Larsson, Susanna C.
Stroke is the third leading cause of death in Western countries and a major cause of mental and physical impairment. About 20% of the stroke survivors require institutional care after 3 months and 15−30% are permanently disabled . There are two main types of stroke: the ischemic stroke, accounting for 80−90% of all strokes, and the hemorrhagic stroke. Ischemic stroke results from an inadequate supply of blood and oxygen to the brain due to a blockage of an artery that supplies the brain. Hemorrhagic stroke occurs when a blood vessel in the brain leaks or ruptures, leading to a blood flood that can injure the surrounding tissue.
Nearly 80% of strokes are first events . Therefore, primary prevention is of particular importance. Hypertension is a strong and well documented modifiable risk factor for both ischemic and hemorrhagic stroke [2▪▪]. Other well established risk factors include physical inactivity, obesity, type 2 diabetes, dyslipidemia, atrial fibrillation and certain other cardiac conditions, carotid artery stenosis, sickle cell disease, cigarette smoking, and postmenopausal hormone therapy [2▪▪]. Examples of less well documented or potentially modifiable risk factors are the metabolic syndrome, excessive alcohol consumption, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection [2▪▪]. Moreover, chronic kidney disease is an important risk factor for stroke . Diet can also influence the risk of stroke, for example by affecting blood pressure, blood lipid concentrations, platelet aggregation, endothelial function, and inflammation.
This review summarizes the present epidemiologic evidence regarding the associations of dietary fat and other nutrients with risk of stroke.
With regard to coronary heart disease (CHD), convincing evidence indicates that specific fatty acids and types of fat, but not total fat, play a role in the cause and prevention of CHD [4▪▪,5▪▪]. Modest reductions in risk of CHD have been observed when saturated (animal) fat is replaced by unsaturated fats (monounsaturated or polyunsaturated fat), whereas little or no benefit is likely when saturated fat is replaced by carbohydrates [4▪▪,5▪▪]. Although blood cholesterol concentrations are directly related to CHD, there is no consistent association between blood cholesterol and risk of total stroke . Statins and other lipid-lowering therapy have been shown to reduce the risk of stroke in CHD patients . However, statins and fibrates may lower stroke risk independent of blood cholesterol for example through anti-inflammatory effects, by improving endothelial function, and through effects on hemostatic variables .
As for CHD, total dietary fat intake is not associated with risk of stroke. In the Women's Health Initiative Randomized Controlled Dietary Modification Trial, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of stroke in postmenopausal women during a mean follow-up of 8.1 years . Furthermore, prospective studies have not observed any significant association between total fat intake and stroke after adjustment for other risk factors for stroke [9–13].
Results from a meta-analysis of eight prospective studies with a total of 2362 stroke cases showed no significant relation between saturated fat intake and stroke risk [relative risk (RR), 0.81; 95% confidence interval (CI), 0.62–1.05] . Moreover, the most recently published studies conducted in Western populations, including two large prospective cohorts of women with over 1000 stroke cases [9,10], a small cohort of middle-aged men , and a cohort of women and men  found no association between saturated fat intake and risk of stroke.
Randomized controlled trials (RCTs) have shown that substitution of carbohydrates with unsaturated fat or protein can lower blood pressure and improve lipid levels . However, recent large prospective studies have not supported an association between monounsaturated or polyunsaturated fat intake and risk of total, ischemic, or hemorrhagic stroke [9,10,12,13]. Studies of specific plant-derived unsaturated fatty acids in relation to stroke risk are sparse. In a nested case–control study conducted in France, plasma oleic acid concentrations at baseline were inversely associated with incidence of stroke (RR 0.25; 95% CI 0.08–0.86, for highest vs. lowest tertile). Dietary intake of α-linolenic acid was not associated with risk of stroke in prospective studies from the USA  and Sweden . A Dutch prospective study found an inverse association of dietary but not plasma α-linolenic acid with stroke risk [17,18].
Long-chain omega-3 polyunsaturated fatty acids
The long-chain omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid and docosahexaenoic acid, which are present in fish, other seafood, and fish oil supplements, have been shown to reduce blood pressure and plasma triglycerides, decrease inflammation, and improve vascular function [19▪▪]. Compelling evidence from RCTs and prospective studies indicate that high intakes of long-chain omega-3 PUFAs reduces the risk of sudden cardiac death and CHD mortality [19▪▪]. Prospective studies of long-chain omega-3 PUFAs in relation to risk of stroke have yielded inconsistent results. Two large cohorts of Swedish  and US  women observed a statistically significant 16 and 28%, respectively, lower stroke risk for women in the highest compared with the lowest category of long-chain omega-3 PUFA intake. In a cohort of Dutch men and women, long-chain omega-3 PUFA intake was significantly inversely associated with risk of stroke in women but not men . There was no significant association between long-chain omega-3 PUFA intake and stroke risk in cohorts of US health professionals [12,16], US male physicians , or Swedish , Finnish , or Chinese  men and women. In a case–control study of 120 Koreans, long-chain omega-3 PUFAs in erythrocytes were statistically significantly lower in stroke patients than in the control group . Results from a RCT of 11 324 patients with prior myocardial infarction showed a significant reduction in risk of cardiovascular death but not stroke in the group-allocated long-chain omega-3 PUFA supplementation (1 g/day during 3.5 years) . Consumption of fish was associated with a modest, but statistically significant, reduction in stroke risk in a recent meta-analysis of 15 prospective studies .
Trans fatty acids
A high intake of trans fatty acids from partially hydrogenated vegetable oils could increase the risk of CVD through adverse effects on blood lipid profile, inflammation, and endothelial function . Although studies on trans fatty acids in relation to CHD indicate an increased risk with higher intakes, studies of the association between trans fatty acids and risk of stroke are few and inconsistent. Results from a large prospective cohort of postmenopausal US women showed a positive association between trans fatty acid intake and stroke risk (RR 1.08; 95% CI 1.00–1.13, for each 2 g/day increase in intake) . In contrast, another prospective study of US women found an excess risk of intraparenchymal hemorrhage in the lowest quintile of trans fatty acid intake . Intake of trans fatty acids was not associated with risk of stroke in a prospective study of US men .
Dietary cholesterol is present in animal products such as egg, liver, and other meats. High consumption of red meat and processed meat has been associated with increased risk of stroke in Western populations . RCTs have shown that increased cholesterol intake raises blood total and LDL cholesterol concentrations [31,32]. Recent findings from a prospective cohort of Swedish women showed a statistically significant 29% higher risk of ischemic stroke among women in the highest quintile of cholesterol intake (median, 168 mg/day) compared with women in the lowest quintile (median, 302 mg/day), and the association was independent of red meat consumption . In contrast, a small Japanese cohort study found an inverse relation between cholesterol intake and mortality from ischemic stroke . Other prospective studies have not found an association of cholesterol intake with risk of ischemic stroke [9,12,29], total hemorrhagic stroke , or intraparenchymal hemorrhage [29,33].
VITAMINS AND MINERALS
Fruit and vegetable consumption has consistently been inversely associated with risk of stroke . Fruit and vegetables are rich sources of antioxidants (e.g., vitamin C and carotenoids), folate, magnesium, potassium, dietary fiber, flavonoids, and other phytochemicals, which may protect against stroke. Use of multivitamins combined with vitamin A, C, or E supplements was associated with a statistically significant 16 and 14% lower stroke mortality in men and women, respectively, in a prospective cohort of 1 063 023 adult Americans . Another prospective cohort of US women found no relation between multivitamin use and stroke .
Although antioxidants such as β-carotene and vitamins C and E have generally been inversely associated with risk of stroke in observational studies [37–42], there is no support from RCTs that supplementation with single antioxidants lowers the risk of stroke or other cardiovascular events [43,44,45▪,46]. However, in one RCT, those in the active groups for both vitamin C and vitamin E experienced fewer strokes compared to those in the placebo group for both agents (RR 0.69; 95% CI 0.49–0.98) .
The B vitamins, including folate, vitamin B6, and vitamin B12, have been hypothesized to reduce the risk of stroke through favorable effects on plasma homocysteine concentrations, antioxidant defenses, and endothelial function . Homocysteine concentrations can be lowered by up to 25% with folic acid supplementation and by a further 7% with vitamin B12 supplementation . Some prospective studies conducted in CVD-free populations have reported an inverse association between dietary folate intake and stroke risk . A meta-analysis of 13 RCTs, including individuals with pre-existing CVD or other conditions, showed no overall significant effect of folic acid supplementation (with or without vitamins B6 and B12) on stroke risk (RR 0.93; 95% CI 0.85–1.03) . Nevertheless, a beneficial effect was observed in trials testing combination therapy of folic acid and vitamins B6 and B12 (RR 0.83; 95% CI 0.71–0.97) . A benefit from B vitamin supplementation for stroke prevention may only be seen in populations with low folate intake .
Vitamin D may reduce the risk of cardiovascular disease through several mechanisms, for example by lowering blood pressure, improving endothelial function, anti-inflammatory effects, and by increasing insulin sensitivity [52▪]. In a recent meta-analysis of seven prospective studies, low 25-hydroxyvitamin D concentrations were associated with an increased risk of stroke compared with high concentrations (RR 1.52; 95% CI 1.20–1.85) [53▪]. Furthermore, low dietary vitamin D intake was a risk factor for 34-year incidence of total stroke and thromboembolic stroke in a cohort of Japanese–American men . Rich food sources of vitamin D are oily fish and fortified dairy foods.
Magnesium supplementation modestly reduces blood pressure . In addition, experimental studies of animals have demonstrated that magnesium deficiency accelerates atherosclerosis and magnesium supplementation suppresses its development [56,57]. A recent meta-analysis of seven prospective studies, including a total of 6477 stroke cases, found an inverse association between dietary magnesium intake and stroke [58▪]. Each 100-mg/day increase in magnesium intake was associated with an 8% reduction in total stroke risk (Fig. 1) [58▪]. A prospective cohort of US women and men found a statistically nonsignificant inverse association between serum magnesium concentrations and risk of ischemic stroke (RR 0.83; 95% CI 0.65–1.05) . Foods rich in magnesium include green leafy vegetables, bananas, whole grains, nuts, and legumes.
A high potassium intake could potentially lower blood pressure but RCTs have provided inconsistent results . In a meta-analysis of 10 prospective studies, including 8695 cases of stroke, every 1000-mg/day increment in potassium intake was associated with a statistically significant 11% lower risk of stroke (Fig. 1) [61▪]. A recent prospective study of patients with established CVD or diabetes observed that higher estimated urinary potassium excretion (surrogate for intake) was associated with a reduced risk of stroke [62▪]. Rich food sources of potassium include fruits, vegetables, potatoes, legumes, and dairy foods. These foods are also rich in dietary fiber, magnesium, vitamin D (fortified low-fat dairy foods), antioxidants, and phytochemicals, which alone or in combination with potassium may account for the observed relation between potassium intake and stroke.
Experimental studies in vitro and in vivo have shown that calcium may lower the risk of CVD via multiple mechanisms, including blood cholesterol concentrations, insulin secretion and sensitivity, vasodilation, inflammatory profile, thrombosis, obesity, and vascular calcification [63▪]. Prospective studies of dietary calcium intake and risk of stroke have yielded inconsistent results [64–74]. In general, an inverse association between calcium intake and stroke has been observed in populations with low calcium intake but not in populations with high intakes (Table 1). In addition, dairy but not nondairy calcium intake has been inversely associated with risk of stroke, suggesting that calcium per se may not be beneficial. In contrast to the observational findings, a meta-analysis of RCTs showed an increased risk of stroke (RR 1.15; 95% CI 1.00–1.32) and myocardial infarction (RR 1.24; 95% CI 1.07–1.45) among individuals allocated to calcium supplementation, with or without vitamin D [75▪].
It is generally accepted that dietary intake of salt (sodium) is directly related to blood pressure [76▪], which is strongly positively associated with risk of stroke [2▪▪]. A high dietary salt intake may also increase the risk of stroke independent of its effects on blood pressure [76▪]. A meta-analysis of prospective studies showed a statistically significant 23% higher risk of stroke for an average daily difference in sodium intake of 86 mmol (equivalent to about 5 g of salt) . Recent results from a prospective study of patients with established CVD or diabetes showed a positive association between estimated 24-h sodium excretion and risk of stroke [62▪]. Sodium reduction has further been demonstrated to lower the risk of cardiovascular events in individuals with prehypertension .
Recent research indicates that total dietary fat intake and absolute intakes of saturated, monounsaturated, and polyunsaturated fat are not associated with risk of stroke. Present evidence indicates that diets high in magnesium and potassium may reduce the risk of stroke, whereas a high sodium (salt) intake and low dietary vitamin D intake likely increase the risk. In addition, available evidence suggests that calcium intake does not reduce the risk of stroke in individuals with high calcium intakes, but might play a role in individuals with low intakes. Future studies should assess whether exchanging saturated fat with unsaturated fat or protein lowers stroke risk. More studies of dietary cholesterol, long-chain omega-3 PUFAs, trans fatty acids, and other specific fatty acids in relation to stroke are warranted. There is also a need for RCTs that assess the effect of magnesium and potassium supplementation on stroke incidence.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 91–92).
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