MALCOLM KENDRICK, MbChB, MRCGP (email - malcolm@llp.org.uk )

November 28, 2002

Part 1, Part 2, Part 3, Part 4, Part 5

WHY THE CHOLESTEROL-HEART DISEASE THEORY IS WRONG

Having previously demonstrated that neither cholesterol, nor saturated fat consumption, can have any impact on LDL levels. I now intend to make it clear that a raised LDL level has no impact on heart disease (CHD).

As most of you probably know, current thinking in CHD is that when the level of Low Density Lipoprotein (LDL) is raised, LDLs travel through the artery wall and form a big lumpy cholesterol deposit (plaques) that narrow the arteries. Cholesterol is found in plaques because LDL contains lots of cholesterol.

As these plaques get bigger they narrow the artery so much that blood flow is obstructed - causing symptoms such as angina. Finally a plaque may burst, causing a blood clot to form over the ruptured area. This blocks the artery completely. A myocardial infarction results, which may or may not kill you.

I agree with this basic mechanism underlying CHD, but there are about eight million problems with the idea that a raised LDL is the cause. Lets just concentrate on three:

1: People with normal and even low LDL levels develop plaques and die of CHD.

Which means that we have a disease process on our hands that can occur when the LDL is level is high, average or low. The first ever example in medical history whereby a normal level of a normal (and vital) substance in the blood can cause a disease.
Yes, LDL is so terrible that any level at all can kill you. The only good LDL is a dead LDL - or words to that effect. This concept, that a normal level of substance in the blood can cause disease, is absolutely nuts and runs contrary to all of biological science, or any other type of science. My goodness you have a NORMAL LDL level, it must be lowered.
Leaving that aside, for the moment, lets move to problem number two.

2: LDL cant get through the lining of the artery wall

The endothelium - single cell lining of the artery wall - is impermeable to LDL - unless you get the level to about three times normal, which is 15mmol/l, rather than 5.0mmol/l. So how does LDL get through in the first place? Considering that 99% of the population has an LDL level below 10.
Answer, you cant get it through. And even if it could, you run into problem number three:

3: Plaque distribution

Plaques are discreet lesions in the artery wall, they are not present everywhere in all artery walls. So, if LDL leaks through the arteries when the concentration is raised, then it should leak through all artery walls everywhere, and what we should see, therefore, is thickened artery walls full of LDL everywhere, which is exactly what we don't see.

To use an analogy, if you lie in the sun for too long, all of your body will become sunburned, not just a few bits here and there. But we are expected to believe that, if you bathe the artery wall in a high level of LDL, it will only leak through in a few discreet areas. Hmmmmm? Again, quite frankly, bonkers.
I know what you are thinking at this point, I think. Aha, you are thinking, obviously you need to damage the artery wall, in discreet areas, to get LDL through………… Exactly. And this could hardly be more obvious. So, the underlying process that starts a plaque is damage to the endothelium. Of course it is; there is no other possible explanation.

But, to admit this, is to admit that LDL has nothing whatsoever to do with causing atherosclerotic plaques, because LDL doesn't damage the endothelium.

Faced with this major, and I would say insurmountable problem, what has the cholesterol/LDL brotherhood chosen to do? Discard the diet-heart/cholesterol/LDL (whatever it is now called) hypothesis. Or keep trying to find ways to explain the causal role of LDL in plaque formation.

No surprise to find that no-one was remotely willing to discard the hypothesis. This square peg of orthodoxy had to be rammed into the circular hole of CHD causation at all costs. Otherwise the entire diet-heart/cholesterol/LDL hypothesis collapses into a little heap of dust.

So where are we now? How exactly does LDL cause CHD?

Because it is oxidised.

You may faintly detect the sound of me beating my head against a wall in the distance, somewhere just south of Manchester UK.

Because, dear reader, LDL is oxidised! You have probably heard of anti-oxidants, and their magical protection against CHD. But how are they thought to provide this protection? Mainly because oxidised LDL can be absorbed by the endothelium, as there are receptors for oxidised LDL on endothelial cells (called Lox-1 receptors, if you are interested).

So, the thinking goes, once oxidised, the LDL binds to the Lox-I receptor it is then transported into - then through - the endothelium and into the artery wall behind. At which point, white blood cells, designed to get rid of all nasty substances in the body, attack, engulf and try to clear away all of the oxidised LDL molecules.

But these white cells have no means to tell them to stop engulfing oxidised LDL, allegedly, so they just get bigger and bigger until they explode, releasing a horrible goo of dead white blood cells, bits of LDL, cholesterol and triglyerides etc. into the artery wall. Once you have enough exploding white blood cells, the lump of goo becomes big enough to start an atherosclerotic plaque. And that is why oxidised LDL is such a bad thing, and why anti-oxidants are protective.

There are so many problems with this proposed mechanism of action that it is almost impossible to know where to start. Perhaps the best place to start is with a previous example.

If there are receptors for oxidised LDL on endothelial cells, then oxidised LDL will be absorbed through all artery walls everywhere, and therefore we would not see discrete plaques forming, just general thickening of all artery wall as they fill up with the residual goo from exploding white blood cells. But we do see discreet plaques, and therefore? Therefore the hypothesis is wrong as it does not match the observed disease process.

The other problem is just as serious, although a little more difficult to explain.

If plaques are created by oxidised LDL, then the cause of CHD must be excess oxidisation of LDL in the bloodstream. If this is true, then the level of LDL is completely irrelevant, it is only the amount of oxidised LDL that counts. Therefore, if you believe in this hypothesis, then the raised LDL causes CHD hypothesis has to be discarded.

In essence, you cant have this argument both ways. You can claim a raised LDL causes CHD - in which case how can people with a low level get CHD? Or you can claim that excess oxidised LDL causes CHD. In which case CHD has nothing to do with LDL levels.

Ironically, the oxidised LDL hypothesis - which was supposed to protect the LDL hypothesis - actually destroys the LDL hypothesis. But by throwing up so much jargon and incomprehensible mechanisms of actions into the air, it appears that you are keeping both hypotheses going. But you cant, its one or the other, you cant have both.

And by the way, in the Heart Protection Study (HPS), which lasted five years, ten thousand patients received the antioxidants and ten thousand patients did not.
And the results?

There was no evidence of any benefit at all from antioxidant vitamins. On the other hand, there was no evidence of any harm. Dr Rory Collins BMJ Nov 2001

So, bang goes the anti-oxidant hypothesis. Please spare me the claim that they used the wrong antioxidants

Once again, as with almost every part of the diet-heart/cholesterol hypothesis, when you start to examine the facts objectively, the whole thing starts to disintegrate in front of your very eyes. There is no way that LDL, oxidised or otherwise, can cause CHD, and here are a few more facts to back this up.

Framingham first:

There is a direct association between falling cholesterol levels over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD death rate increase per 1 mg/dL per year drop in cholesterol levels). Anderson KM JAMA 1987

In Framingham therefore, as LDL/cholesterol levels fell, CHD rates went up.

Then Honolulu:

Our data accord with previous findings of increased mortality in elderly people with low serum cholesterol, and show that long-term persistence of low cholesterol concentration actually increases the risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater the risk of death. Lancet Aug 2001

In Honolulu, the lower the LDL/cholesterol, the greater the risk of dying - of everything, including CHD.

Then Russia:
The main author of the report on this study was Shestov, of the Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg. And the main conclusion of this study was as follows:

The results disclose a sizeable subset of hypocholesterolemics in this population at increased risk of cardiac death associated with lifestyle characteristics. Russian Lipid Research Clinics Prevalence Follow-up Study Shestov

In Russian, a greater risk of death from heart disease in those with low blood LDL/cholesterol levels

Then Japan:

Between 1980 and 1989, age-adjusted total serum cholesterol levels increased from 4.84 to 5.22 for men and from 4.91 to 5.24 mmol/l for women. Prevalence of age-adjusted hypercholesterolaemia of > or = 5.68 mmol/l increased from 15.8% to 29.4% for men and from 18.4% to 30.6% for women……. Considerable increases in total serum cholesterol levels do not offer an explanation of the recent decline in mortality from coronary heart disease in Japan. Okayama A, Marmot MG Int J Epidemiol Dec 1993

In Japan, as cholesterol/LDL levels went up, death rates from CHD went down.

How much more evidence would you like? Perhaps another study from the USA?

Kummerow and colleagues from the UI and Carle Foundation Hospital in Urbana, Ill., studied 1,200 patients who were cardiac-catheterized. Sixty-three percent had at least 70 percent of their arteries blocked -- enough to warrant bypass surgery. Of the 506 men who had a bypass, only 71 (14 percent) had plasma cholesterol levels above 240 (6.2mmol/l); 50 percent had levels below 200 (5.2mmol/l). Thirty-two percent of the 244 women who had bypass surgery had levels above 240 (6.2mmol/l); 34 percent were below 200 (5.2mmol/l)……

…… a 3-to-1 ratio of LDL (bad cholesterol) to HDL (good cholesterol) is a low heart-disease risk? with a total cholesterol of less than 200 (5.2mmol/l) being the most desirable. However, in this study, Kummerow noted, 51 percent of the catheterized men had levels below 200 (5.2mmol/l) but needed a bypass. Paper by Kummerow Atherosclerosis March 2001

In this study, the majority of men who needed a bypass had cholesterol levels below 5.2mmol/l.

These were not, I will add, small studies, with surrogate end-points. These were great big studies done on thousands and thousands of people, and they measured death rates and blockages in coronary arteries, which are hard end-points. They include Framingham - the study that is used to set the CHD prevention guidelines! And they all demonstrate very clearly that the rate of CHD has nothing whatever to do with the level of LDL/cholesterol in your bloodstream.

These studies were also published in journals as prestigious as the Lancet, Atherosclerosis and JAMA. This is not wacky, fringe research, carried out by people with a distrust of mainstream medicine. This is as mainstream and conventional as it gets, and all of this research utterly and completely contradicts the current cholesterol/LDL theory of CHD. And I will bet that you have never, ever, come across these facts before. For some strange reasons this research doesn't get a lot of publicity.

Ah but, you might say, statins reduce LDL levels and protect against CHD. Surely that proves - despite your clever arguments, and all of the evidence - that a raised LDL truly is the cause of CHD, even if it is biologically impossible.
Well, for those of you who are interested, I can easily prove that the LDL lowering effects of statins have nothing whatsoever to do with their impact on CHD.