Diet-Heart: The Role of Vegetarian Diets in the Hypothesis

A recent publication from the EPIC-Oxford cohort with 15,000 vegetarians and 30,000 non-vegetarians found that the vegetarians had a 32% lower risk of hospitalization or death from coronary heart disease.1 These findings are consistent with a previous meta-analysis of 5 cohort studies with 48,000 non-vegetarians and 28,000 vegetarians which found that lacto-ovo vegetarians had a 34% lower risk of fatal coronary heart disease compared to regular meat eaters.2 These findings remained significant even after adjusting for non-dietary factors and alcohol intake. In addition, in each of these 6 cohort studies, vegetarians and non-vegetarians shared a similar interest in healthy lifestyles or were of a similar religious background, therefore limiting the number of potential confounders that could have obscured these findings.

This review will focus on the evidence from randomized controlled trials and long-term prospective cohort studies addressing the influence of vegetarian dietary patterns on the risk of coronary heart disease, and how these findings have contributed to the current understanding of the diet-heart hypothesis. This review will also consider the question as to whether the simple definition of a vegetarian diet is meaningful in the context of a healthy diet to reduce the risk of coronary heart disease. Regarding cohort studies, this review will primarily consider the influence of lacto-ovo vegetarian diets on the risk of coronary heart disease due to limited evidence from these studies addressing the long-term adherence to other types of vegetarian diets. A more informative analysis maybe possible after a longer follow-up of the on-going and largest cohort of vegetarians, the Adventist Health Study 2, which has observed more favorable cardiovascular risk factors within different vegetarian subgroups, particularly vegans.3

Skeptics of the diet-heart hypothesis often suggest that there are no plausible mechanisms in which a vegetarian dietary pattern can lower the risk of coronary heart disease, and often ascribe the observed benefits of vegetarianism to factors other than the avoidance of animal foods. Typically either ignored or downplayed by these skeptics is the convincing evidence that vegetarian dietary patterns can lower LDL cholesterol, which is an established risk factor for coronary heart disease.4 5 6

Establishing Causation

In the 6 cohorts described, a sizable portion of the non-vegetarians consumed significantly less meat than the general population. For example, in the EPIC-Oxford cohort, most participants were either occasional meat eaters, or affiliated with vegetarians or with vegetarian societies. Also, a potential problem in these cohorts is that measurement error of usual dietary intake of meat may have resulted in misclassifying a sizable portion of non-vegetarians as vegetarians. For example, in the Health Food Shoppers Study included among these cohorts, a validity assessment of the survey used to classify the participants vegetarian status suggested that 34% of the participants classified as vegetarians actually consumed meat. This data strongly suggests a much smaller than otherwise expected difference in dietary intake between the groups classified as vegetarians and non-vegetarians, potentially masking a stronger protective effect of a vegetarian dietary pattern.7

Another potential problem in these cohorts is the possibility that a sizable portion of participants classified as vegetarians stopped consuming meat or other animal foods in response to deteriorating health or unfavorable risk factors that would ultimately become life-threatening. This has been referred to as the ‘sick quitter effect’, which is known to mask the protective effect of smoking cessation in studies due to participants quitting in response to deteriorating health.8 In regards to diet, it has been documented that people tend to lower intake of saturated fat and cholesterol in response to unfavorable serum cholesterol levels, which has actually been shown to bias the association between diet and serum cholesterol in the opposite direction than expected [reviewed previously]. This bias is known as reverse causation, and may explain why in the Adventist studies that participants with short-term adherence (less than 5 years) to a vegetarian diet experienced an increased risk of mortality, while participants with long-term adherence (more than 17 years) to a vegetarian diet experienced a significantly lower risk of mortality compared to non-vegetarians (Fig. 1).8

Figure 1. Life expediencies for long-term vegetarians and short-term vegetarians in the Adventist Health Study and Adventist Mortality Study*

These factors should be taken into account when testing for causality as failing to do so may mask a protective effect of a vegetarian dietary pattern. One of the most important factors in order to establish causality is to address whether the association is biologically plausible, which in this case requires examining how vegetarian dietary patterns can influence cardiovascular risk factors.

Serum Lipids

In 1922, de Langen published what was perhaps the first study that provided strong evidence that a vegetarian dietary pattern favorably effects serum cholesterol when he placed five native Indonesians consuming a rice-based vegetarian diet into a metabolic ward and shifted the diet to one rich in meat, butter and egg fats, resulting in significant elevations in serum cholesterol [reviewed previously]. In 1954, Hardinge and Stare published what was perhaps the first observational study comparing the serum lipids of vegetarians to non-vegetarians in an affluent population. Lacto-ovo vegetarians and especially vegans had significantly lower serum cholesterol concentrations despite relatively high intakes of saturated fat.9 10 In 2009, Ferdowsian and Barnard published a systematic review of 27 randomized controlled trials and observational studies on either vegetarian or predominantly plant-based diets, and found that certain plant-based dietary patterns can lower LDL cholesterol by up to 35%, independent of changes to body weight (Figs 2, 3).4

Figure 2. Effects of plant-based diets in normolipidemic individuals: Randomized controlled trials*

Figure 3. Effects of plant-based diets in hyperlipidemic individuals: randomized controlled trials*

In the Lifestyle Heart Trial lead by Dr. Dean Ornish, intensive lifestyle changes including a vegetarian diet that allowed a small amount of non-fat dairy foods successfully reduced LDL by 37.2%, angina episodes by 91% and regressed coronary atherosclerosis in the experimental group after 1 year. In both the experimental and control group LDL and total cholesterol was correlated with changes in coronary atherosclerosis.11 

A recent meta-analysis of statin based randomized controlled trials found that lowering LDL cholesterol to less than 100 mg/dl was associated with regression of coronary atherosclerosis in participants with coronary heart disease.12 Similarly, a recent mendelian randomization study of over 100,000 individuals found that genetically-predicted higher LDL cholesterol was associated with greater carotid atherosclerosis, but there was no causal association for HDL cholesterol and triglycerides.13 Consistent with these lines of evidence, it has been consistently demonstrated in experiments on non-human primates that coronary atherosclerosis induced by feeding of dietary cholesterol and saturated fat can be reversed by a cholesterol lowering diet [reviewed previously]. Therefore the preponderance of evidence strongly suggests that the findings from the Lifestyle Heart Trial of a correlation between lower LDL cholesterol and regression of coronary atherosclerosis was causal, and can at least partly be explained by the intervention of a cholesterol lowering vegetarian diet. 

In the meta-analysis of 5 cohorts it was found that in a sample of participants from 3 of the cohorts that serum cholesterol ranged from between 13 mg/dl to 23 mg/dl lower in the vegetarians compared to non-vegetarians. The researchers suggested that the difference in serum cholesterol could have largely explained the difference in fatal coronary heart disease between these groups.2 In the EPIC-Oxford cohort, serum lipids and blood cholesterol were measured in a sample of the participants. Non-HDL cholesterol was 17 mg/dl lower and systolic blood pressure was 3.3 mmHg lower in the vegetarians compared to the non-vegetarians. The researchers calculated that the differences between these two risk factors alone would expect to lower the risk of coronary heart disease by 24%, which is less than the observed 32% lower risk.1 

The researchers from the EPIC-Oxford cohort suggested that the high ratio of polyunsaturated fat to saturated fat largely explained the difference in non-HDL cholesterol between groups, but failed to mention that a number of other plant based nutrients may have also contributed to this difference.1 It has been repeatedly demonstrated in randomized controlled trials that intake of plant protein, particularly from soy, plant sterols, and dietary fiber can also lower LDL cholesterol.14 15 16 In fact in many of the interventions with the greatest diet induced decrease in LDL cholesterol, the decrease could not be explained by changes in dietary fat and cholesterol intake alone, but also likely due to the additive effects of a number of plant based nutrients.17 18 19

It is clear that the LDL cholesterol levels of the vegetarians in these cohort studies far exceeded optimal levels, likely due to a diet deficient in whole plant foods and still relatively rich in animal foods. If these vegetarians had adhered to a much more phytonutrient rich cholesterol lowering diet such as that used in the aggressive dietary experiments, an even significantly lower risk of coronary heart disease may have been observed. Plant Positive recently referred to this informative statement made by Michael Brown and Joseph Goldstein the year before they were awarded the Nobel Prize for their research on the LDL-receptor:20

If the LDL-receptor hypothesis is correct, the human receptor system is designed to function in the presence of an exceedingly low LDL level. The kind of diet necessary to maintain such a level would be markedly different from the customary diet in Western industrial countries (and much more stringent than moderate low-cholesterol diets of the kind recommended by the American Heart Association). It would call for the total elimination of dairy products as well as eggs, and for a severely limited intake of meat and other sources of saturated fat.

Evidence from over one hundred randomized controlled trials has proven beyond plausible doubt that changing from a diet rich in animal foods to a dieter richer in certain whole plant foods significantly lowers LDL cholesterol.4 14 15 16 21 22 Similarly, evidence from over one hundred randomized controlled trials has proven beyond plausible doubt that lowering LDL cholesterol decreases the risk of coronary heart disease and all-cause mortality.5 6 Therefore consistent with the diet-heart hypothesis, there is convincing evidence that an appropriately designed vegetarian diet would reduce the risk of coronary heart disease, and that this reduction can at least be partly explained by lower LDL cholesterol.

Beyond Cholesterol

There are likely a number of dietary related factors that contribute to the lower risk of coronary heart disease observed in people with vegetarian dietary patterns that cannot entirely be explained by lower LDL cholesterol. For example, it has been shown in randomized controlled trials that a number of plant based nutrients can lower blood pressure, which may explain the lower blood pressure observed in vegetarians in a number of observation and intervention studies [reviewed previously]. Furthermore, appropriately designed vegetarian diets likely reduce the risk of being overweight and developing type II diabetes.23 24 25 26 27 Other factors such as reduced oxidation of LDL and changes in blood clotting have also been suggested as explanations for the lower risk of coronary heart disease observed in vegetarians.28 29

Perhaps the main concern with an inappropriately designed vegetarian diet is that it may result in elevated homocysteine due to an inadequate intake of vitamin B12, suggested to be a risk factor for coronary heart disease. Although deficiency of vitamin B12 is rarely observed in some populations in the developed world consuming a predominantly plant based diet, perhaps due to regular contact with vitamin B12 producing bacteria, health authorities strongly recommended that vegetarians diets be supplemented regularly with a bioavailable source of vitamin B12.30 31 Jack Norris, RD regularly posts informative reviews on the latest research on vitamin B12 intake and homocysteine, and updates his recommendations for vitamin B12 supplementation in response to new findings.

In all of the cohort studies, and perhaps most intervention studies carried out on vegetarians, there is little doubt that only very few vegetarians were actually consuming a diet predominantly based on whole plant foods, and as expected although these vegetarians experienced a significantly lower risk of coronary heart disease than their omnivorous counterparts, they still experienced a substantial residual risk of coronary heart disease.32 In Dr. Caldwell Esselstyn’s more recent decade long study (pending publication) of around 200 patients that were advised to consume a whole foods, plant-based diet, it was found that recurrent cardiac events only occurred in 0.5% of adherent participants. This is an approximately 40 fold lower risk than achieved in other dietary or statin based trials, strongly suggesting that these results can only partially be explained by the use of LDL cholesterol lowering medication [reviewed previously]. This is an excellent example of how a whole foods, plant-based diet can confer significant benefit over-and-above favorable changes to traditional risk factors.

Caldwell Esselstyn on making heart attacks history

The definition of a vegetarian diet typically only defines which type of animal foods are restricted and not the quantity and quality of plant foods consumed. As all vegetarian diets are not created equal, studies on vegetarians may only provide limited information of the influence a more nutrient dense vegetarian dietary pattern on the risk of coronary heart disease.33 The restriction of certain animal foods however may encourage at least a modest increase of intake of high quality plant matter, including fruits, vegetables, whole grains, legumes and nuts in order to make up for calories and certain nutrients otherwise consumed from animal foods. Nevertheless, even the studies examining less than optimal vegetarian diets may contribute more to the knowledge of optimal dietary patterns than many studies on homogenous populations due to greater differences in intake of specific foods and nutrients. Vegetarian diets should be designed according to not only which animal foods are restrict, but also the quality of plant foods consumed in order to minimize and preferably eliminate the risk of developing coronary heart disease. There is very strong evidence that such a diet would also lower the risk of numerous other chronic and degenerative diseases.

Diet-Heart Posts

Part I - Diet-Heart: A Problematic Revisit
Part II - Diet-Heart: Saturated Fat and Blood Cholesterol
Part IV - Cracking Down on Eggs and Cholesterol
Part V - Cracking Down on Eggs and Cholesterol: Part II

Please post any comments in the Discussion Thread.

Traditional Diets in Asia Pacific and Implications for Health, and the History of Disease Prevention

I previously reviewed the health of a number of primitive populations, including evidence from numerous preserved Inuit mummies that predate western contact, demonstrating that without consuming a morsel of modern processed food throughout their entire lifetimes, the traditional Inuit developed atherosclerosis, osteoporosis, breast cancer and numerous other chronic and degenerative diseases that are evidently partly explained by their carnivorous diet. The diets and incidence rates of disease in traditionally living populations can provide implications for disease prevention, which can be used to supplement the current knowledge of the impact of dietary and lifestyle factors on diseases from other forms of evidence, including observational, laboratory and clinical studies in order to achieve maximum protection.

The Nomadic Kirghiz and Dzungarian Plainsmen

In the 1920’s, Kuczynski reported on the nomadic plainsmen of the Kirghiz and Dzungarian Steppes in Central Asia and estimated that they consumed an astonishing 20 liters of fermented mare’s milk, and between 10 to 20 pounds (4.5 to 9kg) of meat per day.1 2 Lack of systematically documented dietary data however suggests that these findings could have been slightly overestimated, as evidently has been the case for early researcher's estimates of the Masai's intake of milk, meat, cholesterol and total energy.3 Nevertheless, these nomadic plainsmen consumed enormous quantities of organic pasture raised animals foods, perhaps among the largest ever documented. 

Kuczynski noted that these nomads, evidently largely as a result of their diet experienced a high incidence of obesity, premature extensive atherosclerosis, contracted kidney, apoplexy, arcus senilis, and gout.4 5 In specific, Kuczynski asserted that:2

They get arteriosclerosis in an intense degree and often at an early age as shown by cardiac symptoms, nervous disordes, typical changes of the peripheral vessels, nephrosclerosis and, finally, apoplectic attacks. Even in men thirty-two years old I frequently observed arcus senilis.

The Nomadic Kirghiz Plainsmen

Kuczynski compared the diet and health of these nomadic plainsmen with Russian peasants, who had an apparent low incidence of these conditions while consuming a vastly different diet. Their diet was based on soup, bread, pickles, potatoes, with very little meat, but consumed large amounts of alcohol.5 In comparison to the nomadic plainsmen, Kuczynski asserted in regards to these Russian peasants that:2

Repeatedly I found at the age of about seventy years no signs of arteriosclerosis, no arcus senilis, etc.; they were men of youthful appearance, with no grey in their still abundant growth of hair, and with their sexual functions still intact.

For more information regarding the health of nomadic populations, Don Matesz has previously posted an informative review addressing the high rates of obesity, cardiovascular disease and cancer among the modern, still largely nomadic Mongols consuming diets rich in organic pasture raised animal foods.

The Native Indonesians 

In 1916, Cornelis D. de Langen observed that the native Javanese, the indigenous people of the Indonesian island of Java who consumed a diet which was 'mainly vegetarian with rice as the staple, that is very poor in cholesterol and other lipids', had very low levels of serum cholesterol and incidence of coronary heart disease.6 Conversely, de Langen observed that their Javanese counterparts who worked as stewards on Dutch passenger ships and consumed traditional cholesterol laden Dutch food had much higher levels of serum cholesterol and incidence of coronary heart disease.7 Blackburn noted in regards to de Langen's classical findings from Indonesian hospitals that:6 

Pursuing this clinical impression, he reviewed 10 years of admissions charts and found only 5 cases of acute gallbladder disease among many thousands of patients passing through the medical wards and only 1 case on the surgery service among 70,000 admissions surveyed. 

Following these observations, de Langen stated in regards to the rarity of vascular disease among the Javanese that:6 

thrombosis and emboli, so serious in Europe, are most exceptional here. This is not only true of internal medicine, but also on surgery, where the surgeon needs take no thought of these dreaded possibilities among his native patients. Out of 160 major laparotomies and 5,578 deliveries in the wards, not a single case of thrombosis or embolism was seen.

These findings closely resemble observations from over 15,000 operations carried out in Norway during the period around World War II, where the changes in incidence of post-operative thrombosis was consistent with changes in the availability of cholesterol laden foods [reviewed previously]. Blackburn also noted in regards to de Langen’s 1922 experiment, which is regarded as apparently the first ever systematic feeding experiment of diet in relation to serum cholesterol levels, that:6

…he found an average 40 mg/dl increase in cholesterol in 5 Javanese natives who were shifted from a rice-based vegetarian cuisine to a 6-week regimen high in meat, butter, and egg fats.

These findings were reproduced decades later in hundreds of tightly controlled feeding experiments, firmly establishing that dietary cholesterol and isocaloric replacement of complex carbohydrates and unsaturated fat by saturated fat raises LDL and total cholesterol in humans.8

In 1908, Williams noted in regards to the findings of early doctors who practiced in Indonesia and the rarity of cancer among the Javanese that:9

...a single example of a malignant tumour in a native being esteemed a great rarity.

The Okinawans

In 1949, a government survey found that in Okinawa, known to have the highest concentration of centenarians in the world, the population consumed about 85% of their total energy intake from carbohydrates, with the staple at the time being the sweet potato. The dietary survey also showed that the Okinawans derived about 9% of their energy intake from protein and less than 4% of energy from all sources of animal foods combined (Table 1).10 These findings were largely consistent with previous dietary surveys dating back to 1879 and 1919.11

In 1946, Steiner examined autopsies of 150 Okinawans, of which 40 were between the age of 50 and 95. Steiner noted only seven cases of slight aortic atherosclerosis, all of which were found in those over the age of 66, and only one case of calcification in the coronary arteries. In 1946 Benjamin reported similar findings from a study of 200 autopsies on Okinawans.12

Even in 1995 the observed rates of coronary heart disease and dietary related cancers, including that of the colon, prostate, breast and ovarian in Okinawa were not only many fold lower than that of the United States, but even significantly lower than that of mainland Japan.10 This may be explained by the likelihood that these diseases are slowly progressive diseases and therefore the more traditional Okinawan diet consumed several decades prior would still have played a major role in the development and manifestation of these diseases.13 14 15

The Papua New Guineans

The Papua New Guineans traditionally subsisted on a plant based diet, of which a number of varieties of sweet potatoes typically supplied over 90% of dietary intake. They also grew a number of other crops including corn, as well as sugar cane which was consumed as a delicacy. Pig feasts are organised a few times a year, but at which pork is not consumed in excess of 50 grams. A dietary survey on the Papua New Guineans highlanders estimated that carbohydrate accounted for 94.6% of total energy intake, among the highest recorded in the world. Total energy intake was adequate, however only 3% of energy intake was derived from protein (25g for men and 20g for women), yet there was no evidence of dietary induced protein deficiency or anemia. Furthermore, this surveyed population was described as being muscular and mostly very lean, physically fit and in good nutritional state.16 17 They also drank 'soft' water which is considered a risk factor for cardiovascular disease. It was estimated that tobacco was smoked by 73% of males and 20% females. Also, the highlanders spend up to twelve hours a day inside a smoke-filled house due to centrally placed open wood fires with little ventilation and no chimneys in their homes, resulting in a very high exposure to hazardous smoke in this population.16 

Despite cardiac risk factors including high exposure to smoke and soft drinking water, a number of authors observed a great rarity of incidence of atherosclerosis, coronary heart disease and stroke among the traditional Papua New Guineans, but also noted an increase in incidence paralleling the Westernization of the nation. In 1958, Blackhouse reported on autopsies of 724 individuals between 1923 and 1934 and found no evidence of heart attack incidence and only one case of slight narrowing of the coronary arteries. However, it has been suggested that this study was selective as only a small portion of the autopsies were performed on females or the elderly. In 1969, Magarey et al. published a report on the autopsy results of 217 aortas and found a great rarity of atherosclerosis. The authors noted that the prevalence and severity of atherosclerosis was less than had been reported in any previously investigated population.18 In 1973, Sinnett and Whyte published findings from a survey of 779 highlanders using electrocardiograms among other methods, and found little probable evidence of coronary heart disease, and no clinical evidence of diabetes, gout, Parkinson’s disease, or any previous incidence of stroke.16

For a population that consumed virtually the highest intake of carbohydrates out of any population to also have virtually the lowest incidence of atherosclerosis and diabetes ever recorded highlights the vital importance of the health properties of specific carbohydrate rich foods. These findings further question certain 'carbohydrate-induced dyslipidemia' hypotheses, emphasized by certain researchers, who perhaps intentionally do not always take the quality of carbohydrate rich foods into careful consideration.19

In 1900, Sir William MacGregor reported in the Lancet in regards to the observed rarity of cancer among the native Papua New Guineans, asserting that:20

For nine and a half years I never saw a case in British New Guinea ; but at the end of that time there occurred an example of sarcoma of the tibia in a Papuan, who had for seven or eight years lived practically a European life, eating tinned Australian meat daily.

In 1974, Clezy brought to attention the rarity of mortality from colorectal cancer among the Papua New Guineans, for which the observed annual rate per 100,000 was 0.6 for men and 0.2 for women. These rates were 100 fold lower than that of many developed nations during the same time period, although this could have been in part explained by underdiagnosis.17

Even in more recent statistics after modest changes towards a western diet, the Papua New Guineans still had among the lowest rates of hip fractures in the world, which Frassetto et al. observed was more than 50 fold lower than that of the Scandinavian nations.21 Although these researchers ascribed the worldwide differences in rates of hip fractures to the ratio of vegetable to animal protein, evidence from prospective cohort studies and randomized controlled trials, as well as experimental animal models suggests that saturated fat may be at least as great, if not an even greater contributor to poor bone health.22 23 24 25 26

The Tokelauans and Pukupukans

In the video below, Plant Positive reviews the diet and health of the Tokelauans and Pupukans whose diet is rich in coconuts, as well as the diet and health of other South Pacific island populations.

The Tokelauns, and more on the Masai

A 1908 Review on the Causation of Cancer

In 1908, William Roger Williams published an extensive review of the medical literature and documentations from a large number of populations around the world before the widespread use of intensive farming practices. Williams observed that compared to the nations with carnivorous dietary patterns there was a significantly lower incidence of cancer among the nations subsisting predominantly on a plant-based diet. He also noted that groups within nations with carnivorous dietary patterns that largely abstained from animal foods, such as nuns, monks, slaves and prison inmates had a similar low incidence of cancer.9

Williams reported on the cancer rates of the area inhabited by the Gaucho of the Argentina Pampas, another nomadic population that subsisted predominantly on organic pasture raised animal foods, noting that:9

Cancer is commoner in Argentina which comprises the pampas region inhabited by the Gauchos, who for months subsist entirely on beef, and never touch salt than in other parts of South America. On the other hand, among the natives of Egypt, who are of vegetarian habits, and consume immense quantities of salt, cancer is almost unknown.

The Nomadic Argentinean Gaucho

These findings are largely consistent with modern reviews from prominent health authorities, including the report from the expert panel of the World Cancer Research Fund that produced convincing evidence that red meat is a major risk factor for cancer and that dietary fiber provides significant protection [reviewed previously]. However, these findings raise questions as to whether the Egyptians plant-based diet that is centered on wheat provides significant protection against salt sensitive cancers. In regards to the cancer incidence among the different ethnic groups of Egypt, Williams quoted from a 1902 publication in the British Medical Journal authored by Dr. F. C. Madden of Cairo that:9

The consensus of opinion among medical men in Egypt is, that cancer is never found either in male or female, among the black races of that country. These include the Berberines and the Sudanese, who are all Mussulmans, and live almost entirely upon vegetarian diet. Cancer is fairly common, however, among the Arabs and Copts, who live and eat somewhat after the manner of Europeans.

Williams also observed that the increases in incidence of cancer within populations coincided with increases in animal food intake. For example, in regards to the observed marked increase cancer incidence among the Native American’s after gaining easier means to hunt buffaloes, Williams asserted:9 

In this connexion it should be borne in mind, that in their primitive condition these savages had no horses and no firearms ; consequently it was no easy matter for them to kill the fleet buffaloes, on which they mainly depended for subsistence ; hence, in their primitive condition, they were generally less well nourished than when, after contact with whites, they had, by the acquirement of horses and firearms, become assured of a constant supply of their favourite food [coinciding with an increase in cancer incidence].

Historical Overview of the Reversal of Chronic Diseases 

In 1903, John Harvey Kellogg, the founder of the Kellogg Company asserted:

Dr John Bell, who was, about a hundred years ago [now two hundred years ago], professor in a leading college in London, wrote that a careful adherence to a vegetarian dietary tended to prevent cancer. He also stated that in some cases persons who had already acquired cancer had been cured by adherence to a non-flesh dietary. When I first read this book, I did not agree with the author; I thought he was mistaken; but I have gradually come to believe that what he says on this subject is true. 

These findings are consistent with Dr. Dean Ornish’s on-going Prostate Cancer Lifestyle Trial which has already produced strong suggestive evidence of reversal of prostate cancer growth.27 These findings are also consistent with experiments showing that dietary restriction of methionine, typically found in higher quantity and bioavailability in protein rich animal foods compared to unprocessed plant foods can inhibit and even reverse human tumor growth in animal models and in culture [reviewed previously]. 

Publications producing evidence of regression of atherosclerosis in humans dates back to the periods following both the World Wars in Scandinavia and the low countries of Europe, where a number of researchers found a trend between changes in intake of cholesterol laden foods throughout periods of food scarcity in the war and changes in the severity of atherosclerosis at autopsy [reviewed previously]. Several decades later during the 1960's and 70's experiments involving modest dietary and lifestyle changes or drugs produced the first angiographic evidence of modest regression of atherosclerosis.28

In experimental animal models, the first suggestive evidence of regression of atherosclerosis came from rabbit models produced by Anichkov and colleagues during the 1920’s. Beginning from 1957 much more substantial evidence of regression was produced in rabbits and then later replicated in a number of other species, including non-human primates.29 30

In 1970, Armstrong et al. published the first study producing substantial evidence of regression of atherosclerosis in non-human primates. Armstrong et al. induced severe autopsy proven atherosclerosis in Rhesus monkeys resembling that of human atherosclerosis by feeding a diet with 40% of energy from egg yolks for 17 months. The egg yolks were then removed from the diet of the remaining monkey’s and replaced by either linoleic acid rich chow or sugar rich low fat chow for three years reducing serum cholesterol to 140 mg/dl and resulting in a marked regression of atherosclerosis.28 31 These results were later reproduced in well over a dozen experiments in various primate species in which severe atherosclerosis was induced typically by feeding diets rich in dietary cholesterol and saturated fat and then reversed the process either by removing these atherogenic components, or by other means which significantly reduce serum cholesterol.30

During the late 1980’s, Dr. Dean Ornish and Dr. Caldwell Esselstyn began reversing atherosclerosis, and more importantly greatly decreased the number of reoccurring cardiac events in participants who adhered to a plant-based diet and often other lifestyle modifications.32 33 34 35 More recently Dr. Esselstyn has replicated his initial findings in around 200 participants over the period of a decade, with publication pending results showing a phenomenal success rate of a 99.5% reduction in reoccurring cardiovascular events [reviewed previously].

Caldwell Esselstyn on making heart attacks history

Please post any comments in the Discussion Thread. 

Diet, Blood Cholesterol, Blood Pressure and Risk of Stroke: Part II

In Part I I reviewed evidence showing that while randomized controlled trials found that lowering LDL cholesterol significantly reduces the risk of coronary heart disease, ischemic stroke and all-cause mortality, but has little appreciable effect on hemorrhagic stroke, prospective cohort studies found suggestive evidence that serum cholesterol, including LDL and possibly triglycerides and the risk of hemorrhagic stroke is modified by blood pressure. The largest meta-analysis of prospective studies found that while serum cholesterol was inversely associated with risk of hemorrhagic stroke mortality in participants with high blood pressure, in participants with near optimal or ‘physiological’ blood pressure, lower cholesterol was actually associated with a significantly reduced risk of hemorrhagic, ischemic and total stroke mortality. Furthermore another very large prospective study found suggestive evidence that the inverse association between cholesterol and risk of hemorrhagic stroke confined to participants with hypertension may not be causal but acts as a marker of binge drinking.

Taking this potential modification by blood pressure and risk of stroke into consideration, as blood pressure is universally high in developed nations among people in the age range most susceptible to stroke, this may result in biasing the results of studies towards finding a lower risk of stroke for dietary changes that raise cholesterol. Therefore this justifies considering this potential bias when evaluating the evidence regarding dietary changes and the risk of stroke.

Foods rich in fiber and flavonoids may lower blood pressure and risk of stroke*

Red Meat

Despite the possibility of the above mentioned bias, a recent meta-analysis of 6 prospective studies including >329,000 participants and >10,600 cases of stroke found that each per-day serving increase of fresh red meat and processed meat was associated with a 11% and 13% increased risk of stroke respectively, without heterogeneity among studies.1 The authors not only explained that these findings could partly be attributed to saturated fat, dietary cholesterol and sodium content in fresh red meat and processed meat, but also provided the following explanation regarding how these findings may be in part explained by intake of heme iron:

Moreover, red meat is a source of heme iron. It is well-known that iron is a redox-active metal that catalyzes the formation of hydroxyl free radicals in the Fenton reaction. High doses of iron may lead to oxidative stress, a state with increased peroxidation of lipids, protein modification, and DNA damage. If continued for a long time, oxidative stress induced by iron may lead to the development of many diseases, such as cardiovascular disease, type II diabetes, atherosclerosis, neurological disorders, and chronic inflammation.

Don Matesz previously posted an informative review addressing the evidence on the absorption animal and non-animal sources of iron and the risk of developing chronic and degenerative diseases. Similarly, Dr. Michael Greger reviewed the evidence of absorption of heme and non-heme iron and the associated risks (video below).

Risk Associated With Iron Supplements

Meat, in particular red meat intake has been consistently associated with an increased risk of weight gain in large prospective studies, suggesting that this meta-analysis may have underestimated the true association between red meat and risk of stroke, as all included studies adjusted for BMI.2 3 4 5 6 7 Furthermore, a recent meta-analysis of prospective studies found that body iron stores and intake of heme iron from meat, but not non-heme iron was associated with a significantly increased risk of developing type II diabetes, which in-turn increases the risk of stroke.8

Fish and Stress

Several recent meta-analyses of randomized controlled trials, including the highest quality double-blinded, placebo-controlled trials found no association between fish oil and risk of stroke, all other cardiovascular end points and all-cause mortality.9 10 Conversely, a recent meta-analysis of prospective studies including >402,00 participants and >10,500 cases of stroke found that fish intake was associated with a decreased risk of stroke in studies conducted in North America, but not in Europe and Asia.11 However, compared to the Asian and European cohorts, the participants in the North American cohorts may have been displacing fish with less healthful foods such as red meat which is a typical characteristic of North American cohorts, therefore possibly explaining these inconsistent findings.12 In addition, another recent study of >30,000 participants from the Stroke Belt in the U.S. not included in this meta-analysis found that fried fish was associated with a 2.8 fold increased risk of ischemic stroke.13

Another study on British adolescents whose diet was measured between 1937 and 1939 found that while childhood intake of vegetables cut the risk of developing stroke later in life in less than half, higher childhood intake of fish was associated with a two-fold increased risk of stroke.14 The researchers provided the following possible explanation for these findings:

A detrimental effect of higher fish intake on stroke risk would fit with temporal trends in fish consumption and stroke in the UK and Japan. It is also consistent with the suggestion that fish intake in early life may influence risk of stroke, particularly hemorrhagic stroke through an effect on membrane concentrations of arachidonic acid.

Perhaps another explanation for these findings is that fish contains high levels of mercury and other contaminants that may increase the risk of stroke and other neurological disorders, which adolescents maybe especially susceptible to.15 16

Uffe Ravnskov, the spokesman for The International Network of Cholesterol Skeptics responded to this study explaining his alternative hypothesis:17

Dear Editor,
To estimate children’s intake of fish from total household dietary intake is a daring enterprise. Most children hate fish because of the bones. Here is a likely scenario:
Father or mother: “There is no dessert before you have eaten up that fish!”
Therefore, if the figures aren’t a result of chance, they may rather reflect the effect of childhood stress rather than the result of a high intake of fish.

This attempt to downplay the results of this study seems to be somewhat desperate coming from someone who is considered to be one of the most prominent figures in the cholesterol skeptic community. Ravnskov’s claims have long been demonstrated as being faulty by prominent researchers.18 Plant Positive has also addressed a number of his faulty claims in the Primitive Nutrition Series.

Indeed prospective studies found that depression and perceived stress is associated with a modest increased risk of stroke and coronary heart disease respectively.19 20 However, the observed plummet of cardiovascular mortality in Scandinavia and the low countries of Europe during the World Wars casts doubt as to whether stress can be considered as a primary cardiovascular risk factor as opposed to significant dietary modifications and weight loss [reviewed previously]. This plummet was also observed in what can be arguably described as the most stressful environment in modern history, as the researchers from a landmark Israelian study explain:21

…physicians who survived the Nazi concentration camps reported that during the years of their imprisonment, they never encountered patients with myocardial infarctions or patients with anginal syndrome, even in persons over 50 years of age. Moreover, persons who were previously known to them as patients with atherosclerotic heart disease became free of clinical manifestations of their disease after losing considerable weight due to the conditions prevailing in the concentration camps.

Cocoa and Beverages

A meta-analysis of 5 prospective studies with >4,200 cases of stroke found that chocolate intake was associated with a decreased risk of stroke. As the researchers suggested, these findings are likely explained by nutrients found primarily in cocoa solids such as flavonoids and antioxidants, and therefore does not support an increased intake of other ingredients typically included in chocolate.22

A large meta-analysis of observational studies provided suggestive evidence that alcohol consumption is associated with a slightly lower risk of ischemic stroke but higher risk of hemorrhagic stroke.23 A meta-analysis of 11 prospective studies with >479,000 participants and >10,000 cases of stroke found that moderate coffee intake was associated with a modest decreased risk of stroke.24 In addition, a meta-analysis of 14 prospective studies with >513,000 participants and >10,000 cases of stroke found that tea intake was associated with decreased risk of stroke in a dose response matter, therefore making it likely the favorable beverage for stroke prevention.25

Fruits and Vegetables

A meta-analysis of 9 prospective studies including >257,000 participants and >4,900 cases of stroke found that fruit and vegetable intake provided significant protection against both ischemic and hemorrhagic stroke, and that optimal intake is above five servings per day.26 These findings are consistent with more recent large prospective studies, although some found suggestive evidence that the association was stronger for white fruits and vegetables, raw fruits and vegetables, cruciferous vegetables, citrus fruits and tomatoes.27 28 29 30 31

Fiber and Micronutrients

A very recent meta-analysis of 6 prospective studies including >314,000 participants and >8,900 cases of stroke found that a 10 g/day increment of dietary fiber was associated with a 12% reduction in stroke.32 In addition, a meta-analysis of 10 prospective studies including >268,000 participants and >8,600 cases of stroke found that an increment of 1000 mg/day of dietary potassium was associated with a 11% reduction of stroke.33 Furthermore, a meta-analysis of 8 prospective studies including >304,000 participants and >8,300 cases of stroke found that dietary potassium was associated with a decreased risk of stroke.34 There is also growing evidence that dietary flavonoids decrease the risk of stroke.35

These findings should be interpreted with caution as these nutrients maybe markers of other protective constituents in whole-plant foods. Increasing intake of these nutrients with supplements or fortified foods may provide little benefit, and therefore would be advisable to increase intake of whole-plant foods naturally rich in these nutrients.36

Regarding supplements, a meta-analysis of placebo controlled trials including >28,000 participants found that calcium supplements with or without vitamin D increased the risk of cardiovascular events, including stroke.37 Consistent with these findings a meta-analysis of prospective studies found that circulating calcium in >22,000 participants was associated with a significantly increased risk of total stroke.38 Conversely, this meta-analysis found that circulating vitamin D in >47,000 participants was associated with a significantly lower risk of stroke, consistent with suggestive evidence from a meta-analysis of randomized controlled trials that evaluated the efficacy of sunlight exposure.39

A meta-analysis of 12 studies with >225,000 participants and 3,100 cases of stroke found that high salt intake was associated with an increased risk of stroke.40 In addition, a recent large prospective study also found that dietary cholesterol was associated with an increased risk of stroke.41

Macronutrients

Although prospective studies have found that saturated fat, trans fat and animal protein are associated with an increased risk of coronary heart disease mortality, studies of these cholesterol raising macronutrients and the risk of stroke have been less consistent.42 43 44 This could be because as previously explained the association between serum cholesterol, which is typically raised by these nutrients and risk of stroke maybe modified by blood pressure. A limited number of studies have tested whether the association between macronutrient intake and the risk of stroke is modified by hypertension status, but not whether it is further modified by optimal compared to high normal blood pressure.

In the Nurses’ Health Study intake of trans-fat, saturated fat and animal protein was inversely associated with risk of hemorrhagic stroke. The researchers found that the inverse association for saturated fat was confined to women with a history of hypertension, but did not observe this interaction for trans-fat or animal protein.45 However, a recent study on Swedish women with a significantly larger number of stroke cases found that the inverse association between animal protein and risk of stroke was confined to participants with hypertension.46 A Japanese study found that the findings of an inverse association between saturated fat and hemorrhagic stroke was not confined to participants who were hypertensive at study baseline, but noted that many cases of stroke were recorded in participants who had high-normal blood pressure at study baseline and that blood pressure likely increased as the participants aged during the follow-up period.47

This Japanese study raises two important limiting factors typically not accounted for that should be considered in future studies. Firstly as previously explained, the majority of the participants who are in the age range most susceptible to stroke typically have either high normal blood pressure or hypertension, and secondly that many participants will likely develop high blood pressure as they age during the follow-up period. As studies at most usually only examine whether hypertension status at study baseline modifies the risk of stroke and not whether this association is further modified by maintaining an optimal blood pressure throughout the follow-up, this may explain the inconsistency of the results for different cholesterol raising macronutrients and the risk of stroke.

Another recent study on Swedish women found that carbohydrate restricted diets rich in animal protein was associated with an increased risk of subarachnoid hemorrhage and overall cardiovascular disease.48 In the Health Professionals Follow-up Study, there was a non-significant positive and inverse association for animal protein and vegetable protein and risk of stroke respectively.49 Another study in a U.S. population found that higher intake of total fat, especially >65 g/day was associated with an increased risk of ischemic stroke. The excess risk was primarily explained by intake of saturated fat, which showed a trend towards an increased risk of ischemic stroke.50

A recent study of >71,000 Norwegians found that intake of trans-fat from hydrogenated vegetable oils decreased and risk of stroke mortality and cancer incidence, but increased the risk of coronary heart disease mortality. Conversely, intake of trans-fat from hydrogenated fish oil increased the risk of stroke mortality and cancer incidence. Intake of ruminant trans-fat from meat and dairy was not associated with stroke mortality but increased the risk of coronary heart disease mortality, sudden death and cardiovascular mortality in women, and increased the risk of cancer incidence and all-cause mortality in both sexes.43 51 As any increase in intake of trans-fat has significantly unfavorable effects on serum lipids, which in-turn increases the risk of chronic diseases, it is advisable to eliminate all forms of trans-fat from the diet.52 53

Plant Based Diets

A meta-analysis of 5 prospective studies that compared vegetarians to health conscious non-vegetarians found that male vegetarians had a near statistical significant 23% lower risk of stroke and 14% lower risk of all-cause mortality, independent of age and smoking status. For female vegetarians, only ischemic heart mortality was noted to be significantly lower.54 However, this meta-analysis included studies where a large percentage of the participants in the non-vegetarian group were actually infrequent meat eaters and at least one study where one third of the participants in the vegetarian group were found to include meat in their diets, thus minimizing the differences in dietary intake between groups and essentially biasing the true association towards null.55

In Dr. Caldwell Esselstyn’s follow-up of 18 compliant participants with severe coronary artery disease, there were no cases of cardiac events during the 20 year follow-up among compliant participants. This is despite the fact that these 18 participants experienced 49 cardiac events, including 3 cases of stroke during the eight years prior to the study, of which during this time all had been receiving state-of-the-art cardiac care at the Cleveland Clinic.56 In the newer decade long study of over 200 patients, recurrent cardiac events only occurred in 0.5% of compliant participants, which is approximately 40 fold lower than other dietary or statin based trials [reviewed previously].

The Better Way to Prevent Stroke

The preponderance of evidence demonstrates that for stroke prevention, diets should be predominantly composed of minimally refined plant based foods rich in fiber and low in added salt, with an emphasis on reducing LDL cholesterol, blood pressure and body fat to optimal levels. In addition healthy lifestyles should include regular exercise and sunlight exposure for maximum protection. In the presence of these factors, increasing the intake of cholesterol lowering plant foods will not only likely result in a decreased risk of stroke, but also a decreased risk of many other chronic and degenerative diseases.


Please post any comments in the Discussion Thread. 

Forks Over Knives and Healthy Longevity: A Missed Opportunity for the Cholesterol Skeptics

This is the first part of a series of posts that addresses the science regarding plant based diets and the documentary Forks Over Knives and the very serious inaccuracies and omissions that compromise the critiques authored by the cholesterol skeptics, in particular Denise Minger. 

Food Shortages, Cardiovascular Disease and All-Cause Mortality in the World Wars

In Forks Over Knives, Dr. Caldwell Esselstyn described the classical findings from a paper authored by Strom and Jensen, who observed that in Norway between 1938 and 1948 there was a strong relationship between cardiovascular mortality and changes in intake of fat in the form of butter, milk, cheese and eggs, with the changes in mortality lagging behind dietary changes by approximately one year (Fig. 1).1 Denise Minger not only ignored these findings in her critique despite citing the mortality data from the same paper, but instead claimed in regards to a paper on rationing in Norway that animal foods did not decline until after cardiovascular disease mortality had already started declining.2 Minger misleads her readers by confusing the period when rationing was introduced with the period when the intake of animal foods declined. It can be deduced from the data from the Ministry of Supplies cited by Strom and Jensen that rationing was introduced as a result of a declining availability of such products, and therefore introduced after the intake of animal foods had already declined.1

Figure 1. Mortality from circulatory disease, correlated for age; consumption of fat in form of butter, milk, cheese and eggs, Norway 1938-48

Minger also misleads her readers into believing that there was almost an inverse relationship between the changes in animal protein intake and cardiovascular disease mortality in Norway during World War II by inaccurately reporting animal protein intake for the periods of 1936-37 and 1945. In order to verify Minger's interpretation of the statistics (Fig.3), please refer to the table below of macronutrient intake not present in Minger's post (Table 1), as well as the graph illustrating cardiovascular mortality rates (Fig. 2).1 2 In Minger’s own words, 'I pity da fool who doesn’t enlarge this image.'

Table 1. Macronutrient and micronutrient intake for Oslo men from 50 families, 1936-45 

Figure 2. Mortality from circulatory diseases, Norway 1927-48 

Figure 3. Denise Minger’s inaccurate interpretation of the Norwegian statistics 

Minger even posted a 'Fake Correlated Variable' graph, in an apparent attempt to ridicule Dr. Esselstyn, stating that 'For comparison’s sake, this is what a graph would look like if these variables were tightly linked'. Interestingly the 'Fake Correlated Variable' graph was actually remarkably consistent with the actual data (Figs. 4, 5).

Figure 4. Denise Minger’s 'Fake Correlated Variable' graph 

Figure 5. Actual animal protein intake and age-corrected circulatory disease mortality from the cited papers

In Minger’s critique she conveniently omitted the table from this study detailing animal protein intake despite posting the table of intake of individual food groups, and also failed to provide a free link to the paper claiming that she ‘couldn’t find any free copies to link’ despite one being easily locatable by googling the title of the paper, "Food Conditions in Norway during the War, 1939-45". These facts raise very serious questions as to whether Minger's inaccurate report of the data that appears to be heavily biased in favor of an agenda to promote animal foods was in fact intentional.

Minger also claimed that cardiovascular health did not actually improve in Norway during the war years, and that the decrease in cardiovascular mortality was obscured by an increase in mortality from infectious diseases. Minger appears to be either ignorant or unaware that Strom and Jensen provided additional data demonstrating that from over 15,000 operations carried out in Norway that were complicated by danger of thrombosis, the same surgeons found that the occurrence of these complications declined significantly during the period of deprivation of foods rich in animal fats, which then sharply increased after the resumption of intake.3 4 These findings provided strong evidence of actual improved cardiovascular health in Norway during the period of deprivation of animal foods. In Sweden where mortality from infectious diseases actually decreased during the war, there was a record decline in both cardiovascular disease and all-cause mortality during the war years when animal food intake decreased (Fig. 6).2 5 Other researchers also observed a striking decline in advanced atherosclerosis in Finland and Western Germany during the periods of deprivation of animal foods that returned to near pre-war levels after increasing intake.4 6

Figure 6. Percentage of energy from animal foods and mortality from arteriosclerosis and all-causes, Sweden 1940-1944

These observations from the World Wars are unlikely coincidental as they are consistent with the significant decline in serum cholesterol, and mortality from cardiovascular disease and all-causes in former communist nations of Eastern Europe, beginning in the early 1990's when the communist subsidies on meat and animal fats were abolished after the breakup of the Soviet Union (Fig. 7).7 8 Likewise, the significant decline in serum cholesterol, and mortality from cardiovascular disease and all-causes in the pre and early statin period of the second half of the century in developed nations throughout Western Europe, North America and Australasia is partly explained as a result of successful government policies that emphasized dietary changes, particularly a decreased intake of saturated animal fat. One of the best examples is Finland which experienced the most rapid decline of coronary mortality in the world, which was predominantly explained by a significant decline in serum cholesterol as the result of a large reduction in saturated animal fat and an increase in fruit and vegetable intake (Figs. 8, 9).9 10 

Figure 7. Trends in mortality from heart disease in former communist and western nations in men age ≤64

Figure 8. Observed and predicted declines in coronary mortality in males in Eastern Finland 

Figure 9. Observed and predicted decline in serum cholesterol based on dietary changes in Finish men and women without lipid-lowering medication (1, PUFA; 2, dietary cholesterol; 3, SFA; 4, PUFA + dietary cholesterol + SFA; 5, PUFA + dietary cholesterol + SFA + trans fatty acids; 6, observed serum cholesterol)

Randomized controlled trials provide further evidence of a causal association. A meta-analysis of 395 controlled feeding trials established that dietary cholesterol and isocaloric replacement of complex carbohydrates and unsaturated fat by saturated fat raises LDL and total cholesterol.11 In addition a meta-analysis of 108 randomized controlled trials of  various medical and dietary based lipid modifying interventions found that lowering LDL cholesterol significantly decreased the risk of coronary heart disease and all-cause mortality, while modifying HDL or triglycerides provided no clear benefit after controlling for LDL cholesterol.12

Not only does it appear that Denise Minger resorted to distorting the Norwegian data, she was even spineless enough to refer to the number of lives saved from cardiovascular mortality in Norway as being 'nothing to sneeze at' in an apparent attempt to downplay the importance of saving thousands of lives.

Dr. Caldwell Esselstyn and Treating the Cause of CAD

In regards to Dr. Esselstyn’s study of his initial coronary artery disease patients, Denise Minger misleads her readers into believing that 'half' the patients dropped out of the study by confusing the number of patients who had a follow-up angiogram with the number of adherent patients, simply ignoring the 7 patients who adhered to the diet but did not have a follow-up angiogram. There was actually a 75% adherence rate throughout most of this study, and in the more recent and larger decade long study of over 200 patients (known as Treating the Cause of CAD), there was an adherence rate of 91% (Vid. 1).13 14

Minger also suggested that Dr. Esselstyn’s results may have been due to luck as his study was an uncontrolled intervention study. Dr. Esselstyn however did compare the adherent and non-adherent patients. Despite having similar measurable amounts of disease at baseline as the other 18 patients, the 6 non-adherent patients had 13 new cardiac events within the first 12 years of the study despite the fact that they were still receiving standard care. On the other hand, the 18 compliant participants had no further cardiac events while being fully compliant, despite having 49 events during the 8 years prior to the study, of for which most of this time were receiving standard care.13 14 In the newer decade long study of over 200 patients, recurrent cardiac events only occurred in 0.5% of adherent participants, which is approximately 40 fold lower than other dietary or statin based trials (Vid. 1). Minger suggests that these results were due to luck but provided no evidence demonstrating that coronary artery disease can be spontaneously halted or reversed this frequently even when years of medical intervention have failed.

Video 1. TEDxCambridge - Caldwell Esselstyn on making heart attacks history

Dietary Cholesterol, Cardiovascular Disease and All-Cause Mortality

In regards to the information in Forks Over Knives about the disease promoting effects of dietary cholesterol, Denise Minger claimed that one of the reasons the consensus of the medical community that dietary cholesterol raises serum cholesterol and is unhealthy is due to experiments performed on ‘obligate herbivores’, primarily being ‘rabbits’. Minger is ignorant of the fact that literally hundreds of experiments on numerous different omnivorous species, the most relevant being non-human primates have demonstrated that dietary cholesterol has unfavorable effects on serum lipids and induces atherosclerotic lesions.15 Experiments on non-human primates have demonstrated that intake of even small amounts of dietary cholesterol as low as 43µg/kcal, the equivalent found in only half of a small egg in a human diet of 2,000 kcal induces atherosclerotic lesions. Furthermore, there was no evidence of a threshold for dietary cholesterol with respect to an adverse effect on arteries (Figs. 10, 11).16 [Click here for more information regarding study 16]

Figure 10. Subclavian artery from a Rhesus monkey supplementing 43µg/kcal dietary cholesterol. Sudanophilia (black area) is intense in the area of major intimal thickening.

Figure 11. Fermoral artery from a Rhesus monkey supplementing 43µg/kcal dietary cholesterol. Intimal fibrous thickening and disruption of internal elastic membrane differentiate this artery from control vessels of monkeys supplementing 0 dietary cholesterol.   

Minger also failed to mention that several large forward-looking prospective studies on humans found that dietary cholesterol was associated with a significantly increased risk of all-cause mortality, and that it has been consistently shown in studies on diabetic participants that intake of dietary cholesterol and eggs significantly increased the risk of cardiovascular disease and all-cause mortality.17 18 19 20 21 22

Protein Restriction and Healthy Longevity

Denise Minger suggested in regards to the original Indian study cited by Dr. Colin Campbell that in the presence of aflatoxins rats on low protein compared to high protein diets experience an increased risk of premature death. Minger appears to be ignorant in light of the fact that in the majority of studies on rats, especially those that have not been complicated by the administration of large doses carcinogens, protein restriction actually significantly increased maximum lifespan. For example, a review found that in 16 out of 18 studies protein restriction increased average maximum lifespan by approximately 20%, independent of caloric restriction.23 As for carbohydrate intake, increased intake has either been associated with no change or increased longevity.23 The association between protein restriction and longevity has been primarily attributed to methionine restriction, which has shown to increase both mean and maximum lifespan in rodents by on average up to 40%.23 24

Dietary restriction of methionine has also been shown to inhibit and even reverse human tumor growth in animal models and in culture demonstrating that tumors are methionine dependent, yet is relatively well tolerated by normal tissue.25 A review found that the benefit of replacing casein with soy protein on tumor suppression in the animal model was explained in part by the lower quantity of methionine and in part by numerous beneficial plant based compounds.26 For the sake of comparing 'apples and apples' as Minger put it, studies have found that casein is still far more cancer promoting compared to soy protein even when the casein and soy protein diets were formulated to contain equivalent amounts of the 'limiting amino acid' methionine (Fig. 12).26

Figure 12. Total number (A) and total weight (B) of mammory tumors in rats, 25 weeks after N-nitrosomethylurea injection. Diet Groups: Casein, 20% casein; SPI, 19% soy protein isolate; SPI +Met., 19% soy protein isolate formulated to contain the equivalent amount of methionine as the casein group

Compared to whole plant foods, both methionine content and bioavailability is significantly higher in most protein rich animal based foods, with little overlap.24 Therefore protein combining of unrefined plant foods will result in a quality sufficient to support normal tissue, but not the quality found in animal foods that promote cancer and premature death. These rodent studies are consistent with a number of prospective studies on humans that found that diets higher in protein and often fat, primarily of animal origin at the expense of vegetable protein or carbohydrates are associated with an increased risk of all-cause mortality.27 28 29 30

Minger suggested in regards to a study on non-human primates that in the presence of lower amounts of aflatoxins, higher compared to lower intakes of casein do not promote tumor growth. These findings are in disagreement with other studies that administered low amounts of aflatoxin cited by Dr. Campbell that Minger apparently ignored.31 However, the study on non-human primates did not test intermediate levels of protein intake or specific amino acids such as methionine, and Minger failed to cite any studies comparing casein with plant protein, therefore not allowing for a clear interpretation of these results. In studies on non-human primates, compared to casein, soy protein not only leads to genetic changes that are associated with a decreased risk of cancer, but also improvements in body weight, insulin sensitivity, lipid profile, and even decreases atherosclerosis plaques by on average up to 90% (Fig. 13).32 33 34 35

Figure 13. a, Proportion of each group of Cynomolgus monkeys with CAA plaques, defined as intimal thickness greater than half the medial thickness. b, Average lesion size for those monkeys with atherosclerotic plaques. Soy(-), Soy protein with phytoestrogens mostly extracted. Soy(+), Soy protein with phytoestrogens.

A number of randomized controlled trials have demonstrated the damaging effects of animal protein in human cancers. For example, a randomized, placebo-controlled trial found that among men at high risk, those supplementing with milk protein were more than six times likely to develop prostate cancer compared to men supplementing with soy protein.36 Also, a number of tightly controlled feeding trials with human participants have established that heme iron from the protein portion of meat increases the production of NOCs (N-nitroso compounds) in the digestive tract to concentrations similar to that found in cigarette smoke, of which most are cancerous.37 38 Furthermore, a controlled feeding trial found that NOCs arising from heme iron in meat forms DNA adducts in the human digestive tract, and DNA adducts are a well-established marker of cancer.39 These findings are consistent with recent meta-analyses of prospective studies that found that intake of both fresh red meat and heme from meat is associated with a significant increased risk of colorectal cancer.37 40 Based partly on these lines of evidence, in 2011 the expert panel from the World Cancer Research Fund reviewed over 1,000 publications on colorectal cancer and concluded that there is convincing evidence that both fresh and processed red meats are a cause of colorectal cancer.41 Furthermore, a more recent prospective study with over 2.24 million men and women found that compared to participants who consumed less than 1 serving per week, consuming 2 or more servings of meat significantly increased the risk of colorectal cancer.42

The China Study

Denise Minger suggested in regards to the raw data from the China Study that the counties who had the lowest serum cholesterol levels and had the lowest intakes of animal foods had an increased risk of mortality. However, in the China Study animal protein intake was very strongly associated with numerous favorable socioeconomic factors, with household income explaining between 60% and 80% of the variance of intake between counties, likely biasing towards such findings.  Animal food intake was also associated with other favourable socioeconomic factors including access to doctors and hospitals for antenatal consultation and child births, immunisation, avoidance of famine, owning a fridge, a toilet and the ability to read, of which many were associated to some degree with a lower risk of mortality.43 Among the younger population studied in the China Study II, animal food intake was actually a significant predictor of an increased risk, and plant foods of a decreased risk of all-cause mortality despite the fact that the significant inverse relationship between mortality and household income would have biased these results towards the opposite direction (Tables. 2, 3).43 This resembles Dr. Campbell’s observations in the Philippines where the children from the wealthier families that consumed diets rich in animal foods were more likely to develop liver cancer.31

Table 2. Significant predictors of all-cause mortality in the raw data from the China Study II, ages 0-4

Table 3. Significant predictors of all-cause mortality in the raw data from the China Study II, ages 5-14

Forward-looking prospective studies that controlled for socioeconomic factors found that plant based dietary patterns are associated with a decreased risk of all-cause mortality.27 44 45 46 Furthermore, it has been well established from evidence from over 100 randomized controlled trials that lowering LDL cholesterol significantly reduces the risk of all-cause mortality, even in individuals who already have very low baseline LDL cholesterol concentrations similar to that observed in the rural Chinese.12 47 The great majority of the surge in coronary heart disease mortality in Beijing between 1984 and 1999 has been attributed to a significant increase in serum cholesterol explained largely by a 5-fold increase in red meat and egg intake as well as a decline in fruit and vegetable intake. Without improvements in medical interventions the increase in deaths would have been substantially higher.48

Minger also previously claimed that Dr. Campbell’s findings of an relationship between fat, a marker of animal food intake, and an increased risk of breast cancer mortality in the China Study was attributed to the intake of ‘hormone-injected livestock’. She however provided no evidence that consumption of such livestock was widespread in rural China long enough before the mortality data was collected almost four decades ago for this questionable claim to be plausible. However, she did agree that Dr. Campbell’s findings of early menarche as a risk factor for breast cancer as perhaps reflecting a causal relationship ‘given what we know about hormone exposure and breast cancer’. Not surprisingly she failed to mention that animal protein was associated with elevated circulating estrogen in the China Study, and has been associated with a higher risk of early menarche in numerous studies including a cohort of girls born during the 1930s and 1940s, before the widespread consumption of ‘hormone-injected livestock’.31 49 50 51

In addition, Minger previously criticized a number of Dr. Campbell's statements that he made apparently in regards to both the China Study I & II, yet she cited data only from the China Study I.52 With the addition of the data from the China Study II, the relationship between animal foods and an increased risk of breast cancer mortality became significantly stronger, as did plant foods with a decreased risk (Table 4).43

Table 4. Significant predictors of female breast cancer mortality in the raw data from the China Study II, ages 35-69

Furthermore, consistent with the findings from the China Study, the expert panel from the World Cancer Research Fund concluded in 2011 that there is convincing evidence that dietary fiber protects against colorectal cancer, clearly refuting Minger's claims that research on dietary fiber 'outside' of the China Study does not support Dr. Campbell's findings.41 52

Many of Dr. Campbell’s findings in regards to plant based diets and the risk of chronic diseases in China are consistent with much earlier studies from China and around the world. For example, Williams reviewed the medical literature and documentations on cancer from around the world in 1908 long before the widespread use of intensive farming practices, finding strong evidence of an association between plant based dietary patterns and exceptional longevity and very low rates of cancer. Williams also documented that compared to the less affluent parts of Asia that subsisted on plant based diets, cancer was relatively common in the affluent parts of China that could afford animal foods on a frequent basis. He asserted that:53

…cancer is comparatively uncommon in those parts of China where the bulk of the people live on an almost exclusively vegetarian diet, being too poor to purchase any of the various flesh foods which are there used for culinary purposes.

Consistent with Williams's findings on cancer, Snapper found a similar phenomenon for vascular disease. He asserted that:54

In 1940, I confirmed De Langen’s results... by the observation that in North China, coronary disease, cholesterol [gall]stones and thrombosis were practically nonexistent among the poorer classes. They lived on a cereal-vegetable diet consisting of bread baked from yellow corn, millet, soybean flour and vegetables sautéed in peanut and sesame oil. Since cholesterol is present only in animal food, their serum cholesterol content was often in the range of 100 mg. per cent. These findings paralleled the observation of De Langen that coronary artery disease was frequent among Chinese who had emigrated to the Dutch East Indies and followed the high fat diet of the European colonists.

Overall Impressions of Forks Over Knives

Overall, Forks Over Knives provides a lot of very useful information to help viewers make life saving and longevity promoting dietary changes, and best of all comes directly from the doctors who have actually reversed many of the chronic diseases which are leading causes of disability and death. Ignoring the preponderance of evidence favoring a predominately plant based diet, low in saturated fat that is recommended by virtually every respected healthy authority around the world, and instead blindly following the unfounded dietary advice of the cholesterol skeptics can result in absurd consequences and a missed opportunity for healthy longevity.55


Part II: Forks Over Knives and Health Longevity: Perhaps the Science is Legit After All

Please post any comments in the Discussion Thread.