Dietary fats and other nutrients on stroke

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1 REVIEW C URRENT OPINION Dietary fats and other nutrients on stroke Susanna C. Larsson Purpose of review This review summarizes current epidemiologic evidence regarding the associations of dietary fat and other nutrients with risk of stroke. Recent findings Recent epidemiologic studies show no association of total fat intake or absolute intakes of saturated, monounsaturated, or polyunsaturated fat with risk of stroke. Data on long-chain omega-3 polyunsaturated fatty acids in relation to stroke risk are inconclusive but may favor fewer strokes in women. Insufficient evidence exists for trans fatty acids, other fatty acids, and dietary cholesterol intake. Present evidence indicates that high dietary magnesium and potassium intakes may lower the risk of stroke, whereas a high sodium (salt) intake and a low dietary vitamin D intake likely increase stroke risk. Calcium does not prevent stroke in populations with moderate-to-high calcium intakes but might play a role in populations with low calcium intakes. Supplementation with single vitamins likely has no protective effect on stroke in well nourished populations. Summary Available epidemiologic evidence indicates that diets high in magnesium and potassium may play a role in the prevention of stroke, whereas a high sodium intake is a risk factor. It remains unclear whether specific fatty acids, dietary cholesterol, and combinations of vitamins affect the risk of stroke. Keywords dietary fat, minerals, nutrients, stroke, vitamins INTRODUCTION 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 [1]. 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 [1]. 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 [3]. 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. DIETARY FAT With regard to coronary heart disease (CHD), convincing evidence indicates that specific fatty acids Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence to Susanna C. Larsson, PhD, Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, PO Box 210, Stockholm SE-17177, Sweden. Tel: ; fax: ; Susanna.Larsson@ki.se Curr Opin Lipidol 2013, 24:41 48 DOI: /MOL.0b013e eea ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins

2 Nutrition and metabolism KEY POINTS Recent epidemiologic evidence indicates that total dietary fat intake and absolute intakes of saturated, monounsaturated, and polyunsaturated fat do not affect the risk of stroke. Omega-3 polyunsaturated fatty acid intake has been inversely associated with risk of stroke in women but not in men. Current evidence indicates that low 25-hydroxyvitamin D concentrations are associated with increased risk of stroke. High dietary magnesium and potassium intakes are associated with reduced risk of stroke, whereas a high sodium intake increases the risk. Calcium does not prevent stroke in populations with moderate-to-high calcium intakes but might play a role in populations with low calcium intakes. 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 [6]. Statins and other lipid-lowering therapy have been shown to reduce the risk of stroke in CHD patients [7]. 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 [7]. Total fat 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 [8]. 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]. Saturated fat 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), ] [14]. 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 [11], and a cohort of women and men [13] found no association between saturated fat intake and risk of stroke. Unsaturated fat Randomized controlled trials (RCTs) have shown that substitution of carbohydrates with unsaturated fat or protein can lower blood pressure and improve lipid levels [15]. 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 , for highest vs. lowest tertile). Dietary intake of a-linolenic acid was not associated with risk of stroke in prospective studies from the USA [16] and Sweden [10]. A Dutch prospective study found an inverse association of dietary but not plasma a-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 [10] and US [20] 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 [21]. There 42 Volume 24 Number 1 February 2013

3 Dietary fats and other nutrients on stroke Larsson 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 [22], or Swedish [13], Finnish [23], or Chinese [24] 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 [25]. Results from a RCT of 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) [26]. Consumption of fish was associated with a modest, but statistically significant, reduction in stroke risk in a recent meta-analysis of 15 prospective studies [27]. 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 [28]. 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 , for each 2 g/day increase in intake) [9]. In contrast, another prospective study of US women found an excess risk of intraparenchymal hemorrhage in the lowest quintile of trans fatty acid intake [29]. Intake of trans fatty acids was not associated with risk of stroke in a prospective study of US men [12]. Dietary cholesterol 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 [30]. 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 [10]. In contrast, a small Japanese cohort study found an inverse relation between cholesterol intake and mortality from ischemic stroke [10]. Other prospective studies have not found an association of cholesterol intake with risk of ischemic stroke [9,12,29], total hemorrhagic stroke [12], or intraparenchymal hemorrhage [29,33]. VITAMINS AND MINERALS Fruit and vegetable consumption has consistently been inversely associated with risk of stroke [34]. 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 adult Americans [35]. Another prospective cohort of US women found no relation between multivitamin use and stroke [36]. Vitamins Although antioxidants such as b-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 ) [44]. 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 [47]. Homocysteine concentrations can be lowered by up to 25% with folic acid supplementation and by a further 7% with vitamin B12 supplementation [48]. Some prospective studies conducted in CVD-free populations have reported an inverse association between dietary folate intake and stroke risk [49]. A metaanalysis of 13 RCTs, including individuals with preexisting 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 ) [50]. Nevertheless, a beneficial effect was observed in trials testing combination therapy of folic acid and vitamins B6 and B12 (RR 0.83; 95% CI ) [50]. A benefit from B vitamin supplementation for stroke prevention ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins 43

4 Nutrition and metabolism may only be seen in populations with low folate intake [51]. 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 ) [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 [54]. Rich food sources of vitamin D are oily fish and fortified dairy foods. Magnesium Magnesium supplementation modestly reduces blood pressure [55]. 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 Study Country Publication year Relative risk (95% CI) Magnesium intake (100 mg/day) CVDFACTS Taiwan 2008 ARCS USA 2009 NHS USA 1999 ATBC HPFS Finland USA WHS USA 2005 SMC Sweden 2011 Overall 0.62 (0.36, 1.05) 0.88 (0.81, 0.97) 0.90 (0.79, 1.02) 0.94 (0.87, 1.02) 0.95 (0.77, 1.17) 0.95 (0.80, 1.14) 0.99 (0.82, 1.20) 0.92 (0.88, 0.97) Potassium intake (1000 mg/day) SCS CVDFACTS HPFS CHS JACC NHANES I SMC ATBC NHS RS CHS Overall USA 1987 Taiwan 2008 USA 1998 USA 2002 Japan 2008 USA 2001 Sweden 2011 Finland 2008 USA 1999 Netherlands 2007 USA (0.12, 0.60) 0.64 (0.45, 0.91) 0.83 (0.67, 1.03) 0.83 (0.72, 0.96) 0.88 (0.70, 1.11) 0.89 (0.79, 1.01) 0.91 (0.78, 1.05) 0.93 (0.88, 0.99) 0.95 (0.75, 1.21) 1.03 (0.65, 1.62) 1.10 (0.92, 1.31) 0.89 (0.83, 0.96) FIGURE 1. Relative risks of stroke associated with magnesium and potassium intake in prospective studies. The relative risks are for an increment of 100 mg/day in magnesium intake and 1000 mg/day in potassium intake. Squares represent studyspecific relative risk estimates (size of the square reflects the study-specific statistical weight); horizontal lines represent 95% CIs; diamonds represent summary relative risk estimates with 95% CIs. The Cardiovascular Health Study provided separate results for nonusers of diuretics (first estimate) and users of diuretics (second estimate). ARCS, Atherosclerosis Risk in Communities Study; ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CHS, Cardiovascular Health Study; CVDFACTS, CardioVascular Disease risk FACtor Two-township Study; HPFS, Health Professionals Follow-up Study; JACC, Japan Collaborative Cohort Study; NHANES, National Health and Nutrition Examination Survey; NHS, Nurses Health Study; RS, Rotterdam Study; SCS, Southern California Study; SMC, Swedish Mammography Cohort; WHS, Women s Health Study Volume 24 Number 1 February 2013

5 Dietary fats and other nutrients on stroke Larsson Table 1. Prospective studies of dietary calcium intake and stroke Reference Study name (country) Sample size, sex, and age Cases (n) Follow-up Average calcium intake (mg/day) Adjustments a RR (95% CI) for highest vs. lowest category A B C D E F G H Abbott et al. [64] Ascherio et al. [65] Honolulu Heart Program (USA) Health Professional Follow-up Study (USA) Iso et al. [66] Nurses Health Study (USA) Marniemi et al. [67] Umesawa et al. [68] 3150 men, years men, years women, years NA (Finland) 755 men and women, years Japan Collaborative Cohort Study (Japan) men and women, years 229 total strokes 22 years 406 T: 0.56 ( ); D: 0.67 ( ); N: 1.25 ( ) X X X X X X 328 total strokes 8 years 800 T: 1.05 ( ) X X X X X X X 386 ischemic strokes 14 years 670 T: 0.73 ( ); D: 0.70 ( ); N: 0.91 ( ) 70 total strokes 10 years 1420 T: 1.34 ( ) X X 566 total stroke deaths 9.6 years 449 b ; 462 c T: 0.68 ( ) b ; D: 0.53 ( ) b ; T: 0.94 ( ) c ; D: 0.57 ( ) c X X X X X X X X X X X X X X Larsson et al. [69] Umesawa et al. [70] Weng et al. [71] Goldbohm et al. [72] Larsson et al. [73] Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (Finland) Japan Public Health Center Study (Japan) CardioVascular Disease risk FACtor Two-township Study (Taiwan) Netherlands Cohort Study (Netherlands) Swedish Mammography Cohort (Sweden) Li et al. [74] Heidelberg Cohort (Germany) men, years men and women, years 1772 men and women, >40 years men and women, years women years men and women, years 3281 total strokes 13.6 years 1379 T: 1.14 ( ) X X X X X X X 1321 total strokes 12.9 years 439 T: 0.71 ( ); D: 0.70 ( ); N: 0.85 ( ) X X X X X X X 132 ischemic strokes 10.6 years 591 T: 0.66 ( ) X X X X X X X 842 total stroke deaths 10 years 950 b ; 904 c T: 0.91 ( ) b ; X X X X X T: 0.73 ( ) c 1680 total strokes 10.4 years 1012 T: 1.08 ( ) X X X X X X X X 260 total strokes 11 years 748 T: 1.12 ( ); D: 1.01 ( ); N: 1.26 ( ) X X X X X X X CI, confidence interval; D, dairy calcium; N, nondairy calcium; RR, relative risk; T, total dietary calcium. a Adjustments: A, age; B, smoking; C, BMI; D, physical activity; E, diabetes; F, history of hypertension of measured blood pressure; G, alcohol consumption; H, other nutrients. b Men. c Women ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins 45

6 Nutrition and metabolism 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 ) [59]. Foods rich in magnesium include green leafy vegetables, bananas, whole grains, nuts, and legumes. Potassium A high potassium intake could potentially lower blood pressure but RCTs have provided inconsistent results [60]. 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. Calcium 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 ) and myocardial infarction (RR 1.24; 95% CI ) among individuals allocated to calcium supplementation, with or without vitamin D [75 ]. Sodium 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) [77]. 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 [78]. CONCLUSION 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. Acknowledgements None. 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 ). 1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics: 2010 update a report from the American Heart Association. Circulation 2010; 121:e46 e Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42: This is an excellent overview of the evidence on established and emerging risk factors for stroke. It summarizes evidence-based recommendations for primary prevention of stroke Volume 24 Number 1 February 2013

7 Dietary fats and other nutrients on stroke Larsson 3. Shimizu Y, Maeda K, Imano H, et al. Chronic kidney disease and drinking status in relation to risks of stroke and its subtypes: the Circulatory Risk in Communities Study (CIRCS). Stroke 2011; 42: Willett WC. Dietary fats and coronary heart disease. J Intern Med 2012; 272: This is a comprehensive review on the association between dietary fat and coronary heart disease. The conclusions were that specific fatty acids play important roles in the cause and prevention of coronary heart disease, but total fat as a percentage of energy is unimportant. 5. Hooper L, Summerbell CD, Thompson R, et al. Reduced or modified dietary fat for preventing cardiovascular disease. Cochrane Database Syst Rev 2012; 5:CD This review assesses the effect of reduction and/or modification of dietary fats on total mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomized clinical trials. The conclusion was that findings from longer trials are suggestive of a small but potentially important reduction in cardiovascular risk on modification of dietary fat, but not reduction of total fat. 6. Cholesterol, diastolic blood pressure, and stroke: strokes in people in 45 prospective cohorts. Prospective studies collaboration. Lancet 1995; 346: Corvol JC, Bouzamondo A, Sirol M, et al. Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003; 163: Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295: Yaemsiri S, Sen S, Tinker L, et al. Trans fat, aspirin, and ischemic stroke in postmenopausal women. Ann Neurol doi: /ana [Epub ahead of print] 10. Larsson SC, Virtamo J, Wolk A. Dietary fats and dietary cholesterol and risk of stroke in women. Atherosclerosis 2012; 221: Atkinson C, Whitley E, Ness A, Baker I. Associations between types of dietary fat and fish intake and risk of stroke in the Caerphilly Prospective Study (CaPS). Public Health 2011; 125: He K, Merchant A, Rimm EB, et al. Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study. BMJ 2003; 327: Wallström P,SonestedtE,HlebowiczJ,et al. Dietary fiber and saturated fat intake associations with cardiovascular disease differ by sex in the Malmo Diet and Cancer Cohort: a prospective study. PLoS One 2012; 7:e Siri-Tarino PW, Sun Q, Hu FB, Krauss RM. Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease. Am J Clin Nutr 2010; 91: Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005; 294: He K, Rimm EB, Merchant A, et al. Fish consumption and risk of stroke in men. JAMA 2002; 288: de Goede J, Verschuren WM, Boer JM, et al. N-6 and n-3 fatty acid cholesteryl esters in relation to incident stroke in a Dutch adult population: A nested casecontrol study. Nutr Metab Cardiovasc Dis [Epub ahead of print] 18. de Goede J, Verschuren WM, Boer JM, et al. Alpha-linolenic acid intake and 10-year incidence of coronary heart disease and stroke in middleaged men and women in the Netherlands. PLoS One 2011; 6:e Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011; 58: This is an excellent review of available evidence for cardiovascular effects of longchain (seafood) omega-3 polyunsaturated fatty acids, including their main dietary sources, effects on physiological risk factors, potential molecular pathways and bioactive metabolites, effects on specific clinical endpoints, and current dietary guidelines. 20. Iso H, Rexrode KM, Stampfer MJ, et al. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA 2001; 285: de Goede J, Verschuren WM, Boer JM, et al. Gender-specific associations of marine n-3 fatty acids and fish consumption with 10-year incidence of stroke. PLoS One 2012; 7:e Morris MC, Manson JE, Rosner B, et al. Fish consumption and cardiovascular disease in the physicians health study: a prospective study. Am J Epidemiol 1995; 142: Montonen J, Järvinen R, Reunanen A, Knekt P. Fish consumption and the incidence of cerebrovascular disease. Br J Nutr 2009; 102: Yuan JM, Ross RK, Gao YT, Yu MC. Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China. Am J Epidemiol 2001; 154: Park Y, Park S, Yi H, et al. Low level of n-3 polyunsaturated fatty acids in erythrocytes is a risk factor for both acute ischemic and hemorrhagic stroke in Koreans. Nutr Res 2009; 29: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto miocardico. Lancet 1999; 354: Larsson SC, Orsini N. Fish consumption and the risk of stroke: a doseresponse meta-analysis. Stroke 2011; 42: Mozaffarian D, Aro A, Willett WC. Health effects of trans-fatty acids: experimental and observational evidence. Eur J Clin Nutr 2009; 63 (Suppl 2):S5 S Iso H, Stampfer MJ, Manson JE, et al. Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women. Circulation 2001; 103: Kaluza J, Wolk A, Larsson SC. Red meat consumption and risk of stroke: a meta-analysis of prospective studies. Stroke doi: /STRO- KEAHA Ginsberg HN, Karmally W, Siddiqui M, et al. Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women. Arterioscler Thromb Vasc Biol 1995; 15: Ginsberg HN, Karmally W, Siddiqui M, et al. A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men. Arterioscler Thromb 1994; 14: Iso H, Sato S, Kitamura A, et al. Fat and protein intakes and risk of intraparenchymal hemorrhage among middle-aged Japanese. Am J Epidemiol 2003; 157: He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 2006; 367: Watkins ML, Erickson JD, Thun MJ, et al. Multivitamin use and mortality in a large prospective study. Am J Epidemiol 2000; 152: Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women s Health Initiative cohorts. Arch Intern Med 2009; 169: Kubota Y, Iso H, Date C, et al. Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: the Japan Collaborative Cohort Study (JACC) study. Stroke 2011; 42: Myint PK, Luben RN, Welch AA, et al. Plasma vitamin C concentrations predict risk of incident stroke over 10 y in participants of the European Prospective Investigation into Cancer Norfolk prospective population study. Am J Clin Nutr 2008; 87: Voko Z, Hollander M, Hofman A, et al. Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 2003; 61: Hak AE, Ma J, Powell CB, et al. Prospective study of plasma carotenoids and tocopherols in relation to risk of ischemic stroke. Stroke 2004; 35: Kurl S, Tuomainen TP, Laukkanen JA, et al. Plasma vitamin C modifies the association between hypertension and risk of stroke. Stroke 2002; 33: Yochum LA, Folsom AR, Kushi LH. Intake of antioxidant vitamins and risk of death from stroke in postmenopausal women. Am J Clin Nutr 2000; 72: Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial. JAMA 2008; 300: Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women s Antioxidant Cardiovascular Study. Arch Intern Med 2007; 167: Bin Q, Hu X, Cao Y, Gao F. The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomised controlled trials. Thromb Haemost 2011; 105: In this meta-analysis of 13 randomized controlled trials, no protective effect of vitamin E supplementation on stroke of any type was observed. 46. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003; 361: Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 2002; 22: Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005; 82: Larsson SC, Männistö S, Virtanen MJ, et al. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers. Am J Epidemiol 2008; 167: Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke 2010; 41: Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011; 378: Van der Schueren BJ, Verstuyf A, Mathieu C. Straight from D-Heart: vitamin D status and cardiovascular disease. Curr Opin Lipidol 2012; 23: This is a comprehensive overview of available evidence linking vitamin D status, including the effect of vitamin D supplementation, to the risk of cardiovascular events. It concluded that the evidence to support a beneficial role for vitamin D in preventing cardiometabolic diseases, although plausible, is not available yet ß 2013 Wolters Kluwer Health Lippincott Williams Wilkins 47

8 Nutrition and metabolism 53. Sun Q, Pan A, Hu FB, et al. 25-Hydroxyvitamin D Levels and the Risk of Stroke: a prospective study and meta-analysis. Stroke 2012; 43: A prospective study and meta-analysis of seven prospective studies of the association between 25-hydroxyvitamin D concentrations and risk of stroke. This study showed that low vitamin D concentrations are associated with an increased risk of stroke. 54. Kojima G, Bell C, Abbott RD, et al. Low dietary vitamin d predicts 34-year incident stroke: the honolulu heart program. Stroke 2012; 43: Dickinson HO, Nicolson DJ, Campbell F, et al. Magnesium supplementation for the management of essential hypertension in adults. Cochrane Database Syst Rev 2006; 3:CD Altura BT, Brust M, Bloom S, et al. Magnesium dietary intake modulates blood lipid levels and atherogenesis. Proc Natl Acad Sci U S A 1990; 87: Orimo H, Ouchi Y. The role of calcium and magnesium in the development of atherosclerosis. Experimental and clinical evidence. Ann N Y Acad Sci 1990; 598: Larsson SC, Orsini N, Wolk A. Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. Am J Clin Nutr 2012; 95: This is a meta-analysis of seven prospective studies of dietary magnesium intake and stroke. The overall results showed an 8 and 9% reduction in risk of total stroke and ischemic stroke, respectively, for each 100-mg/day increment in dietary magnesium intake. 59. Ohira T, Peacock JM, Iso H, et al. Serum and dietary magnesium and risk of ischemic stroke: the atherosclerosis risk in communities study. Am J Epidemiol 2009; 169: Dickinson HO, Nicolson DJ, Campbell F, et al. Potassium supplementation for the management of primary hypertension in adults. Cochrane Database Syst Rev 2006:CD Larsson SC, Orsini N, Wolk A. Dietary potassium intake and risk of stroke: a dose-response meta-analysis of prospective studies. Stroke 2011; 42: This meta-analysis of 10 prospective studies found that the risk of stroke decreased by 11% for every 1000-mg/day increase in dietary potassium intake. An inverse relation between dietary potassium intake and stroke was only observed for ischemic stroke but the number of hemorrhagic strokes was limited. 62. O Donnell MJ, Yusuf S, Mente A, et al. Urinary sodium and potassium excretion and risk of cardiovascular events. JAMA 2011; 306: This is a prospective study of patients with established cardiovascular disease or diabetes mellitus of the association between estimated 24-h urinary sodium and potassium excretion (surrogates for intake) and cardiovascular events. This study found a positive relation between sodium excretion and stroke risk, whereas higher potassium excretion was associated with a reduced risk. 63. Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs 2012; 12: This is a review of experimental, epidemiologic, and clinical evidence regarding the role of calcium intake in the development of cardiovascular disease. 64. Abbott RD, Curb JD, Rodriguez BL, et al. Effect of dietary calcium and milk consumption on risk of thromboembolic stroke in older middle-aged men. The Honolulu Heart Program. Stroke 1996; 27: Ascherio A, Rimm EB, Hernan MA, et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation 1998; 98: Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999; 30: Marniemi J, Alanen E, Impivaara O, et al. Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis 2005; 15: Umesawa M, Iso H, Date C, et al. Dietary intake of calcium in relation to mortality from cardiovascular disease: the JACC Study. Stroke 2006; 37: Larsson SC, Virtanen MJ, Mars M, et al. Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male smokers. Arch Intern Med 2008; 168: Umesawa M, Iso H, Ishihara J, et al. Dietary calcium intake and risks of stroke, its subtypes, and coronary heart disease in Japanese: the JPHC Study Cohort I. Stroke 2008; 39: Weng LC, Yeh WT, Bai CH, et al. Is ischemic stroke risk related to folate status or other nutrients correlated with folate intake? Stroke 2008; 39: Goldbohm RA, Chorus AM, Galindo Garre F, et al. Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands. Am J Clin Nutr 2011; 93: Larsson SC, Virtamo J, Wolk A. Potassium, calcium, and magnesium intakes and risk of stroke in women. Am J Epidemiol 2011; 174: Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 2012; 98: Bolland MJ, Grey A, Avenell A, et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040. This is a reanalysis of the Women s Health Initiative Calcium/Vitamin D Supplementation Study as well a meta-analysis of three randomized controlled trials assessing the effect of calcium supplementation, with or without vitmain D, on risk for cardiovascular events. Theresults showed that combined calcium and vitamin D supplementation modestly increased the risk of myocardial infarction and stroke. 76. Susic D, Frohlich ED. Salt consumption and cardiovascular, renal, and hypertensive diseases: clinical and mechanistic aspects. Curr Opin Lipidol 2012; 23: This review discusses relevant and novel studies on the association between sodium intake and cardiovascular structure and function, with focus on blood pressure-independent effects of salt on the heart, arteries, and kidneys. 77. Strazzullo P, D Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 2009; 339:b Cook NR, Cutler JA, Obarzanek E, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ 2007; 334: Volume 24 Number 1 February 2013