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

[Guest guest]

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

> 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.

I agree that this is still the pop science version of the theory, but

none of the researchers, writers of textbooks, lecturers, etc, that I

have seen talk/write about this assert anything of the sort. A book

that addresses the issue should address the actual scientific theory

rather than the pop science version of it, except to point out where

the two differ. Otherwise, it is combating a straw man.

> 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).

And it is caused by oxidized LDL too, so that is why the

response-to-injury hypothesis and the oxidized-lipid hypothesis are

not in competition but rather cooperate in explaining the disease.

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

> amongst other

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

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).

> Because of the

> structure of

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

> through normal

> thrombolytic enzymes.

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.

> 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.

Is there evidence for it?

> 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 already addressed these questions elsewhere and do not consider it

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

==========

http://www.ncbi.nlm.nih.gov/pubmed/18000162?ordinalpos=2 & itool=EntrezSystem2.PEn\

trez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

The atorvastatin group exhibited clinically significant reductions

(mean +/- SD) compared with controls in total cholesterol (-21.7 +/-

41.7 vs -3.2 +/- 40.0 mg/dL, respectively; p = 0.017) and LDL-C (-13.1

+/- 32.0 vs -1.1 +/- 38.4 mg/dL, respectively; p = 0.058) levels, as

well as Lp(a) (-10.6 +/- 27 vs 3.5 +/- 17.8 mg/dL, respectively; p =

0.046).

==========

So insofar as your criticism detracts from the support for the ox-LDL

hypothesis, it does the same for Kendrick's hypothesis.

(I don't think it really hurts either hypothesis, personally.)

> 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.

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.

> 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.

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.

> 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?

No, I don't think anything has been shown " conclusively. " The studies

with torcetrib, for example, showed that the treatment had small

effect in improving atherosclerosis, despite increasing mortality.

The improvement was not very impressive. So, there is pretty

convincing evidence that this is a bad area to try to make

interventions in, but it isn't at all clear that HDL doesn't have some

relatively minor protective effect, which is what I suspect it has.

For the folks that think it is really important, it provides some

indication they are wrong.

Chris

[Guest guest]

> > 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. "

Does he provide a reference? That is quite easy to do even while

providing the information simply.

Isn't a lipoprotein " plugging shut " a damaged area of artery something

quite different than acting as a " clotting factor " ?

> > 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 read another post of his where he suggested that there was no

functional difference between n-3 and n-6 fatty acids becuase the

location of an electron is not concrete, but rather exists as a

probability. I'm sure he's been studying for a while, but sometimes I

am rather unimpressed by the information he seems to have gathered or

invented.

> > 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?

I have no idea because I didn't read it. I just assumed that statins

reduce Lp(a) so did a quick search and it popped up.

I am just pointing out that if statins failing to reduce heart disease

risk in certain subgroups even though they lower ox-LDL is evidence

against the causality of ox-LDL, then statins failing to reduce heart

disease risk in those same subgroups is evidence against the causality

of Lp(a) because statins also reduce Lp(a).

> > 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.

First of all, that would be a perfectly valid practice. Obviously

when you have information supporting and refuting a hypothesis

simultaneously, you have to modify the hypothesis to account for all

the evidence, and forming a new sub-hypothesis to explain the refuting

evidence is part of that process.

But that is not what I was doing. There was never any information

refuting the ox-LDL hypothesis because there was no trial showing that

ox-LDL was lowered to the degree expected to decrease heart disease

risk but heart disease was not lowered.

Instead, you are citing two different sets of data showing, on the one

hand, statins reduce ox-LDL, and on the other, (apparently) fail to

reduce CHD risk in certain subgroups, without even analyzing whether

statins successfully lowered ox-LDL in those specific trials.

Moreover, you are citing an intervention (statins) that has a

multi-faceted mode of action, that does many things besides lower

ox-LDL, rather than citing a single-variable intervention that only

lowers ox-LDL. Me pointing that out is not an ad-hoc hypothesis to

explain conflicting results; it is explaining why the results do not

conflict in the first place.

> 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.

Exactly. It is not just difficult, it is preposterous. I would not

interpret the success of statins to support the ox-LDL theory, at

least not in and of itself, and I would argue against anyone who did

that. Like I said, I believe a huge part of statins' efficacy is due

to its inhibition of geranylgeranyl-pyrophosphate synthesis and

subsequent activation of Rho, but it is impossible to distinguish

between the contribution of this effect and the contribution of

lowered LDL because they correlate with one another. I'm not sure,

but I'm guessing the lowering of ox-LDL also correlates with both of

these.

> > 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?

They should be, but the question of how important they are remains to

be hashed out. My personal opinion is they probably exert a very

modest beneficial effect, and should not be the main focus.

> 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?

Probably because the benefit is not nearly as important as thought to

be, and possibly because the methods used have unintended adverse

effects.

> 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.

The main function of Rho activation appears to be activation of " actin

stress fibers, " which seems to be a stress response, and it correlates

with cholesterol increases, so I think this is true. Also, mental

stress, EMF, and some other things induce increases in cholesterol and

other alterations of lipids while probably exerting harm through

independent effects.

Chris