Nutrition and prevention of ischemic stroke: present knowledge, limitations and future perspectives

Nutr Metab CardiovascDis (2004) 14:97-114

97

REVIEW ARTICLE

Nutrition and prevention of ischemic stroke: present knowledge, limitations and future perspectives P. Strazzullo 1, L. Scalfi2, E Branca3, G. CaireUa3, E Garbagnati 3,A. Siani4, G. Barba 4, P. Rubba 1, and G. Mancia5 1Department of Clinicaland Experimental Medicine, 2Department of Food Science,Federico II University of Naples, 3NationalInstitute for Research on Foods and Nutrition, Rome, 4Institute of Food Sciences,CNR, Avellino, and 5Departmentof ClinicalMedicine,Preventionand Applied Biotechnologies,Universityof Milano-Bicocca,Monza,Italy

Abstract Stroke, particularly ischemic stroke, has a major impact on public health due to its high incidence, prevalence and rate of subsequent disability in Italy as in most industrialised countries. Apart from age, many modifiable factors, such as hypertension, smoking, diabetes, dyslipidemia, obesity, physical inactivity, alcohol abuse and hyperhomocysteinemia, have been recognised as playing a role in the pathogenesis of this disease. While appropriate pharmacological therapy has proven effective in the prevention of stroke in particular categories of patients, most of the above mentioned predisposing conditions are amenable to be affected by nutrition. Unequivocal demonstration of a protective or adverse role of single foods and nutrients against the risk of stroke has been however difficult to achieve due to confounding by biological variability, methodological inadequacies in the assessment of individual nutritional habits and difficulty to carry out long-term randomised controlled trials in the nutritional area. Notwithstanding, in several cases, causal relationships could be inferred from case-control and cohort studies in the presence of plausible and reproducible associations, evidence of dose-dependent effects and consistency in the results of different studies.

Key words: Nutrition, ischemicstroke, prevention, foods, nutrients. Correspondence to: Pasquale Strazzullo,MD, Department of Clinical and Experimental Medicine, Federico II University of Naples Medical School, via S. Pansini 5, 80131 Naples, Italy. Received: 15 February 2004;accepted:3 March 2004

The aim of this paper was to review present knowledge and highlight limitations and future perspectives about the role of nutrition in the prevention of ischemic stroke. Nutr Metab Cardiovasc Dis (2004) 14:97-114 ©2004,Medikal Press

Introduction Industrialised countries pay a heavy tribute to cerebrovascular diseases in terms of morbidity and mortality (1). In Italy, stroke causes 10-12% of all deaths and impacts extensively on public health due to its high incidence (187,000 new cases per year), prevalence (870,000 cases in 1999) and rate of subsequent disability (2). Unfortunately, both prevalence and incidence of stroke are expected to rise further in the next years mainly because of population ageing (75% of strokes occur in people over 65 years) (3). Eighty percent of all strokes are recognised as being due to cerebral ischaemia (1). Never perhaps as in the case of stroke, is prevention easier and more effective than treatment. While waiting for more conclusive identification of genetic traits predisposing to stroke, a growing body of evidence has accumulated concerning the factors involved in the pathogenesis of stroke (4-10). Apart from ageing (9, 10), many modifiable factors have been identified, such as hypertension, smoking, diabetes, dyslipidemia, asymptomatic carotid stenosis, atrial fibrillation, obesity, physical inactivity, alcohol abuse, hyperhomocysteinemia (1, 5, 11-18). While appropriate pharmacological therapy of modifiable factors has proved effective in the prevention of stroke (19), hypertension,

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TABLE 1

Nutrition and preventionof stroke: methodologicallimitations. A. Factors hampering the demonstration of cause/effect relationships between foods/nutrients intake and risk of stroke

Biological variability (interaction between different nutrients in multiple combinations) Biological variability (multiple mechanisms of disease) Heterogeneity in individual genetic background

be reasonably inferred from statistical associations provided that: 1) the association is biologically plausible (best if supported by experimental studies); 2) a "dose-effect" relationship is detectable between degree of exposure and rate of disease; and 3) the results of several studies are consistent with each other (Table 1, panel B). The aim of this paper was to review present knowledge and highlight limitations and future perspectives about the role of nutrition in the prevention of ischemic stroke.

Inaccurate estimate of individual lifetime dietary intakes Long-term RCTs difficult to perform B. Conditions allowing to infer causality when evidence from RCTs is not available

The associations detected are biologically plausible (best if supported by results of clinical and/or laboratory experimental investigation) A dose-effect relationship is apparent between exposure to the nutrient and the probability of disease The results of the various studies are consistent with each other RCTs= randomized controlled trial

diabetes, dyslipidemia, obesity, alcohol abuse, and hyperhomocysteinemia, are all amenable to be affected by nutrition: it follows that nutrition has a great potential role in the prevention of stroke and the disabilities that ensue. Nevertheless, in spite of this widely shared belief (7-8, 10, 18), unequivocal evidence of a protective or adverse role of single foods and nutrients has been difficult to achieve for a number of reasons (Table 1, panel A). The most important one is biological variability, deriving from the interaction between genetic background, food components and multiple pathogenic mechanisms, which make the same nutrient or food elicit dissimilar responses in different individuals. Still another reason of confounding is the nosological heterogeneity of stroke which is not accounted for by many epidemiological surveys. Furthermore, the accurate estimate of the usual intake of foods and nutrients is hampered by methodological inadequacies that reduce the likelihood to detect true biological associations. Last but not least, long-term randomised controlled trials in the nutritional area are difficult to implement. In fact, most of our present knowledge on the relationship between nutrition and stroke is based on statistical associations observed in case-control and cohort prospective studies. Notwithstanding, causality may

Role of single nutrients andfoods in the determination of the risk of stroke Fats Fat intake influences the overall risk of cardiovascular disease through its effects on blood lipids, blood pressure (BP), endothelial function, arrythmogenesis and inflammation (10). At least for coronary heart disease (CHD), the type of dietary fatty acids (FA) is a better predictor than total fat intake (10, 20), unsaturated FA intake being associated with decreased risk and saturated FA intake with increased cardiovascular risk (10). Compared with the evidence about the effects on CHD, the relationship between dietary FA intake and the risk of stroke is controversial. A recent cohort study on more than 40,000 men aged 40-75 years with 14 year follow-up failed to provide evidence that the intake of total fat (or animal fat) modifies the risk of ischemic stroke (21); paradoxically, an inverse relationship between dietary fat intake and risk of ischemic stroke had previously been observed in a sample of middle-aged men (22). In other studies, however, dietary saturated FA intake was positively and significantly related to the risk of stroke (23, 24) as well as to carotid artery wall thickness (25). Furthermore, plasma saturated FA concentration, which is expected to reflect dietary intake, was found significantly related to the risk of stroke, although the relationship was attenuated in multivariate analysis (26, 27). Saturated FA intake may negatively affect BP (27b). In addition, because of their well-known effect on serum cholesterol levels (27c), the possible association of serum cholesterol with the risk of stroke should also be evaluated. In an intervention trial in North Karelia (28), a decrease in average serum cholesterol intake was associated with a significant reduction in stroke mortality. Similar results were obtained in other randomised control trials aiming at evaluating the impact of dietary or pharmacological interventions to reduce serum cholesterol, on stroke and total mortality (29-34). However, pharmacological studies were mainly per-

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formed using statins, which may exert other important effects in addition to lowering serum cholesterol levels (35): thus, it is difficult to infer from these observations the extent to which a simple reduction in serum cholesterol is responsible for the observed decrease in mortality from stroke. Noteworthy, no relationship has been found between dietary intake of cholesterol and risk of stroke (21, 36). The possible influence of monounsaturated FA intake has also been investigated. In a case-control study, patients suffering an acute stroke were found to have lower levels of oleic acid in their red cell membranes, most likely as a consequence of a diet poor in these FAs (37). A protective role of higher intake of monounsaturated FAs was found in one study (22) but was not confirmed by a more recent report (21). No relationship has been found between stroke and total polyunsaturated FA intake (21, 22). Linoleic acid is by far the most abundant polyunsaturated FA in the human diet and has a definite effect on lipid profile, mainly on total cholesterol and LDL-cholesterol (10). Lower proportions of linoleic acid in serum polyunsaturated FAs were associated with decreased risk of ischemic stroke (27). However, no relationship with dietary intake was found in two other studies (21, 22). Concerning n-3 polyunsaturated FAs, serum levels of a-linolenic acid were inversely associated with the risk of stroke (26) and, accordingly, higher dietary intakes were associated with lower prevalence of carotid plaques and reduced carotid intima-media thickness (38). As recently reviewed (39, 40), fish consumption is considered a likely protective factor in view of its high n-3 FA content [especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]: indeed, an inverse relationship between fish con-

HGURE 1 Cohort studies of fish consumption and risk of stroke. Higher

~

INTAKE

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lower _-

Western Electric (1996) Zutphen (1996) NHANES I (1996)

_-

Physicians' Health (1995) Nurses'Health (2001)

• OddsRatioand 95% C.I. 0.25

0.50

0.75

1.00

1.25

1.50

sumption and risk of stroke has been observed in ecological and case-control studies (41-45) (Fig. 1). One of these studies (41) found that a minimum of one portion of fish per week was associated with lower incidence of stroke. In another study, a protective effect of fish intake was observed in white women and black individuals of both genders (46). More recently, women reporting higher intake of fish were found to have a lower risk of both total and thrombotic stroke (44, 45) although this inverse association might not be linear. At variance with these positive findings, no effect of fish consumption on the risk of stroke has been reported by other authors (46-49) and in a recent case-control study in a Spanish population, featuring high fish consumption and high incidence of stroke, the risk was paradoxically increased with higher fish consumption (50). On the other hand, no effect of n-3 FAs has been detected on the risk of hemorrhagic stroke (44, 45) with the possible exception of very high "Eskimo" intakes of these fats (39). As recently reviewed (39), dietary n-3 polyunsaturated FAs might exert a beneficial effect on the risk of stroke not only by reducing serum triglyceride levels, but also by their influence on BP, platelet aggregation, endothelial function and arterial compliance. In addition, they may affect insulin resistance, modify the metabolism of adhesion and inflammatory molecules, and compete with arachidonic acid for the synthesis of eicosanoids. Sodium High BP is the most powerful risk factor for stroke and there is unequivocal evidence that habitual sodium intake affects BP (51). In a landmark experiment in chimpanzees, switching from low to high salt diet for five months led to a significant rise in BP which was completely reversed by removal of excess salt (52). The INTERSALT (International Study of Salt and Blood Pressure) cross-sectional investigation estimated, after adjustment for confounders, an average 10/6 mmHg greater increase in BP from age 25 to 55 for a 100 mmol (2.3 g) higher habitual sodium intake (53). The effect of sodium on BP is dose-dependent according to a well conducted one-year long randomised controlled trial (54). The metanalyses of sodium reduction trials (55-57) have provided consistent evidence of such an effect, showing it to be greater in hypertensive (-4.8/-2.5 mmHg) than in normotensive individuals (-1.9/-1.1 mmHg) (56). Is a BP reduction of this magnitude clinically significant? The answer is yes based on epidemiological evidence. The 11.6year follow-up of 347,978 MRFIT (Multiple Risk Factor Intervention Trial) screenees (58) showed that the relative risk of stroke increases gradually across BP deciles and that individuals with BPs in the upper part of the normal range

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have a 3.5-fold increase in the risk of stroke compared with subjects with very low BPs. Thus a large number of cerebrovascular events occur in individuals with only mild BP elevation. Accordingly, it may be inferred that a small downward shift in the entire distribution of BP in the general population could significantly contribute to reduce the burden of cerebrovascular events (59). The recognition of significant inter-individual differences in the BP response to low sodium diet does not challenge the concept that this measure may be beneficial to the majority of individuals (60). Also, there is growing evidence that, apart from its effect on BP, dietary sodium intake may affect the risk of stroke through different and independent mechanisms. The National Health and Nutrition Examination Survey (NHANES) of a large sample of U.S. population (14,417 subjects followed for 19 years) indicated that a 100mmol/day (2.3 g/day) higher sodium intake was associated with higher morbidity and mortality for stroke in overweight participants after adjustment for BE age, gender, race, cholesterol, body mass index (BMI) and smoking (61), thus suggesting that the adverse influence of sodium was in part independent of its effect on BP (61). These results were partly confirmed by the prospective observation of a sample of Finnish population, showing that a 100 retool/day (2.3 g/day) greater 24-hour urinary sodium excretion (representative of sodium intake) was associated with a significantly greater relative risk of stroke, albeit only in women (62). In both studies, a statistically significant interaction was detected between the effects of sodium intake and overweight, suggesting that in overweight individuals high sodium intake may have a particularly detrimental effect. Several clinical and experimental studies provide some clues as to what mechanisms might be involved in the relationship between sodium intake and stroke, independently of BP. A direct association has been reported between sodium intake and pulse wave velocity in healthy normotensive men, suggesting that arterial stiffness is increased in subjects consuming a sodium-rich diet (63). In another study, sodium intake was shown to increase ADP-stimulated platelet aggregation in a dose-dependent way (64). Moreover, sodium chloride appears to influence the rate of cell protein synthesis and cell growth. In an in vitro study, myocardial myoblasts as well as vascular smooth muscle cells exhibited an increased rate of protein synthesis upon raising the sodium chloride concentration in the medium within the physiological range (65). In a recent experimental study in spontaneously hypertensive (SHR) and WKY control rats, a sodium-enriched diet increased the amount of collagen synthesis and deposition in the

heart, stimulated perivascular fibrosis in intra-myocardial vessels and increased collagen deposition in the renal cortex (66), as a result of the stimulation of protein synthesis, cell growth and cell proliferation. It has also been proposed that a high dietary sodium intake promotes end-organ damage by affecting the production of reactive oxygen species (ROS) (67). This effect could be mediated by sodium pump inhibition induced by excess sodium intake (68, 69), in turn causing increased intracytosolic Ca++ concentration and greater vascular smooth muscle cell contractility - both factors leading to oxidative stress and mitochondrial ROS accumulation. Free oxygen radicals stimulate multiple cellular pathways in both vascular and non-vascular tissues, resulting in growth promoting effects in different cell types (67). There is experimental evidence that antioxidant substances may antagonise the increase in ROS induced by sodium-pump inhibition (70). Based on this hypothesis, a novel pathway is envisaged whereby reduction of dietary salt intake might protect from cardiovascular damage (Fig. 2). FIGURE 2

Hypotheticalpathwaywherebya high dietarysodiumintakecould promote end-organdamageby affectingthe productionof reactive oxygenspecies(ROS) (modifiedfromAvivA, J. Hypertens2001). The effectof sodiumcouldbe mediatedby Na-pumpinhibition leadingto increasedcytosolicCa++concentration,greater vascular smooth musclecellcontractilityand thus to oxidativestress and mitochondrialROS accumulation.Free oxygenradicalsstimulate multiplecellularpathwaysin both vascularand non-vasculartissues, resulting in growthpromotingeffectsin differentcelltypes. Growing experimentalevidencesuggeststhat antioxidantsmay antagonisethe increasein ROS inducedby sodium-pumpinhibition (see text). High Sodium Intake ~' ECf- vo ume

,

Nat-pump inhibition

Antioxidants (fruits & vegetables)

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Potassium Several epidemiological studies have detected an inverse relationship between dietary potassium intake and BP both within and across populations (71). In the INTERSALT study, potassium intake was associated with lower BP values after adjustment for age, gender, BMI, alcohol intake, and sodium excretion (72). In the Nurses' Health Study, after accounting for age, BMI and alcohol intake, a potassium intake at baseline greater than 3.2 g/day was associated with a relative risk of 0.77 of developing hypertension in four years compared with an intake lower than 2g/day (73). In the Health Professionals Study, participants with a potassium intake greater than 3.6 g/day had a relative risk of hypertension in four years of 0.65 compared with those reporting an intake lower than 2.4g/day (74). A meta-analysis of randomised controlled trials of potassium supplements indicated that increasing potassium intake by at least 20 mmol/day (0.5 g/day) is associated with significant falls in BP (75). This BP lowering effect was more pronounced in the presence of an elevated sodium intake, in more "salt-sensitive" individuals and in blacks in comparison to whites (75). Similarly, a randomised controlled trial testing the effects of increasing potassium intake by natural sources (fruits, vegetables and legumes) showed that, at the end of one-year follow-up, in the patients assigned to the intervention potassium-rich diet, BP control was achieved with less than half the amount of drugs needed in the control group (76). The nutritional strategies aiming at enhancing dietary potassium intake have been recently reviewed (77, 78). Finally, most observations suggest that the ratio of sodium to potassium intake may be even more important than the individual intakes of the two electrolytes (75). Only a few epidemiological surveys have directly explored the relationship between dietary potassium intake and stroke-associated morbidity and mortality (79, 80). In a 12-year follow-up study on the Rancho Bernardo cohort of 859 men and women (79), the rate of stroke for individuals in the lowest tertile of baseline potassium intake was compared with that of individuals in the highest tertile: the relative risk of stroke was 2.6 in men and 4.8 in women and was unrelated to age, cholesterol, BMI, smoking and BE It was inferred from these data that a 10 mmol (0.4 g) higher potassium intake would be associated with a 40% reduction in stroke mortality. In the INTERSALT study analysing the relationship between urinary electrolyte excretion and all stroke mortality in age-standardised population samples from 25 countries (80), a statistically significant negative association was detected between urinary potassium excretion and cere-

I

i

brovascular mortality in women. A similar association was observed in both men and women in another international study of diet and stroke mortality (23). The relationship between dietary potassium intake and the risk of stroke was evaluated in a representative sample of U.S. men and women participating in the National Health and Nutrition Examination Survey with an average followup of 19 years. Stroke hazard was significantly greater for participants in the lowest quartile (reporting an intake of less than 35 mmol/day or 0.9 g/day of potassium) compared to the remaining study population, after adjustment for other established cardiovascular risk factors (81). In the aforementioned studies the protective effect of potassium was actually only partly mediated by its effect on BP. Accordingly, a number of experimental studies confer biological plausibility to the hypothesis that an elevated potassium intake has a direct protective role against vascular damage. A high potassium diet was able to dramatically reduce the elevated death rate associated with feeding stroke-prone SHR a high-sodium diet (82). In Dahl salt-sensitive rats, increased potassium intake counteracted the sodium-induced renal damage (83) as well as the release of endothelium- and macrophage-derived growth factors (84), suggesting an antiproliferative effect of potassium. The effect of potassium on oxidative endothelial stress was examined by measuring lipid peroxides in the aortic intima and in the plasma of SH stroke-prone rats exposed to a high potassium intake: a significant reduction in lipid peroxide accumulation (85) was detected together with lower endothelial permeability (86) and decreased macrophage adherence to the vascular wall (87). In in vitro experiments, increasing potassium concentration in the medium to values within the physiological range reduced ROS generation by endothelial cultures and human white blood cells (88) and caused a significant inhibition of vascular smooth muscle cell proliferation (89). Taken together, these results provide sound biological plausibility to epidemiological findings and suggest a favourable influence of dietary potassium on vascular function, exceeding the simple relationship with BP control. Magnesium and calcium A role of dietary calcium and magnesium in the prevention of stroke has been claimed based on the results of observational studies (90-92). An inverse association was reported between the intake of magnesium from drinking water and cardiovascular risk (93), magnesium in water being absorbed more easily than magnesium in food.A large cohort study carried out in U.S. men provided strong support for a preventive effect of a diet rich in potassium, magnesium and fiber against

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stroke (91). The protective effect of magnesium was stronger in men with high BP than in normotensive individuals. In this study, there was no association between estimated calcium intake and rate of stroke. A more recent study showed that low serum magnesium concentrations are associated with an increased risk of neurological events, among which stroke, in patients with atherosclerosis (94). In a study carried out in U.S. women, the intakes of calcium, magnesium and potassium were inversely related to stroke risk but the correlation remained significant only for calcium after adjustment for history of hypertension and other cardiovascular risk factors (92). Specifically,this study supported an independent inverse association of ischemic stroke with both dairy and non-dairy calcium intake or calcium supplements. The association between calcium and magnesium intake with the risk of stroke could be partly mediated by their influence on BP, however small this may be (95-98). These effects appeared to be somewhat greater in subjects with higher baseline BP. Magnesium can induce vasodilation by competing with calcium ions for membrane-binding sites (99, 100). Alterations in the concentration of extracellular and/or intracellular free magnesium ions have been associated with proatherogenic mechanisms, eg increase in platelet aggregation and free radical production (101). Moreover, in animal models, low plasma levels of magnesium have been shown to stimulate lipid peroxidation and increase lipid deposition in the vascular wall (102). Noteworthy, an inverse association has been reported between magnesium intake and carotid intima-medial thickness in a study in women (103). In aggregate, the results of the studies on the relationship of calcium and magnesium with stroke are not thoroughly consistent possibly also due to the difficulty to dissect out

i

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Zutphen (1996) Gale (1996)

13-carotene l

m

Western Electric (1995)

Antioxidants When cerebral ischemia takes place, irreversible damage may occur to part of affected neurons; further damage may then be caused by oxygen reperfusion. In the course of ischemia, high amounts of free radicals are formed by several mechanisms and their increase causes oxidative stress, ie an imbalance between cellular ROS production and antioxidant defence. Under these conditions, antioxidants may limit cerebral infarct size and help functional recovery (105-108). Antioxidants are also expected to play a preventive role against stroke thanks to their effects against LDL-cholesterol oxidation, vascular smooth muscle cell proliferation and platelet aggregation (109). Several cohort studies investigated the relationship between dietary intake or plasma level of antioxidants and the rate of stroke (Fig. 3). In the Western Electric Study (110) and the Zutphen Study (111), high [3-carotene (vitamin A) intake was associated with decreased rate of stroke. In the Nurses' Health Study, a moderate not significant inverse association was seen between dietary tocopherol (vitamin E) intake from foods or supplements and the risk of ischemic stroke (112). In the Iowa Health Study on 34,492 women followed for 9 years, dietary tocopherot was associated with decreased stroke mortality; noteworthy, however, this relationship disappeared when total tocopherol intake (ie tocopherol in the diet plus exogenous supplements) was considered (113). No association between dietary tocopherol intake and risk for total and ischemic stroke was found in other two prospective studies (114, 115). Supplemental use of a-toco-

ct-toc¢ )herol

Ascorbic acid Basel (1993)

the effect of these minerals from that of the many other nutrients associated with them in foods such as fruits, vegetables and dairy products (104).

II

Shanghai (1997) ATBC (2000) Iowa Women Health (2000)

i."l.-

0.50 0.75 1.00 1.25

n ii l

0.50 0.75 1,00 1.25

0,25 0.50 0.75 1.00 1.25

FIGURE 3

Cohort studieson dietaryintake or plasma levels of antioxidantsand risk of stroke. The symbolsin the figurerepresentodds ratio and 95% confidenceintervals(see text for details).

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pherol, 13-carotene and ascorbic acid (vitamin C) did not reduce the risk for ischemic stroke in adult men (114), this finding being consistent with the results of another cohort study on postmenopausal women (113). Clinical trials have generally failed to demonstrate that antioxidant supplementation is beneficial to reduce stroke mortality or incidence. The t~-tocopherol-13-carotene(ATBC) study involving a sample of Finnish male smokers, evaluated the effect of ~-tocopherol (50 mg/day) and [3-carotene (20 mg/day) supplementation on the incidence of stroke and mortality (116, 117). Pre-trial serum ~-tocopherol and 13carotene levels were inversely associated with the risk of cerebral infarction (116). t~-tocopherol supplementation decreased the risk of cerebral infarction, whereas concomitantly increasing the risk of fatal hemorrhagic stroke; 8carotene supplementation also increased the risk of fatal hemorrhagic stroke and had no effect on the risk of cerebral infarction (117). In the Linxian Trial, a randomized nutritional intervention trial conducted in China, t~-tocopherol (40 mg/day), 13-carotene (15 mg/day) and selenium (50 lag/day) supplementation did not reduce the risk of death from stroke (118). The GiSSI-P is the largest among all secondary prevention trials; it was carried out on 11,324 patients who had suffered a myocardial infarction. In this study vitamin E (300 mg/day) did not significantly lower the risk of non-fatal stroke as well as risk of occurrence of other primary endpoints (all-cause death, fatal myocardial infarction) (119). Also in the MRC/BHF Heart Protection Study, vitamin E supplementation (600 mg/day) in 20,536 UK adults (aged 4080) with CHD, other occlusive arterial disease, or diabetes, did not produce any significant reduction in mortality or incidence of any type of vascular disease, including stroke (120).The ran-

First Author

Cohort Follow-up No of Size (years) events

Fallon (2001) 2254 Stehouwer (1998) 878 Alftham (1994) 7424 Bostom (1999) 1947 Bots (1999) 7983 Vollset (2001) 4766 Petri (1996) 337 Perry (1995) 5661 Combined 31250

10 10 9 10 3 4 5 12

domised Heart Outcome Prevention (HOPE) trial used natural vitamin E (266 mg/day) in patients at high risk for cardiovascular events. This study also failed to find evidence of any beneficial effects on occurrence of cardiovascular events, or other outcomes, among which stroke (121). The role of vitamin C in the prevention of stroke incidence and mortality remains still unclear. The Basel Prospective Study reported a negative association between death from stroke and serum vitamin C concentration (122), a finding also confirmed in other prospective studies (123-125). Recently, the Rotterdam Study, carried out on 5197 participants followed up for 6.4 years, confirmed that higher intake of antioxidants (vitamins A, C, E and fiavonoids) was associated with lower risk of stroke, with a dose-dependent relationship for vitamin C. This relationship was suggestive, but significant only for vitamin C, and was most pronounced in smokers. In the group of smokers, the relationship was also significant for a-tocopherol (126). On the other hand, in most prospective studies vitamin C intake was not related to the risk of stroke (110, 111,113,115, 127). The association between intake of flavonoids and risk of stroke was evaluated in few epidemiological prospective observational studies (111, 113, 115, 119, 128). In general, results were not consistent and only in two studies was a higher intake of flavonoids (111) and flavonols or flavonones (128) inversely associated with the rate of stroke. Folic acid, vitamin B 6 and B12 Recent meta-analyses of the cohort studies on serum homocysteine (hcy) concentration and stroke (129, 130) showed a consistent association between hyperhomocysteinemia and rate of stroke (Fig. 4). Although the association was attenuat-

FIGURE 4

Odds Ratio (95%C.I.) for 51xmol/Lincrease

Odds Ratio for 5 ~mol/L increase 1.15 1.19 1.21 1.36 1.39 1.76 1.86 3.52 1.42 (1.21 to 1.66)

[]

107 58 74 165 120 16 29 107 676

[] [] [] [] [] [] [] -l0.50

.00

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Results of prospectivestudiesof serum homocysteineconcentrationand stroke (modifiedfrom Wald M et al, BMJ 2002).

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ed when accounting for BP and cigarette smoking, still a predictive role for plasma hey concentration was sustained. On the basis of these data, it was estimated that a decrease in serum hcy by 3 ~tmol/Lcould be associated with an approximately 20% reduction in the risk of stroke. This goal is difficult to achieve by dietary intervention alone as enrichment of the habitual diet with folate-rich food is associated with approximately 10% (1.0-1.5 pmol/L) lower plasma hcy levels (131-135). A greater reduction can be achieved by supplementation with folic acid, vitamin B12 and vitamin B6, which modulate hcy levels by acting on methionine metabolism (129, 136). When supplements are used - a folate dosage of 10005000 mg/day or a multivitamin preparation including vitamin B6 and Blz - favourable changes in surrogate vascular endpoints (arterial reactivity and microalbuminuria) (137-139) or in the rate of clinical events (140) have been demonstrated. In the aforementioned studies the goal of at least 25% reduction in plasma hcy concentration was attained in all cases. In one study, the benefit in terms of vascular effects was observed only in the subgroup in which plasma hcy reduction of >2.0 ~tmol/L had been achieved (138). On the other hand, two studies using folate supplementation around 500 pg/day turned out negative (140, 141). In subjects with flank hyperhcymia supplements are also needed in order to obtain a detectable impact on cardiovascular risk. In addition, it has been suggested that high-dosage folate supplements might be protective per se, independently of hcy reduction (142-144). Hemodialysis patients have severe hyperhomocysteinemia, which is relatively refractory (145, 146) even to high-dosage folate supplements (5-15 mg/day): there is controversy as to whether one mg/day of vitamin B12 (or even higher dosages) may be beneficial to patients at high cardiovascular risk (146, 147). An inverse relationship with dietary intake of folate and the risk of stroke was described in the National Health and Nutrition Survey- Epidemiologic Follow-up Study (NHEFS) on 9,764 men and women (148) while a case-control study suggested that low vitamin B 6 concentrations are strongly associated with cerebrovascular disease (149). High folate dosages in combination with vitamin B 6 and Blz have been proposed for secondary prevention of stroke: an approximately 40% reduction in plasma hey concentration was obtained in these patients by this type of intervention (150). However, these results should be taken with caution in view of the spontaneous oscillations in plasma hcy levels seen acutely after stroke (151). High folate dosages are also being evaluated for patients with dementia (152154), but the results have been so far inconclusive. Randomised controlled trials of correction of hyperhomocysteinemia are currently on the way (155-157): it is expected

P. Strazzullo,et a!

that the results of these studies will conclusively demonstrate the beneficial effect of folate and vitamin supplements on cardiovascular risk and in particular on the risk of stroke. A recent trial on recurrent stroke prevention using high dosage of multivitamin preparation produced a mean reduction of plasma hcy by 2 ~tmol/L as compared with controls on low dosage multivitamin preparation. No detectable effect on recurrent cerebral infarction was demonstrated. However, in this population, a 3 ~tmol/Llower baseline hcy level was assodated with a 10% lower risk of stroke, a 26% lower risk of CHD and a 16% lower risk of death.Therefore, further exploration of the preventive potential of high-dosage multivitamin preparation is warranted and longer trials in different populations with elevated plasma hcy may be necessary (158). It has been proposed that some individuals could be more susceptible to vascular damage due to low folate intake and high circulating hcy levels (130): this is another example of how a certain nutrient might be effective in stroke prevention by acting on specific susceptibility pathways. Alcohol

Several cohort studies examined the possible association between alcohol consumption and stroke and the large majority of them reported a J- or a U-shaped relationship, both low- and high-alcohol consumption being associated with a higher risk of stroke compared with moderate consumption (159-163). Many methodological problems may affect research in this area (163). The most important one is inaccurate self-reporting of alcohol intake by study participants: this introduces a potential bias in the classification of exposure, although validation of questionnaires on alcohol consumption by parallel assessment of plasma levels of liver enzymes has sometimes been attempted (164). Another difficulty is the choice of an appropriate reference group, which is composed in some studies by never-drinkers (abstainers) and in some others by both never-drinkers and former drinkers, many of whom could have stopped alcohol consumption because of cardiovascular or other health problems. Moreover, the U- or J-shaped relationships described are sometimes the result of analyses that do not take into account possible confounders such as gender, age, pre-existing cerebrovascular disease, drinking pattern (eg binge or regular drinking, acute or chronic alcohol load), type of beverage (beer, wine, spirits) and type of stroke (hemorrhagic or ischemic) (163). With regard to the latter, a recent metaanalysis of cohort and case-control studies on alcohol consumption and stroke (165) reported a J-shaped relation between alcohol consumption and relative risk of total and ischemic stroke but a linear association between alcohol con-

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sumption and hemorrhagic stroke. In particular, intakes below 12 g/d or between 12 and 24 g/d were both associated with lower relative risk of ischemic stroke when compared with abstinence from alcohol (RR=0.80 and 0.72, respectively); on the other hand, an alcohol consumption of more than 60g/d was associated with an increased risk of both ischemic (RR=l.69) and hemorrhagic (RR=2.18) stroke. Possible mechanisms explaining the adverse effects of excess alcohol intake are alcohol-induced hypertension, cardiomyopathy, vascular damage (spasm) and atrial fibrillation (165). On the other hand, moderate amounts of alcohol increase high-density lipoprotein levels, decrease platelet aggregation (165) and slow down the rate of smooth muscle cell proliferation (166). To some extent, the effects on platelet aggregation and other clotting mechanisms might be responsible for the relative increase in the risk of hemorrhagic stroke. In the aforementioned meta-analysis (165), the relative risk of stroke as related to alcohol consumption was also analysed separately for men and women.Although a J-shaped relationship was observed in both genders, women drinking more than 60 g/d of alcohol tend to have a higher relative risk of all strokes in comparison with abstainers than men who drink heavily (RR=4.29 vs 1.76, respectively). In another recent study analysing the relationship between alcohol consumption and mortality from any cause, the beneficial effect of moderate alcohol consumption in women was much lower in comparison with men (167), thus implying that, in women, even a moderate alcohol consumption that is protective against stroke may be associated with a higher all-cause mortality. With regard to binge drinking,some studies suggest that it may precipitate cardiovascular events and stroke possibly because of the effects of an acute alcohol load on BP (168).Moreover, acute ingestion of large doses of alcohol has been found to enhance thromboxane-mediated platelet activation (169). Limited evidence is available on the role of different types of alcoholic beverages on the risk of stroke (170-172). Data from the Stroke Prevention in the Young Women Study (170) indicated a protective effect of wine consumption in the previous year that was not observed for those drinking beer or liquor~ Also in a meta-analysis of the effect of wine and beer consumption on cardiovascular risk (171), subgroup analysis for cerebrovascular events suggested a significant protective effect of moderate amounts of wine (RR=0.43) but not beer (RR=0.67) consumption. In beverage-specific analysis of the Framingham Study dataset, only wine consumption was associated with a reduced risk of ischemic stroke (172). Noteworthy, in the same Framingham population, upon stratification by age, alcohol consumption was associated with lower risk of ischemic stroke in subjects aged 60 to 69 years

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independently of the type of beverage, thus focusing on the problem of age as confounder in the statistical association between alcohol consumption and stroke. Recent data from the Physician's Health Study also support a role of alcohol in the secondary prevention of stroke (173). Patients having suffered a stroke who reported a moderate, light or very light consumption of alcohol experienced a significantly lower age-adjusted cardiovascular death rate in comparison with patients who rarely or never drank alcohol, although stroke-specific mortality was not associated with alcohol intake.

Fruit and vegetables The relationships between the intake of fruit and vegetables and the incidence of stroke has been investigated in prospective studies performed worldwide in various cohorts and across different socio-economic groups (111, 174-181). Six very large studies recently published (177-182) have consistently shown a 27 to 55% lower incidence of stroke and reduced mortality from stroke in the groups with highest consumption of fruit and vegetable foods, with the exception of the ARIC study where this beneficial effect could not be demonstrated (182). The studies on the effects of different vegetables (177, 181) indicated that all categories of fruits and vegetables may play a protective role, with a more marked effect for cruciferous vegetables, green leafy vegetables and citrus fruits. Potatoes are not included among the protective vegetables nor are mushrooms, onions, garlic and stalk vegetables (181). A protective effect of fruit and vegetables has been demonstrated for a consumption of at least 500 g/day (177-181). An inverse relationship between risk of stroke and consumption of whole-grain products was observed in a cohort of 75,521 US women (183); this finding, however, was not confirmed by the ARIC study (182). Apart from being rich in vitamins C and E, fruit and vegetables may also act through their content of other antioxidant compounds (first of all, carotenoids and phenolic molecules) (184,185) as well as substances such as potassium, fiber, folate, phytoestrogens, plant enzymes and hormones. The interactions between the molecules occurring in food matrix may produce different, complex effects. Thus, for instance, a reduction in plasma hcy (70), an improvement in antioxidant status and a reduction of BP (185,186) were observed in randomized controlled trials that increased fruit and vegetable intake to approximately 400 g/day.The intake of antioxidants from fruit and vegetables was also significantly correlated in

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humans with an increase in plasma antioxidant capacity (184); in particular, flavonols may have anti-thrombotic properties by protecting LDL molecules from oxidation, inhibiting platelet aggregation and reducing inflammation (107, 187). Dietary patterns

The classical investigations over dietary factors and risk of stroke have included the assessment of food and/or nutrient intake by food histories and food composition tables or by the measurement of nutrient concentrations in the blood or other tissues. Very often, inaccuracies in the estimate of intake and confounding by different factors have made it difficult to attribute associations with risk to specific nutrients or foods. In other cases, the results of these studies have led to hypotheses regarding specific nutrients/foods thought to induce protective or negative effects. While sometimes these hypotheses have been confirmed by the results of in vitro and/or in vivo experimental studies, in several cases the results of controlled clinical trials have been disappointing (188-191). The discrepancy between the findings of observational studies and the results of randomised controlled trials on single nutrients or foods may also suggest that dietary patterns as a whole may be more than the sum of their single components. Thus, for instance, while the beneficial effect of large consumption of fruit and vegetables on the risk of stroke has been supported by several epidemiological surveys, identification of the specific nutrient(s) or molecule(s) responsible for this protective effect is hampered by the huge number of bioactive compounds contained in these food items. Actually, it may well be that it is the synergism between the various components of certain foods or food combinations that produces the health benefits observed. These considerations may have profound implications in both research planning and in delivering preventive and clinical recommendations. At variance with the traditional analytic approach used in nutritional epidemiology (192), some recent studies have attempted to identify dietary patterns associated with endpoints such as total mortality (193), coronary risk (194,195), biochemical markers of coronary artery disease, obesity (196) and peripheral arterial disease (197). Unfortunately, no specific data are available about the effects of overall dietary patterns on the risk of stroke. A Mediterranean dietary pattern was associated with reduced total and CHD mortality in a Greek general population sample (193) and with reduced risk of peripheral arterial disease in an Italian cohort of type 2 diabetic patients (198). According to the classical definitions (198,199), the tradition-

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al Mediterranean diet is characterised by a large intake of vegetables, legumes, fruits and nuts, a high intake of olive oil, with low intake of saturated fats, and a regular moderate intake of ethanol in the form of wine: all these factors have been associated with reduced risk of cardiovascular disease and, in particular, stroke. Other factors, such as physical activity and lifestyle factors, may also contribute to the low cardiovascular disease risk associated with the Mediterranean dietary pattern. In particular, the social support typical of traditional Mediterranean communities and the usual practice of consuming meals with family or friends were both considered factors providing relaxation and relief from daily stress (200). Two remarkable trials, although having endpoints different from stroke, deserve special consideration since they provided suitable models for the investigation of complex dietary patterns in the prevention of chronic diseases (201,202). In the Dietary Approach to Stop Hypertension (DASH) study (203), two different dietary patterns were tested against a control (typical American) diet: a) a fruit and vegetables rich diet, featuring greater intakes of potassium, magnesium and fiber, and b) the DASH combination diet that allowed for a lower total fat content (through reduction of saturated fat) and a higher calcium intake as compared to both the control diet and the fruit and vegetable rich diet (204). During the 8week follow-up period, BP decreased significantly on both the fruit and vegetable rich diet and the DASH combination diet whilst it remained unchanged during the control diet (204). However, the DASH combination diet was more effective in reducing both systolic and diastolic pressure in comparison with the DASH fruit and vegetable rich diet (203). The DASH findings help to understand some aspects of the complex interactions between nutrients and different risk factors for stroke. For instance, the combined effects of the DASH combination diet and a moderate reduction in salt intake were tested in a subgroup of participants (203): sodium reduction from 142 to 65 mmolJday (3.3 down to 1.5 g/day) was associated with a further decrease in systolic BP by as much as 4.6 and 1.7 mmHg, respectively during the control diet and the DASH combination diet. The greater BP decrease observed on the control diet could be explained by the fact that, as previously mentioned, the high potassium content of the DASH diet was probably more effective in reducing BP in the presence of higher sodium intake (203). In the Lyon Diet Heart Study (201,202), a modified Cretan diet was chosen as the experimental dietary intervention in 600 coronary patients. The rationale of the study was based on earlier observations of lower coronary mortality in Cretan males (205) associated with higher concentrations of 18:1n-9 (oleic acid), lower concentrations of 18:2n-6 (linoleic acid)

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and higher concentrations of 18:3n-3 (alpha-linolenic acid) (206). The main objective of the Lyon secondary prevention trial was thus to affect plasma FAs and antioxidant profile through profound modifications of dietary fat and natural antioxidant intake. The summary instructions for the intervention group were: "more bread, more root vegetables and green vegetables, more fish, less meat, no day without fruit, butter and cream to be replaced with canola-oil-based margarine because of its higher ~-linolenic/linoleic acid ratio". Control patients followed a "prudent Western-type diet" based on recommendations by the hospital dietitians or the attending physician. After a mean follow-up of 27 months, there was a 73% reduction in cardiac deaths and non-fatal myocardial infarction. Overall, mortality was reduced by 70% (201). The study was terminated earher by its scientific and ethics committee because of the striking benefit in the experimental group, and patients were notified of the results, but data continued to be collected until all patients had their final close-out visit. The final report of the Lyon Heart Study indicated that the positive effects of intervention had not diminished much over the mean follow-up time of 46 months (202). Although in this study stroke was not a separate end-point, four subjects developed a stroke in the control group vs none in the group following the modified Mediterranean diet. Thus, the results of the DASH and the Lyon Heart Study provide compelling evidence that complex dietary modifications have potential impact at the same time on a number of cardiovascular and cerebrovascular risk factors, such as hypertension, insulin resistance and dyslipidemia, with a possibly synergistic effect (7, 8).

Conclusions and future perspectives In the foregoing sections the scientific evidence supporting a protective or detrimental effect of diet on the risk of stroke has been reviewed. For a number of nutrients and foods, consistent evidence has been obtained from case-control and cohort studies demonstrating significant associations with the risk of stroke. The hypotheses generated by epidemiological observations have often been tested by in vitro and in vivo experimental studies that shed light on the metabolic pathways possibly involved in these relationships. Given the well recognised difficulty to implement long-term randomised controlled trials in this area, consistency in the findings of epidemiological studies, combined with convincing demonstration of the mechanisms possibly involved, is of paramount importance. The conclusions that can be drawn at the present time can be summarised in the following points:

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• There is convincing evidence from randomised controlled trials that both reduction of dietary sodium chloride intake and increased consumption of potassium rich foods may favourably affect BE the main known risk factor for stroke. In addition, consistent and growing evidence from cohort studies suggests that these two nutritional measures may both reduce the risk of stroke, at least in part independently of their effects on BE Plausible mechanisms have been envisaged by experimental investigation whereby these effects might take place. Thus, the current guideline recommendations to limit sodium chloride intake to less than 100 mmol or 6 grams per day and increase potassium intake to at least 80 mmol or 2 grams per day should be intensively pursued. A substantial increase in dietary potassium can be achieved by increasing the consumption of vegetables and fruits, and to a lesser extent, of legumes and nuts. • There is also consistent evidence of an inverse association between fruits, vegetables and to a lesser extent whole grains intake and the risk of stroke. According to several observational studies, increasing the consumption of these vegetable products may help prevent stroke. Fruits and vegetables may act through their content of different substances such as potassium, fiber, folate, flavonoids, phytoestrogens, plant enzymes and hormones, many of which having antioxidant, antithrombotic and antiinflammatory properties. A greater intake of vegetable products (at least six servings per day) is consistent with a wide variety of eating patterns and lifestyles. On the other hand, there is no reliable evidence of the efficacy of dietary supplementation with specific antioxidants; a possible explanation of the failure of supplementation trials is that bolus doses of selected chemical species of antioxidants have been used, thus leading to non physiologic pharmacodynamics,as opposed to the balanced combination of compounds naturally present in food. • The results of epidemiological studies on the dietary intake of total fat or different FAs and risk of stroke are inconclusive with the only possible exception of n-3 FAs, which may exert a protective role. A prudential advice is to limit the intake of saturated FAs to less than 10% of total energy by substituting monounsatured for saturated FAs. Although the optimal n-6:n-3 FA ratio is not established, there is reasonable evidence that consuming at least two servings of fish per week may confer a protective effect. • There is epidemiological evidence that a moderate consumption of alcohol may exert a protective effect on the risk of ischemic stroke. Nevertheless, taking into account

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that alcohol intake can be associated with serious adverse consequences, including overweight, hypertension, liver disease, risk for different cancers and vehicular accidents, people should be advised to consume the equivalent of no more than two drinks (U.S. definition: 1 drink=12 g of ethanol) per day for men and one drink per day for women. Although limited evidence is available about the role of different types of alcoholic beverage on the risk of stroke, consumption of wine in low to moderate amount and with meals is compatible with general dietary advice for prevention of cardiovascular diseases. • At the present time, no controlled clinical trials have been conducted to explore the effects of complex dietary patterns on the risk of stroke. The positive results of two studies aiming at evaluating the effects of complex dietary changes on other cardiovascular endpoints support the need to implement similar clinical trials also on stroke. The identification and development of intermediate end-points for evaluating the effect of the intervention would shorten the time required to obtain accurate information about the final end-point. Until definite scientific evidence is available, a Mediterranean-like dietary pattern as recently reviewed (198) seems to be compatible with all the foregoing statements. In conclusion, the role of nutrition in the prevention of stroke with its high impact on public health and socio-economic costs must not be disregarded and may indeed be even stronger than that supported by present scientific evidence.

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