High adherence to MeD seems to be associated with a lower risk of incident IS independent of potential confounders. Adherence to MeD is not related to the risk of incident hemorrhagic stroke.

Incident stroke was identified in 565 participants (2.8%; 497 and 68 cases of ischemic stroke [IS] and hemorrhagic stroke, respectively) of 20 197 individuals fulfilling the inclusion criteria. High adherence to MeD (MeD score, 5–9) was associated with lower risk of incident IS in unadjusted analyses (hazard ratio, 0.83; 95% confidence interval, 0.70–1.00; P =0.046). The former association retained its significance (hazard ratio, 0.79; 95% confidence interval, 0.65–0.96; P =0.016) after adjustment for demographics, vascular risk factors, blood pressure levels, and antihypertensive medications. When MeD was evaluated as a continuous variable, a 1-point increase in MeD score was independently associated with a 5% reduction in the risk of incident IS (95% confidence interval, 0–11%). We documented no association of adherence to MeD with incident hemorrhagic stroke. There was no interaction of race ( P =0.37) on the association of adherence to MeD with incident IS.

We prospectively evaluated a population-based cohort of 30 239 individuals enrolled in REasons for Geographic and Racial Differences in Stroke (REGARDS) study, after excluding participants with stroke history, missing demographic data or food frequency questionnaires, and unavailable follow-up information. Adherence to MeD was categorized using MeD score. Incident stroke was adjudicated by expert panel review of medical records during a mean follow-up period of 6.5 years.

There are limited data on the potential association of adherence to Mediterranean diet (MeD) with incident stroke. We sought to assess the longitudinal association between greater adherence to MeD and risk of incident stroke.

Introduction

Recent data from American Heart Association indicate that cerebrovascular diseases account for ≈1 of every 18 deaths in the United States, whereas an American has a stroke every 40 seconds on average.1,2 By 2050, the incidence of stroke is estimated to more than double, with particularly large increases in the elderly and in minority groups (particularly Hispanics).3 Despite recent advances in acute stroke treatment, effective primary stroke prevention, by means of improved control of vascular risk factors, has the greatest potential to reduce its burden.4 However, ≤25% of all strokes are not attributable to these recognized risk factors.4,5 In recent years, several dietary factors, including salt or high saturated fatty acids intake, dietary fiber, olive oil, fresh fruit/vegetable intake, and moderate alcohol consumption, have been shown to exhibit harmful or protective effects on the risk and stroke mortality.6,7

The traditional Mediterranean diet (MeD) is a dietary pattern characterized by high consumption of plant foods, high intake of olive oil as principal source of monounsaturated fat, low intake of saturated fat with limited consumption of meat and dairy products, and moderate intake of fish and alcohol.8 It has recently received increased attention because high adherence to MeD has been associated with longer survival, reduced risk of cardiovascular or cancer mortality, and lower likelihood of neurodegenerative disorders, including the Alzheimer disease or incident cognitive impairment.9–13 Furthermore, a systematic review ranked the Mediterranean-style diet as the most likely dietary model to provide protection against coronary heart disease.14 There are limited prospective data15–18 investigating the potential relationship of adherence to MeD with incident stroke and these are mainly in white populations,15,16 whereas blacks have been under-represented in a single North-American study.18

The present study aims to extend previous research by capitalizing on the large, geographically dispersed, black-white race- and sex-balanced sample of REasons for Geographic and Racial Differences in Stroke (REGARDS) subjects.19 We sought to determine longitudinally the potential association between higher adherence to MeD and lower risk of stroke before and after controlling for potential confounders. Moreover, we investigated potential relationships of MeD patterns with specific stroke subtypes, including ischemic and hemorrhagic stroke (IS and HS), using the validated REGARDS protocol for the verification of incident stroke subtypes.19 Finally, we evaluated the potential interaction of race (blacks versus whites) on the association of adherence to MeD with incident stroke subtypes.

Subjects and Methods

Study Design

REGARDS is a national, population-based, longitudinal cohort study with oversampling from the stroke-belt region of the United States, an area that has stroke mortality rates higher than the rest of the United States.19 From January 2003 to October 2007, a total of 30 239 individuals ≥45 years were enrolled and were followed by telephone twice a year for incident stroke. Detailed descriptions of REGARDS cohort have been published elsewhere19–22 and are available in the online-only Data Supplement.

Data Collection and Definitions

Data variables were gathered at baseline via a computer-assisted, telephone interview followed by a home visit 3 to 4 weeks later during which blood, urine, blood pressure, ECG, medication audit, and anthropometric data were collected. Self-administered questionnaires (including a food frequency questionnaire) were left with the participant to gather information and e-mail back. Variables included in the present analysis are age, race, sex, region of residence, height, weight, body mass index, waist circumference, income, education, smoking status, sedentary behavior, myocardial infarction, diabetes mellitus, atrial fibrillation, systolic blood pressure, diastolic blood pressure, high cholesterol, antihypertensive regimen (specific drug classes), and perceived general health status. Additional details on definitions of data variables are available elsewhere.13,19–22

Dietary Assessment and MeD

Average food consumption information at baseline was obtained using the self-administered Block 98 Food Frequency Questionnaire,23 which was left with each participant during the in-person visit with instructions for completion and a stamped envelope in which to return the questionnaire. Detailed description of construction of MeD is available in the online-only Data Supplement.

The MeD score was computed as the sum of scores in the 9 food categories (range, 0–9), with a higher score indicating a higher adherence to MeD.11–13,24–26 Adherence to MeD was categorized as high, moderate, and low using MeD score tertiles (MeD score, 6–9, 4–5, and 0–3, respectively).11–13 The diet score was also analyzed in a median split (low adherence range, 0–4; high adherence range, 5–9).11–13 Adherence to MeD was assessed using both dichotomization and trichotomization of MeD score to yield comparable results to previous studies evaluating potential associations of adherence to MeD with incident neurological disorders11–13 and to be consistent with the findings of a recent meta-analysis that assessed the relationship of MeD with the risk of cerebrovascular diseases by dichotomizating and trichotomizating MeD score.26

Stroke Ascertainment

REGARDS participants were contacted via telephone for every 6 months to ascertain vital status and to obtain information on reasons for hospitalization, including stroke, transient ischemic attack, and stroke symptoms. Medical records were pursued if the participant reported seeking medical care for stroke or transient ischemic attack or was hospitalized for stroke symptoms or unknown reason. Once a medical record was received, it was reviewed by a committee of clinicians to verify that a stroke occurred and to provide stroke subtyping as hemorrhage versus infarction. Stroke was defined either according to the World Health Organization definition of focal neurological deficit lasting >24 hours or as a nonfocal neurological symptoms with imaging consistent with stroke, as previously described.24,25 The National Death Index was also queried annually to identify stroke deaths that might not have been hospitalized.25

Because this is a national epidemiological study, the adjudication of potential stroke events included review of medical records collected from hospitals and emergency departments all across the county. For the most part, imaging reports associated with the suspected stroke were available and were used in determination of whether a stroke occurred. In addition, it should be noted that measures of stroke severity were not abstracted from these medical records. For the present analysis, strokes occurring through September 1, 2012, were included.

Statistical Analyses

The 2-tailed Pearson χ2 test for categorical variables and ANOVA or Kruskal-Wallis test for continuous variables was used to assess intergroup differences between participants with high, moderate, and low adherence to MeD. The relationship between adherence to MeD and incident IS, as well as HS, was evaluated separately in a set of incremental Cox proportional hazards models (with high adherence to MeD as reference group), as previously described.22 Additional information about the incremental Cox proportional hazards models and the presence of potential interactions is available in the online-only Data Supplement. Analyses were conducted using SAS version 9.2 (SAS Institute, Inc, Cary, NC).

Results

A total of 30 239 individuals were included in REGARDS. After excluding participants with the history of stroke (n=2088), incomplete dietary data (n=7738), and missing follow-up (n=216), the sample of 20 197 (67%) individuals included in the present analyses had a mean age of 65±9 years, 33% were black (n=6670), 44% were male (n=8853), and 56% (n=11 368) were from the stroke-belt region. The MeD score ranged from 0 to 9 with a bell-shaped (ie, approximately normal) distribution, with 42% of participants (n=8354) having a score of 4 or 5. The mean MeD score was 4.4±1.7. A total of 9181 individuals (53%) had a low adherence to MeD (MeD score, 0–4). Demographic characteristics and environmental and vascular risk factors in participants with low, moderate, and high adherence to MeD are presented in Table 1. MeD adherence was greater among men, black race, residents of regions other than the stroke belt, and nonsmokers and was lower among those with hypertension, diabetes mellitus, obesity, and sedentary lifestyle.

Table 1. Baseline Characteristics by Tertile of Mediterranean Diet Score in the REGARDS Study Variables Mediterranean Diet Score 6–9 (n=5211) 4–5 (n=8354) 0–3 (n=6632) P Value Demographics Male, n (%) 2465 (47) 3614 (43) 2774 (42) <0.001 Black, n (%) 1780 (34) 2820 (34) 2070 (31) <0.001 Age <65 y, n (%) 4225 (51) 3675 (55) 2462 (47) <0.001 Mean age (SD), y 66 (9) 65 (9) 64 (9) <0.001 Residence in the stroke belt, n (%) 2721 (52) 4800 (57) 3847 (58) <0.001 Income >$75 000, n (%) 1168 (22) 1488 (18) 902 (14) <0.001 College graduate, n (%) 2517 (48) 3277 (39) 1891 (29) <0.001 Comorbid conditions, n (%) Diabetes mellitus 771 (15) 1531 (18) 1250 (19) <0.001 Heart disease 842 (16) 1331 (16) 1057 (16) 0.947 Hypertension 2426 (47) 4075 (49) 3225 (49) 0.019 Atrial fibrillation 409 (8) 685 (8) 540 (8) 0.733 Obesity 1559 (30) 3071 (37) 2687 (41) <0.001 Lifestyle factors, n (%) Sedentary 376 (7) 994 (12) 1087 (16) <0.001 Current smoking 428 (8) 1034 (12) 1246 (19) <0.001 Blood pressure levels, mm Hg (SD) Mean systolic blood pressure 126 (16) 126 (16) 127 (16) 0.001 Mean diastolic blood pressure 76 (9) 76 (9) 77 (10) 0.006

During a mean follow-up period of 6.5±2.2 years, incident stroke was identified in 565 participants (2.8%). IS and HS were documented in 497 (88% of all strokes) and 68 participants (12% of all strokes), respectively. Results of incremental Cox proportional hazards models estimating the association of adherence to MeD (evaluated by dichotomization of MeD score) with incident IS appear in Table 2. High adherence to MeD was associated with lower risk of incident IS in initial unadjusted analyses (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.70–1.00; P=0.046). After adjusting for demographics, environmental and vascular risk factors, blood pressure levels, and antihypertensive medications use (model IV), high adherence to MeD was independently associated with a reduction of 21% in the risk of incident IS (HR, 0.79; 95% CI, 0.65–0.96; P=0.016). When MeD was evaluated in Cox proportional hazards models as a continuous variable, a 1-point increase in MeD score was independently associated with a 5% reduction in the risk of incident IS (95% CI, 0% to 11%) after adjustment for all potential confounders (model IV).

Table 2. Association of Adherence to Mediterranean Diet (MeD) Stratified by Dichotomization of MeD Score With Incident Ischemic Stroke on Incremental Cox Proportional Hazards Models Association MeD Score High Adherence (MeD Score, 5–9); n=9234 Low Adherence (MeD Score, 0–4); n=10889 n strokes =208 n strokes =284 Crude Reference HR=0.83 (95% CI, 0.70–1.00); P=0.0460 Model I Reference HR=0.76 (95% CI, 0.64–0.91); P=0.0030 Model II Reference HR=0.80 (95% CI, 0.67–0.96); P=0.0140 Model III Reference HR=0.82 (95% CI, 0.68–0.98); P=0.0336 Model IV Reference HR=0.79 (95% CI, 0.65–0.96); P=0.0164

There was no interaction of race (P=0.37) on the association of MeD with the risk of incident IS in the unadjusted analyses. The associations of MeD with the risk of incident IS separately for blacks and whites, as well as the effect modification by race, are presented in Table I in the online-only Data Supplement. After adjustment for all potential confounders (model IV), high adherence to MeD was associated with a lower risk of stroke in blacks (HR, 0.61; 95% CI, 0.44–0.87) but not in whites (HR, 0.89; 95% CI, 0.70–1.12; P for interaction=0.07). We also detected no interaction of age (P=0.46), sex (P=0.76), stroke-belt region (P=0.67), atrial fibrillation (P=0.47), history of heart disease (P=0.42), diabetes mellitus (P=0.85), hypertension (P=0.90), and systolic blood pressure (P=0.67) on the association of adherence to MeD with incident IS.

Results of incremental Cox proportional hazards models estimating the association of adherence to MeD (dichotomized in low and high adherence to MeD groups) with incident HS are shown in Table II in the online-only Data Supplement. We documented no association of high or moderate adherence to MeD with incident HS both in the initial univariate (P=0.418) and in the multivariate analyses adjusting for potential confounders (model II; P=0.762). When MeD was evaluated in Cox proportional hazards models as a continuous variable, a 1-point increase in MeD score was not associated with the risk of HS (HR, 0.91; 95% CI, 0.78–1.05) after adjustment for all potential confounders (model IV). There was no interaction of age (P=0.28), sex (P=0.21), race (P=0.38), stroke-belt region (P=0.67), and systolic blood pressure levels (P=0.39) on the association of adherence to MeD with incident HS.

All analyses were repeated after trichotomizing MeD score in the groups of low (MeD score, 0–3), moderate (MeD score, 4–5), and high (MeD score, 6–9) adherence. Table 3 presents the findings of incremental Cox proportional hazards models evaluating the association of adherence to MeD with incident IS. High adherence to MeD was associated with a low risk of incident IS (HR versus low adherence=0.78; 95% CI, 0.61–1.00; P=0.047) in the unadjusted analyses. After adjustment for all potential confounders, the former association was slightly attenuated (HR versus low adherence=0.78; 95% CI, 0.60–1.01; P=0.057).

Table 3. Association of Adherence to Mediterranean Diet (MeD) Stratified by Tertiles of MeD Score With Incident Ischemic Stroke on Incremental Cox Proportional Hazards Models Association MeD Score Low Adherence (MeD Score, 0–3); n=6632 Moderate Adherence (MeD Score, 4–5); n=8354 High Adherence (MeD Score, 6–9); n=5211 n strokes =167 n strokes =222 n strokes =108 Crude Reference HR=1.03 (95% CI, 0.84–1.26); P=0.779 HR=0.78 (95% CI, 0.61–1.00); P=0.047 Model I Reference HR=0.94 (95% CI, 0.77–1.15); P=0.559 HR=0.69 (95% CI, 0.54–0.88); P=0.003 Model II Reference HR=0.97 (95% CI, 0.80–1.19); P=0.802 HR=0.73 (95% CI, 0.57–0.94); P=0.013 Model III Reference HR=1.00 (95% CI, 0.82–1.23); P=0.996 HR=0.76 (95% CI, 0.60–0.98); P=0.034 Model IV Reference HR=0.96 (95% CI, 0.78–1.20); P=0.752 HR=0.78 (95% CI, 0.60–1.01); P=0.057

The results of incremental Cox proportional hazards models investigating the association of trichotomized MeD score with incident HS are presented in Table III in the online-only Data Supplement. High adherence to MeD was not associated with the risk of HS in either the unadjusted or the adjusted Cox proportional hazards models (model II: HR versus low adherence=1.58; 95% CI, 0.83–2.99; P=0.164).

Discussion

Our longitudinal study showed that low adherence to MeD was associated with a higher risk of incident IS in a large population-based sample of US black and white adults during a mean follow-up period of 6.5 years. This relationship persisted after adjustment for numerous potential confounders. Moreover, we found no evidence for interaction among race, sex, or region of residence and the relationship of adherence to MeD and incident IS, while we failed to document any association between adherence to MeD and risk of HS.

Our findings are in-line with the results of a recent meta-analysis that quantitatively synthesized all studies evaluating the association between adherence to MeD and risk of stroke, depression, cognitive impairment, and Parkinson disease.26 The protective association of high adherence to MeD with likelihood or risk of incident stroke has been replicated in both case-control and longitudinal studies. In addition, the former association was detected in studies conducted in non-Mediterranean countries. Our study puts more insight in the examined relation for US populations, notably concerning both races. Interestingly, when stroke subtypes were separately examined, the meta-analysis detected no association between moderate or high adherence to MeD and likelihood of HS both in case-control (n=1) and in cohort studies (n=2). In contrast, high adherence to MeD was strongly related to a lower likelihood of IS in case-control studies, whereas a nonsignificant trend was documented between high adherence to MeD and lower risk of incident IS in longitudinal cohort studies. Notably, the prior 3 cohort studies15,17,18 that investigated the potential association of dietary patterns with the risk of cerebrovascular diseases had a lower statistical power to identify effects on specific stroke subtypes, and the relationship of high or moderate adherence to MeD with the incidence of IS did not reach the level of statistical significance. Consequently, our study expands the preliminary findings of the prior cohort studies15,17,18 and comprehensive meta-analysis26 that detected a trend toward lower incidence of IS in persons with higher adherence to MeD.

Our observations are consistent with the mounting literature underscoring a potential beneficial role of a healthy dietary pattern, such as MeD in cerebrovascular disease protection. More specifically, a detailed analysis within the Nurses’ Health Study showed that 70% of incident stroke (both ischemic and hemorrhagic) could be avoided by healthy food choices that are consistent with the traditional MeD in combination with regular physical exercise and smoking abstinence.27 Moreover, a recent population-based cohort study undertaken in a setting in which the traditional MeD is still prevalent (Greece) found evidence that closer adherence to this diet was associated with reduced incidence of cerebrovascular diseases defined using International Classification of Diseases, Tenth Revision, codes.28 Finally, the results of a recent randomized-controlled trial provided additional evidence that among persons at high cardiovascular risk, a MeD supplemented with extravirgin olive oil or nuts reduced the incidence of major cardiovascular events, with comparisons of stroke risk being the only component of the primary end point that reached statistical significance in secondary analyses.29

The association of high adherence to MeD with lower incidence of IS but not HS is intriguing. Neuroimaging studies have provided preliminary evidence demonstrating protective relation between MeD and white-matter hyperintensities,30 as well as infarcts detected in brain MRI.31 However, high adherence to MeD was not cross-sectionally or longitudinally related to a lower risk of cerebral microbleeds or intracerebral hemorrhages.30,31 These observations are suggestive of a vascular protective component of this diet that may preferentially reduce the risk of cerebral ischemia. Another plausible explanation may be related to the fact that MeD has been shown to exert salutary effects in risk factors that are associated with a high risk of IS (but not HS), including diabetes mellitus32 and metabolic syndrome.33 Interestingly, recent randomized-controlled trial data indicate that MeD is associated with a higher rate of regression and a lower rate of progression of common carotid artery intima-media thickness in patients with diabetes mellitus in comparison with a standard low-fat diet.34 Common carotid artery intima-media thickness has been repeatedly shown to be strongly associated with the risk of IS (but not HS) both cross-sectionally35 and longitudinally.36 However, high saturated fats reflecting low adherence to MeD have been shown to be protective for HS.37 Consequently, it may be postulated that the lack of association between adherence to MeD and risk of HS may be attributed to the limited intake of high saturated fats in MeD.

The findings of the present study are subject to certain limitations. For one, methodological shortcomings related to the construction of MeD score (equal weighting of underlying food categories and underestimation of total food and caloric intake) need to be acknowledged. Moreover, the assessment of dietary intake was performed only at baseline, and thus, we were unable to capture potential changes in dietary patterns during the follow-up period that may have affected the reported associations.

In addition, it should be noted that the dietary assessment was self-administered and subject to differential return by patients, and this may have resulted in selection or recall biases because patients were sent information on how to complete the questionnaires, which were mailed back to the study center. This is the reason why data on food frequency questionnaires were available in 74.4% of the participants. However, it should be noted that the completion rate was similar to previously published REGARDS analyses13,25,38 and was as good as compared with even interviewer administered rates from other large epidemiological studies. More specifically, we have recently compared baseline characteristics between excluded and included individuals in a similar analysis that investigated the longitudinal association of adherence to MeD with risk of incident cognitive impairment (with incomplete data on food frequency questionnaires being by far the most common reason for study exclusion).13 Patients who were excluded from the analyses differed from included subjects in terms of income, education, and race. Included individuals were more likely to have graduated college, have an income >$75 000, and self-identify as white. There were no other differences between individuals excluded and included in the analyses in terms of age, sex, location of residence, smoking and exercise habits, vascular risk factors, depressive symptoms, and self-reported health status.13 Similar findings were reproduced in the present analyses, and the lack of imbalances between included and excluded study participants in terms of demographics and vascular risk factors provides further reassurance (in addition to the large sample size) for limited risk of selection bias.

Moreover, the observational design of the present study cannot rule out the possibility of residual confounding by unknown risk factors, such as general healthier lifestyle or higher adherence to medication intake of individuals adhering to a MeD. In addition, it should be noted that the definition of HS was broad and grouped together clinical syndromes with different pathophysiology (eg, parenchymal hemorrhage, subarachnoid hemorrhage) that might have different potential associations with dietary and other factors. This, combined with the lower overall incidence of HS in the study (and hence lower statistical power), could partly explain the lack of an association with adherence to MeD. Lastly, it should be kept in mind that REGARDS findings focus on black/white disparities in stroke risk and fail to examine other racial/ethnic groups.

In conclusion, greater adherence to MeD was associated with lower risk of incident IS in REGARDS data set independent of potential confounders. The former association was not reproduced for HS, while we detected no evidence for race, sex, or region interactions in the relationship of adherence to MeD with incident cerebrovascular events (both ischemic and hemorrhagic). Our findings lend support to the accruing data, indicating that healthy dietary habits are critical to effective primary stroke prevention and their beneficial effects seem to apply to different racial subgroups and different regions across the United States.

Sources of Funding This research project is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke , National Institutes of Health , and Department of Health and Human Service . The content is solely the responsibility of the authors and does not necessarily represent the official views and positions of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health . The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. Dr Georgios Tsivgoulis has been supported by European Regional Development Fund—Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123 ).

Disclosures Dr Tsivgoulis had the idea for the paper and data analyses and wrote the first version of the manuscript. Dr Psaltopoulou contributed to the study design, analysis plan, and editing of the manuscript. Dr Wadley contributed to editing of the manuscript. Drs Alexandrov, Howard, Unverzagt, Moy, and Howard contributed to editing of the manuscript. Dr Kissela contributed to the study design and editing of the manuscript. Dr Judd analyzed the data, contributed to study design, analysis plan, and editing of the manuscript.

Footnotes