Re: Question for Chris M. - LDL receptors in endothelium?

[Guest guest]

On 2/17/08, chriskjezp <chriskresser@...> wrote:

>

>

> In Malcom Kendrick's book and in this online article

> (http://www.thincs.org/Malcolm.emigration.htm) he states that the

> endothelium does not

> have receptors for LDL (normal LDL - he doesn't mention oxidized LDL). He

> comes to the

> conclusion that LDL can't penetrate the endothelium because of this, unless

> LDL

> concentrations are extremely high (above 580 mg/dl).

> I know you've done a lot of research in this area - what's your take on

> this?

I am not an expert on this, so I might be missing something, but I

don't understand his point. First, no one asserts that non-oxidized

LDL makes any substantial contribution to atherosclerosis. Second, it

is macrophages, not the endothelium, that are asserted to take up

oxidized and glycated LDL.

> Also, elsewhere in the book he expresses skepticism (disbelief, actually)

> that HDL can

> penetrate the fibrous cap of an atheroma, " suck " out the cholesterol, get

> back out and

> then transport the cholesterol to the liver. Here's a quote:

> " Firstly, atherosclerotic plaques are almost universally covered over by a

> lining, or cap

> separating the plaque from the bloodstream, and this cap is impermeable to

> HDL.

> Secondly, a great deal of the cholesterol in plaque is in clefts, even

> crystals (how do you

> think Virchow recognized it 150 years ago?). It is not free and floating

> about inside a

> plaque, and you would need a pneumatic drill to extract it, and I can't see

> HDL wielding a

> pickaxe to a cholesterol cleft. Thirdly, no one has explained, or

> identified, any sort of

> mechanism by which HDL gets cholesterol out of the plaque. It just sort

> of... does it.

> Speaking personally, I always like to see some sort of plausible biological

> mechanism to

> explain why something works. "

> Is there such a mechanism?

I don't know if there is a mechanism by which HDL can get cholesterol

from behind a fibrous cap, but the fibrous cap exists in the advanced

stage of the disease and the lipid buildup precedes it (and partially

causes it). So, it may be the case that HDL is relevant in the early

stages but becomes irrelevant in the later stages. In fact, maybe

Kendrick just provided the explanation for why the HDL-boosting

treatments have not been as successful in treating established CHD as

was hoped.

Lipoproteins work by receptor-mediated transport, so I would not try

to draw an analogy between the tools a human would need to extract

something and the mechanisms by which biological molecules would

accomplish it -- of course physical barriers such as fibrous caps and

crystallization would still be biological barriers.

Chris

[Guest guest]

> I am not an expert on this, so I might be missing something, but I

> don't understand his point. First, no one asserts that non-oxidized

> LDL makes any substantial contribution to atherosclerosis. Second, it

> is macrophages, not the endothelium, that are asserted to take up

> oxidized and glycated LDL.

Well, perhaps no researchers assert that non-ox LDL causes CHD, but I'd say

about 99% of

the population including most physicians still do.

Kendrick's theory is that endothelial damage is always the first step of the

atherogenic

process, and that damage is likely to be caused by most of the known risk

factors for CHD

(smoking, turbulent blood flow [hypertension], elevated blood glucose, elevated

cortisol

levels [due to deranged HPA axis], hyperinsulinemia & hypertriglyceridemia).

The endothelial damage stimulates thrombus formation and attracts Lp(a), amongst

other

clotting factors, which then adheres to the area of damage. Because of the

structure of

Lp(a), clots formed this way are fibrous and rigid and can't be destroyed

through normal

thrombolytic enzymes.

Over time the endothelium grows back over the blood clot, effectively drawing

the clot

into the arterial wall. As the clot is drawn in, so is Lp(a). Lp(a), being a

lipoprotein, is full

of cholesterol.

This is his description of how cholesterol gets into plaques.

I understand the ox-LDL hypothesis and the mechanism seems clear enough.

However, the problem I still have with the hypothesis that ox-LDL is a

significant risk

factor is that statin drugs have been proven to significantly lower ox-LDL, and

yet statins

show little or no benefit for women and the elderly. If statins lower ox-LDL,

and ox-LDL

is a major risk factor, then why aren't statins reducing CHD in these

populations?

I suppose it's possible that statins have some negative effect, like decreasing

CoQ10

levels, that offsets the benefit of lowering LDL. But this sounds like an

ad-hoc hypothesis

to me.

> I don't know if there is a mechanism by which HDL can get cholesterol

> from behind a fibrous cap, but the fibrous cap exists in the advanced

> stage of the disease and the lipid buildup precedes it (and partially

> causes it). So, it may be the case that HDL is relevant in the early

> stages but becomes irrelevant in the later stages. In fact, maybe

> Kendrick just provided the explanation for why the HDL-boosting

> treatments have not been as successful in treating established CHD as

> was hoped.

>

Yes. This brings up another question. Raising HDL levels should theoretically

reduce

levels of ox-LDL in the bloodstream, which would in turn reduce CHD rates. Dr.

Kendrick

explains the reason HDL can't remove LDL from plaques, but HDL should still

remove ox-

LDL from the blood, and thus reduce CHD.

However, it has been shown conclusively that raising HDL has no such effect. In

fact,

there isn't a single study which demonstrates that increasing HDL protects

against CHD at

all. As far as I know, these studies were not only performed on people with

" advanced "

CHD (significant plaque formation); they were performed on a general population

which

would include early and late stages of CHD.

What do you think, Chris?

Chris

[Guest guest]

> I didn't know Lp(a) was a clotting factor. It is a selective risk

> marker for the proportion of oxidized phospholipids in LDL particles,

> and it is currently thought to function in " mopping up " the oxidized

> phospholipids by the authors publishing this research. (e.g. Tsimikas

> et al, not sure if I spelled that right).

> How does Lp(a) form clots, and what aobut its structure creates clots

> that can't be broken down? Since when do lipoproteins form clots? I

> didn't know this.

Unfortunately, Dr. Kendrick gears his articles towards the general public, so he

doesn't go

into detail. I wish he did. He simply says that the " primary function of Lp(a)

is to stick to

areas of damaged artery and " plug " them shut. "

> Is there evidence for it?

No. Again, I wish he did. I know he has been a very active cholesterol skeptic

for many

years, and has studied this extensively. But that doesn't make me simply accept

what he

says without evidence. That's one reason I posted it here, hoping you might

know

something about it.

> I already addressed these questions elsewhere and do not consider it

> evidence against the ox-LDL hypothesis. Statins also reduce Lp(a):

So, this study suggests that statins are reducing ox-LDL, because Lp(a) is

thought to mop

up excess ox-LDL and a lower level of Lp(a) could indicate less ox-LDL?

> That was not the only point I made before, but it is a good one. I

> don't know what you mean by " ad-hoc hypothesis " -- it is just one of a

> number of points that demonstrate those trials are not tests of the

> ox-LDL theory. They are not single-variable interventions.

I used that term to indicate the practice of creating a new hypothesis to

explain away the

facts that refute the underlying theory, rather than changing the underlying

theory. In any

event, I am coming to better understand that (as you suggest) the mechanisms of

statin

drugs are very complex and therefore it's difficult to use statin trials to

support or refute

the role of a single variable in CHD pathogenesis.

> I don't think it would remove ox-LDL from the blood per se, but it

> would prevent LDL from oxidizing. It also delivers vitamin E to

> endothelial cells and exerts anti-inflammatory effects, suppresses

> adhesion molecules, etc.

All the more reason higher levels of HDL should be protective, right?

I agree that the data are not " conclusive " , but there certainly isn't any data

indicating a

clear benefit. I wonder why that would be?

P.S. In the article I cited, Dr. Kendrick presents an interesting theory that

stress

(dysregulated HPA axis) is the mechanism which ties together the

response-to-injury

hypothesis, the higher incidence of CHD in emigrant populations and Syndrome-X.