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.
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:
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).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.
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:
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 16A 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.
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.
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