles is to look at ApoB.

00:33:25.580 The ApoB concentration to me is the most important number you want to understand to predict from a

00:33:32.480 biomarker standpoint, your cardiometabolic risk, ASCVD risk, because it captures all of the

00:33:38.300 atherogenic particles. So ApoB counts the total of the LDLs, inclusive of the LT little A's, 0.61

00:33:44.920 the IDLs, although they virtually never exist. They have such a short residence time and the VLDLs,

00:33:49.300 which can become problematic in people with metabolic syndrome and high triglycerides.

00:33:52.820 So ApoB gives you the total atherogenic burden of those lipoproteins. And therefore,

00:33:57.540 I think it's the preferred metric by which we want to assess risk. But if you want to look at LDL,

00:34:02.520 you have to look at LDL-C, LDL cholesterol. And HDL, you have to look at HDL cholesterol.

00:34:08.880 Now, is the cholesterol in the HDL any different from the cholesterol in the LDL? No, of course not.

00:34:15.360 Therefore, it is totally erroneous to say HDL is good cholesterol and LDL is bad cholesterol.

00:34:21.640 No, instead, what is true is that LDLs themselves as lipoproteins are bad actors because of what they

00:34:31.140 do. What they do is they go into artery walls where they get oxidized and they basically dump

00:34:39.180 their oxidized sterile contents into the subendipelial space, which elicits an immune

00:34:45.280 response and a whole bunch of other things that lead to atherosclerosis, which I'm not going to get

00:34:48.340 into now. But the point of this discussion that I want people to understand that LDLs and HDLs are

00:34:54.900 lipoproteins. If you want to talk about the cholesterol, you talk about LDL cholesterol and

00:34:59.060 HDL cholesterol, but the cholesterol in them is the exact same. And there is no such thing as good

00:35:03.800 cholesterol or bad cholesterol. And so you just have to be careful when you see things written

00:35:09.980 that are written through that lens, because what it tells you is the person writing this doesn't

00:35:15.040 understand the basics of lipids and lipoproteins. And if they don't understand the basics of lipids

00:35:20.960 and lipoproteins, because what I just told you guys is literally the 101 on this subject,

00:35:25.700 we didn't get to the senior level class, let alone the graduate level class. And this is complicated

00:35:31.920 stuff once you get into that level. So if someone writing to me is butchering the 101,

00:35:37.520 you can stop reading. Because whatever else they're saying, they're undoubtedly screwing

00:35:43.200 it up. So there it is. There's the TLDR on lipids.

00:35:48.180 If a doctor gets a report now, he gets total cholesterol, triglycerides, non-HDLC, LDL-C,

00:36:02.920 HDL-C. Five numbers. Do you think he actually looks at any of those numbers? He's trying to do a good

00:36:09.360 job. He does. But let's say the triglycerides are high. Can he do anything with that? Nope.

00:36:15.440 Because everything is based on LDL-C. So he's got, in reality, four numbers that are doing nothing.

00:36:23.300 Let's explain that to people, Alan, because you and I know the ins and outs of that very well. But

00:36:27.960 I think most people here don't understand the difference between the calculated and measured

00:36:33.100 LDL. So let's start with that. And then let's talk about how VLDL has been estimated. And let's

00:36:39.680 bring this all back in terms of some other work you've done, which is understanding the role of

00:36:44.680 triglyceride in ApoB. So let's start with the basic. You go to the doctor, you get a set of labs done,

00:36:51.060 and the LDL number comes back at 140 milligrams per deciliter. Is that actually what it is? Or is

00:36:57.120 that an estimation? That's an estimation. It's almost always a calculation. And there are at least

00:37:04.100 eight different methods to calculate LDL cholesterol. So if there are eight different methods, they don't all

00:37:09.840 give the same answer or you wouldn't have eight different methods. LDL cholesterol can also be

00:37:15.320 measured directly. That assay has never been validated in disease patients. And no one has

00:37:21.780 ever published a paper showing that it's more accurate in terms of disease identification than

00:37:28.920 calculated LDL cholesterol. And yet people have paid good money for that lab test. There's no question

00:37:37.160 that the number of LDL particles is a more accurate index of risk than the LDL cholesterol. The VLDL

00:37:45.960 cholesterol is a cholesterol that's in the very low density lipoprotein particles, the particles that

00:37:52.160 come out of the liver. That cholesterol is atherogenic. There's a lot of triglyceride in that particle.

00:37:59.440 So the people who measure triglyceride say, well, the triglycerides are high. That must be the

00:38:05.000 problem. And there's no question that people with high triglycerides are at increased risk of heart

00:38:10.360 disease. But the people with the high triglycerides who are at increased risk of heart disease have a

00:38:16.320 higher number of LDL particles and VLDL particles. It's the particle. And when you're measuring the

00:38:22.900 triglyceride, you're just measuring a blob of liquid in a bunch of particles and you need to know

00:38:29.600 the number of them. So it's an important number in the sense of if you're a lipoprotein guy trying

00:38:37.520 to figure things out. If it's extremely high, it increases the risk of pancreatitis. But I haven't

00:38:43.920 seen any solid evidence that triglyceride itself is pro-atherogenic. What's atherogenic is the

00:38:50.020 cholesterol inside the VLDL particles. It's the number of those particles that get into the wall. Now,

00:38:55.660 there's a complicating reality. Because in general, all I need to know is the ApoB. But there is a

00:39:03.180 disorder called remnant, type 3 dyslipoproteinemia. And that's a very specific, highly atherogenic

00:39:12.140 condition that manifests with high triglycerides, high cholesterol, but get this, you know, low ApoB.

00:39:21.360 So when I measure my lipids in ApoB, I can recognize that. But if you don't measure the ApoB,

00:39:28.720 and this applies to most of the people who are listening to this podcast,

00:39:32.900 if they go to see their doctors, that condition can't be diagnosed.

00:39:41.700 Our last out of clips will focus on why I think ApoB is a superior lipid metric

00:39:45.700 to LDL cholesterol or even non-HDL cholesterol when trying to predict risk.

00:39:51.360 Are you optimistic? I mean, is this just a question of time? I mean, in 10 years,

00:40:01.580 will kids in med school be learning about ApoB instead of LDL?

00:40:06.180 I'm pessimistic. Europe, the 2019 guidelines were very pro-ApoB. The evidence from Mendelian 0.81

00:40:13.340 randomization, like the newer technologies, Mendelian randomization, they've just been

00:40:17.880 slam dunk for ApoB. Let's explain that to folks, because I want to talk about the causality

00:40:23.220 of this, and this might be the perfect way to actually explain the causality of ApoB in the

00:40:29.660 context of this tool. So can you explain to folks what a Mendelian randomization is? People see this

00:40:36.640 all the time in studies, but I don't think it's entirely clear for the average person what it means.

00:40:41.040 I'll try, okay? It's not my expertise, but I'll try. The conventional ways of taking things apart

00:40:49.480 with prospective observational studies like Framingham, there's a limited amount of the

00:40:55.340 certainty of your conclusions because of confounding you can't deal with. You take measurements at age 20

00:41:02.400 and you follow someone for the next 30 years. Well, a lot of things change in the next 30 years that

00:41:08.420 you don't have a handle on. Your inferences are probable but not causal. What Mendelian randomization

00:41:17.040 allows you to do is to come a lot closer to causality because, for example, you can identify

00:41:26.280 groups of genes that are associated where changes in the gene are associated with a little lower

00:41:31.980 cholesterol or a little higher cholesterol. And when you lump together a bunch of those different

00:41:38.440 genes that can have different makeups because you can change the makeup of a gene pretty easily,

00:41:44.540 you can see fairly substantial differences in cholesterol. So what you've got is information on

00:41:52.400 somebody that's fixed at birth. And you see, is that associated with a difference in outcome?

00:42:00.260 You've gotten rid of a lot of stuff in the middle. And what a number of Mendelian randomizations have

00:42:07.640 shown is that ApoB includes all the information in triglycerides, LDL cholesterol, and even HDL

00:42:15.380 cholesterol. It sums them, which in the sense of VLDL and LDL makes perfect sense. So there are caveats

00:42:23.260 in Mendelian randomization. You can't just push a button and say, give me the answer. But George

00:42:30.920 Davies Smith, really arguably one of the founders of Mendelian randomization, or not arguably, he was,

00:42:37.660 he's the author of a number of the Mendelian randomizations saying ApoB incorporates and therefore

00:42:45.520 beats triglycerides and LDL cholesterol. So that's a huge level of information

00:42:53.800 that isn't even mentioned in almost any of the guidelines.

00:42:59.580 Yeah. So let's make sure people understand everything you just said, because you said a lot

00:43:02.880 of things in there. When you prospectively follow a cohort, the way the Framingham cohort was followed

00:43:09.760 or the Framingham offspring or the MESA cohort, or any of these cohorts have been followed. You can

00:43:15.100 take a bunch of people and you could measure their ApoB or their LDL-C or whatever metric it is that

00:43:20.760 you're trying to determine if it in fact has a causal relationship to the disease of interest.

00:43:25.520 You can follow them over decades and you would demonstrate as has been demonstrated that the

00:43:31.780 people with higher B, higher LDL-C, higher non-HDL-C and lower HDL-C all have a higher risk of developing

00:43:41.200 atherosclerosis over time. But it's hard to say that that's causal just based on that information,

00:43:47.520 because over the ensuing 20 years that you follow them, they are free to make other choices that may

00:43:54.960 impact those variables of interest and other variables. So the Mendelian randomization attempts

00:44:01.440 to get around that by saying, at the time of, I was going to say birth, but really at the time of

00:44:08.000 conception, we all get randomized to a set of genes. We get assigned a set of genes. I guess they're not

00:44:15.060 perfectly random because they come from our parents, but for the purpose of not changing,

00:44:19.780 they are indeed a random assignment that is fixed. If we can identify which genes map to which

00:44:29.400 phenotype and we can figure out the genes that map to the phenotype of our interest, namely driving up

00:44:37.500 or down a variable of interest such as APOB, then we don't really have to worry about the confounders

00:44:43.620 that occur in between because the genes can't change. Just to put a bow on that, basically,

00:44:50.560 now when you see a difference in outcome, it's much more likely to be causally related to the

00:44:58.720 phenotype of interest because the gene has not changed that underlies it. Now, what are some of

00:45:04.580 the ways that we can get tripped up with Mendelian randomization? I mean, there's some pretty big ones.

00:45:09.500 Yeah. Before we get there, HDL cholesterol was the rage, okay? The total rage because the epidemiological

00:45:18.980 evidence couldn't be clearer. In fact, it was four times more clear. My recollection

00:45:24.480 was that Framingham demonstrated low HDLC was four times more predictive of cardiac events than high

00:45:33.400 LDLC. Am I remembering that correctly? I'm not sure it's that multiple. Yeah, but it's multiples.

00:45:38.500 And it turns out, as we know now, at least from the CTP inhibitors, that you can't manipulate HDL

00:45:45.900 and change outcomes. And that's one of the elements of demonstrating an overall causal relationship.

00:45:53.040 And the Mendelian randomization show HDL is not causal, whereas they show APOB is. And cholesterol

00:45:59.760 is too, by the way. Those are two very important studies, Alan. I mean, and both of those have been

00:46:05.300 in the last 10 years. Yeah. It's an incredible technical advance in being able to examine questions

00:46:15.720 and look at numbers of people that would be unimaginable in conventional studies. The Mendelian

00:46:23.680 randomization, they're always talking hundreds of thousands of people because they've got these huge

00:46:27.480 data banks with genes. And those numbers get you around the confounding of things. You have huge

00:46:34.460 numbers. But it's like any methodology. No method is perfect. This one can mislead you too,

00:46:43.420 particularly when you've got a sequence of associated variables. For example, people show using MR that

00:46:50.720 triglycerides were, quote, causal or associated with increased risk. But when you took into account

00:46:57.300 the non-HDL cholesterol or the APOB, it disappears. So when you've got a linked metabolic chain,

00:47:03.680 you've got to be careful that you've gone to the end of it. You've got the real actor,

00:47:09.580 not act one leading to, that you've got the real persona dramatis. Which is why it's surprising that

00:47:16.460 HDL didn't, at least at the first order, demonstrate causality. Because there's no doubt that phenotypically,

00:47:24.700 the high triglyceride, low HDL phenotype is so associated with metabolic syndrome that it makes up two

00:47:33.040 of the five criteria. That's an incomplete description. That's like you describing yourself

00:47:40.720 as six feet tall, I wish, and not giving your weight and letting me guess your BMI. You cannot

00:47:49.820 characterize any phenotype without the APOB. It really drives me around the bend. When people

00:47:57.700 speak saying, I got somebody because I got their triglycerides and their HDL. Well, I say, okay,

00:48:03.760 what's their APOB? How can you pretend you've evaluated the system when you haven't counted the

00:48:10.640 number of atherogenic particles? Because they could be normal, they could be high, or you can have a type

00:48:17.040 three. They don't know. And it's not a phenotype. There is no phenotype without putting any APOB in

00:48:26.300 there. They're lipoprotein particles. They're disorders of lipoprotein particle metabolism. Of

00:48:35.860 course, the triglycerides and cholesterol are important. But my analogy, I didn't do a good

00:48:40.680 analogy there. But it's so fundamental that it drives me to distraction as to why you wouldn't

00:48:51.460 want to know a core element of knowledge. But it doesn't seem to bother many of my friends.

00:48:58.880 You walked through the pathophysiology of how the APOB-bearing particle wreaks havoc in the artery wall

00:49:05.340 many, many years before we see clinical events. And you also mentioned that there are other

00:49:10.640 factors that can amplify or exacerbate that. I can't remember exactly how you said it, but that

00:49:15.120 was the gist of it. Well, two of those things that are widely accepted to exacerbate risk are smoking

00:49:23.040 and hypertension. In fact, smoking and hypertension probably carry a greater risk for atherosclerosis

00:49:30.620 than APOB, or is that not the case? It all depends the way you think about it. Because if you just

00:49:37.400 say, what's the risk somebody with hypertension faces, they have high risk, no question. But then

00:49:42.440 you say, what is hypertension? The last 30 or 40 years, there have been almost an infinite number

00:49:50.480 of basic science studies on hypertension. And when you were in medical school, and even before that,

00:49:56.300 when I was in medical school, we talked about pathophysiology of hypertension. And what strikes me

00:50:02.560 is, we don't talk about the pathophysiology of hypertension anymore. But the basic science

00:50:09.780 goes on in rats, is healthier than ever. And there isn't anything I know of that's come out of that

00:50:17.100 basic science that's been clinically useful in the last 30 years. The drugs we use, we use them

00:50:23.680 because they work. So what is hypertension? It's a higher blood pressure than we should have.

00:50:31.480 And where is the disease that produces that higher blood pressure? Is it resistance? We don't have a

00:50:37.980 clue. Okay? We don't have a clue. And it strikes me it's the same thing as much of the debate in lipids

00:50:44.320 about APOB, or the drunk looking for the key under the light, because this is where the light is,

00:50:50.120 not where he lost it. Everybody who's anybody has the same viewpoint. My bet is it's in the proximal

00:50:57.120 aorta. My bet is that it isn't that complicated. We lose elastins in the proximal aorta. And that's

00:51:04.140 systolic hypertension. Thank you very much. What could accelerate that process?

00:51:09.700 What's the mainstream view that this is renal?

00:51:12.520 When I read hypertension, I get lost because I get page after page after page of peripheral

00:51:18.820 arteriolar tone and very complex metabolic studies and very sophisticated animal models.

00:51:27.400 And there's some renal left. It's a miasma for me, an absolute miasma.

00:51:33.240 I hadn't heard about the proximal aorta. So say a bit more about that.

00:51:36.480 Well, this is me. The proximal aorta is elastic. And if you look at a flow curve,

00:51:42.320 a hydrostatic pressure curve, when we're young, it's rounded because as the left ventricle ejects

00:51:49.620 blood rapidly into the aorta, the aorta expands. So it absorbs some of that energy. You know that

00:51:56.440 wind kessel that they mentioned in school? That's not that big a deal, but the energy is partially

00:52:03.380 captured, partially regained. But the wall isn't battered. The wall can give way. Me, personally,

00:52:13.460 just in the middle of my brain, imagine that if those elastic fibers start to go, then the wall's

00:52:20.280 stiff. So now when the left ventricle ejects blood, the pressure goes up more rapidly and it falls more

00:52:27.360 rapidly and diastole. And that's why you get systolic hypertension with normal diastolic pressures.

00:52:33.440 So my bet would be, if I was not the age I am, I would be looking at factors like cardiac output

00:52:40.100 again, which used to be way back when, or factors that alter the behavior of the proximal aorta.

00:52:46.460 As much as something that's, to me, pathophysiologically, much more likely to be involved. So once I got

00:52:55.180 hypertension, okay, then I've got a driving force to push particles into the wall.

00:53:00.720 And so you think it's the actual increase in the pressure of the plasma?

00:53:06.780 And the response of the wall. I think there are responses to the wall. The wall thickens up. It

00:53:11.300 gets harder for particles to go through.

00:53:13.300 Does it also damage the endothelium? Do you think that plays a role?

00:53:16.360 That's right. I don't understand endothelial dysfunction. It's more a language thing to me

00:53:21.860 than it is a reality. I know the endothelium is critically important. It functions abnormally,

00:53:27.220 and that's endothelial dysfunction. How that fits into the overall thing, I don't know.

00:53:33.160 My bet is ApoB particles are part of the process of inducing endothelial dysfunction,

00:53:38.400 but I don't know that clearly experimentally. So going back then to the question at the top,

00:53:46.680 does it make sense to even compare hypertension to ApoB? They both seem to play a causal role.

00:53:53.020 Is one more causal than the other, or is that a silly question because they're not binary and static?

00:53:59.600 I think that's not the right question. I think our blood pressure goes up as we age.

00:54:04.060 I mean, hypertension involves so much of the population, it's not clear to me what the word

00:54:10.420 disease means. The prevalence as we age is so high that to me, it's becoming almost an aging process

00:54:19.480 because we're lasting a lot longer than we were probably designed to go. So you have this repetitive

00:54:25.000 injury to the proximal aorta. It gets a little progressively less able to deal with it. So in the

00:54:31.880 time we're 50, what percent? 60% have higher blood pressure. I mean, the figures are staggering.

00:54:37.960 Is it really that high?

00:54:39.140 I'm not sure. Don't quote me on that, but it's high, high, high.

00:54:42.920 But doesn't ApoB also rise with age?

00:54:45.640 It does rise with age, but not that much. When we look at people at age 35, we can pretty

00:54:53.600 accurately categorize the group they belong to at age 35. Not that they won't change somewhat. So

00:55:00.440 if you're high at age 35, you got about a 95% chance of staying high. 5% will go out of the high

00:55:08.800 zone. They won't go low, low. So if you're high at age 35, I wouldn't bet anything's going to move

00:55:16.780 you down. That's why I think it's such a good signal for when we should start thinking about

00:55:22.160 treating people. And if you're low, some people go from low towards high, but the majority don't,

00:55:29.100 and we keep following them. But if you're high, no, we've published a fair amount of this. If you're

00:55:36.060 high, it's not a hundred percent, but it's about 90% that you're going to be high.

00:55:41.780 Is there a gender difference? At least clinically, I seem to see women as they go through menopause

00:55:46.740 experience dyslipidemia that men wouldn't experience over that same decade or even five-year

00:55:52.140 transition.

00:55:52.600 I think there are changes and ApoB goes up with menopause. I'd like there to be more data. I think

00:55:59.520 part of the reason it's held ApoB back is that people didn't measure it. So they were sort of,

00:56:05.080 well, what I measured has to be important because I can't answer your question. Hopefully more data

00:56:10.320 will be coming. But I agree with you. People can change at the menopause. So I'm not saying we don't

00:56:15.300 keep looking at people. But when you have somebody at age 35 to 40 who's high, the odds are high that

00:56:22.420 they're going to stay high.

00:56:24.100 Are we doing a better job treating hypertension than dyslipidemia?

00:56:28.040 I have no idea. The incidence of coronary disease is going up in the last five years. And that's

00:56:34.580 despite statin therapy. And that's the obesity diabetes. So I think we've been too quick to congratulate

00:56:43.460 ourselves at how well we're doing. There are many reasons that treatment is not succeeding as well

00:56:50.060 as it should. And I think the complexity of the lipid phenotype of the lipid model is part of the

00:56:57.100 answer. It's easy for me. I get the ApoB where I want it to go. Yeah. I mean, an explanation for your

00:57:03.600 observation would be if in the last five to 10 years, the incidence of atherosclerosis or major adverse

00:57:09.480 cardiac events is rising, despite the advances we have, you would argue or could argue that if

00:57:16.060 we're measuring LDL-C, and that's our proxy for treatment, but as dyslipidemia is growing in the

00:57:24.380 metabolic context, meaning if you have more medicine and more insulin resistance and more type 2 diabetes,

00:57:29.860 we know that those phenotypes are associated with greater discordance between ApoB and LDL-C,

00:57:34.600 suggesting that you'd have a greater and greater portion of the population that is being undiagnosed

00:57:40.520 or being underdiagnosed because you're treating their LDL-C and you believe that it's lower than

00:57:47.120 their risk actually is because their ApoB is higher. I know you know what I just said. I hope the listener

00:57:51.620 understands what I just said. Yeah. What you just said was important. It's another example,

00:57:58.360 an unfortunate, sad example. They're trying to quantify lipoproteins based just on lipids,

00:58:04.600 is not adequate. You're not capturing all the information that you should.

00:58:15.000 Let's go back to kind of the macro point here around ApoB, which is a greater coalescing around

00:58:22.060 the idea that ApoB concentration matters. So I think it's very well understood that two of the

00:58:30.640 biggest risk factors for cardiovascular disease are smoking and hypertension. I don't think there

00:58:36.440 is any ambiguity that cigarette smoking and high blood pressure increase the risk of cardiovascular

00:58:42.740 disease. And they both appear to do so through a mechanism that weakens the endothelium or creates

00:58:49.480 an injury to the endothelium. The question now becomes, as you put it, Tom,

00:58:56.020 how ironclad is the story that it's the ApoB bearing particle in the presence of injured

00:59:04.440 endothelium that is the Trojan horse that begins this destructive trajectory of taking that cholesterol

00:59:13.240 into the subendothelial space, becoming retained, undergoing this chemical oxidation process,

00:59:21.160 which then kicks off an inflammatory response that paradoxically, as an attempt to repair the

00:59:27.480 damage, results in what can be a fatal injury. There are other hypotheses. For example, there are

00:59:34.780 people who note, and we have, I mean, look, I have a patient in our practice, Tom, you've weighed in on

00:59:39.540 her case, walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams 0.93

00:59:47.580 per deciliter, an ApoB of 170 milligrams per deciliter. She's in her late 60s and her coronary

00:59:56.180 artery calcium score is zero. We have elected to not treat her with any lipid lowering therapy.

01:00:01.700 In other words, there are exceptions to this. How do we reconcile that?

01:00:08.800 Well, it's the human body in medicine. As you know, not all smokers are going to come down with

01:00:13.560 lung cancer or chronic obstructive lung disease. Why not? If that's such a horrible risk factor.

01:00:20.040 I try to explain this, and I've certainly seen cases like you say, where, oh my God,

01:00:25.160 if I was just going to say, give me your ApoB or whatever cholesterol metric, you're going on three

01:00:30.440 drugs right now. You've got no choice. And maybe in the old days, we approach people that way, but no

01:00:35.900 more. I think you have to individualize your whatever risk factors you discover that might wind up

01:00:42.160 causing atherogenesis and then figure it out. So particle number is certainly a major factor that

01:00:49.700 might force it in, but not always. Endothelial function, although you can certainly, if you

01:00:55.060 review the history of this and how do you really determine endothelial function, not everybody has

01:01:00.580 serious endothelial dysfunction who winds up with atherosclerosis. So particle number itself in some

01:01:06.020 people can just make the particles go in. I think if we take most adults, who's not going to have

01:01:12.120 a little bit of endothelial dysfunction. So I agree with you, it's a combination of something

01:01:18.520 about atherogenic particles, be it their number, endothelial dysfunction. But I'm talking more and

01:01:24.500 more now when I discuss any type of lipoprotein, I don't care which subgroup you want to talk about.

01:01:30.240 I think we certainly have to know its particle concentration, but I like to talk about particle

01:01:35.780 quality. So what are the other attributes of any lipoprotein that might contribute to its

01:01:42.540 atherogenicity or in some perhaps not understood, make it relatively, it's not going to generate

01:01:49.700 atherosclerosis. And there certainly have to be things like that going on. So as we're getting

01:01:54.460 smarter, we're looking at other components of the lipoproteins that could be other proteins that are on

01:02:00.480 them, that could be their complex lipidome. And trying to see, aha, can that help us discern

01:02:06.680 whether in you a given particle concentration is more worrisome than it is in the next person.

01:02:14.760 So there's a lot going on. And also from the gist of this conversation, listeners will know

01:02:20.560 atherosclerosis, atherogenesis is a multi-complex, multi-factorial disease.

01:02:26.660 And that's why even when Peter and I, if we consult on a case and we realize in this person,

01:02:33.000 we have to beat up ApoB and get their particle numbers to a more physiologic range, we don't

01:02:38.540 stop once we do that. We examine in great detail for other things that might be injuring the endothelium

01:02:44.680 or the arterial wall and see are any of those treatable or so. So we're getting a little bit

01:02:50.080 smarter on lipoproteins, but there certainly is more to it than just particle number.

01:02:54.080 Do we think that there's a limit to where the benefit of reduction becomes diminishing or even

01:03:01.860 J curves in the other direction? So we discussed it in the first episode significantly. We did so

01:03:08.920 again with Ron Krauss. It wouldn't be the worst idea in the world a couple of years from now to sit

01:03:15.000 down and do it again and re-examine the data. But again, I think the causal relationship between

01:03:19.960 ApoB and atherosclerosis is as strong as virtually anything we see in medicine for which you can't

01:03:28.200 do the perfect experiment where you have to rely on natural experiments. Nevertheless, maybe it's not

01:03:34.900 entirely clear what the dose response looks like. So if you have somebody whose ApoB is 160 milligrams

01:03:41.220 per deciliter, there's a risk reduction that comes to lowering it from 160 to 100 and lowering it from

01:03:48.180 100 to 80 and lowering it from 80 to 60. What do we know about the risk reduction in lowering it,

01:03:56.600 say, from 60 to 40 to 20? And I ask both what we could infer pharmacologically and non-pharmacologically.

01:04:04.920 In other words, from the Mendelian randomization versus the pharmacologic.

01:04:09.600 Well, even using pharmacologic trials and Mendelian randomization, the concept you're going to come

01:04:15.840 across with is lower is better. And with the pharmacologic thing, we're modulating things

01:04:21.820 that either have clinical trial proof that if you lower them, it's good, or the Mendelian

01:04:26.440 randomization, looking at genes where that drug might be doing something, it works. Now, you do need

01:04:33.560 a few ApoB-containing lipoproteins. They do traffic other lipids. They traffic fat-soluble lipoproteins.

01:04:40.100 But we must never confuse A-beta lipoproteinemia, where nobody or that person can't make them,

01:04:46.800 or hypo-beta lipoproteinemia, where they make a few enough to traffic those other things that

01:04:52.720 a lipoprotein might have to traffic. But even the guidelines where they examine people looking at

01:04:59.760 their baseline ApoB or LDL cholesterol, the first thing they suggest, at least in the higher risk

01:05:05.260 people, is try and get a 50% reduction. And that's where most of the bang for the buck is

01:05:10.500 going to be. Now, if you still have options that you can lower it further, yeah, the trials show,

01:05:17.300 yeah, there is incremental reduction events, but it's a much smaller absolute risk reduction and

01:05:23.280 dropping at the 50% or so. So I don't know if that answers your question. So most people don't have

01:05:31.140 the type of levels where with modern therapeutics, with modern lifestyle, we can more often than not

01:05:38.940 attain physiologic concentrations. And if I want to talk about ApoB, that's probably under 50 milligrams

01:05:45.540 per deciliter if we can get there. That's what the newborns have. That's when you go in clinical trials,

01:05:52.520 if you take it down that low, you see your most risk reduction. And so far, at least with pharmacologic

01:05:58.860 lowering of ApoB with the currently FDA-approved drugs, there is no signal of harm.

01:06:06.200 Yeah, again, it's funny because I was just about to say, with the current crop of drugs,

01:06:11.400 specifically the PCSK9 inhibitors, we are routinely seeing patients who easily can get an ApoB into the

01:06:20.740 20 to 40 milligram per deciliter range. You and I actually sat down a couple of months ago and did a

01:06:27.820 calculation to estimate how much cholesterol is actually contained in the circulating lipoproteins

01:06:36.520 versus that which is in cell membranes. Do you remember doing this with me?

01:06:41.500 Not per se, but we're developing equations. You're the master of that.

01:06:47.680 Well, it was one of these things, right? It was sort of like, look, when you look at a person's

01:06:51.840 plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body glucose.

01:06:59.380 And similarly, there's such a concern about plasma cholesterol level, but given how essential

01:07:07.200 cholesterol is, it's understandable why people would be concerned that low cholesterol could be

01:07:12.200 problematic. But once you do the calculation and realize virtually all of the cholesterol in the

01:07:17.740 body is contained within the cell membrane or within the steroidal producing tissue, the circulating

01:07:25.620 amount is a very narrow window into the total amount of cholesterol and therefore a reduction of say

01:07:33.720 60 milligrams per deciliter to 50 milligrams per deciliter of ApoB or even something more extreme,

01:07:42.060 like a full 50% reduction of total cholesterol, 200 milligrams per deciliter to 100 milligrams per

01:07:49.380 deciliter does not represent a significant reduction in total body cholesterol. This is a very important

01:07:55.000 point, right? Let me repeat it. You have a total body cholesterol that you measure in the plasma that

01:08:01.500 says, oh, it's 200 milligrams per deciliter. That goes down to 100 milligrams per deciliter. Let's say

01:08:06.640 the LDL fraction reduced from, you know, 150 to 75 or something. Someone might say, God, you just cut

01:08:13.500 cholesterol in half. That can't be good for you given the importance of cholesterol. But my point is,

01:08:19.280 no, you simply cut the amount of cholesterol being carried by the lipoproteins in the plasma

01:08:24.120 in half. That doesn't capture the majority of the cholesterol. 0.98

01:08:28.680 Yes. Thanks for refreshing my memory. What you're talking about now, it's really pools of cholesterol

01:08:34.600 throughout the body. And I think I'm so glad you brought this up because this is just not even

01:08:40.220 understood. Even in the lipidology community, we have a total body cholesterol. There are basically

01:08:46.460 three pools. There's your brain and nothing we're talking about today has anything to do with brain

01:08:52.020 cholesterol. It's a separate system. It doesn't interact with the other cells in your body or

01:08:56.780 certainly with the cholesterol in your plasma. So if it's not in your brain, where is cholesterol in

01:09:02.480 your body? Well, it's either in all your peripheral cells, perhaps some more than others,

01:09:07.560 or it's circulating in your plasma. And if it's in the plasma, where is it? There's an

01:09:14.200 eatsy-weensy amount bound to albumin. There's more bound within all of the lipoproteins that are

01:09:20.920 trafficking in your body, meaning your ApoB and your ApoA1 particles. But believe it or not,

01:09:26.900 if I wanted to search down blood cholesterol for you, I would suck out your red blood cells and 0.99

01:09:32.480 extract cholesterol from them. Red blood cells carry far, far more cholesterol than do all of

01:09:38.900 your lipoproteins put together. And the other crucial point you made subtly, and I hope everybody

01:09:44.740 understood you, the amount of cholesterol within your lipoproteins has no correlation with your

01:09:51.020 cellular cholesterol or even your red blood cell cholesterol. So however you're modulating some

01:09:57.880 LDL, total cholesterol, HDL cholesterol metric, that tells you nothing about what might you be

01:10:04.780 doing to the cholesterol content of your cells. So don't have a panic attack if you're making LDL

01:10:11.760 cholesterol 30, because I can assure you virtually every cell in your body, even if that's your

01:10:17.300 plasma LDL cholesterol, has more than enough cholesterol because it can de novo synthesize

01:10:22.880 it. It can put it in its cell membranes or other organelles that require cholesterol. If it's a

01:10:28.100 steroidogenic tissue, it can produce a little more or perhaps delipidate some. So there's no cell that's

01:10:35.240 being deprived of cholesterol in the periphery when you are modulating lipids through lifestyle or drugs.

01:10:47.300 So on ASCVD, I've also become far more aggressive on the timing and magnitude of ApoB reduction.

01:10:59.280 So take a step back and ask, what are the leading causes or modifiable causes of ASCVD? The big three

01:11:08.600 are pretty unambiguously smoking, hypertension, and hyperbeta lipoproteinemia, which is just a really

01:11:16.840 fancy word for saying too many lipoproteins that have ApoB on them. So that's LDL, IDL, VLDL, LP little

01:11:25.960 a. By measuring ApoB, why I'm such a fan of measuring ApoB as opposed to just measuring LP, LDL particle

01:11:34.040 number or LDL cholesterol number is we have one single number that captures the total concentration

01:11:40.840 of ApoB. And while that's pretty well associated with non-HDL cholesterol, which is a far better

01:11:46.500 surrogate than LDL cholesterol, it's still better. And that's been demonstrated. And I think we even

01:11:52.220 covered that in a previous podcast where we went over the discordance between non-HDL cholesterol

01:11:58.380 and ApoB. So now the question becomes, well, when should you start ApoB reduction and how much

01:12:05.340 should you lower it? And I'll tell you, I used to take a point of view that if a 40-year-old

01:12:11.040 had an elevated ApoB, let's just put some numbers to this, right? So the 20th percentile of ApoB is

01:12:19.000 about 80 milligrams per deciliter. I used to say that, let's say somebody was at the 50th percentile,

01:12:26.260 they're 40 years old, their calcium score is zero, and they were ambivalent about lipid-lowering

01:12:31.940 therapy. And let's assume that they're not insulin resistant, and you've done all of the things that

01:12:36.460 you can do reasonably with nutrition. I wouldn't push that hard. I've now taken a very different

01:12:42.140 stand, which is I've basically taken the stand with others that I've taken with myself, which is

01:12:47.040 the evidence is overwhelming that infantile levels of ApoB are not deleterious in any way. Meaning

01:12:56.140 an ApoB of 30 to 40 milligrams per deciliter, which is the level that children would have,

01:13:01.940 poses not only no risk to children as evidenced by the fact that, I mean, that doesn't require

01:13:07.080 an explanation, but as evidenced by what we see in the literature on adults with levels that have

01:13:14.280 been pharmacologically reduced, tells me that we need to be lower. And the amount of time it takes

01:13:19.960 to see a benefit tells me we don't want to wait until there's an issue. In other words, if the reason

01:13:26.120 we begin therapy is because somebody has a positive calcium score, which again, we covered this in

01:13:31.640 great detail. So for people listening, we have a dedicated ASCVD AMA, which goes into heavy detail

01:13:39.480 for about 90 minutes on all this stuff, where if this is of interest, that's a great AMA that goes

01:13:45.980 super deep on basically all of the reasons why I think my point of view now is treat early and treat

01:13:53.440 aggressively. And I will now also make a very bold statement. Again, it's let's start with the thought

01:13:58.600 experiment, right? If the thought experiment for colon cancer was do a colonoscopy every day on a

01:14:05.240 person's life, starting at the age of 30, would you eliminate colon cancer deaths? I think the answer

01:14:11.220 is yes. And similarly, I would say pharmacologically lower ApoB to somewhere in the 20 to 30 milligram

01:14:20.440 per deciliter range for everybody in the population. While someone is in their 20s, can you eliminate

01:14:27.540 ASCVD? And I think the answer is probably yes. In other words, I think what you're basically going to

01:14:33.200 do is eliminate death from atherosclerotic causes. And that would need to be started in 20s?

01:14:40.960 I think so. Yeah. Very early on. Yeah. So again, how do you take that thought experiment and turn it

01:14:46.300 into a practical implication? Because I don't think it's practical to take every 20-year-old

01:14:51.600 and obliterate their ApoB. Although it's clearly something we do in the subset of patients who have

01:14:59.080 significant genetic abnormalities, such as the cluster of genetic abnormalities that coalesce

01:15:05.660 around a condition called familial hypercholesterolemia. We certainly do medicate those

01:15:10.060 patients, usually as teenagers. So this is not some completely crazy idea. But I think practically

01:15:16.300 what it means is basically by the time you're in your late 30s or early 40s, if you have any measure

01:15:22.140 of ApoB that's even north of the 20th percentile, that should be completely lowered. So in some ways,

01:15:29.880 I would view an ApoB ceiling of 60 as the limit. And that's probably at about the fifth percentile.

01:15:36.720 You'd sort of want everybody to be below the fifth percentile.

01:15:46.240 We hope you enjoyed this special episode of The Drive. This is one of the most talked about topics,

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