Sunday, 28 October 2012

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