Thursday, August 06, 2009

Cholesterol: statins and oxLDL

I would just like to recap the lipid hypothesis for a moment. The basic idea is that an elevated level of LDL cholesterol, estimated by the Friedewald equation, makes these lipoprotein particles stick to your arterial walls, causes plaque to develop and eventually rupture. Saturated fat is the main dietary cause of heart disease because it is purported to elevate LDL cholesterol.

The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.

The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.

This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.

So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!

Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.

You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!

If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.

It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!

If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?

Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.

So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.

Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised

An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.

Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.

Does it seem incomprehensible that we could have made such a mistake with statins?

Yes, I think so.

Peter

15 comments:

Nick said...

Hi Peter,

Nice to have you back on line! I'm wondering if you caugt this presentation on HFCS, which this doc says is the true cause of the problems of the SAD.

http://www.youtube.com/watch?v=dBnniua6-oM

It came from Ted in the comments section on the Heart Scan Blog (http://heartscanblog.blogspot.com/2009/08/fructose-is-coronary-risk-factor.html)

I'm curious about how you would react to his thesis.

mtflight said...

Peter,
Glad to have you back!! brilliant post. glycated ApoB... what a lovely concept!

I guess with an A1c of 4.8% I should not be too concerned. I still have quite a high LDL, we should start a club! 221 mg/dL thanks to Friedewald.

While reading your post about ox-LDL I had confused it with Lp (a). There is some literature at the VAP test website that lowering LDL below 80 mg/dL removed any significance of Lp(a) values (hmmm because the big C gets them before they have another coronary?).

I plan to get that test done perhaps in a couple months, just out of curiosity to see my HDL2 and to verify I have large LDL. Only because it's cheap. It was one year ago I had the EBTC heart calcium scan @ 0, but I need continued peace of mind.

Cheers and welcome back! hope you're doing great.

Venkat said...

Pete,

Could you please explain this one?

//up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles//

if it ingests circulating LDL particles - LDL should increase in the blood, correct? Am I missing something?

Thanks for your time.

Thanks

Venkat

Peter said...

Hi Nick,

It's on my list to listen to but that sort of time is not for the weekend!

Alex (mtflight),

I have a paper somewhere on my hard drive which suggests Apo(a) specifically marks oxLDL and may even transfer oxidised phospholipids from mildly oxLDL to Apo(a) modified oxLDL giving concentrated oxidised phospholipids in Lp(a). If your total LDL is very low on a SAD or AHA diet it will probably be mostly oxLDL under a coating of Lp(a) and the numbers will change together... That's the impression I get.

Hi Venkat,

It's the intracellular cholesterol which falls with statins, the fall in plasma LDL is because the cells do not like being cholesterol deficient. To replace the deficit they can can use extra LDL receptors to get whole LDL particles from plasma and "eat" them. Mostly this is the liver doing this as it loses cholesterol derivatives in the digestion process, but it happens whole body, if that's where the statin gets to. Of course brain cells cannot ingest LDL and, oddly enough, there are a lot of neurological case reports of statin side effects, from behavioural to total global amnesia.

Peter

mark said...

I just found this paper today. Haven't looked through it in any detail, but the title is:

Higher Total Serum Cholesterol Levels Are Associated With Less Severe Strokes and Lower All-Cause Mortality: Ten-Year Follow-Up of Ischemic Strokes in the Copenhagen Stroke Study.

And it's from the American Stroke Association, A Division of the American Heart Association.

Crazy.

Mark.

mark said...

http://stroke.ahajournals.org/cgi/reprint/38/10/2646

Forgot the link.

lightcan said...

Hi Peter,
I do not really understand the whole thing with the lip a and apo b, etc. I just go intuitively, I suppose, and when something doesn't click I have a question. But generally there's nobody to answer so no progress.
Remember the study with the low fat high vegetables that you brought up regarding veg consumption (for which I don't think it is a good example) It appeared in Stephan's blog regarding OxLDL, so because this post is about this too it might be relevant.
Changes in Dietary Fat Intake Alter Plasma Levels of Oxidized Low-Density Lipoprotein and Lipoprotein(a) From the discussion:
"Increased Lp(a) would result in increased transport of oxidized phospholipid away from tissues, such as the artery wall. (...) In turn, Lp(a) binds the oxidized phospholipids that are being mobilized, which is reflected in the enhanced OxLDL-EO6 levels in plasma. Thus, it can be postulated that with respect to this parameter, both of these diets are *beneficial*. Support for this hypothesis can be found in our recent observation that in response to statin therapy in humans, a similar increase in OxLDL-EO6 occurs, possibly reflecting enhanced mobilization of oxidized phospholipids from the artery wall."
Why beneficial? Where do the oxpl go? (On these intervention diets LDL didn't go down.)
The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am coll Card 2008
In this study OxLDL (mercodia oxidised LDL) went down but oxpl/apob went up as you mentioned in your post.
It seems that the researchers do not know what this means, they are just talking about numbers, hypothesising and asking for more studies to be done.
It makes me feel better ;)

lightcan said...

Well, actually
OxPL/apoB and Lp(a) predicted 10-year cardiovascular events independently of traditional risk factors, hsCRP, and the Framingham risk score. according to Tsimikas et al (prospective results from the Bruneck study) so they just don't want to accept it. Typical.

Peter said...

Nick,

Got a chance to listen yesterday, pretty well correct, I don't think any part had me grinding my teeth and I heard some interesting bits of biochemistry which are new to me. The basic message is good.

Mark,

Nice link, the twisted logic to the conclusion needs some thinking about, bear in mind they are only looking at stroke victims, not the general population. If, and as far as I know it is, elevated cholesterol in the general populace is protective against stroke, they are talking a load of mealy mouthed garbage. They see severe thrombotic strokes as being somehow spontaneous and mild strokes as being caused by hypercholesterolaemia. The mild strokes are trivial and CAUSED by cholesterol. The severe ones are obviously caused by alien ray guns focused on people's brains. Duh.

As the Japanese might say about the healthiest centenarians:

"Higher blood pressure, higher serum total cholesterol concentration and higher serum high-density lipoprotein cholesterol concentration were associated with better physical and cognitive function"

Not an isolated finding.

Lightcan,

Yes, low fat diets in insulin resistant populations will be a disaster, but they can't say that. The effect is also remarkably similar to the first of the Fruit and Vegetables posts... But that paper was published by people with brains. Oh, and morals too...

Peter

Venkat said...

Peter,

I understood it now. thanks. It is clear in my mind...

Thanks for the clarification.

Venkat

Dr. B G said...

Peter,

Thank you for your BRILLIANCE and this POST. Glad to hear your move went well (and nice neighbors *wink*)!

Did you know that Nissen was one of the co-authors of the 2nd link on increased oxPL/apoB by statins (lipitor and pravachol)? I guess he still thinks that Crestor is superior... which is such a joke since Crestor causes diabetes more than any other statin... *haa* I wonder why...?

Nissen and these authors' conclusions are worth repeating. 100% of all prematurely elevated EBT scores at TrackYourPlaque are secondary to Lp(a). Some may exhibit only tiny amounts of toxic dense (?oxidized, I guess so!) Lp(a) of 100 nmol/L (goal < 70 nmol/L or roughly < 7 mg/dl) but it's enough to accelerate atheroma and plaque growth.

Lp(a) is basically one LDL particle attached to one apo(a). I didn't realized that apo B and apo a could be glycosylated! But that makes sense.


You know I believe in the 'warrior' Lp(a) -- if it's all fluffy stuff, it's a Good Thing. When it's all small and dense... and that is exactly what statins do.

Statinators invariably try to take a 'shortcut' with synthetic drugs like statins, fibrates and/or zetia... and it just does not work. (in fact, even with a great fab high-SFA diet... the statin suppresses nearly ALL LARGE LDL PARTICLE formation)

Now, we are starting to truly see why (though we all KNEW why).

Nissen and Authors' conclusions *DOLT*:
"Statin therapy results in significant increases in . . . lipoprotein (a) levels..."



Incidentally, other studies also show that crestor, lipitor and zetia ALL raise Lp(a):
--COMPELL
--PROVE-IT


They definitely raise %-sdLDL. Naturally, oxLDL must follow...

Wonderful.

-G

Peter said...

G,

You know I have a very favourable view of Lp(a). As you have said before, Lp(a) has a certain amount in common with "running with scissors". But scissors are very useful implements. You just shouldn't run with them.

Time to go inflate some LDL particles!

Peter

O Primitivo said...

The "Statinth" wonder of the world: a panacea for all illnesses or a bubble about to burst - http://www.biomedcentral.com/content/pdf/1477-5751-4-3.pdf

cgldsmth said...

http://www.time.com/time/health/article/0,8599,1878543,00.html

Peter said...

cgldsmth, keep swallowing, Big Pharma needs you. And millions more like you.