0:00

Hey

0:00

there. I've got a very quick message

0:02

to share with you before we jump into the

0:05

episode. Let's keep this under

0:07

thirty seconds, shall we? This

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I'll pop a link to that. in the show notes.

0:44

What

0:45

they're framing as their scientific

0:48

kind of approach to this is really

0:50

just storytelling and creating narratives

0:52

that they tend to use information that

0:55

they call science in order to, like, uphold

0:57

their narratives. So I just don't think this is

0:59

about science anymore. I don't think this is about

1:01

interpretations of evidence. think it's about

1:03

narcissistic indifference. I think it's about

1:05

ego.

1:08

Welcome to the proof podcast, the

1:11

space for science based conversation exploring

1:13

the health and longevity benefits. that

1:15

come with mastering nutrition, physical

1:18

exercise, mindfulness, recovery,

1:20

sleep, and alignment. facts,

1:23

nuance, and trustworthy recommendations minus

1:26

the hyperbole. How

1:28

do friends great to be here with you? I'm

1:30

your host, Simon Hill. I'm a qualified physiotherapist

1:33

and nutritionist with an undergraduate science

1:35

degree, and a master's in the science of human

1:37

nutrition. Today, we have doctor

1:39

Alan Flanagan and Danny Lennon, both

1:42

previous guests on the show, back to explore

1:44

nutrition, cholesterol, and heart

1:46

disease. This is a topic we've

1:48

covered in previous episodes. But with these guys

1:50

visiting Sydney, I wanted to take the opportunity

1:52

to sit down and in a single episode

1:55

cover the evidence we have on cholesterol and heart

1:57

disease and address claims made by

1:59

certain dietary camps

1:59

online. Claims

2:02

like Well,

2:03

if you're metabolically healthy, high

2:05

cholesterol doesn't matter. Or

2:07

if cholesterol was the problem,

2:09

why don't veins get atherosclerosis?

2:12

And why would our body make cholesterol if

2:14

it's bad for us? We

2:16

cover all of these and more.

2:19

Importantly, While this topic can be

2:21

often very hard to follow with lots

2:23

of scientific terminology, jargon,

2:25

I did leave this convo feeling like we did

2:27

a pretty good job breaking things down.

2:30

and using analogies to help make it more

2:32

interesting and accessible. Although

2:34

I'll let you be the judge of that. Perhaps you can

2:36

leave a comment on YouTube under the video

2:38

or on Instagram and share your

2:40

thoughts. Alright. Let's

2:42

do this. Please enjoy. This

2:44

is doctor Alan Flanagan, Danny Lennon,

2:47

and myself. Coming at you

2:49

from Bondi Beach, Australia. Alan.

2:53

Yeah. Welcome back. Danny

2:56

welcome. Thanks for having me.

2:58

It's nice to be doing this in person.

3:00

It is Had a fun dinner last night. Yes.

3:03

Yes. Yeah. You look very you

3:05

look like you're

3:06

in a very cheeky mood. I'm a bit worried.

3:09

I may be. I think dinner

3:11

last night probably tears us up for this.

3:14

I was thinking actually if you were sitting around

3:16

us. They

3:18

kinda got a podcast. Oh

3:20

my god. Right? Yeah. Yeah.

3:22

I think there was that, like, couple that were, like, next

3:24

to us on this. I wonder whether they're interested in nutrition

3:27

and why they keep hearing this person

3:29

wanting people to die. Like

3:32

I must mention, at least three people that

3:34

I I visited cardiovascular events

3:37

on. Yes.

3:40

Well, not nice people. Let's

3:42

see where this this episode takes

3:44

us. So

3:46

I thought we could kind of channel

3:49

our energy into all

3:51

things cholesterol -- Mhmm. --

3:53

heart disease. I know you guys covered this brilliantly

3:56

on your show. So I think perfectly placed

3:58

to kind of bridge the

3:59

gap between academia

4:02

and the science that's

4:04

in the literature and all

4:07

of the various claims made online. Mhmm.

4:09

And just to help that person, that's kind of

4:11

caught middle, which is a lot of obviously

4:13

what you guys do so well. So

4:16

I'm interested in in trying to kind of

4:18

step through this understand

4:21

what we do and and and don't

4:23

understand about cardiovascular

4:26

disease and the kind of pathophysiology. And

4:30

then along the way, let's

4:32

try and bring up the play devil's

4:34

advocate and bring up. Okay. Well, this is

4:36

where this claim might be made.

4:38

Mhmm. And as you often say,

4:40

Alan, the there are lot of

4:42

claims, but one of the great things is that there

4:44

is evidence that can actually be

4:46

pointed to to help explain those. Yeah.

4:48

And so along the way, if we can kind of

4:51

draw attention to that claim that someone may have

4:53

come across and then speak to

4:55

the evidence that

4:57

may help refute that and and clear things

4:59

up. I think that could be really instructive.

5:02

Yeah. Probably the first the best

5:04

place. And I was thinking about where

5:06

to start, there's a lot of different

5:08

times that get thrown around. A

5:10

cholesterol, triglycerides --

5:12

Mhmm. lipids, LDL

5:14

cholesterol, LDL particles, APO

5:16

B, and so

5:18

if you are seeing lots of claims online and there's

5:21

terminology that you're not fully

5:23

sort of

5:26

understanding or familiar with. It can

5:28

make it very hard to

5:30

track all of this conversation. And I think we can

5:32

probably take some of those terms

5:34

a little bit for granted, what they actually

5:36

mean. So Why

5:38

don't we start there with the kind of basics

5:41

of what lipids

5:43

are, you know, how our body is

5:46

is transporting cholesterol

5:49

and triglycerides and

5:52

then through that we might be able to kind of

5:54

step into what

5:56

the actual pathophysiology is

5:58

and and what's going wrong.

5:59

So I'll start with some basics

6:02

and you

6:02

guys can both fill in any gaps I think from

6:05

there. The way I I start at

6:07

a very simple level for

6:09

people just hearing about some of those terms

6:11

you mentioned is they probably

6:13

have some familiarity with getting

6:15

a lipid test with their doctor

6:17

or their GP. And this will be a collection

6:20

of different markers, many of which we'll

6:22

probably discuss today. And

6:24

within that, they will hear things

6:26

like total cholesterol, LDL

6:29

cholesterol, HDL cholesterol, maybe

6:31

triglycerides, But most of

6:33

the time, they'll typically hear

6:35

about the good and bad cholesterol, and we can

6:37

certainly talk about whether that's appropriate

6:39

ways to think about. But within

6:42

that kind of class of

6:44

different types of lipids.

6:47

When we focus in on cholesterol,

6:50

this LDL or HDL

6:52

designation relates to the density

6:54

of lipoproteins, which are

6:56

what to carry this cholesterol around. So

6:58

probably the first important distinction that

7:00

needs to be made is that

7:03

the something like LDL cholesterol

7:06

relates to the cholesterol content within

7:08

a certain particle that we call

7:10

a lipoprotein. And in this case if

7:12

it's LDL, it's it's of a low density.

7:14

And so already now we have a few different

7:17

branches that we should maybe highlight

7:19

from people to to keep track of

7:21

that, first of all, we can move

7:23

cluster all around the body in

7:25

certain particles. These are called

7:28

lipoproteins. And based on

7:30

the density of those, we have a different a

7:32

whole range of different lipoproteins, many

7:34

of which we'll probably talk about LDL,

7:37

which is the most common type

7:40

of of lipoprotein we'll probably discuss

7:42

today is low density lipoprotein

7:44

and we have intermediate density lipoproteins

7:46

or IDLs We can have high density

7:49

lipoproteins. We can also have VLDLs

7:51

of very low density lipoproteins. And

7:54

within all those, there's a cholesterol content associated.

7:57

So when someone gets an LDL cholesterol

7:59

test, that is measuring what

8:01

is the cholesterol content within

8:04

all your LDL particles

8:06

or at least it's a calculation of that.

8:08

And so I think that's the first

8:10

distinguishing feature. We we

8:12

can say that we have

8:14

cholesterol that could be moved

8:18

around the body essentially within lipoproteins.

8:21

There's different classes of these. they

8:23

relate to

8:24

the the

8:25

kind of atherogenic profile

8:28

as we will probably talk about depending

8:30

on which lipoprotein we're

8:32

talking about. And,

8:34

yeah, that would be the the starting point I

8:36

would typically outline, but I think even within

8:38

that can start to get quite confusing. So

8:40

I don't know if there's any particular points for you guys.

8:43

Hammerhead? I think the main the

8:45

main kind of additional point is

8:47

with the distinction between LDL, HDL

8:49

as lipoproteins. I think

8:51

the best way for listeners to

8:54

conceptualize the importance of the

8:56

difference is we

8:58

can

8:58

relate to each of these as

9:00

forward cholesterol transport and

9:02

reverse cholesterol transport. So

9:05

LDL is responsible for

9:08

forward cholesterol transport. As Donny

9:09

said, that means that the cholesterol is

9:12

contained within these lipoproteins,

9:14

low density lipoproteins it's

9:16

being transported to tissues

9:18

in the body, old tissues, and

9:20

it's delivering this cholesterol to cells.

9:22

And this

9:22

is gonna be important because I think at some point

9:25

today, we're gonna discuss a really

9:27

common claim, which is, well, the body needs

9:29

cholesterol. Yeah, absolutely, it does.

9:31

Or they'll say, it's a raw material we

9:33

needed for hormone production. Yeah. We

9:35

do. That's the whole memory too.

9:37

Yeah. That doesn't speak to how much

9:39

we need and how much ourselves

9:41

actually require to do that job.

9:43

so we'll circle back to that. So

9:45

forward cholesterol transport

9:48

LDL bringing cholesterol to tissues for

9:50

it to use and then reverse cholesterol

9:52

transport HDL bringing

9:54

cholesterol back to

9:56

the liver in order to

9:58

drop it off and recycle it basically.

10:01

There are other lipoprotein subclasses. I

10:03

don't necessarily know that we need to

10:05

get into all of them. But

10:07

one important potential

10:09

distinction as well is to

10:11

do with kind of internal

10:13

versus external, cholesterol,

10:16

intake in production. So

10:18

with VLDL, which

10:20

ultimately will become

10:22

LDL over when when the cholesterol

10:24

content, the triglyceride content is

10:26

broken down in those lipoproteins,

10:28

is produced in the liver, and

10:30

then it's kind of produced to

10:33

put in new fast triglycerides

10:36

and fatty acids and it will carry out and it will

10:38

come out as a particle

10:40

that has a lot of triglycerides, a lot of

10:42

fat carried in it, and it will have cholesterol. And

10:44

then as that triglyceride gets broken

10:46

down, it essentially over

10:48

time becomes smaller --

10:50

Right. -- and ends up

10:52

as a low density. So it's the same

10:54

particle, but it's just been

10:56

transcended. It's just been renamed by us. it's

10:59

transcends because it's it's changed its kind of

11:01

form. Yeah. It's changing its form over time. And

11:03

a and a real diff you know, Donnie mentioned

11:05

the term density of the lipoprotein

11:07

so that the reason that this is important as

11:09

as we get kind of a more refined understanding

11:12

of how all of

11:14

these interact, essentially, is

11:17

the density refers to the relationship

11:19

between the fat content of the

11:21

lipoprotein, the lipid content, and the protein

11:23

content. Mhmm. So a

11:27

lipoprotein with high density like

11:29

HDL has a lot

11:31

more protein

11:33

relative to lipids. whereas a

11:35

VLDL has a lot more fat

11:37

basically and lower protein. And

11:40

the relevance of that is For

11:42

a component, for a lipoprotein like HDL,

11:44

it doesn't really have much

11:46

capacity to take

11:48

on fat, take

11:50

on triglycerides. And

11:52

so if we have high

11:55

levels of triglyceride, for

11:57

example, HDL and

11:59

LDL, can end up being

12:01

overburdens and remodel.

12:03

And so we end up with kind of

12:05

low HDL. We end up with

12:07

LDL in small denser particles.

12:09

And again, these are factors that

12:11

are just accepted as part

12:13

of what happens with like

12:15

a protein metabolism, but they're

12:18

they're jumped on by

12:20

people who say, well, you see it's not

12:22

really LDL. It's these other factors.

12:24

Well, They're all important in the

12:26

overall picture. But

12:28

LDL is by far and away the most

12:30

important because it's the most

12:32

abundant. like a protein

12:35

carrying cholesterol in circulation.

12:37

Okay. And because it's going forward

12:39

cholesterol transport, meaning

12:41

that it's got way more circulating

12:43

time and way more contact

12:45

time essentially with our arteries.

12:48

Okay. And so I

12:49

think some folks will

12:51

be exposed to the the term

12:54

APOB. Mhmm. And it seems like the

12:56

conversation has started to shift a

12:58

little bit from LDL

13:00

cholesterol to APOB being

13:03

potentially, at least in

13:05

certain circumstances, a better predictor of

13:07

cardiovascular disease or

13:09

marker of kind of risk of atherosclerosis.

13:11

Where does APO B

13:13

come into this conversation? with

13:16

regards to these different types of

13:18

lipoproteins and why is it important?

13:20

And this probably starts to take us down

13:22

the path of

13:24

the pathology and what's going wrong. Yeah.

13:26

Yeah. It's gonna go. Yeah. So this

13:30

is kind of something

13:31

that has refined our understanding

13:33

over time. And so the best way to

13:35

think of this is, as I just

13:37

noted, for something like an LDL

13:39

cholesterol or an LDL C, that someone

13:41

might get measured, that is measuring the

13:43

cholesterol content of that lipoprotein.

13:45

But we can also care

13:47

about how many of these

13:49

lipoproteins we have. What is the number

13:51

of particles And so

13:53

one way to try and

13:55

assess the number of not only

13:57

LDL but other lipoproteins

13:59

apart from HDL importantly, which I'll come

14:02

back to, is by measuring

14:04

this apolipoprotein B or

14:06

as we call an apolipoprotein that

14:08

sits on these lipoproteins.

14:11

Now importantly, this

14:13

doesn't sit on the HDL

14:15

particle. but on the LDL,

14:17

IDLs, BLDLs, these

14:19

other lipoproteins that we consider to

14:21

be more atherogenic than

14:23

HDL. And I'm sure we'll explain that in a bit more detail

14:25

in a while. And some of that relates

14:28

to the density of that lipoprotein and

14:30

therefore its size. And also

14:32

this forward and over a transport.

14:34

But so we have

14:35

a way to

14:37

measure the number of those atherogenic

14:40

lipoproteins LDLs, IDLs, VLDLs,

14:43

etcetera, that all contain, that have

14:45

this APOB sitting on them. So there's

14:47

one of these APOBs on each of

14:49

those particles So by measuring

14:51

APOB, it's giving us a good idea

14:53

of the number of these different

14:55

particles. And that

14:57

refinement in understanding risk

14:59

over time has essentially highlighted

15:01

that it's not necessarily

15:03

the cholesterol content per se of

15:05

those particles, but that

15:08

is an important part, but the overall

15:10

number of those particles, if we have much

15:12

more APOB containing lipoproteins, that

15:16

elevates risk. There's a there's a

15:18

concept of concordance and

15:20

discordance, which we're gonna explore more,

15:22

where in certain cases, if they're concordance,

15:24

that means that pretty much the

15:26

an increased amount of APOB

15:29

or number of LDL containing particles,

15:31

let's say, would be

15:33

concordant or rise linearly

15:35

with the increase in LDL cholesterol.

15:37

In some cases, it can be discordant,

15:39

which is where one may be a

15:41

better predictor than the other. So is

15:43

that because in

15:45

in those circumstances, you

15:47

have greater numbers of like VLDLs

15:49

and IDLs, which also

15:51

contain the APOB and

15:54

less LDL. So there's

15:56

– it's interesting that there's a kind of

15:58

– as I understand that kind of heterogeneity

16:00

here in terms of that distribution, where

16:02

you can have either an underestimation or

16:05

overestimation of risk. So let's

16:07

say you take someone that has

16:09

an LDL cholesterol that would

16:11

be in a normal range that would

16:13

indicate is at low risk. But for whatever

16:15

reason, they're

16:18

APO B or even their LDL

16:21

particle count is really high, so that

16:23

would put them in the high risk count. In in a

16:25

situation like that, person

16:27

could be at higher risk than indicated by

16:29

their LDL cholesterol result. But

16:31

you also have it seems on a distribution

16:33

people at the opposite end that

16:35

the LDL cholesterol seat might be

16:39

look a bit higher relative to they actually

16:41

have a maybe a lower APOB

16:44

count or a lower LDL particle

16:46

count? Is that because they have

16:48

they they have kind of

16:50

more large fluffy

16:51

LDL particles that are

16:54

carrying more cholesterol, but there's less of them.

16:56

Is that is that how you'd end up in

16:58

that position? So it'd be essentially, as

17:00

I understand at the – as Alan

17:02

said, this protein and cholesterol content

17:04

that we have generally

17:07

for these different class of lipoproteins. But

17:09

of course, there's some variation. There's some

17:11

kind of range within them of how much each

17:13

of those particles may have.

17:15

So if you in a certain individual

17:18

have a greater cholesterol content

17:20

per liver protein for that

17:22

situation, that would lend itself to Mhmm.

17:24

Okay. So bottom line though, the

17:26

the the best predictor or

17:29

and

17:29

and the best way of kind of avoiding

17:32

misinterpretation if you interpretation

17:34

if you're just looking at LDL is to

17:36

go directly to the number

17:38

of particles and measure

17:41

the APOB. Yeah, I think APOB

17:43

is probably the strongest indicator

17:45

relative to certainly an LDL cholesterol

17:48

number, and that's twofold.

17:50

One, it's your getting the number of

17:52

particles as opposed to the cholesterol content, but

17:54

also you're accounting for other

17:56

lipoproteins apart from LDL, which are also

17:58

atherogenic. Do you think most

17:59

doctors sort

18:01

of recognize that? And is that something that

18:03

you think will start to make its way into routine

18:05

blood tests? So it is recognized.

18:07

the various, the

18:10

EAS have recognized the

18:12

importance of a direct measure of

18:14

APOB generally.

18:16

It's specifically recognized in the

18:18

situations of discordance that Donnie was

18:20

talking about, which seems to affect about

18:22

a quarter of the population around twenty five

18:25

percent So it's not an substantial

18:27

number of people for whom

18:29

only estimating LDL

18:31

cholesterol might mischaracterize

18:34

the nature of their risk. But

18:37

there are calls now to

18:40

just in everyone have have a direct

18:42

measure of APOB as as kind of

18:44

the standard, but that's not going to necessarily

18:47

be something that's happening overnight.

18:50

because it's kind of cheaper and

18:52

easier to measure an

18:54

LDL cholesterol isn't necessarily

18:56

directly measured when you're in primary

18:58

care, it's calculated what's known as the freed

19:00

walled equation. So, you

19:03

know, yes, ApoB is

19:05

more refined as marker

19:07

because it's capturing all of the every

19:10

atherogenic lipoprotein in

19:12

circulation irrespective of its actual

19:14

sub class. But at

19:16

the same time, there's additional

19:19

cost and kind

19:23

of equipment and otherwise

19:25

in in implications here.

19:27

So, yes, it's more ideal, but it's

19:29

it's not necessarily going to be something that that

19:31

happens overnight. Although over time, I can imagine

19:33

that there will be a a push

19:36

to shift. and then screening

19:38

towards direct measures of a puppy. It seems it seems

19:40

to be going in that direction. What do you think

19:42

about non h Dell as a marker.

19:44

So if you because that's that's shows up on most

19:47

routine blood tests. That's pretty similar to

19:49

ApoB. So it's it's a it's a

19:51

good mark prior to the

19:53

ApoB kind of era, so to speak, if we're

19:55

in that now. Non HDL

19:58

was as good a marker as you

19:59

could get for capturing,

20:02

again, all

20:03

heterogenic lipoproteins in

20:06

circulation that were not HDL. So as

20:08

Donnie said, HDL does not contain

20:10

APOB. HDL is reverse cholesterol

20:13

transport. It expresses another

20:15

apop apopular protein.

20:18

And so it's not

20:20

involved in the processes and also

20:22

because of its size as well, you know,

20:24

hypothetically where HDL to get into

20:26

the archery, you could actually kind

20:28

of get out basically. So non HDL

20:31

was providing a relatively,

20:33

you know, crude but

20:36

still, you know, accurate enough for

20:39

prediction, estimates of all

20:41

other lipoproteins in circulation that

20:43

were not HDL and that would have

20:45

covered LDL It would have covered

20:47

the LDL. It would have

20:49

covered, you know, kind of micron

20:51

remnants in these kind of particles. And

20:53

if you look at some of the analyses that we're

20:55

looking obviously in terms of

20:58

predictive value for these

21:00

kind of measurements, then you

21:02

know, non HDL Wasovarian and

21:05

still is in certain context. You know, remember

21:07

that this concept of discordance

21:09

one a quarter of the population is a lot of

21:12

people, you know, in in a lot in

21:14

in a majority of individuals, it

21:16

it is still sufficient

21:18

to you know, have an estimate of their

21:20

LDL C and non HDL C, you can be

21:22

-- Right. -- can be and concordance

21:24

if you're using If you're looking at, and this was

21:26

in one of our statements from Simeon Moores

21:29

research. If you look at LDL

21:31

cholesterol, a non HDL

21:33

cholesterol, there's a lower proportion

21:35

of people are discordants. If you're looking

21:37

at those metrics together, then LDL

21:39

C and LDL Hargical count.

21:42

Okay. So it's still a useful metric. Yeah. And,

21:44

I mean, one additional thing to that is when we

21:46

talk about even cases where there is discordance, that's

21:49

still occurring within a certain range. Right?

21:51

So as some of the cases we make out on to later

21:53

where people have this incredibly

21:56

high LDL cholesterol, like three

21:58

hundred plus milligrams

21:59

per deciliter, you're not gonna have a situation where

22:02

someone's LDL cholesterol is

22:04

that high, but, like, oh, they're April to

22:06

be in here. Yeah. Yeah. Yeah. Yeah. Yeah. So it's

22:08

within a certain range that this score

22:10

didn't and it doesn't at the extremes, it's just

22:12

begun to become irrelevant. That's a good point.

22:14

That's that's also good for folks

22:16

to know if they speak with their physician and for

22:18

whatever reason, they prove easy expensive

22:20

or they can't get it that usually

22:22

non HDL is

22:25

available.

22:26

okay Okay. So the

22:27

way I kind of like to think about this is shipping

22:30

containers, you know, that that analogy of

22:32

like the the shipping containers kind

22:34

of floating through our blood. That's

22:36

the lipoprotein. And then on top of that

22:38

is the sorry, the ship is

22:40

the lipoprotein. And then on top of that,

22:42

the container is the the fright of

22:44

the triglycerides and the cholesterol.

22:48

Mhmm. And some

22:50

of these ships have this

22:52

APOB protein, which makes

22:54

them this kind of special class that

22:56

we have said is atherogenic,

22:58

which I

23:00

guess, is the kind of capacity to

23:02

enter the artery wall and build up

23:04

his plaque, which we'll probably go into.

23:07

Yeah. You agree? Is that a kind of -- Yeah. --

23:09

that's the broadest term for an

23:11

atherogenic potential? Okay. So you've

23:13

got these shifts that have

23:15

this certain protein. They have

23:17

this capacity to go into our artery wall and potentially

23:19

build up. Mhmm. And then you've got some

23:21

other ships that don't have that protein,

23:23

that's HDL, they don't have that

23:25

same sort of arthrogenic potential.

23:29

Mhmm. So

23:29

so and and

23:30

these lipoproteins are playing an important role.

23:33

Right? They're distributing fats

23:35

and cholesterol into tissues.

23:38

So they're meant to be there at

23:40

some level. They're doing a role.

23:42

And I think what's interesting is to about

23:44

that and then talk

23:46

about, well, what goes wrong. Right.

23:48

You know, why would the body have

23:50

this system in place

23:54

that is, you know, for all

23:56

intents and purposes, presumably there

23:58

to actually sustain life and

23:59

and and make us healthy.

24:02

Where did where did things go wrong?

24:04

When it gets retained in

24:06

the artery wall. So

24:08

so one further stratification

24:12

that we can make.

24:14

That's important for the concept

24:16

that we're talking about of arginicity

24:19

is the size of them. So we've we've identified

24:22

density, obviously, and

24:24

importance and the the

24:26

kind of lower the density, the more room

24:28

there is, so to speak, on the ship

24:30

for triglyceride and cholesterol.

24:33

And the expression of

24:36

ApoB is important because

24:38

it's ultimately that

24:40

ApoB mostly that a prop

24:42

compound, so to speak, on the on the

24:44

on the ship, on

24:46

the lipoprotein, that is going

24:48

to be what sticks. It's like

24:50

the anchor, what it hears, exactly. So

24:54

that's a really good analogy because,

24:56

yes, ship goes into archery, so

24:58

to speak. drops anchor and it's

25:00

APOB that is literally

25:02

anchoring to the archery

25:04

wall. And once

25:06

there, This is a whole host

25:08

of immune and inflammatory processes

25:10

that will -- Mhmm. -- then an oxidative

25:12

processes that will result

25:14

from that. But a major factor

25:17

influencing which lipoproteins, which ships

25:19

can get in in the first place

25:21

is the size of the

25:24

lipoprotein itself. And

25:26

size for these compounds would be measured

25:28

in kind of nanometers. And

25:30

what we know is that

25:33

basically any lipoprotein

25:35

under

25:36

about seventy to seventy

25:39

five nanometers in diameter is is

25:42

small enough to

25:44

get into the artery. Any compound under

25:47

that, and any any

25:49

lipoprotein over that size is actually

25:51

too large.

25:51

So when we eat food and

25:53

we digest the dietary fat in that

25:56

meal, that dietary fat

25:58

is absorbed at first very

26:01

large particles known as chylomicrons. They're

26:04

too large to

26:06

penetrate the archery. So

26:08

they so chylomicrons are not

26:11

atherogenic. But what can

26:13

happen is, as the body

26:15

starts to breakdown, as enzymes start

26:17

to break down the triglyceride, the fat that we've

26:19

consumed in the diet that's been packaged

26:21

into these really large fluffy,

26:24

buoyant, lipoproteins gets broken

26:26

down. You end up

26:28

with progressively less triglyceride and

26:30

then as a proportion, more more cholesterol there.

26:33

So it creates what I know is chylomicron

26:35

remnants. Those remnants

26:37

can be atherogenic because their size has been they've been

26:40

depleted. And then we have VLDL, very low

26:42

density of lipoprotein, which is

26:44

synthesized in the liver. So Kylomicrons

26:46

are the exogenous pathway

26:48

of triglyceride intake, dietary fat,

26:50

and then VLDL can be synthesized in

26:52

the liver. If the liver is

26:55

having to up regulate production

26:57

of new fats from an

26:59

overconsumption of calories or from fat being dropped

27:01

to the liver from diet and these kind

27:03

of things. So VLDL in its

27:06

exists in kind of two subclasses.

27:08

VLDL one and two. VLDL one

27:10

is just large enough again, nautness.

27:12

not to be able to penetrate. But VLDL

27:15

two, smaller VLDL can.

27:17

So we so we have smaller

27:20

VLDL we have IDL, kylomicron

27:22

remnants, LDL itself,

27:25

alpilotile, and all of

27:27

these fit both the

27:30

classification of expressing AP0B

27:32

-- Mhmm. -- except for LPLA but that's that's

27:34

just the technicality we can avoid. And

27:38

size. And

27:40

between the two of them, they're able

27:42

to not just get into the arterial

27:45

intima. and then AP0B

27:47

as the analogy of

27:48

the anchor is is what then

27:51

sticks. Right. And adheres to that

27:53

artery wall, and then the processes

27:55

begin Right. So you have these

27:57

different ships. They're they're dropping

27:59

off at certain ports -- Yeah. -- some

28:01

of these up triglycerides and

28:04

and getting cholesterol some of the

28:06

containers are going off in a certain

28:08

point, that ship, the

28:10

size, is now

28:12

a size that enables it to

28:15

enter into the artery wall and --

28:17

Mhmm. -- can drop its anchor and

28:20

get stuck. Okay.

28:23

So something I think

28:25

that often comes up here

28:28

is that what I would be interested

28:30

in sort of understanding and speaking

28:32

about is that sort

28:34

of process of these

28:36

particles going into the artery wall,

28:38

I think endocytosis is the term

28:40

-- Mhmm. -- that that's often used.

28:42

Is that normal? And

28:44

does does sort of do these

28:46

particles flow in and out? And that's

28:50

completely fine and healthy?

28:54

the war Or

28:55

is that pathogenic in and of itself

28:57

because often what I hear is from

28:59

the counterpoint is that, well, actually,

29:01

it's it's not these particles

29:03

that are kind of going

29:05

in there and causing the damage, the

29:08

only time that they would be retained

29:10

is if there is already

29:12

some sort of damage there and

29:15

people point to hypertension

29:18

or smoking or

29:21

seed oils So I'm interested

29:23

in trying to delineate that.

29:25

What is actually causing

29:27

the anchor to to get dropped and

29:29

the cholesterol to get retained?

29:31

Does that make sense? Yeah, it did. So the

29:33

the the two researchers that

29:35

that kind of gave

29:38

us

29:38

one of one

29:40

of probably the the greatest

29:42

breakthroughs in this whole story of the

29:44

last century, Goldstein and Braun, won

29:47

a Nobel Prize for it, discovers

29:49

the LDL receptor

29:51

in the ages.

29:53

And that has from

29:55

there just accelerates almost everything

29:58

we know, not just about these

30:00

processes that we're discussing, but even

30:02

how to intervene, to

30:04

treat atherosclerotic

30:05

cardiovascular disease. And

30:07

in one of

30:09

their papers, they they had this

30:12

really nice analogy where they

30:14

they called cholesterol and

30:17

LDL a Janus faced

30:19

molecule, you know, Janus the the the

30:21

two faced God. price. And what

30:23

they meant by that was we

30:25

have a a need for cholesterol in

30:27

the body. We have

30:30

these lipid proteins,

30:32

but the the the very properties of

30:34

cholesterol. And indeed, of fats in the body,

30:37

fats and water don't mix. someone can

30:39

go and pour out of oil in their glass of water right now

30:41

and they'll see what we're talking about. So we need

30:43

compounds and cholesterol itself is quite

30:45

this waxy kind of

30:47

molecule. Again, not

30:49

particularly good if you're

30:52

AAA circulatory body

30:54

that has blood and

30:56

plasma and fluid essentially. we

30:58

need these compounds to be able to transport beneficial

31:03

material to

31:04

you our cells

31:05

and to our tissues in order to function.

31:08

The problem is that

31:11

the properties from

31:13

a kind of chemical perspective

31:16

or that that that that

31:18

make these compounds what they

31:20

are, paradoxically is

31:22

also what can make them deadly if they get

31:24

to the wrong place. And the wrong place in this

31:26

case is is into our archery

31:29

wall. And so

31:31

we clearly have evolved

31:33

a kind of threshold

31:36

at which there

31:38

is sufficient

31:43

capacity in the body to

31:45

have these compounds on

31:48

the on the ship, so to speak, to

31:52

have enough in circulation

31:54

for meeting our physiological requirements

31:58

at a range of

32:01

levels in the body, that which

32:03

we can have these compounds in the circulation

32:05

where they'll be able to

32:07

do their job. drop the raw

32:10

material that we need into into port,

32:12

so to speak, get it to the tissues that

32:14

require it, and this

32:16

process can can

32:18

go We can forward transport cholesterol and other

32:20

material to cells. We can bring it

32:22

back and recycle it. Within a

32:24

certain threshold, we've we've clearly

32:26

evolved the capacity to have those functions

32:30

actually work

32:32

without causing any additional

32:36

stress or damage to the

32:38

body over certain thresholds is

32:40

when we get into a situation

32:43

where there

32:45

is simply too

32:46

much, so to

32:48

speak, cargo, on too

32:51

many ships. and there

32:55

is an inability at that

32:57

point for the

33:00

requirements for our

33:02

cells for cholesterol specifically are

33:04

very low. We have

33:06

the capacity to synthesize that

33:08

cholesterol in the body endogenously.

33:11

We do require it

33:13

for really important functions, but the

33:15

actual level required for

33:17

optimal function and the level required during maximal

33:19

phases of growth in the human body

33:21

are very

33:22

small. What is that? Like, give us

33:24

give us a number. thirty milligrams

33:26

per deciliter. Right. And and we

33:28

know that because that's that's what Goldstein and Bran

33:30

looked at in kind of like infant development.

33:33

So Is that similar to primates?

33:35

Like, if you if you were to look at

33:38

animals and think

33:41

I've looked at some of this research,

33:43

but if I'm correct,

33:45

they don't intend to get atherosclerosis

33:48

and they have much lower level. I

33:50

mean, in experiments, you can give them

33:52

atherosclerosis. But in the

33:54

wild, do you know what

33:56

they're kind of level of LDL

33:58

cholesterol. So any any other mammals that have

33:59

been looked at? Any other primates that have

34:02

been looked at? None

34:05

of these species or

34:07

or indeed, like, other animal models that

34:09

have been looked at come anywhere

34:11

near to expressing

34:14

the levels of

34:16

lipoproteins and cholesterol that's

34:18

modern human, particularly Western

34:21

industrialized populations exhibit. and

34:24

they don't develop atherosclerosis.

34:26

And we have evidence,

34:29

not just from kind of

34:32

hunter gatherer, quote unquote populations

34:36

who don't

34:38

develop atherosclerosis. there are some myths that have emerged even particularly

34:41

focused on indigenous,

34:44

inuit cultures in the

34:46

Arctic. That's

34:48

just you know, amiss this idea that they

34:50

do not develop coronary artery disease

34:52

is is not the case at all.

34:54

It was based on some

34:56

shiny assumptions in the nineteen seventies that really haven't held

34:59

true beyond that. So,

35:03

really, there there's there's

35:06

very little evidence of atherosclerosis developing

35:08

in any of these other, you know,

35:10

other non human primates

35:13

who have obviously much lower levels of cholesterol

35:15

in other animal species.

35:18

A lot of these animal models are are

35:20

actually how we know the importance of the LDL cholesterol

35:24

receptor of the

35:26

LDL receptor generally. So

35:28

at that level, I'd say

35:30

thirty milligrams per deciliter, let's say, in a human. And

35:32

I think there are a piece of

35:35

study I think is one study I've looked at that

35:37

kind of looked at this and

35:40

was looking at levels of subclinical

35:42

atherosclerosis and different people

35:46

with different

35:48

levels of of cholesterol in that paper. I think it was at forty or

35:50

fifty milligrams per deciliter. Those were the

35:52

only people that didn't have any

35:54

subclinical atherosclerosis.

35:58

But just to kind of summarize what you're saying is if

36:00

atherosclerosis is not inevitable --

36:02

Mhmm. -- so if if you if

36:06

you have an LDL cholesterol level of say thirty,

36:08

forty milligrams per deciliter your

36:10

entire life based on

36:12

the evidence that's

36:14

out there, you're saying that that

36:16

person would not have developed

36:18

cirrhosis. Right. And is that actually

36:21

I mean, clearly, there are some papers looking at it where

36:23

people do have that level. But is that is

36:25

that a level thirty, forty

36:27

is very low? Is

36:29

that actually something you think people

36:32

can achieve without pharmaceutical intervention? In the

36:34

modern context, probably not. But,

36:37

you know, again, a lot of a lot of

36:39

a lot of a lot of on acculturated

36:42

populations don't

36:44

necessarily have cholesterol, LDL cholesterol, that low or total cholesterol,

36:47

that low, you know. So it

36:49

seems that in

36:49

otherwise healthy individuals,

36:52

the thresholds appears

36:54

to be around eighty milligrams -- Mhmm. -- per deciliter. That

36:57

seems to be the

37:00

range up to that

37:02

point where again,

37:04

in otherwise healthy individuals,

37:06

atherosclerosis doesn't progress at

37:09

thresholds under that. And

37:12

so, and from a number

37:14

of studies that have looked at actual

37:17

regression of plaque in

37:18

the arteries from achieving certain targets

37:21

in primary

37:21

prevention. That's now the

37:24

delineation for targets to treat.

37:26

So in primary prevention,

37:28

the aim is to get people's LDL cholesterol

37:30

to seventy milligrams

37:32

per deciliter or less in secondary

37:34

prevention in people who've already had

37:36

a coronary event or a cardiovascular event.

37:38

they're high risk. They're already on, like, maximally tolerated

37:41

statin. Mhmm. The aim is

37:43

to further use additional

37:45

pharmacotherapies, specifically now

37:48

real enthusiasm for PCSK9 inhibitors to get

37:51

that LDL cholesterol down to less than

37:53

thirty milligrams per deciliter in

37:55

order to fully kind of

37:57

rule out almost the the the risk

38:00

of of a second event. But, you

38:02

know, again, in high risk individuals,

38:04

other events still

38:06

occur. Okay. But yeah, they're the two kind of distinctions we can make now

38:08

in terms of primary and secondary prevention and

38:10

kind of targets to treat

38:12

to. So let's

38:14

just to close the loop on, I guess, the damage because

38:17

I think that's a claim

38:19

that's

38:19

often made is

38:22

that, well, It

38:25

might be that you're seeing

38:28

people with higher LDL

38:30

cholesterol have higher risk

38:32

of atherosclerosis It

38:36

may be that these people

38:39

also are insulin

38:42

resistant or metabolically are are unhealthy. They're consuming

38:44

a standard Western diet. And

38:46

so they're damaging the endothelium.

38:51

And then the LDL cholesterol, I mean,

38:53

there's a number of claims here. Some people will go

38:55

as far to say that the LDL cholesterol is

38:57

actually repetitive and is is part

38:59

of the the healing process coming into

39:02

the sub endothelial space to

39:04

actually help with

39:06

the inflammatory process. So what

39:09

do we know with regards to

39:12

what's actually causing the damage

39:14

in the very first place? Is

39:18

there any truth to this idea that you could have

39:21

high LDL cholesterol and it

39:23

wouldn't be retained in the

39:26

wall if you are, you know, completely healthy in all other

39:28

aspects of your life. I

39:30

think this is interesting because as

39:33

far as my understanding goes that even within

39:35

the context of a

39:38

healthy endothelial function,

39:40

let's say, someone can still have

39:42

this

39:43

retention of

39:46

lipoproteins once that amount

39:48

in circulation is high enough. And

39:50

so it it very much similarly

39:53

parallels the conversation around

39:55

oxidized lipoproteins that are here as well,

39:57

right, that it's only a problem if they're

39:59

oxidized. Well, really, this is we know that

40:02

that occurs after they've been

40:04

retained. Right? And then there can be an

40:06

oxidization leading to that process. In

40:08

the same way, I think without

40:11

damage the endothelium, you

40:13

can still have retention

40:15

of these lipoproteins And so the way I think it

40:17

is best to try and think through this

40:20

is that these are are very real

40:22

things that can contribute

40:24

to risk and are

40:26

negative. So if you have worse endothelial

40:28

function -- Right. -- that is certainly

40:30

more negative of an outcome than

40:32

starting compound things. Right? It can

40:34

exacerbate that that problem. In the

40:36

same way, if someone has

40:38

really high levels of inflammation, we know

40:40

this is is gonna lead

40:42

to worse outcomes typically or

40:44

raises risk. But those

40:46

themselves are shouldn't be thought of in the

40:48

same way that we

40:50

think of an elevated

40:52

APOB where we can see this

40:54

as a causal in and of

40:56

itself to drive atherosclerosis.

40:58

Those other factors are more

41:00

gonna moderate someone's risk or

41:02

alter someone's risk if you

41:04

have higher or lower levels of

41:06

information or you have differences in

41:08

endothelial function. at least that's the way I've

41:10

tried to conceptualize that. I don't

41:12

know if so can I add ask

41:14

one question there? Yeah. So

41:16

As you

41:17

mentioned before, if you have low APOB levels --

41:20

Mhmm. -- and particularly across an

41:22

entire lifetime. below

41:24

that threshold. It would be we wouldn't see

41:27

atherosclerosis. Mhmm. Right? So

41:29

is it a

41:32

kind of Another way of looking at this is, you

41:34

know, those different things that people point to,

41:36

whether it's consuming

41:38

seed oils or inflammation. or

41:42

insulin resistance. If

41:44

you have APOB count low and

41:46

you have some of those

41:50

factors, So in that instance, would someone still not develop atherosclerosis

41:52

because the LDL particle

41:55

count, the APOB count

41:57

is so low? Yes. But that doesn't mean that they would

41:59

be

41:59

healthy and avoid all disease

42:02

endpoints. And this is an important

42:04

distinction because

42:07

there's a really important

42:10

way that we have to think

42:12

about biomarkers. And this

42:15

is something done myself discussed with Professor Chris Pockert on

42:17

an episode because it

42:20

was Professor Pockert who who I first

42:22

saw proposed

42:24

this distinction? How do we classify biomarkers? What

42:26

are they telling us? So for something

42:29

like LDL cholesterol, That's

42:31

a biomarker in the causal

42:34

pathway of of disease. Forward

42:36

cholesterol transport, the

42:38

most abundant. transporter

42:40

of cholesterol in the circulation.

42:43

And that's in the

42:45

that's the causal pathway driving these processes when

42:47

it gets into the artery his change

42:49

and causes these processes that lead to the

42:51

development of plaque in that

42:54

artery. And then we have other

42:56

markers, some of which we've like you

42:58

can measure triglycerides and

43:00

you can

43:01

measure HDL. They're not

43:03

causal on their

43:06

but they help to really give you the big picture

43:08

of an individual's risk. So

43:10

we could take someone, we could

43:12

take two people with high LDL.

43:15

and we could take one that has

43:18

low HDL and high

43:20

triglycerides, that would typically mean that

43:22

they have

43:24

central adiposity hepatic fat, liver fat

43:26

accumulation, insulin resistance in the liver.

43:28

So they have a a clustering of of

43:30

risk factors. that

43:32

mean that their overall risk is higher. And what

43:35

people who deny LDL causality do is they

43:37

look at that and they say,

43:40

well,

43:40

You've

43:41

got all this stuff going on, LDL can't

43:43

be causal. No LDL remains causal,

43:45

but that overall risk profile for

43:47

this individual is higher. there's

43:50

amplifies it. It amplifies

43:52

it. And so then we can have someone who's

43:54

isolated high

43:56

LDL and Maybe they're they have high eight HDL and they've

43:58

low triglycerides. But again,

44:00

LDL is the causal pathway.

44:02

HDL is

44:04

not causal. And they

44:06

will post point to those things and

44:08

miss the fact that LDL is

44:10

the cause of pathway and will drive disease. And

44:12

And so one way that we need to kind of think about this is causal

44:16

pathway, systems or reporter

44:18

biomarkers, and then biomarkers

44:20

of damage.

44:22

So coronary calcium,

44:25

artery calcium, CAC

44:28

score people love to point

44:30

at that, but that's just a biomarker of

44:32

damage. Right? So it may not necessarily

44:36

be present a certain point in

44:38

time even if someone has a certain

44:40

cholesterol level because the impact of

44:42

LDL and of atherogenic

44:44

lipoproteins is cumulative across

44:46

a lifespan. So just because you get a a CAC scan at the age of

44:48

forty, and you're like, oh, great. Even though I have higher

44:50

LDL, I'm I'm fine because

44:52

of this. this

44:54

damage is cumulative over decades. That's a very popular

44:56

thing for people in the

44:58

carnival community to tweet. Yes. when

45:01

kind of trying to substantiate

45:04

the fact that they're they're checking

45:06

on the diet for a year. There are deals

45:08

through the roof at their CAC score, and it's

45:10

like, great. Come back in twenty years. And

45:12

this is this is the problem with

45:16

their their almost willful mischaracterization of

45:18

biomarkers. And and biomarkers

45:20

also helps to understand a really important

45:22

concept are these classifications

45:24

of biomarker help us understand a

45:26

really important concept, which

45:28

is the difference between something that is

45:30

causal and something that's an

45:32

effect modifier Right?

45:34

So as Dani said, like, if you've

45:36

got insulin resistance in these other

45:38

factors, they are going to

45:40

amplify or they're going to be an

45:42

effect modifier to the

45:44

magnitudes of impact of

45:46

the causal risk factor.

45:48

But they don't invalidate the

45:51

causality of that risk factor -- Mhmm. -- and they're

45:53

not necessarily direct targets for

45:56

treatment in themselves. So if you

45:58

had someone

46:00

that had high LDL and these

46:02

other factors. And you thought, actually, we're not

46:04

gonna bother with the LDL because

46:07

we're gonna make them we're

46:09

gonna lower their insulin resistance. And otherwise,

46:11

it's literally a void. It's

46:13

it's it's treating

46:16

ancillary. modifying

46:16

factors over intervening to

46:20

eliminate the coal pathway. So you in

46:22

that instance,

46:24

you could still reduce some of that amplification by

46:26

by addressing some of those other factors,

46:28

but you're not getting to the

46:32

root cause. Yeah. Wasn't it the

46:34

maybe? It was targeted

46:36

at lowering triglycerides, which

46:38

again is one

46:40

of these biomarkers aren't mentions that, yeah, can contribute to risk,

46:42

but in of itself is avoiding the

46:44

issue around LDL. And as far

46:46

as I know,

46:48

with that, they had

46:50

a triglyceride lowering

46:52

intervention, but there was no

46:54

change in APOB. And then essentially

46:56

that trial was just stopped for futility

46:59

because it it wasn't doing anything. Yeah. So that kind of

47:01

speaks this idea that doesn't get

47:03

really acknowledged that with something

47:05

like high triglycerides, which we know is an

47:08

important risk factor. And

47:10

that especially people who try and like the

47:12

LDL denialism is like let's

47:14

focus on l d or HDL and triglycerides, let's

47:16

say, that if you lower that in the

47:18

context of APoB staying

47:20

high, it's not really changing

47:23

all that market. Right? And that speaks to what

47:25

Alan said of we have these

47:27

causal risk factors that are going to drive a lot

47:29

of it. These other things can alter

47:31

that. So this again, certainly not to say,

47:33

someone shouldn't care about these other things, right,

47:35

that you shouldn't try and

47:38

have triglyceride level

47:40

within range or shouldn't try to

47:42

have good fasting glucose

47:44

or whatever other marker they

47:46

want to mention, but it's getting LDL down.

47:49

always comes first. Right. And this is what

47:51

these interventions have done. So there's a concept

47:53

of residual risk. Right? We

47:56

take someone with high LDL and they've got

47:58

all these other stuff. they've got high

48:00

triglycerides, they've got high

48:02

inflammation, right? LDL comes

48:04

in all of the interventions that we have

48:06

the target still is LDL comes down first. Right?

48:08

And then you've got residual

48:10

risk if someone still has high

48:13

triglycerides because their LDL is

48:16

low. Now in that and and this is a really important highlighted

48:18

that trial where, oh, we'll just

48:20

target triglycerides. We won't change, you know,

48:22

and and there's no change is

48:24

no change in a puppy in and the risk

48:27

goes nowhere. And then you have the other trials like, say, REDUCE

48:29

IT or JELUS or the trials that

48:31

have looked specifically at

48:34

triglyceride lowering. they're in individuals who've already achieved low

48:36

LDL. So you're furthering

48:38

their risk reduction by

48:40

now intervening to get another

48:44

reporter biomarker down into range as well. We've

48:47

seen this importantly for the kind

48:49

of LDL denialist claims with

48:52

inflammation. So

48:54

high sensitivity C reactive protein marker

48:56

of inflammation. It's a general marker.

48:59

It's systemic kind of general

49:01

marker of inflammation. over

49:04

two milligrams per liter is

49:06

considered kind of high, and

49:08

it's it's and and we do

49:10

see a graded increase observationally with higher

49:14

CRP and cardiovascular disease.

49:16

But if you look at interventions

49:18

that have considered LDL reduction

49:20

in the context of CRP,

49:22

The SHARP trial, for example, so they stratified participants

49:24

by whether they had CRP of

49:26

over three milligrams per liter or

49:30

under and irrespective of their inflammation

49:32

getting LDL to seventy

49:34

milligrams was associated with

49:37

lower cardiovascular risk. And

49:39

then we have the prove it and improve it trials, which

49:42

actually more directly kind of thought

49:44

about this concept of residual risk as

49:46

it related

49:48

to inflammation. And so what you saw in that

49:50

trial was that in patients

49:52

who achieved

49:54

neither getting their

49:55

LDL under seventy milligrams

49:58

or getting CRP under two

49:59

milligrams per liter, they didn't really

50:02

have much of a risk

50:04

reduction. In participants

50:06

who did achieve the LDL target,

50:10

what remains with CRP

50:10

over two milligrams

50:11

per deciliter, there was a risk

50:14

reduction, but

50:16

it wasn't to the

50:18

extent as when LDL

50:21

and CRP were

50:23

reduced to under both seventy and

50:25

two milligrams respectively. So

50:29

so achieving your primary

50:32

goal of LDL reduction, still is what

50:35

will start the risk reduction

50:37

process, and then we have these

50:39

other factors like inflammation or

50:42

triglycerides that become important to consider

50:44

if they're not in optimal ranges.

50:46

And at that point, those

50:48

individuals will benefit from further

50:52

addressing those effect modifying

50:54

risk factors. Mhmm. So

50:57

what do

50:57

you think about and I know what

50:59

you think, but I I wanna to get you

51:02

to kind of comment on this

51:04

because I think a lot of

51:06

people that are say, tuning

51:08

into someone like Paul Saladinho. Mhmm. Right?

51:10

I think he at the center of his message

51:12

is what we're speaking about here.

51:14

Mhmm. He he will say

51:17

that high LDL cholesterol

51:20

or a high APOB is

51:22

not a concern if you are metabolically healthy. Now

51:24

you guys have just covered that brilliantly

51:26

why it still is and

51:28

is an important marker within that

51:32

context. But he'll point, I think,

51:34

quite often to, like, the Framingham

51:36

study. Mhmm. And he'll say, you

51:38

know, this is evidence. And you know what?

51:42

He speaks with quite a lot of conviction. Mhmm. I think we've gone over past

51:44

due. You know, there's there's

51:46

you you can listen to it and I can see

51:48

how for the layperson It

51:52

could be compelling. Right? And it sounds

51:54

like, well, poll cell data

51:56

has looked deeper

51:57

than than

51:59

other than the consensus. He's gonna lay it deeper. This is what it

52:02

sounds like.

52:04

Right. And if

52:07

you look in the comments

52:09

section -- Mhmm. --

52:11

you know, comments like, Paul, you're so

52:13

brave. Thank you for doing this

52:15

humanity taking on big pharma. This is

52:17

the this is the kind of -- Yeah.

52:19

-- narrative among the the

52:22

community who they want to

52:24

believe -- Mhmm. -- that that information he's

52:26

putting forward. Mhmm.

52:28

But it sounds like it's dangerous information.

52:31

and I I wanna know what you

52:34

think about. Firstly, directly,

52:36

his his claim that he makes

52:38

continuously that framing him study, if you look

52:40

deeper, if you look at stratification.

52:42

Mhmm. It it shows that, well,

52:44

actually, when triglycerides and

52:46

when HDL were at healthy levels,

52:49

LDL cholesterol no

52:51

longer associated with cardiovascular disease.

52:53

That's the claim that he

52:56

makes, and I believe I've represented that

52:58

pretty fairly. you know, it's interesting because because we had a look at the

53:00

the clip that you mentioned where he's recently talked

53:02

about this again off the back of his his

53:04

bloods and

53:06

as you or maybe for some context

53:08

for people listening, he he says that LDL

53:10

for him is not necessarily a concern

53:12

because he is insulin sensitive.

53:15

And the way he is at least

53:18

coming to that conclusion is after the basis

53:20

of his HDL and triglycerides.

53:23

So he will point to I have

53:25

high HDL, I have low

53:27

triglycerides. Therefore, I have

53:29

an insulin sensitive and LDL cholesterol is not

53:31

a problem. And as

53:34

you quite rightly outlined,

53:35

he talks

53:35

about the Framingham

53:38

OffSpring Cohort and does this

53:40

kind of stratification of, well, if you look

53:42

at the people with high HDL

53:44

and low triglycerides,

53:46

they are at lower risk than

53:48

the other stratification of, let's say, people

53:50

with low HDL and higher triglycerides, this

53:53

more atherogenic lipoprotein

53:56

phenotype. And indeed, that

53:58

is correct. But it's what he's

53:59

not saying is the problem. That when you actually

54:02

look at that stratification

54:04

let's take those people with the high HDL and the low

54:06

triglycerides. You can also then look

54:08

at of those people if you

54:11

go higher or lower in LDL cholesterol, what is

54:13

the risk? And the same thing that we've talked

54:15

about before, that those with the

54:18

still higher

54:20

LDL cholesterol say over, I

54:22

think was it one hundred and twenty, maybe

54:24

milligrams per deciliter, are going to be at greater

54:26

risk in those that have the lower

54:28

LDL cholesterol. So it just speaks to what Alan's been talking about of

54:30

sure there may be some impact

54:32

on risk of having

54:36

really high triglycerides or low triglycerides,

54:38

but still your risk is going to

54:40

be impacted by your

54:41

LDL cholesterol. That's the primary driver

54:43

of it. So

54:46

it's it's leaving out that inconvenient fact that even in

54:48

your situation, you would benefit

54:50

from LDL cholesterol lowering. Like,

54:52

if you got that lower, you would

54:54

be at lower risk. Do you think he's aware of that?

54:56

because he

54:57

talks about going, you know, deeper into the the I

54:59

don't know with him whether

55:01

he's I don't think he's particularly

55:04

bright. That's the first

55:06

thing. I don't think

55:09

that he's particularly scientifically

55:12

literate even though people will be like, who

55:14

is the doctor? I mean, doing going to

55:16

med school and does

55:18

not necessarily make scientific literacy. So I I don't think I

55:20

don't think he's I don't think he's very

55:22

smart. I don't think he's

55:24

scientifically literate. I think he's probably

55:26

a very good businessman.

55:28

And I think he's and

55:30

I think when you look

55:32

at the the kind

55:34

of underpinnings of conspiratorial thinking.

55:36

A big driver is

55:40

narcissism. So I think when

55:42

I look at that community who

55:44

are building enormous platforms

55:46

with this kind of,

55:48

you know, information, I think

55:50

They like to portray themselves as a truth seeker

55:52

because it feeds their ego. Their narcissism makes

55:55

them indifference to the

55:57

potential for harm from

55:59

that message. And

56:02

they're not they're

56:04

they're so blinded by any

56:08

range of bad thinking practices that they're never really going to

56:10

be able to come

56:12

around to moving away from the positions

56:14

that they've

56:16

adoptives. because they're they're they're not smart enough. They're blinded

56:18

by a range of cognitive

56:20

biases and otherwise. And

56:24

really, they've what they're framing as scientific

56:26

kind of approach to this

56:28

is really just storytelling

56:31

and creating narratives. that

56:33

they to use information, that they

56:36

call science in order to, like,

56:38

uphold their narrative. So I just don't

56:40

think this is a bad science anymore. I don't

56:42

think this is about interpretations of

56:44

evidence. I think it's about narcissistic

56:46

and difference. I think it's

56:48

about ego. and I and I

56:50

see those traits in all of these

56:52

people, whether it's Saladino,

56:54

Ibercommons, a female hatcher or

56:56

otherwise. Mhmm. And and and it's and it's a problem. Right? Because,

56:58

like you said, hundreds of

57:00

thousands, if not in the millions

57:02

of followers, with

57:04

a comment section full of people saying, this is amazing. Thank

57:06

you for bringing me the truth. And a

57:09

lot of those people

57:12

will have a cardiovascular event at some point in the next

57:14

two decades because of this. That

57:16

sucks. Yeah.

57:19

Well, I think you blew any chance of getting an invite onto his

57:22

show. If let's

57:24

let's let's ride a challenge. If,

57:27

you know, he he is self proclaimed as

57:29

a truth seeker. Right? If if he was gonna sit down and

57:31

have a conversation with someone that

57:33

is across the

57:34

path of physiology of atherosclerosis, I

57:37

know you've had and Chris Packard, a number of people on your

57:39

show. Mhmm. Who would you like to see him talk to?

57:41

If he really, really wanted to

57:44

understand the

57:46

mechanisms and and

57:48

and and help his community

57:50

better understand the relationship

57:53

between cholesterol and and heart

57:55

disease. Because I think there might

57:57

be people tuning into this who

58:00

are perhaps coming to this show

58:02

from that community. Not everyone

58:04

in that community is so far

58:06

gone. There's probably a large chunk of people

58:08

who have really good intentions, are a bit

58:10

confused, and they would love to see

58:12

that conversation occur. Who who

58:14

would you Who would you say Paul I this your

58:16

show, and let's see if you really

58:18

are interested in

58:20

the truth. Brian,

58:22

I I can think of three, I

58:24

mean, I guess, Brian Ferrance, who has done the

58:28

genetic studies. on

58:31

LDL cholesterol, genetic variants that influence LDL

58:33

cholesterol. He's done these just

58:36

brilliant analyses

58:38

of synthesizing

58:40

those genetic studies. And

58:43

he led the first consensus statement.

58:45

He was the lead author on the

58:47

first EAS consensus statement on LDL

58:50

causality. So, I mean,

58:52

that would be one.

58:54

Chris Packard would be another even

58:56

my my MSC supervisor, professor Bruce

58:59

Griffin, his knowledge of lipoprotein

59:01

metabolism and everything else, and

59:03

and the dietary influences on

59:05

on heart disease. you know, the the the

59:07

problem here is that you've got a guy who is just totally convinced

59:10

of their own and and, you know, you'll

59:12

have an

59:14

academic who might know the literature inside

59:16

out, but academics don't speak in the way that the quacks do. Right? They don't speak

59:18

with that just total conviction and certainty

59:20

that they're right. So you

59:24

you wonder what utility any sort of conversation like that

59:26

would be. We spoke about that yesterday,

59:28

and academics more likely to

59:32

use less sort of

59:34

absolute language, which to the layperson

59:36

can come across as a

59:38

lack of confidence or understanding of the

59:40

topic. Yeah. Yeah. When you've got a guy with a

59:42

spear and his shirt off shouting into a

59:44

camera that, you know,

59:46

LDL is a piss poor predictor of

59:48

cardio. No. No. It's not. The

59:50

linear predictor of -- Yeah. --

59:52

cardiovascular disease. So

59:54

there's any number of people

59:56

in the cardiovascular science space that

1:00:00

would you know,

1:00:02

rubbish everything that he

1:00:04

says, boss. Well, there's a few there for him

1:00:06

to consider. Would you throw Borne into

1:00:08

that as well? Yeah. Borne. Yeah. More and worse.

1:00:10

Any any of the things, you know, Tom Day Spring

1:00:12

would be in those meetings. Yeah. Especially

1:00:14

in that kind of online communication. It's

1:00:16

really good one to follow on Twitter.

1:00:19

Yeah. Fantastic information. And,

1:00:21

like, yeah, some of his depth of

1:00:23

knowledge on lipidology is phenomenal. So

1:00:25

Peter, it's here. Yeah. Yeah. I feel like I feel like Salvatino

1:00:27

would be open to someone like a tea because a tea

1:00:29

is kinda like a bro basically

1:00:32

and, like, and and,

1:00:34

you know, but but his, again, his his

1:00:36

knowledge of this cardiovascular science.

1:00:38

Yes. I think that's a good one. I can see that

1:00:40

happen. You could see that happening, Raj. And I

1:00:42

think so. So yeah.

1:00:44

But, you know, it's

1:00:48

again,

1:00:48

how many how many people are are

1:00:50

now too far gone? And that's

1:00:52

that doesn't that worry here. There's also

1:00:54

of a worry of how good

1:00:56

faith of a conversation would it be?

1:00:58

It'd be very easy to paint

1:01:01

himself as I'm open to

1:01:03

these different ideas. Right? I'm willing to talk to

1:01:05

these people -- Yeah. -- having

1:01:08

them on talking around because there's ways to

1:01:10

actually avoid -- Definitely. -- or or

1:01:12

make it come across, like, it's a oh,

1:01:14

this is a balanced conversation. Right?

1:01:17

we we both have a difference of opinion, so it's

1:01:19

kind of fifty fifty and we'll let the

1:01:21

listener decide. Whereas this is a topic where there

1:01:23

is no fifty fifty. Right? This is this

1:01:25

is Like -- This is most robust -- RASM

1:01:28

evidence. -- and you can create a false

1:01:30

equivalence -- Yeah. -- and and then that can

1:01:32

stump people because the the net result

1:01:34

as people go, this is unsettling

1:01:36

science. III think that a good

1:01:38

example of that, I think, was his conversation

1:01:40

with Herman

1:01:42

Potter. Right. So I think maybe

1:01:44

that the best format is

1:01:46

actually having a a moderator

1:01:48

and and

1:01:50

you know, I guess, quasi debate. Yeah. I mean, the problem is

1:01:52

if if if if you have someone

1:01:54

who's no matter what is

1:01:56

said, is gonna be

1:01:58

unwilling to change their position. Yeah. Then

1:01:59

by having that conversation, and then the next

1:02:02

week, he puts out a video saying the

1:02:04

exact same things he's always been saying

1:02:06

about LDL being you

1:02:08

know, good. Then what that's doing

1:02:10

is reinforcing to his audience. I've I've

1:02:12

listened to the best arguments out there.

1:02:14

Yeah. Look, I have evidence I sat down with this

1:02:16

person for two hours. and I'm still

1:02:18

unconvinced. Exactly. So it makes it look like

1:02:20

it's a weaker evidence box. I I'm and I'm yeah.

1:02:22

I'm I'm now kind of at the conclusion,

1:02:24

particularly, you know, we had the kind

1:02:27

of interaction with with Dave Feldman this topic. And again, you

1:02:29

know, there's this there's this

1:02:32

professing to want to engage

1:02:34

in good faith but there's zero good faith

1:02:37

from this community at all,

1:02:39

you know. And and

1:02:42

I I'm cautious

1:02:44

now about the utility of these kind

1:02:46

of conversations that we're talking about. For

1:02:48

the reasons Donnie's outlined, you know, this

1:02:50

false equivalence this perception they can

1:02:53

portray to their audience. I've I've sat down with

1:02:55

the best of the best and, you know,

1:02:57

it's still inflammation and and it it

1:02:59

it actually I think is

1:03:01

ultimately more harmful to the

1:03:04

science and the integrity in that

1:03:06

evidence space. than it is of

1:03:08

utility enterprise. So I worry about

1:03:10

that. I'm way more now skeptical

1:03:12

of of how beneficial these kind

1:03:15

of conversations are. and I think that rather

1:03:17

we're probably better off focusing

1:03:20

the on amplifying

1:03:23

the voices in

1:03:24

the evidence based side and and

1:03:27

and and amplifying the science

1:03:29

of this as much

1:03:31

as possible ourselves hoping that that person who maybe is

1:03:33

sitting on the fence, kinda listening to a Paul

1:03:36

Saladino, but also maybe

1:03:38

kinda listening to us,

1:03:40

for example, will

1:03:42

eventually just have the

1:03:46

ability to go this this really

1:03:48

seems more robust

1:03:50

and convincing. And and

1:03:52

to those that don't and

1:03:54

willfully march to the beat of

1:03:56

someone like a Paul Saladinho's drum, I

1:03:58

just don't think we

1:04:00

need to you know, I I think we could

1:04:02

look to them, you know, but I think worrying

1:04:04

about saving them is probably not where we

1:04:06

should put our -- Mhmm. -- energy

1:04:08

and focus. Okay. Just

1:04:10

continue to put out this kind of

1:04:12

information and and and hope

1:04:14

that people, you know, have

1:04:16

enough critical

1:04:18

thinking capacity they don't even need

1:04:20

scientific literacy, but just to just to

1:04:22

recognize the voracity of evidence

1:04:24

in one argument

1:04:26

versus the bluster and rhetoric and another.

1:04:28

Yeah. Let's let's continue going

1:04:30

through some of the,

1:04:32

I guess, various claims

1:04:34

that come up, particularly

1:04:36

around lowering cholesterol and

1:04:40

how that could affect

1:04:42

your health, let's say, even outside of atherosclerosis. So one of

1:04:45

the things that I think is

1:04:47

quite popular online is

1:04:50

and you alluded to this before, people talk about,

1:04:52

well, the benefits of cholesterol,

1:04:54

and and usually there's

1:04:57

a a very they'll rapidly talk about cell membrane

1:05:00

fluidity, hormone production.

1:05:02

And then, again, as a layperson,

1:05:05

it sounds very scary to think about lowering your

1:05:07

cholesterol. Maybe you've had a already had

1:05:10

a cardiovascular event. Your doctor

1:05:12

has put you on a

1:05:14

statin or PCSK9 inhibitor.

1:05:16

Now you're coming across this information that's

1:05:18

saying, well, actually getting your cholesterol down to

1:05:20

that level is going to affect your

1:05:24

hormone production. and

1:05:25

and and all these other aspects of of your health and you're starting to question,

1:05:27

is it such a a good thing? So

1:05:29

what do we know about

1:05:33

I guess adverse effects or

1:05:36

if you are aggressively lowering

1:05:38

cholesterol, is there does it

1:05:40

pose any risk to other aspects of

1:05:42

someone's health. Not that we can see.

1:05:45

So in terms of the

1:05:47

primary interventions that have

1:05:49

looked at us, and indeed this

1:05:52

the secondary prevention interventions because

1:05:54

they're often more instructive in this regard because

1:05:56

of how low they've taken

1:06:00

people deliberately. The

1:06:02

evidence that we have that exists

1:06:04

doesn't really suggest any

1:06:08

adverse effects to going

1:06:10

as low as in one

1:06:12

of the pre specified subgroup

1:06:16

analyses of of one of the secondary

1:06:18

prevention interventions they looked

1:06:20

at getting people down

1:06:24

to six milligrams per deciliter.

1:06:26

Wow. No evidence of of

1:06:28

adverse effects. at that level. And again, you

1:06:30

know, these are people who

1:06:32

were trying to not just

1:06:34

kind of prevent

1:06:36

disease, but at this point, try to reverse

1:06:39

the atherosclerosis that is present

1:06:41

in their arteries by getting LDL

1:06:43

even further low. So

1:06:46

this is a slightly kind of different

1:06:48

context. But and so people

1:06:50

will say, well, we can't, you know, a big pushback

1:06:52

here would be we we can't take people that

1:06:54

are that diseased essentially already. We can't take people that are at that high

1:06:56

risk and and think about this applying.

1:06:58

But but in reality, we can going

1:07:00

back to that threshold we said earlier that

1:07:03

really up to a range of an eighty milligrams

1:07:05

per deciliter. In the

1:07:08

circulation, we have

1:07:10

sufficient capacity to uptake the

1:07:12

cholesterol that is delivered to cells

1:07:14

from LDL. and

1:07:17

to use that and to recycle

1:07:20

it. And and all of those

1:07:22

processes can can kind of

1:07:24

flow, so

1:07:26

to speak. without the accumulation of

1:07:28

LDL and the circulation that eventually

1:07:30

ends up in that LDL getting

1:07:32

into the

1:07:34

artery. So what this comes back to really is that

1:07:36

the critical component in

1:07:38

all of this is is

1:07:41

the LDL receptor itself. And

1:07:44

cells do have the ability to

1:07:47

synthesize their own

1:07:50

cholesterol. but

1:07:52

essentially what ends up happening is the LDL

1:07:54

receptor will be expressed on cells

1:07:58

and when LDL is obviously delivering

1:08:00

cholesterol to those cells, that

1:08:02

receptor is present and can

1:08:04

uptake through this receptor pathway,

1:08:06

that cholesterol into

1:08:08

those cells. What ultimately can

1:08:11

happen then is the

1:08:14

if we have a level of LDL in the

1:08:16

circulation, basically

1:08:18

what happens is cells

1:08:20

are presented with a load

1:08:23

of LDL that exceeds the

1:08:25

capacity of the receptor to

1:08:27

clear that cholesterol out of the circulation. So

1:08:30

this is where the LDL

1:08:32

receptor becomes

1:08:35

saturated. and the LDL receptor becomes saturated at these

1:08:37

levels that we were talking about earlier

1:08:39

that are just sufficient for

1:08:42

bodily function over about

1:08:44

a circulating level of about six milligrams,

1:08:46

the LDL receptor can become saturated. Right? So the the levels,

1:08:49

again, this ties to

1:08:51

the fact that our physiological maximum

1:08:54

for requirements appears to be about thirty milligrams or in that range of up to thirty

1:08:59

milligrams per deciliter. But once

1:09:01

the LDL receptor becomes

1:09:04

saturated, it basically, you know,

1:09:06

that capacity to then clear that

1:09:10

circulate that LDL, that cholesterol from

1:09:12

the LDL and circulation is diminished. It's

1:09:14

kind of like a crane on

1:09:17

the dock. The cranes the receptor.

1:09:19

And

1:09:19

of those of ours, those crazy thought about this. No.

1:09:21

Well, I'm just just just just just

1:09:23

coming out. Right? I've got a

1:09:25

friend who works on the docks

1:09:27

and and drops steers grains,

1:09:29

steers or drives. I'm not sure what you'd say, but operates. And yeah.

1:09:31

So that would be similar to

1:09:34

that. Those there's just not

1:09:36

enough crane

1:09:39

activity to unload -- Yeah. --

1:09:41

those containers? Yeah. Yeah. Basically. And you

1:09:43

end up with them floating

1:09:45

on the ships. and eventually they have

1:09:47

to go somewhere. Mhmm. And

1:09:49

so so this this

1:09:51

this process is

1:09:54

a kind

1:09:54

of gradient

1:09:56

or threshold dependent process

1:09:58

in many respects.

1:09:59

So, you know, we

1:10:01

do need this class. And

1:10:03

this this is where they they take this grain of truth

1:10:05

and they twist it into something that sounds like

1:10:07

it's something you wanna question. or

1:10:10

it sounds like it's something that, you know,

1:10:12

we're not being told full story. But they're not the ones communicating full

1:10:14

story because they are correct. Anyone that says the body needs cholesterol

1:10:19

is in point of fact correct. Anyone says that

1:10:21

cholesterol is used for the

1:10:23

synthesis of sex steroid hormones.

1:10:25

Right? Is in point of

1:10:28

fact correct? There's a single person

1:10:30

in the cardiovascular sciences community that would deny any of this because it's just a fact.

1:10:32

Right. What they're

1:10:35

not telling you is what

1:10:38

levels are sufficient in the body

1:10:40

to actually have these mechanisms and have this

1:10:42

cholesterol be used for these purposes. And those

1:10:44

levels are

1:10:47

far lower than anyone in that

1:10:48

community even walking around the Eldridge. It's

1:10:50

a much more simplified story. Usually,

1:10:53

how it goes is someone sends in a question, a q

1:10:55

and a on their story and says, hey, I went to

1:10:57

the doctor, my LDL cholesterol is super high. They've

1:11:00

told me to

1:11:02

change my diet. and then their responses, no. Well, actually,

1:11:04

you need cholesterol for your hormone. So don't

1:11:06

worry about that. Yeah. Essential for life. It's

1:11:08

found in the brain, all this other thing.

1:11:10

And, yeah, in speaking to that, it's not only

1:11:12

that there's any certain amount needed, it's

1:11:14

that beyond that, there's no beneficial

1:11:17

impact. Right? So their possible

1:11:20

counterclaim of, oh, well, if this

1:11:22

is good for cell membranes or

1:11:24

for the brain or something,

1:11:26

but the more it's gonna be better. It's like Yeah.

1:11:28

No. No. No. Like, this this imagine is

1:11:30

enough thing beyond that. In all in

1:11:33

just nutrition science and science in general or

1:11:35

human biology exposure amount and threshold -- Yeah. --

1:11:37

and understanding for something can be good

1:11:39

and beneficial up

1:11:41

to a point. Mhmm. Yeah. And what happens here, you know, we

1:11:43

have, again, where where LDL is

1:11:46

delivering this cholesterol to cells,

1:11:48

and we have that receptor, take that cholesterol

1:11:50

into cells. One of the net effects is

1:11:53

BAT

1:11:54

cell can downregulate its own cholesterol synthesis. It doesn't need to produce its own

1:11:56

cholesterol.

1:11:59

And

1:12:00

the point is it's just to

1:12:02

the point Danny just said about, you know, more isn't better for these reasons. So

1:12:06

we can deposit cholesterol

1:12:09

two cells and deliver it there. But in the absence of

1:12:11

that, a cell can synthesize its own cholesterol. So there's no

1:12:14

it synthesizes it in the immense

1:12:18

acquirer. So this idea that having

1:12:21

a higher level of

1:12:23

LDL carrying cholesterol

1:12:26

is some It's not doing anything. It's not

1:12:28

going anywhere. It's not being delivered

1:12:30

anywhere. It's just in the circulation.

1:12:32

And that's the

1:12:35

problem. It's the circulating gradient. And as

1:12:37

that gradient increases, the risk of

1:12:39

heart disease, linearly increases. to the

1:12:41

point at the time of that. It's just

1:12:43

not going anywhere. Right? because

1:12:46

the claim is, well, you'll have

1:12:48

better hormones or better immunity. You know,

1:12:50

seladeladel often talks about better immunity. Yeah.

1:12:53

So the I mean, look,

1:12:56

the the immunity thing is IIIIIII

1:12:58

don't know. I've never actually seen it substantiated.

1:13:03

No. I've seen it as broad kind of

1:13:06

claim. And one

1:13:10

one aspect the the one time I've seen any any

1:13:12

one of those offer

1:13:14

a supporting reference or

1:13:17

otherwise for what they typically

1:13:19

looked at. is the relationship, for example, this happened during COVID.

1:13:21

This study came out of a

1:13:23

Chinese group and

1:13:26

it said, ah, People hospitalized with COVID had

1:13:28

low LDL. So they were relating

1:13:30

that then to to the immunity

1:13:32

aspect. But we

1:13:35

we know again It's a point

1:13:37

of fact that having a disease, being

1:13:39

infected, causes, like,

1:13:43

what relates to lowering a LDL

1:13:46

cholesterol, right? When cancer is developing, it influences lipoprotein

1:13:48

metabolism. So

1:13:51

the temporal relationships between these

1:13:53

factors that they're trying to

1:13:56

associate really

1:13:58

are important. So what's happening

1:13:59

isn't that low LDL is

1:14:02

making people more prone to

1:14:04

infection from COVID

1:14:06

or indeed causing cancer. The LDL

1:14:08

is lowering because they have a disease because they are

1:14:11

in effect nineteen, which is acceptable for

1:14:14

the first causality. Right.

1:14:16

So and what what if you looked

1:14:18

at that study, what happens is when they recovered from COVID, they're all deal and back over. So it's not

1:14:20

a causal relationship at all. That

1:14:22

also brings us to the longevity

1:14:26

sort of the longevity claim

1:14:28

where some people will point to a

1:14:30

certain cohort and say, well, if you

1:14:32

if you look at this study folks

1:14:34

with higher LDL cholesterol actually

1:14:36

lived longer at lower risk

1:14:38

of of total mortality. Yeah. Yeah.

1:14:41

And this is the whole old course mortality -- Yeah. -- conundrum. Right? And

1:14:43

and the importance of looking at what studies people are

1:14:46

pointing to and and then looking at,

1:14:48

okay, Number

1:14:51

one, where are we

1:14:52

intervening kind of what's the

1:14:54

age? And then within the follow-up,

1:14:56

are we accounting for the fact

1:14:58

that there could be people undiagnosed

1:15:01

with an illness at the start

1:15:03

of that, right? That hasn't been diagnosed yet, which would speak to this issue

1:15:08

that Alan is raised about if you

1:15:10

have then an illness that develops that then leads to lower LDL cholesterol,

1:15:14

then you're just kind of misinterpreting what is actually

1:15:16

going on. Mhmm. And so I think this gets

1:15:18

wrapped up in that that whole situation. That's

1:15:21

typically where people

1:15:24

point to even if they accept

1:15:26

the issue around atherosclerosis risk, which they probably don't. But even

1:15:30

at that point, then it quickly gets shifted Mhmm.

1:15:32

-- but what about all calls mortality?

1:15:34

And then pointing to the sum

1:15:36

of the stuff, which I

1:15:38

think is largely explained by

1:15:40

by

1:15:41

some of those issues. Yeah.

1:15:43

Yeah. Yeah. Yeah. Explain one that that pops up here. And

1:15:46

I think this is

1:15:49

speaks to, like, lifetime exposure and you just mentioned then, like,

1:15:51

when do you intervene? So one thing that I see up is

1:15:57

someone will say, well, I know someone

1:15:59

who had low LDL cholesterol. Mhmm. You

1:16:01

know? And they still had

1:16:03

a heart attack. So

1:16:06

this person, probably, presumably, in this anecdote, that person was put on, you know, statins or

1:16:08

PCSK9 inhibitors, they

1:16:11

lowered their cholesterol. they

1:16:15

still had a heart attack. Mhmm. Now the kind

1:16:17

of lane interpretation of that is,

1:16:19

see, that's evidence that

1:16:21

low cholesterol is now protecting you against an event. Can you kind of explain

1:16:23

-- Yeah. -- why that's something? This actually back to to

1:16:26

the kind of the

1:16:28

seminal epidemiology

1:16:30

that identifies total cholesterol

1:16:33

as a risk factor, the Framingham,

1:16:35

the original Framingham cohort in the late

1:16:37

four g's and early fifties. And

1:16:39

people like to point to that and say, well, you

1:16:41

know, thirty five percent of the heart

1:16:44

disease in that

1:16:46

cohort occurred in people with normal cholesterol

1:16:48

levels. Mhmm. But recall the concepts

1:16:50

like normal high or low, don't

1:16:53

their abstracts, unless we put definitions on them, and we're the ones putting

1:16:55

definitions on them. Low at the time, as in normal at the time,

1:16:57

when people say thirty five percent

1:17:00

of heart season,

1:17:02

prime income occurred in people with normal cholesterol

1:17:04

is less than two hundred

1:17:07

milligrams total cholesterol. So when

1:17:09

people say, oh, well, someone had low cholesterol

1:17:11

or they were they were put on this drug

1:17:13

and still had a heart attack. It's

1:17:15

highly likely that they and

1:17:18

and what we tend to see

1:17:20

is the attained level of LDL cluster

1:17:22

already matters. So unless and

1:17:24

and this is the reason this

1:17:26

is really important for people to grasp

1:17:28

again, unless those thresholds of less than one

1:17:30

point eight millimole per liter, seventy to eighty milligrams

1:17:36

per deciliter, are being reached,

1:17:38

atherosclerosis can still progress. Now the rate

1:17:40

and the magnitude

1:17:43

of that progression will well

1:17:46

be different. We'll vary relative to

1:17:48

how high that is, someone with an

1:17:51

LDL of two hundred milligrams,

1:17:53

not not totally even just LDL of

1:17:55

two hundred milligrams, they are over one hundred and sixty one eighty. So one with an LDL that high,

1:17:59

we'll we'll have higher,

1:18:02

faster range of progression than someone with an LDL of, say, one hundred and forty or one hundred

1:18:08

and thirty. So the

1:18:10

time course that both of those individuals, you know, take to reach their first cardiovascular

1:18:13

event

1:18:16

might differ. But what

1:18:18

we typically see is that kind of claim of well someone had

1:18:20

normal LDL

1:18:21

cholesterol and they still had

1:18:23

a heart attack. within

1:18:27

our current definitions, normal may

1:18:30

not actually be quite

1:18:32

yet defined at a threshold

1:18:34

that's sufficient to actually offset. the

1:18:37

the

1:18:37

the the progression altogether. Yeah. You know, you you see

1:18:39

a similar thing with this statin denialism. Right?

1:18:41

And something we've

1:18:44

covered of a female hatcher is

1:18:46

a really good example of this talking about, but you give people statins and actually doesn't do

1:18:49

anything for

1:18:52

their risk. Right? We still have events or there's

1:18:54

still mortality. And again, by and large, when you look at any evidence they try

1:18:56

and cite there, it's

1:18:59

where you've had this light prescription of

1:19:01

statins. So you if you give start

1:19:03

giving someone a statins in

1:19:06

their seventies, for example, and

1:19:09

they have an event off of the back of that number

1:19:11

of years later, then you've

1:19:16

had decades worth of plaque

1:19:18

progression potentially for that individual. And so then lowering their LDL in

1:19:20

their seventies. Mhmm. And then seeing

1:19:22

that, oh, they still had a cardiovascular

1:19:26

therefore statins don't do anything -- Mhmm. -- is

1:19:28

is is misleading. because again, it's

1:19:30

this lifetime cumulative exposure to

1:19:33

this why early intervention is very

1:19:36

important. I mean, this is where you see some people

1:19:38

on Twitter joke that statin should be put in the

1:19:41

water in the water supply. But also, there's it. And

1:19:43

and I appreciate you probably haven't read the full study yet,

1:19:45

but we were flicking around the study a

1:19:47

couple of days ago. I think

1:19:49

that four eighty four there. And that kind of almost makes it

1:19:52

easier. Yeah. I mean, it's

1:19:54

it's it's it's it's it's

1:19:56

incredible, I think, to see. And, you know,

1:19:58

haven't read the full study yet.

1:19:59

So the the slides

1:20:02

shared from the ES Congress. And

1:20:07

I

1:20:07

think the implications are kind of

1:20:10

profound for a couple of reasons.

1:20:12

There's been a lot of

1:20:14

people in the cardiovascular space and

1:20:17

and it has been debated,

1:20:19

hasn't been a settled kind of

1:20:21

question at all. But there has

1:20:23

been a general kind

1:20:26

of in terms of the overall interpretation

1:20:28

of the evidence move towards the

1:20:30

idea that not only is is

1:20:33

low or better, for cardiovascular

1:20:36

disease, for for for avoiding the development of

1:20:38

atherosclerosis, or indeed getting it to a

1:20:40

level where if someone does have

1:20:42

a degree, of plaque that that can actually regress because

1:20:44

their LDL is kept in a

1:20:46

range where the escaping of

1:20:49

LDL from the bloodstream is controlled.

1:20:52

But within the lower is better, there

1:20:54

was always there was as well

1:20:56

an earlier is

1:20:58

better. So lower earlier would

1:21:02

be the best, so to

1:21:04

speak. But actually, that evidence was

1:21:06

largely based on an inference of

1:21:09

of a couple of strands

1:21:11

of evidence. Brian Ferron's genetic studies, so you

1:21:14

take people that have genetic variants in PCSK9

1:21:16

gene. they

1:21:18

have the lowest lifetime cardiovascular risk. Their

1:21:21

cholesterol levels are are low from

1:21:23

the from the womb, lucky. You've

1:21:26

got people with variants in hMG

1:21:28

co wear reductase and NLCP

1:21:30

one hundred and one, which

1:21:33

is what is that amide

1:21:35

targets? It's in the guss that controls the absorption of

1:21:37

cholesterol from diet. So you look

1:21:39

at any of

1:21:42

those variants. They all lower cardiovascular disease over the course of

1:21:44

a lifetime to various magnitudes, and those

1:21:46

magnitudes relate to how much lower

1:21:50

their an individual that with that variance LDL

1:21:52

cholesterol is. So that was

1:21:54

looking at genetic studies going,

1:21:58

okay, when people when we when we compare,

1:22:00

you know, the the genetic

1:22:02

studies, the lifelong exposure to

1:22:05

lower LDL levels. there was a fifty five

1:22:08

percent lower risk of

1:22:10

cardiovascular disease. So that

1:22:12

was one strand of evidence. And

1:22:14

then, of course, you have the population studies

1:22:17

where when you stratified for age. Like, Donnie

1:22:19

just mentioned, like, the average baseline

1:22:23

age of people in statin interventions is sixty

1:22:25

three. So they're often older. And indeed

1:22:27

you have trials where

1:22:29

people are in their

1:22:32

70s when treatment is initiated. atherosclerosis is already advanced.

1:22:34

Yeah, you put them on a statin. Yeah, they still

1:22:36

have a heart disease, you

1:22:38

know, endpoint or cardiovascular disease endpoint.

1:22:41

because they're just diseased and older. But when

1:22:43

you stratify the population, blood cholesterol, studies

1:22:48

into decades of life. What you saw was that in

1:22:50

the forty to fifty age group, for example, those

1:22:53

with lower cholesterol

1:22:56

had had significant steep

1:22:58

of how lower their risk was was much greater than

1:23:00

in the sixty to seventy age

1:23:02

bracket. Right? So you'd much lower risk

1:23:07

when you'd low cholesterol in that life stage. But direct

1:23:11

interventions hadn't really kind

1:23:14

of provided anything to the to that

1:23:16

question necessarily in a way that in

1:23:18

a way that this recent

1:23:21

publication has because it's it's

1:23:23

in terms of what they've done,

1:23:25

you've given what they did with a

1:23:27

secondary prevention trial where people were

1:23:30

already on a maximally tolerated

1:23:32

dose of statins, and they

1:23:34

were administered a PCSK9 inhibitor in

1:23:36

the four AR trial. to

1:23:38

get that LDL even lower. And four

1:23:40

year was the trial I mentioned earlier

1:23:42

that pre specified, how low can how

1:23:45

low can we get people safely down

1:23:47

to six milligrams? and the intervention

1:23:49

itself lasted two years and then

1:23:51

after the intervention because

1:23:53

the actual treatment

1:23:56

was so successful the placebo group

1:23:58

are then given the PCSK9 inhibitor. Their LDL drops to basically thirty

1:24:03

millimeters per deciliter and they do get a

1:24:05

significant reduction in risk of a further event. But what's

1:24:07

most profound as a finding from

1:24:10

this trial is the difference in

1:24:12

risk between the timing of

1:24:14

initiation, between the treatment group and the placebo group, the difference in two years of

1:24:20

lowering LDL being much more

1:24:22

significant in the actual original intervention group. And

1:24:26

so this is although a secondary analysis although not

1:24:28

necessarily run, it's a kind of follow-up

1:24:30

period of a randomized controlled trial. I

1:24:34

think it's out as

1:24:36

a really, really strong and convincing piece of

1:24:39

evidence that actually the lower we're

1:24:41

intervening in people

1:24:44

to get people to get Elia

1:24:46

lower the better. Mhmm. Now the question here, of course, is this is a second Elia we intervene.

1:24:48

Yeah. The earlier

1:24:51

we intervene in life. and

1:24:54

get LDL to ranges where atherosclerosis

1:24:56

kind of progressed the better. Now I think

1:24:58

we do have to remember that four

1:25:01

year just to put it in its right

1:25:03

context, is a secondary prevention trial. Mhmm. So what would be really interesting see this

1:25:08

in a primary prevention context. Right.

1:25:10

Nevertheless, when we're thinking about the available converging

1:25:12

lines of evidence from genetic studies

1:25:14

to epidemiology to some of these

1:25:18

of evidence coming out of RCTs

1:25:20

in terms of earlier. The earlier

1:25:22

in someone's life stage that they

1:25:25

can get LDL lower the better

1:25:27

as far as their long term cardiovascular risk.

1:25:29

I think there's gonna be so many interesting

1:25:31

questions in clinical practice going forward. I

1:25:33

think over lunch, we chat about some of

1:25:35

these other day where now conceivably this might

1:25:37

be one of the areas where there

1:25:39

might be conversations between

1:25:42

clinicians and physicians of

1:25:44

saying, okay, even before

1:25:46

we pass a threshold for disease or predease for someone,

1:25:48

we might just

1:25:51

need to intervene pharmacologically as

1:25:55

opposed to go with kind of lifestyle modification for a

1:25:57

while, see how things progress, if it gets

1:25:59

worse, then we'll intervene with

1:26:02

drugs, which is we'd approach many other conditions, I think.

1:26:04

Yeah. Well, this might be one where that

1:26:06

as as we start to

1:26:07

see becomes maybe untenable.

1:26:09

Some people might think of Well, we just Even if we

1:26:11

Yeah. Like, how come we let people go if

1:26:14

we do this whole ten year risk score?

1:26:16

And we say, well, yeah,

1:26:18

I know you're you're LDL's one thirty, you

1:26:21

know, maybe change your diet a little bit, but your your ten year

1:26:23

risk score is low. Come back in a decade, where we're

1:26:25

basically saying go away and

1:26:27

allow atherosclerosis to progress for

1:26:30

ten years. I think there's a big ethical question that will eventually have to be faced where

1:26:32

delaying intervening in

1:26:35

the causal path way.

1:26:39

It's different if has a you know, that's again, this

1:26:42

comes back to this really important

1:26:44

distinction between biomarkers. You

1:26:46

know, if someone someone maybe

1:26:48

had some eye triglycerides,

1:26:50

but their LDL was in particular high, maybe some you know, you you can those

1:26:52

with slightly more leeway in

1:26:54

time in terms of time. But

1:26:59

I think now there is a big

1:27:01

question in terms of if we've got

1:27:03

people with any sort

1:27:05

of LDL cholesterol level that's in this range

1:27:07

where atherosclerosis can progress is kicking the

1:27:10

condom down the road by a decade.

1:27:12

Right.

1:27:13

particularly if someone's say,

1:27:15

like, twenty twenty five and you're only looking out to, like, thirty five. you

1:27:21

know, ideally, that person is is made aware of what their risk is when they're forty and

1:27:23

-- Right. -- fifty. Yeah. Yeah. They still got

1:27:25

a lot of life to

1:27:28

to live. We

1:27:31

can job kids with PCSK9 inhibitors. Yeah. Well, I

1:27:33

had seen something recently. It's a group

1:27:35

that are looking at gene editing

1:27:37

of the of the expert. Yeah.

1:27:39

We talked about Yeah. It's it's so

1:27:41

cool. Explain that for folks just in a sort of so p

1:27:44

PCSK9 is

1:27:47

is a gene. And again, we've

1:27:49

mentioned a couple of times PCSK9 inhibitors. It's a fairly

1:27:52

awkward term to get out

1:27:54

relative to something like statin, but

1:27:57

this is a class of

1:27:59

drugs they're injectable. Basically, what they

1:28:01

do is they kind of inhibit the expression

1:28:03

of this PCSK9 gene which

1:28:08

ultimately comes back to the LDL

1:28:10

receptor that we were discussing. So

1:28:14

PCS can I when it's active and expressed

1:28:16

down regulates the expression

1:28:18

of the LDL receptor. So

1:28:20

we don't have this level of

1:28:23

cholesterol clearance from the blood. So

1:28:25

if you inhibit with a drug or indeed with gene

1:28:27

editing, essentially knockout PCSK9, what

1:28:31

you're doing

1:28:32

is

1:28:33

having a big

1:28:35

op regulation of the expression -- Yeah.

1:28:38

-- LDL receptors, more cranes clearing

1:28:40

cholesterol from

1:28:43

the blood. And Of the three major

1:28:45

class of drugs that are available for lowering LDL, we've got statins

1:28:48

which inhibit HMG

1:28:51

CoA reductase, which is an enzyme in the

1:28:53

pathway of liver synthesis

1:28:55

of LDL. So

1:28:57

by inhibiting that step, you're lowering the synthesis

1:28:59

of LDL in the liver. And then

1:29:02

we have zedamide, which is a

1:29:06

bile acid sequestrant essentially is out of my another on

1:29:09

kind of cholesterol absorption in

1:29:11

the gut. Again,

1:29:15

lowering liver synthesis. an increasing

1:29:17

LDL receptor expression statins increase the expression of the LDL

1:29:19

receptor in the liver and

1:29:22

PCSK9

1:29:24

So Although they

1:29:26

are targeting different pathways, the gosh HMG quay reductase PCSK9

1:29:30

the unifying final pathway the

1:29:32

unifying final pathway

1:29:35

that makes all of these drugs work is they all act

1:29:37

by up regulating the expression of the

1:29:39

LDL receptor. They all act by

1:29:42

making more cranes in the harbor,

1:29:44

clear the cholesterol

1:29:46

from the ship, so to speak. And that is why the LDL

1:29:52

receptor we can say that this

1:29:54

is the causal pathway because there's this unifying final stem between each of these drugs even

1:29:56

though the drugs themselves

1:29:59

target different pathways. So with

1:30:01

the promise of gene editing, you could really target the pathway that has

1:30:03

the most profound impact.

1:30:09

on

1:30:09

lowering cholesterol, LDL cholesterol in

1:30:10

the blood. And again, you know, the

1:30:13

potential for that

1:30:16

to be almost as part

1:30:18

of, like, a vaccination schedule or something, you know. I think we're on the cusp of

1:30:21

of a

1:30:24

revolution in eliminating

1:30:28

hopefully the burden of atherosclerotic cardiovascular disease

1:30:30

from the population. And then this is

1:30:32

why the likes of of

1:30:34

of Paul Saladino and otherwise

1:30:36

are just just

1:30:37

just torns in

1:30:38

the side of scientific progress.

1:30:42

What would that do to lifespan?

1:30:44

Or is it more of a

1:30:46

health span consideration? Like, would would that

1:30:48

change the average lifespan, do you think?

1:30:50

I don't know because I think we're of

1:30:53

this conversation. We're very focused

1:30:55

on atherosclerotic cardiovascular disease. We

1:30:57

have so

1:30:58

many other issues in

1:31:02

society, social, and economic, and environmental, and otherwise, that are influencing life expectancy. You In

1:31:04

the UK, we've

1:31:07

seen life expectancy

1:31:10

in the, what they call, the periphery. Basically,

1:31:13

the areas outside of

1:31:15

London start to decline. And

1:31:18

there there's a burden of ill health involved that extends beyond just disease.

1:31:24

Mhmm. So I think

1:31:26

that this would be specific to cardiovascular disease. What impact it

1:31:28

would translate to as far

1:31:30

as life expectancy? I think that

1:31:34

becomes part of this overall kind of

1:31:37

soup that we have of of

1:31:39

of all these other

1:31:41

factors and catabolic disease is still a

1:31:43

major issue obviously in the population

1:31:45

and these other kinds of, you

1:31:48

know, determinants social and

1:31:50

environmental and economic determinants of health are influencing life expectancy. So I think

1:31:52

it would be kinda hard to

1:31:54

but it's certainly certainly the health

1:31:59

a ton of individuals would would hopefully not be one

1:32:01

where they're facing a coronary events

1:32:03

-- Mhmm. -- or

1:32:05

the surgeries and interventions

1:32:08

requires and you know,

1:32:10

yeah, stroke. These other you'd I guess, you'd hate to say

1:32:13

that come

1:32:16

in and

1:32:16

and for folks

1:32:18

who could change their diet in

1:32:20

some ways, in in ways that would be

1:32:22

meaningful for their overall health, decide

1:32:26

not to make changes. But then there's gonna be AAA

1:32:29

whole host of people that could

1:32:31

access that type of intervention who

1:32:33

would design in the position to

1:32:35

to make changes. Yeah.

1:32:38

So that's that becomes the question.

1:32:40

I mean, someone could then conceivably not develop atherosclerosis, but could

1:32:42

easily develop fatty liver and diabetes, you know. It's like

1:32:48

Talk to me about veins.

1:32:50

This one seems to be

1:32:52

a new one. That's

1:32:55

that sort of popped up and and the idea or

1:32:57

is that, okay, Allen

1:32:59

Denny, if the

1:33:02

there's a threshold whereby you have

1:33:04

a certain number of these

1:33:06

APOB containing lipoproteins, which then essentially

1:33:11

get you to a tipping point where you start

1:33:13

to get accumulation within the wall of the

1:33:16

artery at

1:33:18

this this fatty part buildup, which ultimately leads

1:33:20

to some sort of obstruction

1:33:22

in an event. If

1:33:25

that's the case, presumably

1:33:27

arteries and

1:33:27

veins in the body are exposed to the

1:33:29

same number of APOB

1:33:31

containing lipoproteins. Why

1:33:34

do we not see atherosclerosis in

1:33:37

veins and why are we seeing

1:33:39

it show up just

1:33:42

in arteries? Yeah. So so there's well, there's a couple

1:33:44

of things. So one is is, you know,

1:33:46

it's it's it's it's carried in it's

1:33:48

carried in the plasma. Right? Lipa

1:33:51

proteins are carried in plasma. in

1:33:53

veins.

1:33:53

There's a range of there's a there's a number

1:33:55

of levels. One is that within

1:34:00

the plasma, there are

1:34:02

other factors that are present that

1:34:05

can have protective

1:34:08

effects. Thus, those

1:34:10

protective effects are lost once

1:34:12

kind of trapped and

1:34:14

retained in the artery.

1:34:16

But mainly it's to

1:34:18

do with the fact that within we're

1:34:20

we're talking about kind of the spilling when we're when we're

1:34:22

talking about is, well, LDL, you know, gets

1:34:26

into the archery wall. were

1:34:28

talking about the kind

1:34:30

of spillover of the plasma into that

1:34:34

space. Right? So the

1:34:38

atherosclerosis, like the

1:34:40

processes involved, the APO

1:34:42

B mode bindsing to these

1:34:45

proteobigens in the artery

1:34:47

wall. Like those those

1:34:49

processes don't occur

1:34:50

in the plasma. their

1:34:53

retention, the subsequent inflammatory and immune

1:34:55

processes occur with that retention,

1:34:57

and that retention

1:35:00

doesn't occur. in the

1:35:02

plasma. So it's it's just it's just a fundamental distinction in

1:35:07

relation to the mechanisms involved

1:35:10

in atherosclerosis relative to the particular

1:35:16

circulatory site that we're

1:35:18

that we're looking at. So I I think that that's an interesting one because I think to a to

1:35:24

a listener that sounds really plausible. Or at least

1:35:26

it sounds like a kind of like question to answer. You're like, oh, yeah. Yeah. Yeah.

1:35:28

Why why does

1:35:31

it develop in? in the arteries. But

1:35:34

it's it's to do with that

1:35:35

with that matter of its

1:35:37

of of

1:35:40

LDL circulation and the spillover

1:35:42

then of plasma containing LDL into the artery

1:35:44

and the fact

1:35:46

that those processes are processes

1:35:49

that occur from that initial retention. Mhmm.

1:35:51

So the penetration is obviously

1:35:54

a factor,

1:35:55

but really what

1:35:56

what what

1:35:58

it is is that the the

1:35:59

net retention of that particle in

1:36:02

the arch rewold and those processes don't

1:36:04

occur. don't

1:36:06

occur

1:36:06

in veins necessarily. Is

1:36:09

there something even within

1:36:11

the arterial system that makes

1:36:13

certain spots susceptible.

1:36:15

I haven't looked at this, but

1:36:17

it seems like, you know, the the arteries,

1:36:19

you know, feeding the the the

1:36:21

heart and then also the brain. There it seems like there's certain spots where

1:36:24

it's more likely for this

1:36:26

to be to become an

1:36:28

issue. Yeah.

1:36:30

There there there do appear to be spots that

1:36:33

are sensitive to

1:36:36

the

1:36:36

to the actual process of

1:36:38

retention specific sites within the arterial interims specifically. The

1:36:42

processes that then

1:36:44

occur in response to that. So

1:36:46

let's say we then have the mounting

1:36:49

immune and inflammatory responses occur without the

1:36:51

you know, and and

1:36:54

kind of with the potential

1:36:56

for protective compounds like vitamin

1:36:59

E essentially kind of nullifieds. And

1:37:04

so oxidation of that

1:37:06

particle that

1:37:06

has been trapped occurs in in

1:37:12

ways dash may be specific to

1:37:14