Friday, 17 August 2012

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 1Mortality 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.