Diet, Blood Cholesterol, Blood Pressure and Risk of Stroke

The controversy surrounding the lipid hypothesis, in particular the relationship between elevated total and LDL cholesterol and coronary heart disease was considered largely resolved and regarded as scientific fact within the scientific community by 1984 when the expert panel from the National Institutes of Health (NIH) reviewed the relevant literature and agreed that the relationship was causal.1 2 The panel concluded:

Elevated blood cholesterol level is a major cause of coronary artery disease. It has been established beyond a reasonable doubt that lowering definitely elevated blood cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will reduce the risk of heart attacks due to coronary heart disease… Further, we are persuaded that the blood cholesterol level of most Americans is undesirably high, in large part because of our high dietary intake of calories, saturated fat, and cholesterol… There is no doubt that appropriate changes in our diet will reduce blood cholesterol levels.

Since 1984 evidence accumulated from over 100 randomized controlled trials of various medical and dietary based lipid modifying interventions has further established that lowering LDL cholesterol significantly decreases the risk of coronary heart disease and all-cause mortality, independent of changes to HDL cholesterol and triglycerides, and non-lipid effects of specific drugs.3 4

Controversy however has lingered over whether medical and dietary based interventions to lower total and LDL cholesterol, and perhaps triglycerides may increase the risk of certain stroke subtypes, in particular hemorrhagic stroke. Controversy has arisen in part due to the interpretation of certain statin trials, prospective cohort studies, and observational studies in certain populations with unique cardiovascular profiles, in particular the Japanese.5 6 7 This has led some to suggest that physiological levels of LDL cholesterol (less than 70 mg/dl; 1.8 mmol/l), the levels observed in newborn humans, free-ranging mammals, and human populations on low cholesterol diets that do not develop atherosclerosis [reviewed previously] may somehow increase the risk of hemorrhagic stroke.

There are two major categories of stroke, ischemic and hemorrhagic. Ischemic stroke occurs as a result of an obstruction with the blood supply to the brain, while hemorrhagic stroke occurs as a result of a rapture of a weakened blood vessel. In contrast to the observed decline of stroke incident in Japan where there was a significant improvement in a number of major risk factors but an increase in mean serum cholesterol, Finland experienced one of the highest rates of stroke mortality in the world as well as one of the largest declines, which was in part explained by a decrease in serum cholesterol.8 Unlike Japan, Finland also experienced the highest rate of coronary heart disease mortality in the world as well as the largest decline, which was predominantly explained by cholesterol lowering dietary changes [reviewed previously]. Furthermore, evidence suggests that Japanese Zen monks who consume significantly less meat and fish than the general Japanese population experience lower rates of stroke and all-cause mortality, independent of BMI, alcohol intake and other lifestyle factors.9

At the opposite end of the dietary spectrum higher rates of stroke mortality have been observed among the three main Inuit populations, including those in Greenland, Canada and Alaska compared to their non-Inuit Western counterparts, yet experience similar rates of non-stroke cardiovascular mortality.10 Evidence of atherosclerosis and other chronic and degenerative diseases have been observed in numerous preserved Inuit mummies that date back to pre-western contact, suggesting that their high rate of cardiovascular mortality cannot be entirely explained by influences of modern dietary and lifestyle factors [reviewed previously]. Furthermore, the declining rates of cardiovascular mortality, including stroke among the Inuit undergoing a rapid transition towards a western diet and lifestyle has raised questions regarding the health properties of the traditional Inuit diet based on marine animals.10

Coronary atherosclerosis in a pre-contact Inuit mummy dating back 1,600 years*

The Interaction between Blood Cholesterol, Blood Pressure and Risk of Stroke

Recently the largest meta-analysis of statin based randomized controlled trials on the effect of lowering LDL cholesterol and risk of stroke was published, including 31 trials with >182,000 participants and >6,200 cases of stroke. Statins significantly decreased the risk of total and ischemic stroke and all-cause mortality, without evidence of publication bias, consistent with findings from animal studies.5 11 There was however a small statistically insignificant increase in incidence of hemorrhagic stroke in the statin group which was not related to either the degree of reduction of LDL or the achieved LDL. The researchers provided the following possible explanation for these findings:

In addition to their lipid-lowering properties, statins may have antithrombotic properties by inhibiting platelet aggregation and enhancing fibrinolysis. The antithrombotic affects of statins could account for a theoretically increased risk of bleeding complications.

All of the very large prospective cohort studies that included >300,000 participants have either found no association between total and LDL cholesterol and risk of hemorrhagic stroke, or an inverse association confined to participants with hypertension, or a positive association confined to participants with low blood pressure.6 12 13 14 15 A prospective study with >787,000 Korean participants and >9,900 cases of stroke found that while serum cholesterol was associated with a higher risk of ischemic stroke, the researchers found suggestive evidence that the inverse association between serum cholesterol and hemorrhagic stroke confined to hypertensive participants was not causal, but acted as a marker of binge drinking.14 The researchers explained:

In our study, increased risk of hemorrhagic stroke in people with low concentrations of blood cholesterol (less than 4.14 mmol/l) was restricted to those with high GGT values [a measure of alcohol intake]; this relation was less evident when alcohol consumption was measured by self report. The measures of blood pressure might not have been a true reflection of risk, as transient high blood pressure associated with binge drinking may have an important role in hemorrhagic stroke. At low concentrations of GGT, low serum cholesterol was not associated with a higher risk of hemorrhagic stroke. In effect, low blood cholesterol may act as a marker of the health damaging effects of alcohol, rather than be a cause of hemorrhagic stroke.

There maybe limitations with the studies which only address whether blood pressure considered by hypertension status modifies the association between serum cholesterol and risk of stroke. As with hypercholesterolemia, the definition of hypertension, blood pressure of >140/90 mmHg, far exceeds levels that have been clearly scientifically documented as being optimal. For example, a meta-analysis of 61 prospective studies including >958,000 participants and >11,900 cases of stroke deaths found that lower usual blood pressure was associated with a reduced risk of mortality from stroke and coronary heart disease, without any evidence of a threshold down to at least 115/75 mmHg.16 These findings are consistent with a meta-analysis of 147 randomized controlled trials that administered blood pressure lowering medication.17 This justifies investigating whether optimal blood pressure compared to high-normal blood pressure further modifies the association between serum lipids and the risk of stroke subtypes.

A meta-analysis of 61 prospective studies with >892,000 participants and >11,600 cases of stroke deaths found not only that serum cholesterol was inversely associated with total and hemorrhagic stroke mortality in participants with very high baseline systolic blood pressure (>145 mmHg), but that lower serum cholesterol was actually associated with a significantly lower risk of hemorrhagic, ischemic and total stroke mortality in participants with near optimal or ‘physiological’ baseline systolic blood pressure (less than 125 mmHg)(Fig. 1).6 As most participants in the age range most susceptible to stroke had either high-normal blood pressure or hypertension, the combined results were biased towards finding an inverse association between serum cholesterol and hemorrhagic stroke mortality.

Figure 1. Systolic blood pressure specific hazard ratios for 1 mmol/L lower usual total cholesterol and risk of stroke mortality

If this association is causal and not obscured by other factors such as binge drinking, this may explain why populations with low cholesterol and high blood pressure such as the Japanese have high rates of stroke, in particular hemorrhagic stroke, and populations that maintain physiological levels of both cholesterol and blood pressure throughout life have an observed absence of stroke.18

There is limited suggestive evidence that the atherosclerosis build-up process in the carotid and major cerebral arteries caused by excess LDL cholesterol in-turn reduces arterial blood supply to the brain that would otherwise cause the blood vessels in the brain to rupture in the presence of high blood pressure, thus explaining why elevated cholesterol may lower the risk of cerebral hemorrhage in people with high blood pressure.19 Indeed, a Japanese study found there was an inverse association between cholesterol and hemorrhagic stroke in an earlier cohort when the mean blood pressure was high and atherosclerosis was relatively low, but no association in the later cohort of the same population when mean blood pressure was reduced from hypertensive to high-normal blood pressure.20

Evidence from several but not all observational studies also found that low triglycerides were associated with a statistically significant or non-significant increased risk of hemorrhagic stroke.12 21 22 23 24 25 26 There is limited data regarding whether the association between low triglycerides and hemorrhagic stroke is modified by blood pressure or alcohol intake, but at least one large study found that the association was stronger among participants with high blood pressure.22

As there is convincing evidence that blood pressure increases the risk of stroke at any given cholesterol concentration, it would be advisable that everyone should aim to achieve an optimal blood pressure of less than 115/75 mmHg. Although a number of lifestyle changes including exercise and weight loss can lower blood pressure, a number of dietary changes can also effectively lower blood pressure.27 28 This includes reducing intake of salt and increasing intake of dietary fiber rich foods including whole grains, flavonoid rich foods including berries, soy, cocoa solids, and vitamin C and magnesium.29 30 31 32 33 34 35 36 37 38 These nutrients derived primarily from whole-plant foods may in-turn explain why intervention and observational studies have found that vegetarian diets, in particular vegan diets have favorable effects on blood pressure.39 40 41 42 43 44 45 46

The Better Way to Lower Cholesterol

As statins provide little appreciable protection against cancer, and like all drugs have adverse effects including but not limited to an increased risk of developing type II diabetes and memory loss or impairment, a significantly greater benefit would be achieved by lowering LDL cholesterol with a whole-foods plant based diet combined with regular exercise in order to not only lower the risk of cardiovascular disease but many other chronic and degenerative diseases.47 48 49 50 In Part II I review the evidence of dietary factors and the risk of stroke.


Please post any comments in the Discussion Thread. 

Debate with Dr. Colin Campbell in The Wall Street Journal

Dr. T. Colin Campbell

A recent article in The Wall Street Journal, titled Would We Be Healthier With a Vegan Diet?, featured Dr. Colin Campbell explaining the health benefits of a plant-based diet and the supporting science, with an opposing view given by Dr. Nanacy Rodriguez, a researcher who's profile shows an extensive list of grants from the livestock industry.1

Dr. Rodriguez’s opposing view raises considerable concerns as her statements are compromised by a number of serious methodological issues and relies largely on inaccurate stereotypes, stereotypes scripted and promoted by lobbying efforts of the livestock industry that promote fear of removing animal products from the diet.

Laboratory Experiments and the Promotion of Cancer

Dr. Nancy Rodriguez

Dr. Rodriguez questioned whether the cancer promoting effects of casein observed in Dr. Campbell’s laboratory can be extrapolated to other animal proteins, but provided scant evidence to the contrary. This resembles the misleading claims of the cholesterol sketpics, including Denise Minger that have been discussed in detail here.

It is well documented that dietary restriction of methionine significantly increases both the mean and maximum lifespan in the rodent model.2 3 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.4

Compared to whole plant foods, both methionine content and bioavailability is significantly higher in most protein rich animal based foods, with little overlap.3 In addition plant foods contain thousands of phytonutrients which work together to protect against cancer. For example, studies have found that casein is still far more cancer promoting compared to soy protein even when both the diets were formulated to contain equivalent amounts methionine (Fig. 1). This was attributed largely to the difference in content of a number of protective phytonutrients.5

Figure 1. 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.

Due to the high content and bioavailability of methionine and lack of phytonutrients in other animal proteins, the observed cancer promoting effects of casein will therefore largely apply to other animal proteins. Furthermore, Dr. Rodriguez’s statement 'Casein is one of many proteins found in milk' made in an apparent attempt to disassociate milk protein from casein can be considered misleading when taking into account that casein makes up approximately 80% of the protein in bovine milk.6

Findings from Clinical Trials

The consensus that a number of dangerous substances including cigarette smoke promote cancer is purely based off epidemiologic, metabolic and laboratory studies. Therefore there is little justification for Dr. Rodriguez to claim as she did that a number of risk factors that have not been tested in clinical trials such as smoking play a significant role in the cause of cancer, but at the same time neglect evidence regarding replacing meat and dairy with whole plant foods and a decreased risk of cancer purely because of a lack of clinical trials.

A number of randomized controlled trials have actually 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.7

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.8 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.9 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.8 10

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.11 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.12

There is much controversy regarding the 'Dozens of randomized, controlled, clinical trials' that Dr. Roriguez’s appears to be referring to claiming that 'demonstrated that calcium and dairy products contribute to stronger bones'. For example the Harvard School of Public Health have asserted that:13

...the maximum-calcium-retention studies are short term and therefore have important limitations. To detect how the body adapts to different calcium intakes over a long period of time—and to get the big picture of overall bone strength—requires studies of longer duration.

Walter Willett, the Chair of the Department of Nutrition, Harvard is well known for criticizing the industries unfounded claims about the health properties of dairy. In regards to the 2010 USDA Dietary Guidelines he stated that:14

The guidelines continue to recommend three daily servings of dairy products, despite a lack of evidence that dairy intake protects against bone fractures and probable or possible links to prostate and ovarian cancers.

Willett nevertheless praised parts of the guidelines, stating that:

The guidelines appropriately emphasize eating more vegetables, beans, fruits, whole grains, and nuts and highlight healthful plant-based eating patterns, including vegetarian and vegan diets.

Dr. Rodriguez suggested that 'The Dietary Guidelines are founded on evidence-based, peer-reviewed scientific literature, and take into account the entire body of research, not just a single study', and that therefore her dietary recommendations are justified. However, evidence to the contrary was made clear in the report of the Dietary Guidelines Advisory Committee on the Dietary Guidelines for Americans, 2010 that stated 'The DGAC did not evaluate the components of processed meats that are associated with increased risk of colorectal cancer and cardiovascular disease.'15 Thus the Dietary Guidelines did not sufficiently 'take into account the entire body of research', one of the reasons the guidelines have been scrutinized by the Harvard School of Public Health.13

Nutrient Density of Plant vs. Animal Foods

In regards to 'calorie efficiency', the most nutrient dense foods are dark green leafy vegetables which are leaps and bounds more nutrient dense than the phytonutrient and dietary deficient animal foods Dr. Rodriguez advocates, while also being dense in protein, calcium, iron and zinc.16 In fact, calcium from a number of dark green leafy vegetables is actually much more easily absorbed than that from bovine milk.17 In regards to protein intake, a meta-analysis of nitrogen balance studies found that the estimated requirements in healthy adults for the median and 97.5th percentile are 0.65 and 0.83 grams of protein per kg of body weight respectively,18 amounts easily obtained from plant-based dietary plans formulated by Dr. Campbell and his colleagues.19 Furthermore, there is little justification for Dr. Rodriguez as she has done to advocate dairy on the basis that it is artificially fortified with Vitamin D while at the same time downplaying the nutrient density of plant-based foods due to a lack of certain nutrients such as Vitamin B12 and Vitamin D that can be easily supplemented in plant-based diets.

In regards to lean animal protein, the 95% lean beef that Dr. Rodriguez promotes actually contains a similar amount of dietary cholesterol as that found in similar cuts of full-fat beef.16 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. 2, 3).20 21 Furthermore, several major prospective studies on humans found that dietary cholesterol was associated with a significant increased risk of all-cause mortality.22 23 24

Figure 2. Subclavian artery from a Rhesus monkey supplementing 43µg/kcal dietary cholesterol. Sudanophilia (black area) is intense in the area of major intimal thickening.

Figure 3. 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.   

Conflicts of Interest

Finally, Dr. Rodriguez’s financial tie to the livestock industry may explain why she appears to have misinterpreted the medical literature in regards to the disease promoting effects of animal foods and the nutrient density of plant-based foods, written in a largely textbook manner used by other livestock industry lobbyists. The tactics of the livestock industry may resemble those used by the tobacco industry that misinterpreted the medical literature in the past in order to dismiss the 'junk' science linking smoking to lung cancer and other associated diseases. Brownell et al. reminds us of how serious and real conflicts of interests can really be:25

A striking event occurred in 1994 when the CEOs of every major tobacco company in America stood before Congress and, under oath, denied believing that smoking caused lung cancer and that nicotine was addictive, despite countless studies (some by their own scientists) showing the opposite.

Perhaps the same can be said for Dr. Rodriguez’s claim that 'It is simply untrue to suggest that animal protein causes cancer', which is clearly in discordance with the preponderance of evidence. It maybe largely explained by socioeconomic factors as to why health authorities are unable to reach similar dietary recommendations as Dr. Campbell and his colleagues. For example, Eric Rimm from the Department of Nutrition, Harvard said to Reuters in regards to a major health report produced by the National Academy of Science, which he was an author of that:

We can’t tell people to stop eating all meat and all dairy produces. Well, we could tell people to become vegetarians... If we were truly basing this on science we would, but it is a bit extreme.

As Dr. Rodiguesz’s herself stated, 'appreciating the science behind nutrition helps us make smart choices about the best way to feed ourselves and the world'. Unfortunately her scare tactics illustrated in The Wall Street Journal demonstrated very little appreciation of the preponderance of scientific evidence.

Please post any comments in the Discussion Thread.