“In science, the truth stands by itself” – Prof Noakes on Keys’ Cholesterol Con

As indicated in Part Two of Professor Tim Noakes’ ‘Ancel Keys’ Cholesterol Con’ series, scientific events starting in 1910 laid the groundwork upon which Ancel Keys “produced the greatest scam in the history of modern medicine”. In Part Three, Noakes investigates those events that happened between 1910 and 1948. With reference to graphics and the work of other scientists, particularly Professor Vladimir Subbotin, Noakes shows that “something like two-thirds of patients with coronary heart disease – the ‘forgotten majority’ – will still suffer major coronary events despite using cholesterol-lowering drugs to normalise their blood cholesterol concentrations”. Noakes meticulously introduces the reader to the influence of Procter & Gamble, a well-known American multinational consumer goods corporation, and the effect the company had on changing the source of dietary fat intake from butter and lard to shortening and margarine in the US from 1909 to 1985. Procter & Gamble, which never strayed far from the dietary advice to replace saturated fat with “vegetable” oils, came to be the foundation sponsor that made Ancel Keys’ hypotheses possible. – Nadya Swart

Ancel Keys’ Cholesterol Con. Part 3.

By Prof. Tim Noakes

How an insecure and unproven hypothesis became a global unchallenged dogma. The ultimate victory of commerce over science.

The sequence of events that produced one of the greatest scams in the history of modern medicine.

Table 1 in the previous column (1) lists the sequence of events that, I will argue, were critical in directing the global acceptance of Keys’ unproven hypotheses, the Diet-Heart and Lipid Hypotheses. 

In this column, we investigate those events that happened between 1910 and 1948. 

• 1910. Future Nobel Laureate Adolph Windaus detects the presence of cholesterol in arterial atherosclerotic plaques.

In 1910, as part of his pioneering studies of the role of cholesterol in human metabolism, the German chemist Adolf Otto Reinhold Windaus discovered that atheromatous arterial lesions (arterial plaques) contain six times as much free cholesterol and 20 times as much esterified cholesterol as do healthy arteries (2). Windaus would also describe the pathways by which cholesterol is converted to Vitamin D. For his work he was awarded the Nobel Prize for Chemistry in 1928. 

The assumption at the time was, predictably, that the cholesterol in arterial plaques must arise from the cholesterol circulating in the bloodstream. In time this finding would give rise to the Gofman/Keys’ Lipid Hypothesis which holds that elevated blood cholesterol concentrations (caused by eating a high fat diet, (especially rich in “artery clogging” saturated fats) drive cholesterol across the arterial lining (3), a single layer of cells known as the endothelium, into the subendothelial space, causing the initiation of fatty streaks (4) (Figure 1)). These then progress to the development of more advanced atherosclerosis, termed arterial plaques (Figure 2) that amongst other complications, can cause heart attacks and strokes. 

Legend to Figure 1: This diagram explains the currently accepted theory of how endothelial damage, largely of unknown cause, allows LDL-cholesterol to cross the endothelium and enter a postulated (hypothetical) acellular space, the subendothelial space. There the LDL-cholesterol is taken up by macrophages causing the development of the earliest form of atherosclerosis, known as the fatty streak.

Note that for the atherosclerotic process to happen in this way, the tunica intima must be devoid of all cells other than the single layer of endothelial cells that coat its upper surface, separating it from the blood contained in the lumen of the artery.  According to this model, the subendothelial space is essentially a wide-open vacant space waiting expectantly to accommodate these (complex) processes that produce atherosclerosis. 

Reproduced with additions from reference 4, p.3

The finer details in Figure 1 are not critical to the argument. What is important is the way in which the different cellular structures are depicted.

Here the crucial point is that, according to the currently popular explanation (4), until the endothelium is damaged (by currently unknown biological events), allowing the unrestrained entry of LDL-cholesterol, the tunica intima is depicted as a single thin layer of endothelial cells sitting on top of an acellular space (devoid of cells). This is an important consideration since the presence of any cells in the subendothelial space must impede the entry of LDL-cholesterol directly from the bloodstream and hinder the ability of the macrophages to detect and consume the cholesterol, as depicted in figure 1.

Figure 2 depicts how this model explains the progression of the fatty streak to the full-blown atherosclerotic plaque. Note again that the sub-endothelial space is devoid of cells before the hypothetical endothelial damage allows the free entry of LDL-cholesterol into this conveniently located anatomical space.

Legend to Figure 2: This figure shows how the fatty streak (figure 1) progresses to the atherosclerotic plaque according to the Lipid Hypothesis. For the Lipid Hypothesis to be true, until AFTER the initial “injury” to the endothelium has allowed the entrance of blood-derived LDL-cholesterol, the tunic intima must, as shown in this figure and in figure 1, contains no cells other than the thin layer of endothelial cells on its upper surface. Notice that in this figure, smooth muscle cells (SMC) migrate from the tunica media into the tunica intima to further progress the development of the atherosclerotic plaque.

Reproduced with additions from reference 4, p.8.

In 1910, neither Windaus nor anyone else was aware that cholesterol cannot simply pass through healthy arterial walls, however it might be “shoved” (3). Currently the most popular theory is that shown in Figure 1 and 2. This theory holds that the endothelial cells lining the lumen of the artery wall must first be damaged before this can happen. This is termed “endothelial cell dysfunction” (4) but the immediate cause of “endothelial cell dysfunction”, if this is indeed the mechanism, remains shrouded in secrecy even today, 110 years after Windaus’s discovery. 

This theory also predicts that cholesterol enters damaged arteries down a concentration gradient so that the degree of anyone’s arterial disease can be predicted quite simply as their average blood cholesterol concentration multiplied by the number of years the blood cholesterol concentration has been “elevated” (3,5). 

Also still unknown then was that atherosclerosis is a patchy disease that selectively targets only specific areas of different arteries, exemplified by what happens in the coronary arteries supplying blood to the heart muscle (6). 

Nor was it then known that in some populations, there may be advanced atherosclerosis in the cerebral (brain) arteries with minimal involvement of the coronary (heart) arteries (7,8), placing these populations at greater risk of stroke than of heart attack. In other countries, including the USA, the opposite applies. So, even today, devotees of the Lipid Hypothesis seldom ponder the inconvenient question: If the same (elevated) blood cholesterol concentration bathes the 100 or more miles of blood vessels in the adult human, why is it that only small segments of the arteries ever become diseased? How is it possible that there is some magic borderline dividing those cells that will become atherosclerotic from those that are apparently immune to the (supposedly) direct effects of elevated blood cholesterol concentrations?  And why are veins so seldom affected (unless they are used to bypass diseased coronary arteries)?

But the greatest challenge to this traditional explanation has been presented by Professor Vladimir Subbotin (9-11). It hinges on two facts which are irrefutably true and either of which by itself, irretrievably undermines any proposed theory of how LDL-cholesterol from the blood crosses the lining of the arteries – the endothelium – collects in the sub-endothelial space in the tunica intima, initiating the process of atherosclerosis, as depicted in figures 1 and 2. 

The first point made by Subbotin as early as 2012 (9) and repeatedly since (10,11) is that the tunica intima – including the so-called subendocardial space – is not an empty space without cells and filled only with structural proteins. This is the way it is depicted in Figure 1 and 2.

Subbotin argues that the only reason why the diagram is drawn that way is because Keys’ Lipid Hypothesis demands it to be so. Without that space, the Lipid Hypothesis in its original form is logically disproven. 

For that is the only model which would explain how LDL-cholesterol particles might be able to “slip” – Subbotin uses the word “crawl” (11) – easily through a damaged endothelial lining, to enter the acellular sub-endothelial space where they are engulfed by invading macrophages initiating the process of progressive atherosclerosis depicted in Figures 1 and 2. But if this (hypothetical) acellular sub-endocardial space is not acellular, but instead comprises layer upon layer of mature cells, how will the LDL-particles find their way between those cells? And how amongst all those layers of cells will the macrophages be able to locate the LDL invaders? 

Instead, Subbotin cites the utterly fundamental and completely ignored work of Nakashima et al. (12-14) which reveals two essential findings that destroy Keys’ Lipid Hypothesis. Interestingly Nakashima and colleagues avoid any reference to the possibility that their work disproves Keys’ Lipid Hypothesis. Only Subbotin has had the courage to advance an heretical possibility. 

The first finding is that histological examination of adult coronary arteries shows that the tunica intima does not comprise a single layer of endothelial cells sitting atop an acellular empty space that exists, just waiting to be filled conveniently by LDL-cholesterol and engulfing macrophages. This is shown in Figure 3. 

Legend to Figure 3: The study of Nakashima et al. (12) shows that the tunica intima is not an empty acellular space as depicted in Figures 1 and 2. Instead, the tunica intima comprises multiple layers of cells (panels (a) and (b)) and is in fact thicker than the tunica media. Using a special stain to identify smooth muscle cells, panel (c) shows that the cells in the tunica intima, below the endothelial layer, are indeed smooth muscle cells. Panel (d) stains for the presence of macrophages which are identified with an arrow head. This evidence shows that the diagrams depicted in figure 1 and 2 are fundamentally incorrect in depicting the tunica intima as an acellular space potentially full of macrophages. Reproduced from figure 3 in reference 10.

In contrast, the tunica intima comprises multiple layers of smooth muscle cells – up to 50 such layers – and without any macrophages.

The second critical finding reported by Nakashima and colleagues already in 2007 (13) and essentially forgotten until re-discovered by Subbotin (10,11) is the initial deposition of lipid material in the walls of arteries affected by atherosclerosis, which occurs in the deep layers of the tunica intima. These layers are separated from the endothelial cell layer, by numerous layers of smooth muscle cells, (Figure 4).

Legend to figure 4. The panels on the left (panels (a), (d) and (g)) show the histological evolution of the fatty streaks in arteries of different subjects dying from different causes. The middle panels ((b), (e) and (h)) show the site at which lipid (staining red) begins to accumulate. Note especially in panel (h) that the main site of accumulation is in the deep layers of the tunica intima close to the internal elastic lamina. The panels on the right (panels (c), (f) and (i)) are stained to detect the presence of macrophages. The panels show that despite some degree of lipid accumulation (panels (e) and (h)) there is no evidence for the invasion of macrophages. Figures 1 and 2 require that an invasion by macrophages into the (non-existent) subendothelial space is essential for the development of atherosclerosis. 

Reproduced from figure 6 in reference 10. 

The point of figure 4 is to show that since the first evidence for lipid accumulation in diseased arteries occurs so deep in the tunica intima, it cannot have arisen from the LDL-cholesterol carried in the lumen of the arteries. There has to be another source for this lipid accumulation.

Figure 5 shows the progression of atherosclerosis with further lipid accumulation in the deep layers of the tunica intima and the addition of macrophages in the latter stages – Grade 3 – of the progression of atherosclerosis. 

Legend to Figure 5: This figure shows the further progression of atherosclerosis from Grade 2 Fatty streak to Grade 3 PIT with foam cells. It shows that lipid accumulation increases in the deep layers of the tunica intima (central column of panels) with the addition of macrophages (column of panels on the right). The column of panels on the left shows the histological changes corresponding with this lipid accumulation in the deep layers of the tunica intima. 

Reproduced from figure 6 in reference 10. 

Figures 4 and 5 clearly establish that cholesterol circulating within arteries cannot explain why the atherosclerotic plaque begins to develop deep within the highly cellular tunica intima, far removed from where LDL-cholesterol is circulating in the bloodstream. 

The sole conclusion must be that Keys’ Lipid Hypothesis cannot explain these findings. Hence these findings disprove the essential foundations on which Keys’ theories are based. Subbotin (10) has proposed an alternate hypothesis (that has yet to be fully tested and hence is still just an untested hypothesis). He proposes that the fundamental event leading to the development of atherosclerosis is a triggering of proliferation (multiplication and growth) of the smooth muscle cells in the tunica intima. These are the cells in the arterial system that are known to replicate the most. Their replication can be initiated by any of a number of stimuli including ageing, transplantation, needle puncture, irradiation, hypertension and some pharmaceutical drugs (10). Subbotin postulates that following the triggering of their proliferation, perhaps by initiating stimuli yet to be fully understood, the mass of these cells increases. But a point will be reached at which this enlarged mass of cells can no longer remain viable without the addition of a dedicated blood supply (Figure 6).   

Legend to figure 6: Dr Vladimir Subbotin has proposed that the normal coronary artery may develop diffuse (tunica) intimal hypertrophy (DIT) (right side of top panel) in response to currently unidentified stimuli. The result is that the cells in the outer layer of the tunica intima, furthest from the arterial lumen and their source of oxygen, become oxygen-deficient (hypoxic).  The consequence is that new blood cells grow into the intima (left side of bottom panel) from the vasa vasorum. Blood entering the intima then deposits LDL-cholesterol explaining how lipids enter the deep layers of the intima depicted in Figures 4 and 5.

Reproduced from figure 7 in reference 10.

When that happens, the deepest layers of the intima recruit the development of new blood vessels (neovascularization). These blood vessels arise from the vasa vasorum which exist in the tissue layer outside the tunica media and which normally provide blood (and oxygen) to the muscle cells in the tunica media of muscular arteries. Subbotin postulates that once these new blood vessels enter the deepest layers of the tunica intima, they bring with them LDL-cholesterol which is then deposited in that cell layer, producing the changes depicted in Figures 4 and 5. Importantly there is substantial evidence that the vasa vasorum are intimately involved in the development of atherosclerosis so that: “The present data indicate that vasa vasorum neovascularisation and atherosclerosis are seemingly inseparably linked…” (15, p. 878), 

In his presentation (11), Subbotin makes another extremely relevant point. He states that whilst lowering the blood cholesterol concentration with statin drugs may produce (marginal) health benefits in some, it does not cure the disease. 

In fact, something like two-thirds of patients with coronary heart disease – the “forgotten majority” – will still suffer major coronary events despite using cholesterol-lowering drugs to normalise their blood cholesterol concentrations (16,17). Whilst Harvard’s Cardiology Professor Peter Libby questions whether this is because treatment started too late, or was of too short a duration, or was “too little”, Subbotin suggests that perhaps the hypothesis on which this treatment is based is simply false. 

He quotes Claude Bernard: ‘‘Indeed, proof that a given condition always precedes or accompanies a phenomenon does not warrant concluding with certainty that a given condition is the immediate cause of that phenomenon. It must still be established that when this condition is removed, the phenomenon will no longer appear” (18). 

In other words, because two phenomena are related in time (by association) does not prove that the one causes the other. For proof of causation, elimination of the supposedly causative factor must be followed by elimination of the condition being studied. Or as William Stehbens has written: ‘‘… differentiating between cause and non-causative factors is essential. Reduction in incidence rather than elimination of the disease precludes a causal relationship’’ (19). 

In other words, unless removal of the supposedly causal agent – in this case an elevated blood cholesterol concentration – produces a 100% cure in all persons, then the elevated blood cholesterol concentration cannot be the cause of, in this case, coronary atherosclerosis and coronary heart disease. That lowering the blood cholesterol concentration has not produced a 100% cure of coronary heart disease is clearly expressed in the frustration of Professor Ira Tabas in his 2016 Russell Memorial Lecture in Vascular Biology (20): “… how can the overall lowering of plasma LDL over the past 3 decades, that is, after the introduction of statins, be reconciled with the fact that atherosclerotic vascular disease remains the leading cause of death (21)” (20, p.187). 

He then exposes the bias expressed by all those who accept Keys’ Lipid Hypothesis without question: “Despite the enormous life-saving success of statins, issues related to … patient compliance, and patient and provider education have limited our ability to lower LDL to the types of level, and at an early enough age, that would be needed to remove atherosclerotic disease from the leading killer list” (20, p.187). In other words, “we”, the cardiologists and researchers who accept the dogma of the Lipid Hypothesis, “know” that cholesterol-lowering is life-saving. But when we have evidence that it is not, the blame clearly lies with the patient and her health provider who simply did not lower her blood cholesterol concentration early enough and keep it low enough for her life, to produce the life-saving outcomes that “we” “know” must naturally happen. 

The possibility that the Lipid Hypothesis is false is never considered. That is simply an intellectual step too far.

But the true extent of the failure of the Lipid Hypothesis is summed up in the writing of Goldstein and Brown who, as I described earlier (22) were awarded the 1985 Nobel Prize in Medicine or Physiology for their discovery of the receptor mechanism by which cholesterol is transported into cells. Their discovery assisted in the launch of the cholesterol-lowering drugs, the statins, and the hyperbolic claims that these drugs would eliminate coronary atherosclerosis and coronary heart disease.

So, Brown and Goldstein predicted in 1996 that: “…proof of the cholesterol hypothesis, discovery of effective drugs, and better definition of genetic susceptibility factors – may well end coronary disease as a major public health problem early in the next (21st) century” (23,p.629). 

That this has not happened (21), despite these hubristic predictions, is perhaps the very best evidence that Keys’ Lipid Hypothesis is quite simply wrong. 

What else is not consistent with this traditional explanation of how atherosclerosis develops. 

Keys’ acolytes do not ever acknowledge that the key outcome measures in epidemiological studies such as heart attacks, both fatal and non-fatal, and strokes, are not an exact measure of the extent of coronary atherosclerosis in those populations (19). 

Rather, they are a measure of acute thrombotic events that begin when the arterial plaque ruptures: “Thus the end-point of epidemiological studies and intervention trials is a thrombotic event, but most (researchers) have concentrated only on lipids and lipoproteins, and have made no measurement at all of blood homeostatic factors. However…several prospective studies of the relation between haemostatic function and myocardial infarction have been published, notably the Northwick Park (24) and Framingham (25) studies, and these have consistently shown that an increased level of fibrinogen is at least as significant a predictor as cholesterol. Furthermore, the level of fibrinogen and activity of Factor VIII are increased in hyperlipidaemia (26,27) so that there is a complex interaction between plasma lipids and thrombosis” (28, p. 235). 

Smith concludes that fibrin deposition plays a major role in the development of atherosclerosis. But Keys’ Twin Hypotheses do not allow for this mechanism.

So the practical point is that heart attacks and strokes can occur in persons with minimal atherosclerosis whereas others with extensive disease may not ever develop an acute event. Even in any individual it is not possible to predict which coronary artery plaques, big or small, might rupture. Indeed small plaques are as likely to rupture as are larger ones. This helps explain why the popular and highly lucrative cardiological practices of coronary bypass surgery (29) and coronary artery stenting do not produce beneficial outcomes in most conditions for which either is used (30-32) and at least some of the benefit of stenting (and so perhaps also for coronary artery bypass grafting) is due to a placebo effect (33). 

The reason is because arteries with minimal atherosclerosis are not considered candidates for the placement of a stent. But the absence of severe atherosclerosis in a particular artery does not guarantee the complete absence of risk of plaque rupture in that artery, however minor the disease may be. For similar reasons, coronary artery bypass grafting may be no more beneficial than standard medical care for the majority of patients with CHD (29). So dominant has been the Lipid Hypothesis that there has been little interest in the role of different diets in promoting or limiting the probability of plaque rupture with resultant blood clotting (coronary thrombosis). 

But, by making these inconvenient points so early, I am getting ahead of myself.

• 1910. William Procter and James Gamble with the help of German chemist, E.C.Kayser, produce a novel hydrogenated seed oil, originally called Krispo but subsequently renamed Crisco.

William Procter had come to Cincinatti, Ohio in the 1830s after his candle-making business in England had been destroyed by fire. There he met candlemaker James Gamble, who had left Ireland during the Great Potato Famine of the 1840s. When they married sisters, the brothers-in-law decided to combine their expertise and formed the company, Procter and Gamble (P&G). 

At the time, Cincinatti was known as Porkopolis as it was the centre for the distribution of pork products down the Mississippi to New Orleans and then to the coastal southern United States. Pork fat was a key ingredient for P&G’s business as it provided the fat they needed to produce soap and candles. 

A recession in the 1870s forced the brothers-in-law to search for a competitive advantage. They decided to produce their soaps in individually wrapped bars. But for this they needed cheaper sources of fat. They settled on a mix of palm and coconut oils and created the first soap, Ivory, that floated in water. 

Their next challenge occurred in 1882 when Thomas Edison invented the incandescent electric lighting (the electric light bulb) and formed the Edison Electric Illuminating Company of New York. Electric lighting spread quickly across the US. Edison’s invention posed a very serious challenge to Procter and Gamble’s candle-making business. Their response would impact the health of future generations right up to today’s in ways no one could then possibly have imagined. 

To survive, P&G began the search for an alternative business; to turn their ability to produce soap and candles from rendered fats into some other product that would be widely used. They began by searching for a cheaper source of fat (oil) to be sourced from seeds. They started by building a series of crushing mills to extract oil from cottonseeds. American chemist David Wesson had by then perfected a method to bleach and deodorise cottonseed oil making the extract clear, tasteless and odourless (34). The oil was then sold as a liquid or, when mixed with animal fat, as a cheaper shortening that resembled lard. The composite fat became the chief competitor for lard used as shortening, especially in baking. Soon the P&G chemists became interested “in the possibility of converting cottonseed oil into a sold form (to replace animal fats) for use in shortening…They hoped this (novel compound) could compete in quality and price with lard, butter, and the many compounds already on the market” (35). But they needed a method to convert cottonseed oil into a more solid, less liquid form (like butter, lard or tallow).

In 1907, German chemist, E.C. Kayser contacted P&G (35). He had developed a process by which liquid cottonseed oil could be converted to a solid fat. The process he discovered, is known as hydrogenation. P&G invited Kayser to the US. Impressed by his story, P&G purchased the rights to his process and hired him as a company consultant. Three years later, on November 10th 1910, P&G applied for a US patent for a new “vegetable” (actually seed) shortening produced by Kayser’s hydrogenation process. The shortening consisted of a “vegetable (sic) oil, preferably cottonseed oil, partially hydrogenised (hydrogenated), and hardened to a homogenous white or yellowish semi-solid closely resembling lard. The special object of the invention is to provide a new food product for a shortening in cooking…” (35). The product was called Crisco. By 1912 it was being advertised as: “An absolutely new product – a scientific discovery which will affect every kitchen in America” (35).

The immediate challenge facing P&G was that American housewives associated cottonseeds with clothing, not foods. To circumvent this problem, the true source of the product was never disclosed (34). Instead, P&G’s chief marketing points were that Crisco was cheaper than lard and, unlike lard, it was also tasteless. In addition, the more hydrogenated the “vegetable” oil, the less likely it was to melt on warmer summer days (in the days before the development of the refrigerator). This provided a particular advantage when used as shortening in baked products, in the place of lard or butter which melt at lower temperatures. 

Even better, it was a novel product produced by a novel chemical process (hydrogenation), by a company that everyone could trust. Exactly the features the progressive American housewife of the 1920s would want in a new product. This would show how thoroughly modern and up-to-date she is, the company’s advertisers enthused. They added the unsubstantiated claim that this modern product produced by modern technology was also much healthier than the butter that humans had been eating for tens of thousands of years. They carefully avoided the point that there was (and still is) no evidence that butter is anything other than extremely healthy for humans. 

No one bothered to ask the obvious question: Why should a recently-developed artificial product produced by a complex series of chemical reactions including bleaching, deodorising and hydrogenation, be healthier for humans than foods like butter, lard and tallow that our ancestors evolved to eat over millennia? And still today, no one asks that question. Unfortunately, 50% of the fat content of Crisco comprised trans fatty acids and it would take almost 100 years before the health dangers of trans fatty acids would be fully appreciated.

Skillful marketing ensured that the product was an immediate success; sales increased nearly 30-fold in just the first four years of its production (36, p.88), from 2.6 million pounds of Crisco in 1912 to 60 million pounds four years later. The displacement of the traditional sources of added dietary fat, including butter, lard and tallow by these industrially-produced vegetable-based oils, increased progressively (Figure 7), introducing perhaps the single largest change in dietary habit in the US (and elsewhere) since the beginning of the 20th century.

Legend to Figure 7: The change in the important sources of added dietary fat after 1909. Note the progressive reduction in the consumption of butter and lard, being replaced with shortening and margarine, both produced by the hydrogenation of seed (“vegetable”) oils. The main seed oil now used in this process is soybean oil which overtook cottonseed oil after about 1966 (right panel). 

Reproduced from (37).

Figure 8 shows what this change means in terms of the number of grams of the different added fats eaten daily by individuals in the US. The key difference is the replacement of saturated fat from butter and lard with shortening, margarine and oils now derived from seed oils and which are a rich source of trans fats and omega-6 polyunsaturated fats (PUFAs). 

Legend to Figure 8: The change in average grams of fat consumed daily from butter, lard, shortening, margarine and seed oils by individuals in the US from 1909 to 1985. (Note that Crisco was marketed for the first time in 1910). In 1909 butter, lard and shortening (then also derived from animal sources) provided 43 (91%) of the 47 grams of added fat eaten daily by US citizens. Today the total intake from these sources is 79 grams, of which butter and lard now provide just 8 grams (11%) whereas processed seed oils in shortening, margarines and oils provide 71 (89%) grams. Some argue that it is this dietary change rather than an overall increase in refined carbohydrate consumption that is the real cause of the rise in the modern diseases of “lifestyle” – actually diseases of nutrition. Redrawn from data from reference 38, p.43. 

Whilst a great marketing ploy, P&G’s original 1910 marketing claim that partially-hydrogenated seed oils are healthier than animal fats, was never based on any experimental evidence. With time, it simply became the accepted dogma according to the conclusion that any other fat, however produced, is healthier for humans than saturated fats derived from animal products. To prove this claim, all that “healthier” fat must do is lower the blood cholesterol concentration. Whatever other effects an industrially-produced “vegetable” oil might produce, good or bad, is utterly irrelevant (according to this popular logic). And so, it will remain largely unstudied as is the case today.

Interestingly, Ancel Keys clearly had some misgivings about the ill-effects of hydrogenated fats, for already in 1956 he wrote: “A reasonable, practical conclusion from the present evidence might be to propose for American adults a sharp reduction in the total dietary fat from their current average intake in which fats account for some 40 percent or more of the total dietary calories. In this dietary adjustment, emphasis might be placed on reducing the consumption of margarine, hydrogenated shortenings (my emphasis), butterfat, and meat fats. The great nutritional values of milk and meat would be maintained, and increased, by favouring skim milk, cottage cheese, and lean meat” (39, p.376). 

The reason for Keys’ misgivings were simple. In 1961, he and his colleagues had published a study showing that hydrogenated “vegetable” oils containing a substantial amount of trans fats significantly increased blood cholesterol, phospholipid and triglyceride concentrations (40). Yet remarkably, Keys would never again raise the alarm about the potential hazard of replacing dietary saturated fats with polyunsaturated hydrogenated fats containing substantial amounts of trans fats. Understandably, in 1910, the P&G chemists did not appreciate that the hydrogenation process produced this range of novel fats including trans fats. The extent to which trans fats are produced depends on the seeds being hydrogenated. With the processes being used in the 1960s, 25% of the hydrogenated fats in corn oil were trans fats; in cottonseed it was 35%, in soy 40%, and in canola 50% (41). 

• 1913. Animals fed cholesterol in high doses develop what looks like atherosclerotic arterial disease.

In 1913, the Russian scientist Nikolai N. Anichkov (Anistschkow in the German literature) and his medical student S. Chalatow, “purified cholesterol from egg yolks, dissolved it in sunflower oil, and fed it to normal rabbits” (5,42). This caused the rabbits’ blood cholesterol concentrations to rise to the extraordinarily high values of 500-1000mg/dL (13-26 mmol/L), which is perhaps predictable since rabbits are herbivores that are not designed to eat animal produce. Recall that only animal products contain cholesterol. When force fed cholesterol, rabbits store the excess cholesterol in all their body tissues. 

Anichkov and Chalatow were influenced by other research being undertaken by their colleagues at the St Petersburg Imperial Military Medical Academy (43). Their studies found that rabbits raised on diets high in milk, eggs, and meat developed arterial lesions. Egg yolks, but not egg whites, caused the arterial lesions. Rabbits fed cholesterol extracted from egg yolks and dissolved in vegetable oil developed arterial lesions, superficially resembling human atherosclerosis. The authors concluded: “Since the same (arterial) changes can be observed by feeding pure cholesterol, there remains no doubt that it is precisely this substance that is laid down in the organism as liquid-crystal droplets and evokes extraordinarily damaging effects in various organs” (42,43).  

Anichkow’s findings were largely ignored when others failed to reproduce these findings in other laboratory animals, in particular in rats and dogs, and had only variable success in pigs and primates (38). The strongest criticism remains that this form of experimental atherosclerosis produced by feeding animal products to herbivores is not the same as that found in humans (44). In addition, the potential role of oxidised cholesterol and diets deficient in essential fatty acids in causing arterial damage in some of these studies, was not appreciated (38). Despite these failings, Anichkow’s studies were resurrected in the 1980s by those wishing to find a more solid foundation for the increasingly shaky Lipid Hypothesis. 

Thus, Daniel Steinberg MD, who built his medical legacy on an unflinching support for Ancel Keys (45,46), including his key role in driving the Lipid Research Clinics Coronary Primary Prevention Trial (LRC CPPT) and the National Institute of Health (NIH) Consensus Development Conference which led to the utterly disastrous National Cholesterol Education Program (NCEP), all discussed subsequently (47), would later write: “Anitschkow’s body of work showed clearly and convincingly (my emphasis) that hypercholesterolemia in rabbits was a sufficient cause of atherosclerosis. Of course, it did not necessarily follow that cholesterol – either in the diet or in the blood – was also an important factor in human atherosclerosis. That conclusion would have to await studies showing that hypercholesterolemia in humans was indeed associated with atherosclerosis and, ultimately, clinical trials to establish that relationship as a causal one” (5, p.2948).

This, it should be emphasised, is proof by circular argument. If Anitschkow’s work had “clearly and convincingly” established that high blood cholesterol concentrations are the direct cause of human atherosclerosis, then there would be no need for any more studies, including clinical trials in humans to “establish that relationship”. In science, the truth stands by itself. A theory does not become the truth when bolstered by yet another still unproven theory. This is the lesson that Keys and his acolytes failed to learn. 

My argument, developed subsequently, is that those clinical trials to which Steinberg refers, failed spectacularly to establish that an elevated blood cholesterol concentration is the key or even a necessary factor in the development of atherosclerosis. 

So following the logic of Steinberg’s circular argument, if those clinical trials are inconclusive, then Anitschkow’s finding is equally meaningless. At least as it relates to human atherosclerosis.

But over the years, the most vociferous advocates of that (unproven) relationship have, like Steinberg, been those whose careers have been the most dependent on that relationship being true.

As I describe subsequently (47), the campaign to make cholesterol the principal villain causing atherosclerosis began in earnest in the US in the mid-1980s. It starts with the 1984 NIH Consensus Development Conference (NIH CDC), chaired by none other than Steinberg himself. The principal outcome of the NIH CDC was the National Cholesterol Education Program (NCEP), the main focus of which was to convince the majority of US physicians who at the time were sceptical that cholesterol causes heart disease, so called “cholesterol sceptics”, that their scepticism was misplaced.

Central to all of this was the activism of Steinberg himself. Clearly the man driving the Consensus Development Conference had first to be convinced of the correctness of his theory. But that was not difficult as Steinberg, like Ancel Keys, was never in any doubt: “Today, we know that we are winning the war against coronary artery disease. In fact, clinical trials with the statins have shown remarkable decreases in both coronary heart disease mortality and also total mortality. Decreasing LDL by ~25% is enough to lower coronary heart disease mortality by 30-40%, and that is the result of only 5 or 6 years of intervention. It seems reasonable to extrapolate and expect even greater reductions if treatment is started earlier in life and continued not for just 5 years but for decades” (46, p.1585). 

Later he would add: “Yet the validity of the lipid hypothesis did not become generally accepted until 1984. (Believe it or not, there are still a few pockets of stout resistance!)” (5, p. 2949).  

His militaristic reference (recall his book was also titled The Cholesterol Wars) shows that Steinberg believed the crusade to market cholesterol as the demon causing heart disease, was never simply a scientific process. It had become a war, rife with confirmation bias. Personal egos, funding opportunities and academic reputations had to be protected at all costs. And in the end those costs would be borne by the citizens of the world as they suffered through the global obesity/diabetes epidemic that this “war” initiated. It is as British Prime Minister Neville Chamberlain had said: “In war, whichever side may call itself the victor, there are no winners, but all are losers”. The Cholesterol Wars are no exception.

And those who disagreed with Steinberg’s fake Consensus, described subsequently (47), would quite naturally become the hated enemy who deserved to be exterminated.

Two were quickly dispatched – John Yudkin MD, as I described previously (48), and George Mann (49), who had been the co-founder of Framingham study and who would later describe Keys Diet-Heart hypothesis as the greatest health scam of the (20th) century: “The hypothesis proposed in the late 1950s, that atherosclerosis is caused by the saturated fatty acids and cholesterol in our diet was based upon scanty, imperfect and highly selected information. That hypothesis has been repeatedly tested over the last 40 years in dozens of extraordinarily expensive and complicated trials. In every instance when the outcomes are honestly interpreted, the results have been the same. No dietary modification and no drug treatment has been shown to correct the problem of CHD. The diet-heart hypothesis has been repeatedly shown to be wrong, and yet, for complicated reasons of pride, profit and prejudice, the hypothesis continues to be exploited by scientists, fund-raising enterprises, food companies and even government agencies. The public is being deceived by the greatest health scam of the century” (50, p.1).  

As a reward for his opposition, Mann’s career was essentially terminated. As he told Nina Teicholz: “It was pretty devastating to my career…. ‘One day,’ recalls Mann, ‘the woman who was the study section secretary asked me to step out in the hall. ‘Your opposition to Keys is going to cost you your grant,’ she said. And she was right’” (36, p.67-68).

• 1945. Mortality from coronary heart disease falls in some European countries during World War II, although not in the USA.

A series of articles from European authors (51-57) reported that deaths from CHD fell quite sharply during the latter years of World War II. This was typically associated with a reduced consumption of animal produce “rich in cholesterol”, particularly meat, whole milk, cream, cheese and eggs with an increase in consumption of carbohydrate-rich foods like cereals, potatoes and fruits. Although sugar consumption also fell sharply, it was the reduction in the consumption of animal produce and cholesterol that caught the attention of these authors.

As a result, Malmos (51) produced the first iteration of what would become known as Keys’ Diet-Heart and Lipid hypotheses. Thus: “We ought to avoid all luxury consumption of high-cholesterol foodstuffs. Especially the combination eggs and cream, butter or other fats would seem to be risky…There is much which goes to show that in Denmark, Sweden and the USA, the consumption of eggs, butter, milk and other animalic fats is at present too high and may involve serious risk for public health” (51, p.152-153).

The risk of drawing this conclusion is that many factors in the lives of these civilians changed as a result of the war. Only if one begins with the conclusion that nutrition was THE factor, can one ever draw the conclusion that nutrition was indeed THE factor.  

There is a saying in science that what you believe, determines what you believe. The scientific term for this is confirmation bias. 

Especially when evidence became available in Norway after war that CHD rates were again on the rise, associated with an increased intake of dietary fats (58). Interestingly, intake of dietary trans fatty acids increased dramatically as the Norwegian government subsidised margarine in the post-war years and this margarine contained trans fats in high concentrations.

• April 1945. President Roosevelt dies from a fatal stroke.

The 31st US President, Franklin Delano Roosevelt who was in office from 1932 to 1945, was known to suffer from an elevated blood pressure, rising from a value of 136/78mmHg in 1935 to 188/105mmHg in 1941 (90, p.2). At the time the President’s personal physician reported that his blood pressure was “no more than normal for a man of his age” (90, p.2). But others were less certain. British Prime Minister Winston Churchill asked his personal physician, Lord Charles Moran, whether he too had “noticed that the president is a very tired man” (59, p.2).

In March 1944, Roosevelt was admitted to the Bethesda Naval Hospital for evaluation of increasing shortness of breath on exertion and abdominal distension. There cardiologist Howard Bruenn diagnosed hypertension, hypertensive heart disease and cardiac failure. The treatment then available for the President’s condition was primitive and largely ineffective. A month later the President’s blood pressure had risen to 240/130mmHg. Today that would be diagnosed as malignant hypertension requiring that the patient be hospitalised without delay. 

At the Yalta Conference in February 1945 it was clear to all that the President was gravely ill. Lord Moran wrote in his diary that “the President appears a very sick man. He has all the symptoms of hardening of the arteries….I give him only a few months to live” (59, p.3).  

In April 1945, as the Allied armies fought their way into Germany, the President’s health had deteriorated noticeably. He was weak with an ashen-grey complexion, features in keeping with advanced heart failure. To recuperate and to regain his strength he travelled to the “Little White House” in Warm Spring, Georgia. But on April 12th 1945 at 1:15pm at age 63 years, the President suffered a massive cerebral haemorrhage (stroke) dying two hours later. His blood pressure was 300/190mmHg (60). 

This anecdote makes it clear that in 1945 very little was known about the effective management of hypertension, hypertensive heart disease and cardiac failure. Or of the role of hypertension as a “risk factor” for CHD and of hypertensive heart disease. This level of ignorance exposed by the President’s death would become perhaps the single greatest driver of medical research in modern times. The goal was simple. Understand what causes coronary heart disease so that the disease can be prevented in future.

• 1948. President Harry Truman signs the National Heart Act into law.

The death of the sitting US President from a cerebral stroke captured the attention of the US Congress who soon agreed to support research that would improve the understanding, treatment and prevention of heart disease. The result was that on June 16th 1948 President Harry Truman signed into law the National Heart Act. The Act declared that: “Whereas the Congress hereby finds and declares that the Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure… These diseases are the main cause of death in the United States and more than one in every three of our people die from them…” 

The new law established the National Heart Institute (NHI), today known as the National Heart, Lung and Blood Institute (NHLBI), and granted $500,000 in seed money for a twenty-year epidemiological heart study. That study would become the Framingham Heart Study.

1. 1948.  The Procter & Gamble company donates $1.74 million to the American Heart Association (AHA) 

The American Heart Association (AHA) began its life as a non-government organisation underfunded and with “virtually no income” (23, p.47). And so it might have remained if in 1948, as Teicholz describes, “It got lucky: Procter and Gamble (P&G) designated the group to receive all the funds from its ‘Truth or Consequences’ contest on radio, raising $1,740,000, or $17 million in today’s dollars” (36, 47-48)”. The result was that the AHA was able to hire its first professional director “a former fund-raiser for the American Bible Society” (36, p.48). 

By 1960, the AHA fund-raising efforts had been so successful that it was able to invest hundreds of millions of dollars into heart disease research. 

Thanks to P&G’s contribution, the AHA had become “the authoritative source of information about heart disease for the public, government agencies, and professionals alike, including the media” (36, p.48). Indeed, the organisation would grow to become one of the most trusted NGOs in the world.

But it would never stray far from the dietary advice to replace saturated fat with “vegetable” oils, some of which are conveniently manufactured by its foundation sponsor that made all this possible, P&G.

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