From New Dawn 101 (Mar-Apr 2007)
If you eat too much cholesterol, or saturated fat, your blood cholesterol will rise to dangerous levels. Excess cholesterol will then seep through your artery walls causing thickenings (plaques), which will eventually block blood flow in vital arteries, resulting in heart attacks and strokes….
Scientific hypotheses don’t get much simpler than this: the cholesterol, or diet-heart, hypothesis, has broken free from the ivory towers of academia to impact with massive force on society.
It has driven a widespread change in the type of food we are told to eat, and consequently the food that lines the supermarket shelves. Many people view bacon and eggs as a dangerous killer, butter is shunned, and a multi-billion dollar industry has sprung up providing ‘healthy’ low-fat alternatives.
At the same time, millions of people are prescribed statins to lower cholesterol levels, and each new set of guidelines suggests that ever-more lowering of cholesterol is needed. When it comes to explaining what causes heart disease, the cholesterol hypothesis reigns supreme.
But as the US editor and critic H.L. Mencken put it, “For every complicated problem there is a solution that is simple, direct, understandable and wrong.” This is how we might view the diet-heart hypothesis: just because it is dominant does not mean it is right, and just because it looks simple does not mean that it actually is.
The Development of the Cholesterol Hypothesis
Landmark developments:
1850s
Rudolf Virchow notes the presence of cholesterol in atherosclerotic plaques, and suggests that excess cholesterol in the bloodstream may be the cause.
Early 1900s
Ashoff feeds rabbits on fat and cholesterol, and notes the development of atheroma.
1912
First heart attack described by Herrick.
1940s
Epidemic of heart disease hits the USA, and interest in the area explodes. Many researchers blame the high fat/cholesterol diet.
1948
The Framingham study on heart disease begins. It is still running today.
1954
Ancel Key’s seminal Seven Countries Study is published, demonstrating clear links between saturated fat intake and heart disease.
1961
Framingham confirms the link between raised cholesterol levels and heart disease.
1960s
The first cholesterol-lowering drugs are developed.
1970s
Brown and Goldstein find the gene leading to extremely high cholesterol levels (Familial Hypercholesterolaemia) and premature heart disease.
1980s
Statins are launched.
1985
The Nobel Prize is awarded to Brown and Goldstein.
1990s
Statins trials demonstrate that cholesterol lowering protects against heart disease.
Presented in this way, it’s not difficult to see how the cholesterol hypothesis became the dominant hypothesis, effortlessly swatting alternative ideas. Indeed, to question this theory is to risk being placed on the same shelf as flat-earthers and creationists.
However, all is not what it seems. The cholesterol hypothesis can be likened to a cathedral built on a bog. Rather than admit they made a horrible mistake and let it sink, the builders decided to try and keep the cathedral afloat at all costs. Each time a crack appeared, a new buttress was built. Then further buttresses were built to support the original buttresses.
Although direct contradictions to the cholesterol hypothesis repeatedly appear, nobody dares to say ‘okay, this isn’t working, time to build again from scratch’. That decision has become just too painful, especially now that massive industries, Nobel prizes, and glittering scientific careers, have grown on the back of the cholesterol hypothesis. The statin market alone is worth more than US$14 billion each year.
In reality, cracks in the hypothesis appeared right from the very start. The first of these was the stark observation by Prof. Ancel Keys that cholesterol in the diet has no effect on cholesterol levels in the bloodstream: “There’s no connection whatsoever between cholesterol in food and cholesterol in blood. And we’ve known that all along. Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit.”1
A bit of a blow to a cholesterol hypothesis, you might think, to find that dietary cholesterol has no effect on blood cholesterol levels. However, as everyone was by then fully convinced that something rich and ‘fatty’ in the diet was the primary cause of heart disease, nobody was willing to let go.
So the hypothesis quietly altered, from cholesterol in the diet to saturated fat in the diet – or a bit of both. As if cholesterol and saturated fat are similar things. In reality, this could hardly be further from the truth. Saturated fat and cholesterol have completely different functions in the body, and they have very different chemical structures.
As chemist Joseph Black warned over 200 years ago: “A nice adaptation of conditions will make almost any hypothesis agree with the phenomena. This will please the imagination, but does not advance our knowledge.”2
Unfortunately, this adaptation did not work. It is true that Ancel Keys appeared to have proven the link between saturated fat consumption and heart disease, but when it came to the major interventional trials, confirmation proved elusive.
The MR-FIT trial in the USA was the most determined effort to prove the case. This was a massive study in which over 350,000 men at high risk of heart disease were recruited. In one set of participants, cholesterol consumption was cut by 42 percent, saturated fat consumption by 28 percent and total calories by 21 percent. This should have made a noticeable dent in heart disease rates.
But nothing happened. The originators of the MR-FIT trials refer to the results as “disappointing,” and say in their conclusions: “The overall results do not show a beneficial effect on Coronary Heart Disease or total mortality from this multifactor intervention.”
In fact, no clinical trial on reducing saturated fat intake has ever shown a reduction in heart disease. Some have shown the exact opposite:
“As multiple interventions against risk factors for coronary heart disease in middle aged men at only moderate risk seem to have failed to reduce both morbidity and mortality such interventions become increasingly difficult to justify. This runs counter to the recommendations of many national and international advisory bodies which must now take the recent findings from Finland into consideration. Not to do so may be ethically unacceptable.”3
This quote followed a disturbing trial involving Finnish businessmen. In a 10-year follow-up to the original five-year trial, it was found that those men who continued to follow a low saturated fat diet were twice as likely to die of heart disease as those who didn’t.
It is not as if this was one negative to set against a whole series of positive trials. In 1998, the Danish doctor Uffe Ravnskov looked at a broader selection of trials: “The crucial test is the controlled, randomised trial. Eight such trials using diet as the only treatment has been performed but neither the number of fatal or non-fatal heart attacks was reduced.” As Ravnskov makes clear, no trial has ever demonstrated benefits from reducing dietary saturated fat. At this point most people might think it was time to pull the plug.
Far from it. In 1988, the surgeon general’s office in the USA decided to silence the nay sayers by putting together the definitive report proving a causal link. Eleven years later the project was abandoned. In a circulated letter, it was stated that the office “did not anticipate fully the magnitude of the additional external expertise and staff resources that would be needed.”
Bill Harlan, a member of the oversight committee and associate director of the Office of Disease Prevention at the US National Institute of Health, says: “The report was initiated with a preconceived opinion of the conclusions, but the science behind those opinions was not holding up. Clearly the thoughts of yesterday were not going to serve us very well.”
The sound of a sinking cathedral fills the air with a great sucking slurpy noise. But still nobody let go. Instead, more buttresses were desperately thrown at a rapidly disappearing pile of rocks.
Variations on a theme emerged. It is not saturated fat per se that causes heart disease. It’s the ratio of polyunsaturated to saturated fat that is critical. Or is it the consumption of monounsaturated fats, or a lack of omega-3 fatty acids, or an excess of omega-6? Take your pick. These, and a host of other add-on hypotheses, have their proponents.
As of today nobody can – or will – tell you which type of fat, in what proportions, added to what type of anti-oxidant, vegetable, monounsaturated fat or omega-3 is the true culprit. Hugely complicated explanations are formulated, but they all fall apart under scrutiny.
This may all seem incredible, such has been the level of anti-fat propaganda, but it is true. With the exception of the Ancel Keys’ flawed Seven Countries Study (he pre-selected the seven countries for his study in order to prove his hypothesis), there is not one scrap of direct evidence.
But, of course, there are two parts to the cholesterol hypothesis. The diet part, and the raised cholesterol level part. Leaving diet behind, surely it has been proven beyond doubt that a raised cholesterol level is the most important cause of heart disease?
Cholesterol Levels and Overall Mortality
Before looking at the connection between blood cholesterol levels and heart disease, it is worth highlighting a critically important – remarkably unheralded – fact: After the age of 50, the lower your cholesterol level is, the lower your life expectancy.
Perhaps even more important than this is the fact that a falling cholesterol level sharply increases the risk of dying of anything, including heart disease.
The dangers of a low cholesterol level were highlighted by a major long-term study of men living in 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.”
Somewhat ironically, the danger of a falling cholesterol level was first discovered in the Framingham study: “There is a direct association between falling cholesterol levels over the first 14 years [of the study] and mortality over the following 18 years.”
It seems almost unbelievable that warnings about the dangers of a high cholesterol level rain down every day, when the reality is that a low cholesterol level is much more dangerous than a high level. Given this, why would anyone want to lower the cholesterol level? On the face of it, it would make more sense to take cholesterol-raising drugs. Especially after the age of 50.
Cholesterol Levels and Heart Disease
The reason why everyone is so keen to lower cholesterol levels is that supporters of the hypothesis have decreed the following:
– A high level of cholesterol causes premature heart disease.
– A low level of cholesterol is caused by an underlying disease. It is the underlying disease that kills you, not the low cholesterol.
Ergo, if you lower the blood cholesterol level, you will reduce the risk of heart disease, and you will not increase the risk of dying of any other disease. This could be true, but it is worth reviewing some of the evidence that linked raised cholesterol levels to heart disease in the first place. Let’s begin with women.
Perhaps the largest single analysis of cholesterol levels, and death from cardiovascular disease (and other diseases), was published in 1992. This review included over 100,000 women, aggregated from a number of different studies and countries.
To quote from the study: “The pooled estimated risk for total cardiovascular death in women showed no trend across TC (total cholesterol) levels.” In short, for more than 50 percent of the world’s population – women – raised cholesterol is not a risk factor for heart disease.
Moving to men, it is true that under the age of 50 there does seem to be an association between raised cholesterol levels and heart disease. But after the age of 50, when more than 90 percent of heart attacks happen, the association disappears.
In addition, those populations in the world with the highest rates of heart disease in younger men, including emigrant Asian Indians, Eastern Europeans, Native Americans and Australian Aboriginals, tend to have significantly lower cholesterol levels than the surrounding populations/countries.
Perhaps the single most directly contradictory fact is that, in young Japanese men, the average cholesterol level has risen over the past 20 years, yet the rate of heart disease has fallen. But as with many facts in this area, if they don’t fit the cholesterol hypothesis, they are dismissed.
Lowering Cholesterol Levels with Drugs
Surely, despite everything written up to this point, all previous arguments are refuted by the knowledge that lowering cholesterol levels with statins protects against heart disease? As all good scientists know, ‘reversibility of effect’ provides the most powerful supportive evidence for a hypothesis.
However, the flipside to this argument is as follows. How can lowering cholesterol levels prevent heart disease in people who do not have a high level? The most often quoted clinical trial in the past few years is the UK-based Heart Protection Study (HPS): a veritable triumph for statins, demonstrating protection in almost every group studied.
What is most intriguing, however, is that protection was apparent if the starting cholesterol level was high, average or low. How can this be explained?
At this point we enter Alice in Wonderland territory. A rational person would accept that a normal cholesterol level cannot be a risk factor for heart disease (or anything else for that matter). Therefore, people with normal cholesterol levels can gain no benefit from having their levels lowered. Therefore, if statins do protect those with normal, or low, cholesterol levels – which they clearly do – they must be doing this through some other mechanism of action, unrelated to cholesterol lowering.
In fact, there is a growing body of evidence to support the idea that statins have a whole series of different protective actions. However, accepting that statins work ‘in another way’ would demolish the final buttress keeping the cholesterol hypothesis afloat. And so the latest argument is that nobody in modern society has a normal cholesterol level.
An article in the Journal of the American College of Cardiology best sums up this line of thinking. Under the heading ‘Why average is not normal’, O’Keefe, the lead author, makes the claim that: “Atherosclerosis is endemic in our population, in part because the average LDL (‘bad’ cholesterol) level is approximately twice the normal physiologic level.” In short, according to O’Keefe, our cholesterol level should be about 2.5mmol/l, not 5.2mmol/l.
This argument, if true, does neatly demolish the question, ‘How can people with normal, or low, cholesterol levels be protected against heart disease?’ O’Keefe and others would argue that we all have a high cholesterol level. Everyone is ill, and all shall have statins.
One regularly quoted fact, which superficially seems supportive of O’Keefe’s hypothesis, is that peasant farmers in China have very low cholesterol levels and a very low rate of heart disease (although their average cholesterol levels are actually about four, not two-and-a-half).
But when you study the figures with more care, they reveal something else. As usual, those with low cholesterol levels have by far the highest mortality rates. Liver failure and liver cancer are common causes of death. However, there is a simple explanation for this association. Many Chinese peasant farmers have chronic hepatitis, which creates low cholesterol levels, and also leads to liver failure and liver cancer. This is why people with low cholesterol levels die young.
Does this mean that a low cholesterol level protects against heart disease? No: what the Chinese data tell us is that those with higher cholesterol levels are not chronic hepatitis carriers, so they live longer and have more chance of developing heart disease in old age. On the other hand, those with low cholesterol levels cannot die of heart disease, because they are already dead.
Without chasing too many mad arguments around, the simple fact is that everyone in the West does not have a raised cholesterol level. Repeated studies have shown that a perfectly normal, or healthy, cholesterol level lies between about four and six, and lowering it cannot protect against heart disease, otherwise we will have introduced a new concept into medical science: normal is unhealthy and must be treated.
People are grasping at straws in their attempts to explain why statins protect against heart disease in those with normal cholesterol levels, and in women and the elderly – where a raised cholesterol level is not even a risk factor. The only possible explanation for the results of the statin trials is that statins do not work by lowering cholesterol levels.
The Cholesterol Hypothesis is a Complicated Mess
The cholesterol hypothesis has always exuded the siren song of simplicity. However, once you start to examine it in any detail, the simplicity rapidly mutates into complexity.
Even at the very start, people should have known that cholesterol in the diet was never capable of appearing, unchanged, in the bloodstream. Cholesterol is not soluble in water (thus blood) which means that after absorption, cells lining the gut pack cholesterol into a small protein/lipid sphere, known as a lipoprotein, before releasing it into the bloodstream.
Thus, you do not have any cholesterol floating about in the blood – it is all contained within lipoproteins. You do not actually have a cholesterol level. Instead, you have a level of different lipoproteins, with the low-density lipoprotein (LDL) or ‘bad’ cholesterol being the so-called dangerous one.
Next question, what raises the LDL level? Eating too much fat, or cholesterol? The first problem here is that the cells lining the gut do not make, or release, LDL – they make other forms of lipoprotein. So, no matter what you eat, it can have no direct effect on LDL levels.
So where does LDL come from? LDL is, effectively, the shrunken form of a very low-density lipoprotein (VLDL). VLDLs are made in the liver and used to transport fat and cholesterol from the liver to other cells around the body. As VLDLs lose fat they shrink, transforming into LDL.
Therefore, in order to find out what makes LDL levels rise, we must surely find out, firstly, what makes VLDL levels go up; and what makes VLDL levels go up, primarily, is eating excess carbohydrates. What makes them go down is eating fat!
Recognising this, and a host of other problems, the supporters of the cholesterol hypothesis have twisted and turned. As of today (and this will certainly change), the original – dietary – cholesterol hypothesis has become the following: If you eat too much saturated fat, the body will reduce the number of LDL receptors (things that remove LDL from the bloodstream), forcing the LDL up. A more tenuous, and unproven, link could hardly be imagined, but that is what is left of the originally super-simple cholesterol hypothesis. The diet part anyway.
But the difficulties of trying to establish a dietary link to heart disease actually pale into insignificance when you start trying to work out how the raised LDL level itself may cause heart disease. If it were simply a case of excess LDL seeping through the artery wall when the level gets too high, then why doesn’t this happen in all artery walls, everywhere? If I lie too long in the sun I expect to get sunburned on every bit of skin exposed. I do not expect to get discrete patches of sunburn. Yet we do see little ‘patches’ of atherosclerosis. Some people die of heart disease and are found to have perfectly clean arteries, apart from a single killer plaque (thickening). So why did the LDL seep through at only one place? What protected the rest of the arterial system?
And why do veins never develop atherosclerotic plaques? They are exposed to exactly the same LDL level as the arteries. They are thinner than arteries, but their general structure is identical. I should add that if you use a vein as a coronary artery bypass graft (effectively turning it into an artery), it will develop atherosclerosis.
These questions represent only the tip of a huge iceberg. In an attempt to answer some of them, the cholesterol hypothesis has turned itself into the following, complicated mess:
– LDL, when it is oxidised, travels through the lining of the artery wall (endothelium) into the middle part of the artery. (How oxidised LDL passes straight through an endothelial cell into the artery wall behind is unexplained.)
– In this oxidised state it attracts white blood cells from the bloodstream. They, in turn, migrate into the artery wall and start to ‘digest’ the oxidised LDL in order to remove it. (This bit is plausible.)
– However, white blood cells, once they have started to digest oxidised LDL cannot stop. They get bigger and bigger until they burst. This, in turn, attracts more white blood cells to the area which then burst. (White blood cells that just burst? This makes no sense whatsoever. Why on earth would the body develop a scavenger system that automatically self-destructs?)
– The burst white blood cells, in turn, release substances that trigger a whole cascade of inflammatory reactions in the arterial wall. After a period of time you have a mass of dead white blood cells, cholesterol, oxidised LDL remnants, and a whole series of other inflammatory agents all focused in one area, trapped in the artery wall. (Well, this is what is found in a plaque, among many other things.)
This is allegedly how a plaque starts and grows. I have kept that explanation as simple as humanly possible, but it seems absurdly unlikely. Oxidised LDL – what happened to normal LDL? Well, there’s no way anyone can see of getting that through an arterial wall. Exploding white blood cells…. Another buttress?
In truth, the current ideas on plaque formation used to keep the cholesterol hypothesis afloat are complex nonsense. But the entire area is now protected by a ring-fence of scientific jargon that frightens off all but the most dedicated seeker after truth.
To those who have studied the hypothesis with a critical eye, it seems unbelievable that it can possibly still be standing. Dr. George Mann pronounced it dead in an editorial in the New England Journal of Medicine in 1977, referring to it as the “Greatest scam in the history of medicine.” Yet this hypothesis has never had more followers than today.
Time, I think, that it was consigned to the dustbin of history. It is not simple, direct, or understandable – the only certain thing about it is that it is wrong.
Dr. Kendrick’s book, The Great Cholesterol Con, is available from www.amazon.com.
Footnotes
1. Ancel Keys PhD, professor emeritus at the University of Minnesota, 1997.
2. J. Black, Lectures of the Elements of Chemistry, 1803
3. Professor Michael Oliver, British Medical Journal, 1991
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