Low Fat / Low Cholesterol Study

In 1910, as part of his pioneering studies of the role of cholesterol in human metabolism, German chemist Adolf Otto Reinhold Windaus discovered 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 later describe the pathways by which cholesterol is converted to vitamin D. For his work, he was awarded the Nobel Prize in 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 gave rise to 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, a single layer of cells known as the endothelium, and into the subendothelial space, causing the initiation of fatty streaks (Figure 1). These then progress to the development of more advanced atherosclerosis, termed arterial plaques (Figure 2), which among other complications can cause heart attacks and strokes.

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 and 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 of atherosclerosis (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 will 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 full-blown atherosclerotic plaque. Note again that the subendothelial space is devoid of cells before the hypothetical endothelial damage allows the free entry of LDL-cholesterol into this conveniently located anatomical space.

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 tunica intima must, as shown in this figure and in Figure 1, contain 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 hard it may be “shoved” (3). Currently, the most popular theory for atherosclerosis is that shown in Figures 1 and 2. This theory holds that the endothelial cells lining the lumen of the artery wall must first be damaged before the passing of cholesterol through the wall 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’ discovery.

This theory also predicts that cholesterol enters damaged arteries down a concentration gradient, so the degree of a person’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. This is exemplified by what happens in the coronary arteries supplying blood to the heart muscle (6).

It also was then unknown that in some populations, there may be advanced atherosclerosis in the cerebral (brain) arteries with minimal involvement of the coronary (heart) arteries (7, 8). In such cases, a person is at greater risk of stroke than heart attack. In other cases, as is more prevalent in the U.S., the opposite applies.

The results of analyses of Eskimo foods are presented in Table 1. On the basis of nutritional surveys with individual food weighings in different families from four Eskimo settlements in Alaska and the above-mentioned results of cholesterol determinations in Eskimo foods, supplemented by figures available for the cholesterol content of nonEskimo foods (Okey, 1945; Pihl, 1952), the cholesterol intake of Eskimos has been estimated (Tables 2, 3). From these calculations it is observed that the mean caloric consumption of the 45 adult male and female Eskimos was about 2,700 calories, the fat consumption was 105 g and the mean cholesterol intake was roughly 340 mg daily, varying from 150 mg to 700 mg per day. It should be noted that these cholesterol figures may be considered as minimum values because several of the food items ingested could not be included in the calculation since the cholesterol content was unknown. It may also be noted that the cholesterol intake varies greatly from one Eskimo group to another, depending on the different dietary habits. Thus, it was observed that among the inland Eskimos, the Nunamiuts at Anaktuvuk Pass, some of the men consumed as much as 70 grams or more of boiled brain from mountain sheep in a single evening meal yielding almost 600 mg cholesterol from this food item alone. 

It is thus evident that some Eskimos have fairly high cholesterol intakes compared with healthy American white men, although the mean intake for the 45 Eskimos studied is in the order of 2.5 g per week (varying from 1 to 5 g) . This corresponds to the group of moderate habitual cholesterol intakes reported for normal American men (Keys, 1949) while in the Inland Eskimos the mean figure is in the order of 4 g cholesterol per week, which corresponds to the group of highest habitual cholesterol intakes for normal American men, reported by Keys (1949). 

Keys (1950) has estimated that the American diet varies with regard to cholesterol content from a low of 200-300 mg daily to 700-800 mg, depending on the food consumed. Gubner and Ungerleider ( 1949) have given the figure 200--360 mg for daily cholesterol intake on a mixed diet. 

It thus appears that the estimated mean figures for cholesterol intakes in Eskimos may be comparable to those of Whites on a mixed diet. 

The average figure for the daily fat consumption in the 45 Eskimo subjects reported here was only about 105 g (377 of the calories), while in a larger survey the average daily fat consumption in Alaskan Eskimos was 139 g (40 % of the calories). In normal white men living in Alaska the fat consumed represented 37.5 %( of the calories ingested. 

In the Eskimo subjects the mean serum cholesterol concentration was 203 mg per 100 ml (Table 4) which is about the same as is found in normal Whites. Thus L. J. Milch (personal communications) found an average level of 207 mg cholesterol per 100 ml serum in Whites 30-35 years old. 

On the other hand, the Eskimo serum concentration of Sf 12-20 lipoproteins was 20 mgl100 ml as against 28 mgl100 ml in Whites of similar age, observed by Milch (personal communications). For Whites under 25 years of age Milch found 24 mg/lOO ml, and for Whites 40-45 years of age 38 mg/l 00 m!.

https://www.crossfit.com/health/ancel-keys-cholesterol-con-part-4

Dr Tim Noakes:

In a previous column (3), I described how already in 1950, John Gofman, MD, had formulated the diet-heart and lipid hypotheses (4) two years before Keys would commandeer the ideas as his own.

Gofman posed as a double challenge for Keys and his future disciples. First, Gofman was far more qualified than Keys to undertake research into the dietary and other factors causing heart disease. But perhaps more importantly, Gofman’s diet-heart hypothesis gave equal weight to dietary fats and dietary carbohydrates as the factors driving atherosclerosis and the development of CHD.

According to Gofman:

What is solidly established is that the Sf° 20-400 lipoprotein levels [i.e., blood triglyceride or VLDL concentrations] on the average, can be raised by increasing the dietary carbohydrate intake and can be lowered by decreasing it. … Furthermore, many individuals who are characterized habitually by some type of error in their metabolism that makes their Sf° 20-400 lipoproteins habitually extremely high will experience a marked reduction in the blood levels of these lipoproteins when the carbohydrate intake is lowered. (5, p. 123, my addition)

Gofman continues:

These same lipoproteins are essentially unaffected, in the average case, by changing from animal to vegetable fats. This information is extremely crucial, for in many individuals the risk of coronary heart disease comes primarily from the Sf° 20-400 lipoproteins [VLDL or triglycerides]. For such individuals, any attempt to lower heart attack risk by shifting from animal fat to vegetable fat in the diet would be illogical. There would be no reason whatever to expect any benefits since one would be changing the diet in a manner directed toward affecting the Sf° 0-20 [LDL] lipoproteins, which is not the problem at hand for these persons. For such individuals, the preventive efforts would have to be directed toward lowering the carbohydrate intake, which will, on the average reduce the Sf° 20-400 lipoprotein levels. With respect to the effect of carbohydrates on the Sf° 20-400 lipoproteins, it is a matter of the amount of carbohydrate that is eaten rather than the total number of calories ingested. For example, if one maintains individuals at exactly the same number of calories per day, so that they do not alter the weight in any way, but takes out some of the carbohydrates in their diet and replaces them by vegetable oil, one finds that the Sf° 20-400 lipoprotein levels will fall. Achievement of this result of lowering the Sf° 20-400 lipoproteins requires neither any alteration in caloric intake nor any alteration in body weight. (5, p. 124, my additions and emphasis)

Subsequently, in 1958 Gofman pointed out a key logical flaw that has since been ignored (6). He noted that a number of studies had found increasing the dietary intake of vegetable oils produced a fall in blood cholesterol concentrations, and this has been interpreted as beneficial. But the addition of vegetable oils also reduced total carbohydrate intake, and since carbohydrate increases the Sf° 20-400 lipoprotein levels, which contain approximately 13% of cholesterol by weight, the shift from a higher- to a lower-carbohydrate diet might be the real reason why increasing the intake of vegetable oils causes a reduction in blood cholesterol concentrations.

Thus, Gofman warned: “No consideration was given by them to the possibility that the lowering of cholesterol levels might have been the result of the simultaneous removal of a large amount of carbohydrate from the diet” (6, p. 277).

Gofman next describes the effects of a low-carbohydrate (100 g/day) diet in a 65-year-old male subject with a previous myocardial infarction (Figure 2).

Figure 2: The effects of a low-carbohydrate diet in a myocardial infarction survivor. Note the low-carbohydrate diet produced a very large decrease in the Sf° 20-400 lipoprotein levels, now known as the VLDL-lipoproteins, which transport predominantly triglycerides. Total blood cholesterol concentration was unaffected by this dietary change. Despite this, the patient’s atherogenic index (AI) had fallen, placing him in a more favorable metabolic state according to Gofman’s understanding. Reproduced from data on Table V in reference 6, p. 279.

As Gofman wrote: “It can be seen from these data that a massive fall in the serum Sf° 20-400 lipoprotein levels occurs on the low-carbohydrate diet, without significant changes in the Sf° 0-20 lipoprotein levels. Accompanying this fall in lipoproteins is a highly marked and favourable reduction in the atherogenic index value” (6, p. 278-279).

Thus, the real originator of the diet-heart and lipid hypotheses stated that a low-carbohydrate, high-fat diet can be used in persons with established coronary atherosclerosis, presumably to reverse that disease.

He continued:

These same principles of carbohydrate restriction have been applied successfully in several types of extreme derangement of lipoprotein level control of the Sf° 20-400 lipoprotein class, namely, in xanthoma tuberosum, essential hyperlipidemia, and in diabetes mellitus … . For such a [post-myocardial infarction] patient, it is quite clear that management of the problem of coronary disease by dietary means involves the use of a low-carbohydrate diet, and not a low-fat, high-carbohydrate diet which is so often prescribed when attention is not paid to the lipoprotein findings. (6, p. 279-280, my emphasis)

The importance of this is that this evidence anticipated Peter Kuo’s “discovery” of carbohydrate-sensitive hyper(tri)glyceridemia (7) and its reversal with a low-carbohydrate diet by nine years (Figures 6 and 7 in reference 8).

In his conclusions Gofman wrote:

The increase in risk of future myocardial infarction associated with elevation of lipoproteins of the Sf° 20-400 lipoprotein classes provides the basis for a rational application of dietary measures in this disease … . Dietary carbohydrate intake is a prime factor controlling the serum level of the Sf° 20-100 and Sf° 100-400 lipoprotein classes. Restriction of dietary carbohydrates can provoke marked falls in the serum level of these lipoproteins … . The serum cholesterol measurement can be a dangerously misleading guide in evaluation of the effect of diet upon the serum lipids … . Rational management of patients with coronary heart disease or of individuals attempting to avoid coronary disease depends upon knowledge of the lipoprotein distribution in the individual patient. (6, p. 282-283)

Elsewhere Gofman wrote: “Neglect of [the carbohydrate factor] can lead to rather serious consequences, first in the failure to correct the diet in some individuals who are very sensitive to the carbohydrate action; and second, by allowing certain individuals sensitive to the carbohydrate action to take too much carbohydrate as a replacement for some of their animal fats” (9, p. 156-157).

In one of his last publications, a 1960 editorial, he again emphasized his concern about the carbohydrate factor:

Several investigators have shown that a low-fat high-carbohydrate diet produces opposite trends in the blood cholesterol and the blood lipid levels. The cholesterol level falls because the low fat diet depresses the level of the cholesterol rich Sf° 0-20 lipoproteins. The triglyceride level rises because the high carbohydrate intake elevates the level of the triglyceride-rich Sf° 20-400 lipoproteins. Both the triglyceride-bearing and cholesterol-bearing lipoproteins have been associated with the development of coronary disease. It therefore behoves the physician utilizing the dietary approach to understand the likelihood that a focus on the fat intake without an appreciation of the effect of carbohydrate intake will not lower all the blood lipids associated with the development of coronary heart disease. (10, p. 83)

Blood lipids and human atherosclerosis

https://www.scribd.com/doc/28131415/Kekwick-Pawan-1956-Lancet

https://sci-hub.tw/https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(56)91691-9/fulltext

MANY different types of diet have been successfully used to reduce weight in those considered obese. The principle on which most of them are constructed is to effect a reduction of calorie intake below the theoretical calorie needs of the body. Experience with these patients has suggested, however, that this conception may be too rigid. Many of them state that a very slight departure from the strict diet which can hardly affect calorie intake, results in them failing to lose weight for a time. Though it is realised that evidence from such patients is notoriously inaccurate owing to their approach to this particular condition, it is too constant a belief among them to be entirely discarded. Furthermore, most of the diets in common use not only restrict the intake of calories but also radically alter the proportions provided by protein, fat, and carbohydrate. In this country a healthy sedentary person may be supposed to consume some 2200 calories daily, made up of about 70 g. of protein, 60 g. of fat, and 350 g. of carbohydrate : protein supplies 12% of the calories, fat 24%, and carbohydrate 64%. On most reducing diets, however, the carbohydrate and fat will be restricted while the protein remains about the same ; and in a diet yielding 1000 calories protein may provide 30%, fat 37%, and carbohydrate 33%. Finally, Lyon and Dunlop (1932) observed that patients on isocaloric reducing diets lost weight more rapidly when the largest proportion of the calories was supplied by fat than when it was supplied by carbohydrate. Anderson (1944) attributed these findings to the different amounts of salt (causing water retention) in the diets used by these workers. More recently, Pennington (1951, 1954) has recommended high-fat diets in the treatment of obesity. It therefore seemed important to establish which factor has the greater effectrestriction of calories, or alteration in the proportions of MANY different types of diet have been successfully used to reduce weight in those considered obese. The principle on which most of them are constructed is to effect a reduction of calorie intake below the theoretical calorie needs of the body. Experience with these patients has suggested, however, that this conception may be too rigid. Many of them state that a very slight departure from the strict diet which can hardly affect calorie intake, results in them failing to lose weight for a time. Though it is realised that evidence from such patients is notoriously inaccurate owing to their approach to this particular condition, it is too constant a belief among them to be entirely discarded. Furthermore, most of the diets in common use not only restrict the intake of calories but also radically alter the proportions provided by protein, fat, and carbohydrate. In this country a healthy sedentary person may be supposed to consume some 2200 calories daily, made up of about 70 g. of protein, 60 g. of fat, and 350 g. of carbohydrate : protein supplies 12% of the calories, fat 24%, and carbohydrate 64%. On most reducing diets, however, the carbohydrate and fat will be restricted while the protein remains about the same ; and in a diet yielding 1000 calories protein may provide 30%, fat 37%, and carbohydrate 33%. Finally, Lyon and Dunlop (1932) observed that patients on isocaloric reducing diets lost weight more rapidly when the largest proportion of the calories was supplied by fat than when it was supplied by carbohydrate. Anderson (1944) attributed these findings to the different amounts of salt (causing water retention) in the diets used by these workers. More recently, Pennington (1951, 1954) has recommended high-fat diets in the treatment of obesity. It therefore seemed important to establish which factor has the greater effectrestriction of calories, or alteration in the proportions of protein, fat, and carbohydrate in the diet.

Discussion 

If these observations are correct, there seems to be only one reasonable explanation-namely, that the composition of the diet can alter the expenditure of calories in obese persons, increasing it when fat and protein are given, and decreasing it when carbohydrate is given. This is not surprising as regards protein, whose specific dynamic action has long been recognised. It is, however, surprising as regards fat, whose action in this respect seems to be even greater than that of protein. Direct confirmation of such altered metabolism is hard to obtain. The B.M.R., for example, is measured at a time of day and under .other conditions specifically designed to eliminate the effect of diet or reduce it to a minimum. In some patients the B.M.B. was measured at the beginning and at the end of each dietary period. Table vin shows that neither variation in calories nor variation of the composition of the diet with a constant intake of calories significantly changed the B.M.R. during these short dietary periods.

Summary 

1. Loss of weight can be successfully achieved in obese patients by numerous diets, most of which restrict calorie intake. At the same time almost all such diets alter the proportion of protein, carbohydrate, and fat as compared with the normal, restricting carbohydrate and fat in particular. It seemed desirable to investigate which factor was of the greatest importance in weight reduction-calorie restriction or alteration in the composition of the diet. 

2. The rate of weight-loss has been shown to be proportional to the deficiency in calorie intake when the proportions of fat, carbohydrate, and protein in the diet are kept constant at each level of calorie restriction. 

3. When calorie intake was constant at 1000 per day, however, the rate of weight-loss varied greatly on diets of different composition. It was most rapid with high-fat diets ; it was less rapid with high-protein diets ; and weight could be maintained for short periods on diets of 1000-calorie value given chiefly in the form of carbohydrate. 

4. At a level of intake of 2000 calories per day, weight was maintained or increased in four out of five obese patients. In these same subjects significant weight-loss occurred when calorie intake was raised to 2600 per day, provided this intake was given mainly in the form of fat and protein. 

5. No defect in absorption of these experimental diets occurred to account for the weight-loss. There was neither loss of body-protein stores nor of carbohydrate stores to a degree which significantly contributed to the reduction in weight. 

6. The weight lost on these diets appeared to be partly derived from the total body-water (30-50%) and the remainder from body-fat (50-70%). 

7. As the rate of weight-loss varied so markedly with the composition of the diets on a constant calorie intake, it is suggested that obese patients must alter their metabolism in response to the contents of the diet. The rate of insensible loss of water has been shown to rise with high-fat and high-protein diets and to fall with highcarbohydrate diets. This supports the suggestion that an alteration in metabolism takes place.

A third famous clinical trial that is cited again and again is the Finnish Mental Hospital study. I first heard about this study from a top nutrition expert who assured me that it was really “the best possible proof” that saturated fat is unhealthy.

In 1958, researchers seeking to compare a traditional diet high in animal fats to a new one high in polyunsaturated fats selected two mental hospitals near Helsinki. One they called Hospital K and the other, Hospital N. For the first six years of the trial, inmates at Hospital N were fed a diet very high in vegetable fat. Ordinary milk was replaced with an emulsion of soybean oil in skim milk, and butter was replaced by a special margarine high in polyunsaturated fats. The vegetable oil content of the special diet was six times higher than in a normal diet. Meanwhile, inmates of Hospital K ate their regular fare. Then the hospitals swapped, and for the next six years, Hospital K inmates got the special diet while Hospital N returned to their normal one.

In the special-diet group, serum cholesterol went down by 12 percent to 18 percent, and “heart disease was halved.” This is how the study is remembered and is the conclusion that the study directors, Matti Miettinen and Osmo Turpeinen, themselves drew. In a population of middle-aged men, they said, a diet low in saturated fats “exerted a substantial preventive effect upon coronary heart disease.”

But a closer look reveals a different picture. Heart disease incidence (which the investigators defined as deaths plus heart attacks) did go down dramatically for the men at Hospital N: there were sixteen such cases among men on the normal diet compared to only four on the special diet. But the difference found in Hospital K was not significant. Nor was any difference observed among the women. The biggest problem with the study, however, was that, like the subjects in the LA Veterans Trial, its population was a moving target. With admissions and discharges over the years, the composition of the groups changed by half. A shifting population means that an inmate in the group who died of a heart attack might have been admitted three days earlier and the death would have had nothing to do with his diet; and, vice versa, a patient who was released might have died soon thereafter but would not have been recorded in the study.

This and other design problems were so great that two high-level NIH officials together with a professor at George Washington University felt moved to criticize the study in a letter to The Lancet asserting that the authors’ conclusions were too statistically weak to be used as any kind of evidence for the diet-heart hypothesis. Miettinen and Turpeinen acknowledged that their study design was “not ideal,” including the fact that the study population was far from stable, but asserted in their defense that a perfect trial would be “so elaborate and costly . . . [that it] may perhaps never be performed.” Their imperfect trial, meanwhile, would have to stand: “we do not see any reason to change or modify our conclusions,” they wrote. The research community accepted this “good-enough” reasoning, and the Finnish Mental Hospital study earned a spot as one of the linchpins of evidence for the diet-heart hypothesis.

Nina Teicholz - Page 77