Dietary Magnesium Intake and Risk of Incident Hypertension Among Middle-Aged and Older US Women in a 10-Year Follow-Up Study

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1 Dietary Magnesium Intake and Risk of Incident Hypertension Among Middle-Aged and Older US Women in a 10-Year Follow-Up Study Yiqing Song, MD, ScD a, *, Howard D. Sesso, ScD a, JoAnn E. Manson, MD, DrPH a,b, Nancy R. Cook, ScD a,b, Julie E. Buring, ScD a,b,c, and Simin Liu, MD, ScD a,b,d To assess the hypothesis that magnesium intake is beneficial in the primary prevention of hypertension, 28,349 female United States health professionals aged >45 years participating in the Women s Health Study (WHS), who initially reported normal blood pressure (systolic blood pressure <140 mm Hg, diastolic blood pressure <90 mm Hg, no history of hypertension or antihypertensive medications), were prospectively studied. A semi-quantitative food frequency questionnaire was used to estimate magnesium intake. During a median follow-up of 9.8 years, 8,544 women developed incident hypertension. After adjustment for age and randomized treatment, magnesium intake was inversely associated with the risk for developing hypertension; women in the highest quintile (median 434 mg/day) had a decreased risk for hypertension (relative risk 0.87, 95% confidence interval [CI] 0.81 to 0.93, p for trend <0.0001) compared with those in the lowest quintile (median 256 mg/day). This inverse association was attenuated but remained significant after further adjustment for known risk factors. In the fully adjusted model, the relative risks were 1.00 (95% CI 0.95 to 1.10), 1.02 (95% CI 0.95 to 1.10), 0.96 (95% CI 0.89 to 1.03), and 0.93 (95% CI 0.86 to 1.02) (p for trend 0.03). Similar associations were observed for women who never smoked and reported no history of high cholesterol or diabetes at baseline. In conclusion, the results suggest that higher intake of dietary magnesium may have a modest effect on the development of hypertension in women Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98: ) Magnesium intake from either diet or supplements is believed to be important in maintaining body magnesium status and thereby maximizing its potentially antihypertensive effects. Results from some, although not all, crosssectional studies suggest that magnesium intake is associated with lower blood pressure (BP) levels. 1,2 Many small controlled trials have examined the possible effects of magnesium supplementation on the treatment of hypertension but yielded apparently conflicting results. 1,3 A recent metaanalysis of randomized clinical trials found that oral magnesium supplementation resulted in small overall reductions in BP in a dose-dependent manner in hypertensive patients. 3 However, a fairly small number of prospective cohort studies have focused on the health effects of dietary magnesium intake for the primary prevention of hypertension with weak a Division of Preventive Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts; b Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; c Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts; d Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, California. Manuscript received March 31, 2006; revised manuscript received and accepted July 3, This study was supported by Grants DK66401, DK62290, CA-47988, HL-43851, and HL from the National Institutes of Health, Bethesda, Maryland. *Corresponding author: Tel: ; fax: address: ysong3@rics.bwh.harvard.edu (Y. Song). or equivocal results. 4 7 We therefore investigated the association between magnesium intake and the incidence of hypertension in apparently healthy women participating in the Women s Health Study (WHS), a large cohort of middle-aged and older United States female professionals. Methods Study population: The WHS is an ongoing randomized, double-blind, placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer. 8 In 1992, a total of 39,876 female United States health professionals aged 45 years without previous myocardial infarction, stroke, transient ischemic attack, or cancer (except for nonmelanoma skin cancer) were enrolled and randomized into the study. Of these, 98% provided detailed information about their diets, completing a 131-item semi-quantitative food frequency questionnaire (SFFQ) in We excluded patients with 70 items left blank on their SFFQs and with energy intakes outside the range of 2,514 kj (600 kcal) to 14,665 kj (3,500 kcal). The study population was then restricted to 28,349 women with complete data on magnesium intake and other major lifestyle variables and without hypertension at baseline. The presence of hypertension at baseline was defined as having no self-reported history of hypertension, no history of antihypertensive treatment, reported systolic BP 140 mm Hg, and diastolic BP 90 mm Hg at study entry. Baseline BP was reported in 1 of 9 ordinal systolic BP categories ranging /06/$ see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 Systemic Hypertension/Magnesium and Hypertension in Women 1617 Table 1 Age-adjusted (in 5-year categories) baseline characteristics according to quintiles of total and dietary magnesium intakes in 28,349 women in the Women s Health Study Characteristic Dietary Magnesium Total Magnesium Q1 Q3 Q5 p Value Q1 Q3 Q5 p Value No. of participants 5,668 5,669 5,671 5,669 5,669 5,670 Median intake (mg/d) Mean age (yrs) Mean body mass index (kg/m 2 ) Alcohol consumption (g/d) Systolic blood pressure (mm Hg) % 19% 25% % 19% 25% % 38% 38% % 39% 38% % 30% 26% % 29% 27% % 14% 12% % 14% 11% Diastolic blood pressure (mm Hg) 65 10% 12% 15% % 11% 15% % 41% 44% % 41% 43% % 39% 35% % 39% 35% % 8.3% 6.7% % 8.3% 6.8% Current smoker 18% 14% 10% % 14% 10% Vigorous exercise ( 4 times/wk) 6.3% 11% 19% % 11% 18% Postmenopausal hormones (current user) 37% 41% 42% % 41% 45% Multivitamin use (current user) 25% 29% 34% % 24% 55% Parental history of MI at 60 yrs 12% 12% 13% % 12% 13% 0.30 History of hyperlipidemia 24% 24% 25% % 25% 25% 0.52 Diabetes mellitus 1.0% 1.2% 1.9% % 1.2% 1.5% 0.07 Mean total calorie (kcal/d) 1,696 1,742 1, ,669 1,764 1, Mean total fat (g/d) Mean protein (g/d) Mean total cholesterol (mg/d) Mean glycemic load* All covariate values are according to the quintiles of total magnesium intake. All the means of nutrients are energy adjusted. * Glycemic load was defined as an indicator of blood glucose induced by a subject s total carbohydrate intake. Each unit of glycemic load represents the equivalent of 1 g carbohydrate from white bread. MI myocardial infarction; Q quintile. from 110 to 180 mm Hg and 7 ordinal diastolic BP categories ranging from 65 to 105 mm Hg. This study was conducted according to the ethical guidelines of Brigham and Women s Hospital. Written informed consent was obtained from all participants. Assessment of magnesium intake: On the SFFQ, participants were asked how often on average they had consumed individual foods of a commonly used portion size during the previous year. Nine possible responses ranging from never to 6 or more times per day were recorded. Nutrient intakes were computed by multiplying the frequency of consumption of each unit of food from the SFFQ by the nutrient content of the specified portion size according to food composition tables from the Harvard Food Composition Database. 9 Data on use of multivitamin supplements were taken into account to assess the intake of supplemental magnesium. Total magnesium represented the sum of magnesium intake from dietary and supplemental sources. Each nutrient was adjusted for total energy using the residual method. 10 In populations of nurses and health professionals, this SFFQ has demonstrated reasonably good validity as a measure of long-term average dietary intakes. 11 Pearson s correlation coefficient between magnesium intake assessed by the SFFQ and 2 weeks of diet records was Outcome ascertainment: As described previously, 13 incident hypertension was based on self-reported BP, treatment, and/or physician diagnosis in our cohort. Incident cases of hypertension were defined by meeting 1 of4 criteria: self-reports of a new physician diagnosis on follow-up questionnaires at years 1 or 3 or on 1 of the annual questionnaires thereafter; self-reports of newly initiated antihypertensive treatment at years 1, 3, or 4; self-reported systolic BP 140 mm Hg; or self-reported diastolic BP 90 mm Hg. Women reporting new physician diagnoses of hypertension also provided the month and year of their diagnoses. Those patients developing hypertension after the development of major concomitant diseases, including myocardial infarction, stroke, pulmonary embolism, and peripheral vascular disease, were not considered as having incident cases of hypertension. On the basis of this definition, 8,544 cases of incident hypertension developed during a median follow-up of 9.8 years (mean 8.0). Selfreported BP in health professionals has been shown to be highly correlated with measured systolic BP (r 0.72) and diastolic BP (r 0.60). 14 We performed a separate study in which an 86% validation rate for self-reported hypertension was observed, consistent with other studies. 15,16 In a comparable population in the Nurses Health Study, 99% of

3 1618 The American Journal of Cardiology ( Table 2 Relative risks (RR) (95% confidence intervals [CI]) of incident hypertension according to magnesium intake in 28,349 women in the Women s Health Study Variable Quintile of Magnesium Intake p Value for Trend Total magnesium intake Median (interquartile range) (mg/d) 256 ( ) 298 ( ) 330 ( ) 367 ( ) 434 ( ) No. of cases 1,727 1,753 1,739 1,676 1,649 Age-adjusted RR (95% CI)* ( ) 0.97 ( ) 0.91 ( ) 0.87 ( ) Multivariate-adjusted RR (95% CI) ( ) 0.99 ( ) 0.93 ( ) 0.89 ( ) Multivariate-adjusted RR (95% CI) ( ) 1.03 ( ) 0.96 ( ) 0.94 ( ) 0.02 Multivariate-adjusted RR (95% CI) ( ) 1.02 ( ) 0.96 ( ) 0.93 ( ) 0.03 Dietary magnesium intake Median (interquartile range) (mg/d) 253 ( ) 292 ( ) 320 ( ) 350 ( ) 400 ( ) No. of cases 1,760 1,739 1,794 1,618 1,633 Age-adjusted RR (95% CI) ( ) 0.98 ( ) 0.85 ( ) 0.84 ( ) Multivariate-adjusted RR (95% CI) ( ) 1.01 ( ) 0.87 ( ) 0.88 ( ) Multivariate-adjusted RR (95% CI) ( ) 1.03 ( ) 0.90 ( ) 0.92 ( ) Multivariate-adjusted RR (95% CI) ( ) 1.02 ( ) 0.89 ( ) 0.91 ( ) * Adjusted for age and randomized treatment. Further adjusted for family history of MI before 60 years of age (yes/no), exercise (rarely/never, 1 time/week, 1 to 3 times/week, and 4 times/week), alcohol use (rarely/never, 1 to 3 drinks/month; 1 to 6 drinks/week, and 1 drink/day), postmenopausal hormone use (never, past, and current), multivitamin use (never, past, and current), smoking (never, past, and current), and total energy intake (quintiles). Multivariate model additionally adjusted for body mass index, history of diabetes mellitus, and high cholesterol. A full model with additional adjustment for dietary intakes of saturated fat (quintiles) and cholesterol (quintiles), glycemic load (quintiles), and sodium intake (quintiles). women who reported high BP had confirmation of their diagnoses by medical record review. 15 Statistical analysis: Participants were divided into quintiles according to their intake of total magnesium from diet and supplements. We used Cox proportional-hazards models to estimate the rate ratios (described as relative risks) and 95% confidence intervals (CIs) of incident hypertension for each quintile of magnesium intake, with the lowest quintile as the referent. Models were first adjusted for age and randomized treatment assignment (vitamin E and aspirin). The second multivariate model added total energy intake (quintiles), smoking (never, past, and current), vigorous exercise (rarely or never, 1 time/week, 1 to 3 times/ week, and 4 times/week), alcohol intake (rarely or never, 1 to 3 drinks/month, 1 to 6 drinks/week, and 1 drink/day), postmenopausal hormone use (never, past, and current), the use of multivitamin supplements (never, past, and current), and parental history of myocardial infarction before 60 years of age (yes or no). The third model made additional adjustment for body mass index (in kilograms per square meter; continuous), history of diabetes mellitus (yes or no), and high cholesterol (yes or no), and the final multivariateadjusted model further controlled for dietary factors, including intakes of saturated fat, cholesterol, sodium, and dietary glycemic load (all categorized as quintiles). Tests of linear trend across increasing quintiles of magnesium intake were conducted by assigning the medians of intakes in quintiles (in milligrams per day), treated as a continuous variable. The same analytic approach was used for analyses of dietary magnesium intake (from diet alone). Because magnesium intake from supplements alone contributed a small proportion of total magnesium intake ( 4%), limited variation of supplemental magnesium intake did not allow us to have sufficient statistical power to perform a separate analysis of magnesium supplements. All statistical analyses were conducted using SAS version 8.0 (SAS Institute Inc., Cary, North Carolina). All p values were 2 tailed. Results In the present study, dietary sources accounted for about 97% of the total intake of magnesium. The median intake of magnesium was 330 mg/day for our cohort of middle-aged women, close to the recommended dietary allowance of 320 mg/day for adult women. 17 Age-standardized characteristics of the study population by total and dietary magnesium intakes are listed in Table 1. At baseline in 1993, women with high magnesium intakes were slightly older and leaner, less likely to be current smokers or alcohol drinkers, and more likely to exercise and to take multivitamins or postmenopausal hormones than those with lower magnesium intakes (Table 1). Magnesium intake was also positively associated with dietary protein and glycemic load and negatively associated with dietary fat and cholesterol. Notably, baseline systolic BP and diastolic BP were inversely associated with total or dietary magnesium intake (Table 1). In the age- and randomized treatment-adjusted models, there was a significant inverse association between magnesium intake and the risk for developing hypertension (Table 2). After adjustment for total energy intake, smoking, exercise, alcohol intake, postmenopausal hormone use, use of multivitamin supplements, and parental history of myocardial infarction before 60 years of age, this inverse association was attenuated but remained statistically significant (p for linear trend ). Additional adjustment for body mass index, history of diabetes mellitus, and high choles-

4 Systemic Hypertension/Magnesium and Hypertension in Women 1619 Table 3 Relative risks (RR) (95% confidence intervals [CI]) of incident hypertension according to magnesium intake in 10,799 women who were nonsmokers and had no histories of diabetes mellitus and high cholesterol levels at baseline in the Women s Health Study Variable Quintile of Magnesium Intake* p Value for Trend Total magnesium intake* Median (interquartile range) (mg/d) 256 ( ) 297 ( ) 330 ( ) 366 ( ) 433 ( ) No. of cases Age-adjusted RR (95% CI) ( ) 0.87 ( ) 0.83 ( ) 0.80 ( ) Multivariate-adjusted RR (95% CI) ( ) 0.90 ( ) 0.86 ( ) 0.82 ( ) Multivariate-adjusted RR (95% CI) ( ) 0.95 ( ) 0.91 ( ) 0.90 ( ) 0.04 Multivariate-adjusted RR (95% CI) ( ) 0.96 ( ) 0.91 ( ) 0.90 ( ) 0.06 Dietary magnesium intake Median (interquartile range) (mg/d) 253 ( ) 291 ( ) 320 ( ) 351 ( ) 399 ( ) No. of cases Age-adjusted RR (95% CI) ( ) 0.93 ( ) 0.76 ( ) 0.77 ( ) Multivariate-adjusted RR (95% CI) ( ) 0.98 ( ) 0.79 ( ) 0.82 ( ) Multivariate-adjusted RR (95% CI) ( ) 1.02 ( ) 0.85 ( ) 0.90 ( ) 0.01 Multivariate-adjusted RR (95% CI) ( ) 1.02 ( ) 0.85 ( ) 0.89 ( ) 0.02 * Adjusted for age and randomized treatment. Further adjusted for family history of MI before 60 years of age (yes/no), exercise (rarely/never, 1 time/week, 1 to 3 times/week, and 4 times/week), alcohol use (rarely/never, 1 to 3 drinks/month, 1 to 6 drinks/week, and 1 drink/day), postmenopausal hormone use (never, past, and current), multivitamin use (never, past, and current), and total energy intake (quintiles). Multivariate model additionally adjusted for body mass index. A full model with additional adjustment for dietary intakes of saturated fat (quintiles) and cholesterol (quintiles), glycemic load (quintiles), and sodium intake (quintiles). terol appeared to further attenuate the inverse association (p for linear trend 0.02). Similar associations were observed after additional adjustment for dietary intake of saturated fat, cholesterol, sodium, and glycemic load (p for linear trend 0.03). The same analyses restricting to dietary magnesium intake (without supplements) resulted in similar but more significant associations and trends. Women with major coronary risk factors may have modified their diets to reduce their risk. To evaluate the robustness of our findings, we limited analyses to women who were nonsmokers and did not have diabetes and hypercholesterolemia at baseline (n 10,799; 2,967 incident cases of hypertension) (Table 3). The results were not materially altered in all models. Discussion In this large prospective cohort with a median follow-up of 9.8 years, we found that high intake of magnesium at baseline was modestly associated with a lower risk for incident hypertension in apparent healthy middle-aged and older United States women. Similar associations were observed in those nonsmokers without a history of diabetes mellitus or high cholesterol levels who were less likely to change diet. These data support the notion that higher magnesium intake from consuming magnesium-rich foods, such as whole grains, nuts, legumes, and green leafy vegetables, may have beneficial effects for the primary prevention of hypertension. Dietary magnesium intake has been associated with a host of other metabolic disorders, including insulin resistance, 18,19 systemic inflammation, 20 dyslipidemia, 18,19 type 2 diabetes, 19,21,22 and cardiovascular disease. 23 The hypothetical relation between magnesium intake and hypertension was first suggested by the results from ecologic studies that showed a negative correlation between water hardness and hypertension. 24,25 However, the interpretation of such comparisons at population levels is always problematic, because ecologic correlations on the basis of grouped data at population levels may not reflect the corresponding association at the individual level due to confounding (known as ecologic fallacy). 26 In addition, the intake of magnesium from drinking water is negligible compared with total magnesium intake from diet. 27 Most epidemiologic data relating dietary magnesium to lower prevalence of hypertension have been provided by numerous cross-sectional studies. The results of most, but not all, cross-sectional studies suggest that magnesium intake may reduce BP in diverse populations. 1,2 Yet the cross-sectional evidence does not necessarily imply any causal relation, because of the inherent limitations of this study design. Prospective data investigating the relation of magnesium intake with the development of hypertension are very limited. 5 7 Our results are similar to those of the Nurses Health Study and the Health Professionals Follow-Up Study, which have reported a significant inverse association between dietary magnesium intake and BP. 5,6 In a recent analysis of the Nurses Health Study, Ascherio et al 12 observed an inverse relation of dietary magnesium with self-reported BP, but not with the incidence of hypertension. After adjusting for age, body mass index, and alcohol intake, the relative risk of incident hypertension was 1.10 (95% CI 0.92 to 1.32, p for trend 0.56), and the average BP was 1.3/1.0 mm Hg lower in women with high magnesium intakes ( 350 mg/day) compared with those with low intakes ( 200 mg/day). In contrast, the Atherosclerosis Risk in Communities (ARIC) study failed to detect a significant association between dietary magnesium and hypertension

5 1620 The American Journal of Cardiology ( but found a modest inverse association between serum magnesium levels and hypertension. 7 Besides differences in study characteristics, the use of a simple, 61-item food frequency questionnaire in the ARIC study might have resulted in nondifferential misclassification of dietary intake and thus biased the associations toward the null. Moreover, the correlation between serum and dietary magnesium in this study was very small (correlation coefficient 0.053). 7 Overall, available evidence for the role of magnesium in the primary prevention of hypertension is not compelling, but one should not rule out a small effect of high magnesium intake in reducing blood pressure in normotensive subjects. A body of evidence from in vitro studies and animal models has suggested a pivotal role of magnesium intake in regulating BP. 28 Numerous small clinical trials have assessed the therapeutic effect of magnesium supplements in hypertension but yielded conflicting results. 1,3 A recent meta-analysis of 20 clinical trials showed that magnesium supplementation led to a small overall reduction in BP in a dose-dependent manner. 3 The pooled results of 14 doubleblind, randomized trials showed that a 10 mmol/day (240 mg/day) increase in magnesium intake was associated with a nonsignificant decrease in systolic BP ( 3.3 mm Hg 95% CI 0.1 to 6.8) and a decrease in diastolic BP ( 2.3 mm Hg, 95% CI 1.0 to 5.6) in hypertensive patients. 3 Notably, small sample sizes, incomplete randomization, the lack of blind designs, variable durations of follow-up, high rates of noncompliance, and differences in magnesium treatment protocols, magnesium formulas and concentrations, and study populations have contributed to the inconsistency in previous trials. The long-term benefits and safety of magnesium treatment on reducing BP remain to be determined in future large well-designed controlled trials. Some limitations of the present study warrant consideration. First, measurement errors of dietary intakes and other factors are inevitable. However, because the data were prospectively collected, the misclassification of dietary intake was likely to be nondifferential, which would lead to an underestimation of the observed association in this study. Second, diet was assessed once, at baseline. The lack of repeated measurement would fail to address the changes in dietary intake over time. However, excluding participants who had ever smoked or had a history of high cholesterol and diabetes mellitus, which allows the reduction of the possibility of bias from diet change, yielded a similar association in this cohort. Third, because magnesium coexisted with many nutrients in the diet, it would be difficult to completely separate the independent effect of magnesium from those of other dietary nutrients, such as fiber, folate, calcium, and potassium. Fourth, our observed modest association might be explained by residual confounding due to some lifestyle and dietary factors. Yet our results were unlikely to be explained by recall or selection bias because of the prospective study design and high follow-up rate. Of note, the inverse association between magnesium intake and risk for incident hypertension was not independent of baseline systolic BP and diastolic BP. Adjustment for baseline systolic BP or diastolic BP or both in any models eliminated the observed inverse associations, because baseline BP is most likely to be influenced by long-term magnesium intake assessed by an SFFQ at baseline, which would be an intermediate variable between dietary intake of magnesium and future risk for hypertension. Controlling for baseline systolic and diastolic BP would not be appropriate for evaluating the impact of dietary magnesium on the development of hypertension in the absence of a study design involving an acute dietary intervention. Finally, because our study population included only female health professionals who were predominantly white, the results of the present study may not be generalizable to those in the general United States population. However, because the ranges of basic characteristics are comparable to those of the general population, the associations found in this study most likely are relevant to women in this age range. We conclude that higher magnesium intake from consuming magnesium-rich foods, such as whole grains, nuts, legumes, and green leafy vegetables, may be beneficial for the primary prevention of hypertension. Acknowledgment: We are indebted to the 39,876 dedicated and committed participants of the WHS. We also acknowledge the contributions of the entire staff of the WHS. 1. Mizushima S, Cappuccio FP, Nichols R, Elliott P. Dietary magnesium intake and blood pressure: a qualitative overview of the observational studies. J Hum Hypertens 1998;12: Yamori Y, Mizushima S. A review of the link between dietary magnesium and cardiovascular risk. J Cardiovasc Risk 2000;7: Jee SH, Miller ER III, Guallar E, Singh VK, Appel LJ, Klag MJ. The effect of magnesium supplementation on blood pressure: a metaanalysis of randomized clinical trials. Am J Hypertens 2002;15: Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr 1987;45: Witteman JC, Willett WC, Stampfer MJ, Colditz GA, Sacks FM, Speizer FE, Rosner B, Hennekens CH. A prospective study of nutritional factors and hypertension among US women. Circulation 1989; 80: Ascherio A, Rimm EB, Giovannucci EL, Colditz GA, Rosner B, Willett WC, Sacks F, Stampfer MJ. A prospective study of nutritional factors and hypertension among US men. Circulation 1992;86: Peacock JM, Folsom AR, Arnett DK, Eckfeldt JH, Szklo M. Relationship of serum and dietary magnesium to incident hypertension: the Atherosclerosis Risk in Communities (ARIC) study. Ann Epidemiol 1999;9: Buring JE, Hennekens CH. The Women s Health Study: summary of the study design. J Myocard Ischemia 1992;4: Watt BK, Merrill AL. Composition of Foods: Raw, Processed, Prepared, Agriculture Handbook No. 8. Washington, DC: United States Government Printing Office, Willett WC, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 1986;124: Willett WC. Nutritional Epidemiology. New York: Oxford University Press, Ascherio A, Hennekens C, Willett WC, Sacks F, Rosner B, Manson J, Witteman J, Stampfer MJ. Prospective study of nutritional factors, blood pressure, and hypertension among US women. Hypertension 1996;27: Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA 2003;290: Klag MJ, He J, Mead LA, Ford DE, Pearson TA, Levine DM. Validity of physicians self-reports of cardiovascular disease risk factors. Ann Epidemiol 1993;3:

6 Systemic Hypertension/Magnesium and Hypertension in Women Colditz GA, Martin P, Stampfer MJ, Willett WC, Sampson L, Rosner B, Hennekens CH, Speizer FE. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 1986;123: Giles WH, Croft JB, Keenan NL, Lane MJ, Wheeler FC. The validity of self-reported hypertension and correlates of hypertension awareness among blacks and whites within the stroke belt. Am J Prev Med 1995;11: National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy of Sciences Press, Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA, Hutchinson RG, Metcalf PA. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study. J Clin Epidemiol 1995;48: Song Y, Manson JE, Buring JE, Liu S. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care 2004;27: Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 2005; 28: Colditz GA, Manson JE, Stampfer MJ, Rosner B, Willett WC, Speizer FE. Diet and risk of clinical diabetes in women. Am J Clin Nutr 1992; 55: Kao WH, Folsom AR, Nieto FJ, Mo JP, Watson RL, Brancati FL. Serum and dietary magnesium and the risk for type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Arch Intern Med 1999;159: Song Y, Manson JE, Cook NR, Albert CM, Buring JE, Liu S. Dietary magnesium intake and risk of cardiovascular disease among women. Am J Cardiol 2005;96: Dawson EB, Frey MJ, Moore TD, McGanity WJ. Relationship of metal metabolism to vascular disease mortality rates in Texas. Am J Clin Nutr 1978;31: Stitt FW, Clayton DG, Crawford MD, Morris JN. Clinical and biochemical indicators of cardiovascular disease among men living in hard and soft water areas. Lancet 1973;1: Schwartz S. The fallacy of the ecological fallacy: the potential misuse of a concept and the consequences. Am J Public Health 1994;84: Rubenowitz E, Axelsson G, Rylander R. Magnesium in drinking water and death from acute myocardial infarction. Am J Epidemiol 1996; 143: Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med 2003;24: