International Study Of Macro/Micronutrients And Blood Pressure Research Articles

A Metabolome-Wide Association Study of fruit and vegetable consumption and associations with cardiovascular risk factors: the INTERMAP study

BackgroundEpidemiological evidence linking blood pressure (BP) and body weight-lowering effects with fruit and vegetable consumption mostly relies on self-reported dietary assessment prone to misreport and under- or overestimation of relationships. We characterized objective 24-hr urinary metabolites and a derived metabolite score associated with fruit and vegetable intake and assessed their associations with BP and body mass index (BMI), with validation across cohorts. MethodsWe used untargeted proton nuclear magnetic resonance spectroscopy (1H NMR) of two timed repeated 24-hr urine collections from free-living participants from the US (n=2,032) and the UK (n=449) of the cross-sectional International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). We evaluated correlations between fruit and vegetable intake assessed by 24-hr dietary recalls with 7,100 1H NMR features, adjusted for confounders and multiple testing. We related identified metabolites and a metabolite score with BP and BMI using extensively adjusted multiple linear regression models. ResultsWe characterized eleven 1H NMR-derived 24-hr urinary metabolites related to fruit and vegetable intake, reproducible across multiple 24-hr urine collections of both cohorts. Proline betaine, citrate, N-methylproline, scyllo-inositol, 2-hydroxy-2-(4-methyl cyclohex-3-en-1-yl) propoxyglucuronide, and proline were associated with fruit intake, specifically with Rutaceae intake, while S-methyl-L-cysteine sulfoxide and S-methyl-L-cysteine sulfoxide metabolite were associated with Brassicacea intake. The metabolite score, explaining 39.8% of fruit and vegetable intake, was inversely associated with systolic BP (-1.65 mmHg; 95% confidence interval (CI): -2.68,-0.62, P<0.002) and BMI (-1.21 kg/m2; 95% CI: -1.62,-0.78, P<0.0001). These associations were to a large extent explained by urinary citrate excretion. ConclusionWe identified 1H NMR-derived urinary metabolites associated with fruit and vegetable consumption, consistent and reproducible between urine collections and across populations. A higher fruit and vegetable-related metabolite score showed associations with lower systolic BP and BMI, mainly mediated by citrate, but would need confirmation in further studies. Study registrationThis study was registered at the clinicaltrials.gov registration (https://clinicaltrials.gov/study/NCT00005271?term=NCT00005271&rank=1) as NCT00005271.

Blood pressure interactions with the DASH dietary pattern, sodium, and potassium: The International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP)

ABSTRACTBackgroundAdherence to the Dietary Approaches to Stop Hypertension (DASH) diet enhances potassium intake and reduces sodium intake and blood pressure (BP), but the underlying metabolic pathways are unclear.ObjectivesAmong free-living populations, we delineated metabolic signatures associated with the DASH diet adherence, 24-hour urinary sodium and potassium excretions, and the potential metabolic pathways involved.MethodsWe used 24-hour urinary metabolic profiling by proton nuclear magnetic resonance spectroscopy to characterize the metabolic signatures associated with the DASH dietary pattern score (DASH score) and 24-hour excretion of sodium and potassium among participants in the United States (n = 2164) and United Kingdom (n = 496) enrolled in the International Study of Macro- and Micronutrients and Blood Pressure (INTERMAP). Multiple linear regression and cross-tabulation analyses were used to investigate the DASH-BP relation and its modulation by sodium and potassium. Potential pathways associated with DASH adherence, sodium and potassium excretion, and BP were identified using mediation analyses and metabolic reaction networks.ResultsAdherence to the DASH diet was associated with urinary potassium excretion (correlation coefficient, r = 0.42; P < 0.0001). In multivariable regression analyses, a 5-point higher DASH score (range, 7 to 35) was associated with a lower systolic BP by 1.35 mmHg (95% CI, −1.95 to −0.80 mmHg; P = 1.2 × 10−5); control of the model for potassium but not sodium attenuated the DASH-BP relation. Two common metabolites (hippurate and citrate) mediated the potassium-BP and DASH-BP relationships, while 5 metabolites (succinate, alanine, S-methyl cysteine sulfoxide, 4-hydroxyhippurate, and phenylacetylglutamine) were found to be specific to the DASH-BP relation.ConclusionsGreater adherence to the DASH diet is associated with lower BP and higher potassium intake across levels of sodium intake. The DASH diet recommends greater intake of fruits, vegetables, and other potassium-rich foods that may replace sodium-rich processed foods and thereby influence BP through overlapping metabolic pathways. Possible DASH-specific pathways are speculated but confirmation requires further study. INTERMAP is registered as NCT00005271 at www.clinicaltrials.gov.

Jeremiah Stamler, MD (1919-2022).

Jeremiah Stamler, MD (1919-2022).

The association of fish consumption and its urinary metabolites with cardiovascular risk factors: the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP)

ABSTRACTBackgroundResults from observational studies regarding associations between fish (including shellfish) intake and cardiovascular disease risk factors, including blood pressure (BP) and BMI, are inconsistent.ObjectiveTo investigate associations of fish consumption and associated urinary metabolites with BP and BMI in free-living populations.MethodsWe used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP), including 4680 men and women (40–59 y) from Japan, China, the United Kingdom, and United States. Dietary intakes were assessed by four 24-h dietary recalls and BP from 8 measurements. Urinary metabolites (2 timed 24-h urinary samples) associated with fish intake acquired from NMR spectroscopy were identified. Linear models were used to estimate BP and BMI differences across categories of intake and per 2 SD higher intake of fish and its biomarkers.ResultsNo significant associations were observed between fish intake and BP. There was a direct association with fish intake and BMI in the Japanese population sample (P trend = 0.03; fully adjusted model). In Japan, trimethylamine-N-oxide (TMAO) and taurine, respectively, demonstrated area under the receiver operating characteristic curve (AUC) values of 0.81 and 0.78 in discriminating high against low fish intake, whereas homarine (a metabolite found in shellfish muscle) demonstrated an AUC of 0.80 for high/nonshellfish intake. Direct associations were observed between urinary TMAO and BMI for all regions except Japan (P < 0.0001) and in Western populations between TMAO and BP (diastolic blood pressure: mean difference 1.28; 95% CI: 0.55, 2.02 mmHg; P = 0.0006, systolic blood pressure: mean difference 1.67; 95% CI: 0.60, 2.73 mmHg; P = 0.002).ConclusionsUrinary TMAO showed a stronger association with fish intake in the Japanese compared with the Western population sample. Urinary TMAO was directly associated with BP in the Western but not the Japanese population sample. Associations between fish intake and its biomarkers and downstream associations with BP/BMI appear to be context specific. INTERMAP is registered at www.clinicaltrials.gov as NCT00005271.

Abstract P228: Relationships of Dietary and Supplement Magnesium Intake and Its Urinary Metabolomic Biomarkers With Blood Pressure: The INTERMAP Study

Background: Magnesium (Mg) and other mineral intakes are vital contributors to a healthy diet and appear to have a modest effect on the risk of hypertension. Studies suggest that supplemental Mg can significantly lower blood pressure (BP). Here, we investigate associations of total Mg consumption with the level of its urinary metabolomic biomarkers, and BP. Method: We used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) on 4269 men and women aged 40-59 years from Japan, China, United Kingdom, and United States (US). Regression coefficients with BP per 2 standard deviation (SD) higher dietary Mg from food plus supplement (obtained from 24-hr dietary recalls), urinary Mg (measured by atomic absorption flame photometry) and small molecules (analysed by direct injection mass spectrometry) were estimated using multivariable models, adjusted for age, gender, population sample, intake of total energy and other confounders (see Table). To estimate overall association, country-specific regression coefficients were pooled, weighted by inverse of their variance. Results: Average Mg intakes were 454 (SD=207) mg/day for 770 persons who reported Mg supplementation (89% from US), and 300 (SD=101) mg/day for those who did not. High correlation was found between Mg intake from food plus supplements with urinary Mg ( r =0.38, P&lt;0.0001). Partial correlations of small molecules with total Mg intake ranged from -0.007 to 0.19 for ascorbic acid (P&lt;0.0001). Total Mg intake higher by 261.87 mg/day (2SD) was associated with a systolic BP difference of -2.65 mm Hg ( P =6x10 -5 ). Urinary Mg excretion higher by 2.66 mmol/day was associated with a diastolic BP difference of -1.02 mm Hg (P=0.02). There was a non-significant inversed association between ascorbic acid and BP in some multivariable regression models. Conclusion: Higher intake of Mg, including supplements, was associated with lower BP levels.

Metabolic phenotyping for discovery of urinary biomarkers of diet, xenobiotics and blood pressure in the INTERMAP Study: an overview.

The etiopathogenesis of cardiovascular diseases (CVDs) is multifactorial. Adverse blood pressure (BP) is a major independent risk factor for epidemic CVD affecting ~40% of the adult population worldwide and resulting in significant morbidity and mortality. Metabolic phenotyping of biological fluids has proven its application in characterizing low-molecular-weight metabolites providing novel insights into gene-environmental-gut microbiome interaction in relation to a disease state. In this review, we synthesize key results from the INTERnational study of MAcro/micronutrients and blood Pressure (INTERMAP) Study, a cross-sectional epidemiologic study of 4680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom and the United States. We describe the advancements we have made regarding the following: (1) analytical techniques for high-throughput metabolic phenotyping; (2) statistical analyses for biomarker identification; (3) discovery of unique food-specific biomarkers; and (4) application of metabolome-wide association studies to gain a better understanding into the molecular mechanisms of cross-cultural and regional BP differences.

Food sources of dietary sodium in the Japanese adult population: the international study of macro-/micronutrients and blood pressure (INTERMAP).

It is often reported that Na intake levels are higher in Japan than in western countries. Detailed analysis of food intake and its association with Na intake are necessary for supporting further decreases in Na consumption in Japan. We investigated the association between Na and food intake by food group using data from the Japanese participants of the INTERMAP Study. Results from the Japanese participants of the INTERMAP Study who did not use antihypertensive medication and/or consume a reduced Na diet were used (531 men and 518 women, aged 40-59years), obtained from four 24-h dietary recalls and two 24-h urine collections from each participant. We developed a classification system with 46 food group classifications; food consumption and Na intake from these groups were compared across quartiles of participants determined by 24-h urinary Na excretion per unit of body weight (UNa/BW). Average daily Na intake from Japanese high-Na foods was 2552mg/day. Participants with a higher UNa/BW consumed a significantly greater amount of high-Na Japanese foods, such as salted fish (P=0.001) and miso soup (P<0.001). They also had greater amount of rice (P=0.001). Participants with lower UNa/BW consumed a significantly greater amount of western foods, such as bread (P<0.001) and milk and dairy products (P<0.001). Detailed analyses of various Japanese and western food intakes in addition to Na intake were performed. These results can be used to help draw up effective programs for the reduction in Na intake and prevention of prehypertension/hypertension in the Japanese population.

An Update on Nutrients and Blood Pressure.

Adverse blood pressure (BP) is a major independent risk factor for epidemic cardiovascular diseases affecting almost one-quarter of the adult population worldwide. Dietary intake is a major determinant in the development and progression of high BP. Lifestyle modifications, including recommended dietary guidelines, are advocated by the American Society of Hypertension, the International Society of Hypertension, the Japanese Society of Hypertension, and many other organisations for treating all hypertensive people, prior to initiating drug therapy and as an adjunct to medication in persons already on drug therapy. Lifestyle modification can also reduce high BP and prevent development of hypertension. This review synthesizes results from the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP), a cross-sectional epidemiological study of 4,680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom, and the United States, published over the past few years on cross cultural BP differences. INTERMAP has previously reported that intakes of vegetable protein, glutamic acid, total and insoluble fibre, total polyunsaturated fatty acid and linoleic acid, total n-3 fatty acid and linolenic acid, phosphorus, calcium, magnesium, and non-heme iron were inversely related to BP. Direct associations of sugars (fructose, glucose, and sucrose) and sugar-sweetened beverages (especially combined with high sodium intake), cholesterol, glycine, alanine, and oleic acid from animal sources with BP were also reported by the INTERMAP Study.

Abstract P337: Dietary Intakes of Rice, Bread, Pasta, Potatoes and Blood Pressure: The International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP)

Background: Previous population-based cross-sectional studies have reported modest inverse relations of dietary starch intake and blood pressure (BP). However, studies that have evaluated associations of BP with starchy foods, e.g., rice, potatoes, pasta, bread, are limited. Objective: Data from INTERMAP were used to assess relations between consumptions of starchy foods and BP. Methods: INTERMAP is a cross-sectional epidemiologic study of 4,680 persons ages 40 to 59 years from 17 random population samples in China, Japan, United Kingdom (UK), and United States of America (USA). BP was measured 8 times; data on food and supplement use were obtained from 4 standardized in-depth multi-pass 24-hour dietary recalls and 2 timed 24-hour urine collections. Differences in BP for each food intake higher by two standard deviations (SD) were estimated by multivariable linear regression (2 SD values: rice: 177, pasta: 56, potatoes: 65, bread: 40, sum of these four: 177 g/1,000 kcal). Adjustment for possible confounders was performed sequentially; for age, gender, sample; plus dietary and other lifestyle factors. Results: Rice intake higher by 2SD was associated with systolic/diastolic BP differences of -1.38 /-0.79 mm Hg (p &lt;0.05 and p = 0.08) adjusted for age, gender, and sample. After further adjustment for dietary and other lifestyle factors, these associations were attenuated to -0.36 mm Hg for systolic BP (p = 0.61) and -0.28 mm Hg for diastolic BP (p = 0.55). Cross-country heterogeneity was detected for the associations between rice intake and systolic BP: inverse for Japan, China, and USA; direct for UK. Consumption of other starchy foods were not significantly associated with BP. After adjustment for age, gender, and sample, 2SD difference for the sum of these 4 starchy foods was associated with significant systolic/diastolic BP differences of -1.17/-0.84 mm Hg (p &lt;0.05 for both); associations were not significant with adjustment for dietary and other lifestyle factors. Conclusions: Modest inverse associations were observed with BP and intake of rice and the sum of the four most common starchy foods in four countries. Higher consumption of these starchy foods may contribute modestly to lower blood pressure levels in other populations, and thereby potentially confer preventive benefits regarding hypertension and cardiovascular disease.

Abstract P099: Soy Food, Bean, Total Legume Consumption and Blood Pressure: The INTERMAP Study

Background: Legumes, including soy foods and beans, are nutrient-dense high-quality sources of vegetable protein. Evidence from prospective cohort studies suggests beneficial associations between legume consumption and cardiovascular diseases, however, little is known about their impact on blood pressure (BP). Our objective was to quantify associations with BP of consumption of soy food, beans, and total legume consumption, each considered separately. Methods: We used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) on 4,680 men and women ages 40-59 years from Japan, China, United Kingdom, and United States. During four visits, eight BP and four 24-hr dietary recalls were collected. Regression coefficients per 2SD higher soy food, bean, and total legume intake were estimated using multivariable linear regression models. To estimate overall association, country-specific regression coefficients were pooled, weighted by inverse of their variance. Adjustments were for age, gender, sample, intake of total energy and alcohol, 24-hr urinary sodium excretion, smoking, education, dietary supplement use, adherence to any special diet, history of cardiovascular diseases or diabetes, family history of hypertension, use of antihypertensive, cardiovascular, or diabetes medication, body mass index, and intake of low-fat dairy, vegetables, fibre-rich grain products, red and processed meats, fish and shellfish, and mutually for soy foods or beans. Results: Average daily legume intakes (g/1000 kcal) were 69 in Asian participants and 19 in Western participants. Soy foods contributed 91% of total legume intake in Asian participants; beans were the main source of legumes (68%) in Western countries. In Asian participants, high correlation coefficients were found between intake of soy foods and iron (r=0.34), arginine (r=0.34), aspartic acid (r=0.34), phenylalanine (r=0.32), isoleucine (r=0.30), and magnesium (r=0.30). In Western participants, soy foods were related to dietary magnesium (r=0.30) and beans were highly correlated with dietary fiber (r=0.44) and magnesium (r=0.22). Total legume intake higher by 76 g/1000 kcal (2SD) was associated with a diastolic BP difference of -0.75 mm Hg (P=0.009) in the total population, -0.70 mm Hg (P=0.05) in Asian, and -0.86 mm Hg (P=0.08) in Western participants. In the total population, diastolic BP differences were -0.62 mm Hg for soy foods (P=0.04) and -0.42 mm Hg for beans and peas (P=0.06). With regard to systolic BP, a significant inverse association was found for soy food intake higher by 41 g/1000 kcal in Western participants (-1.78 mm Hg, P=0.05). Conclusion: Higher intake of legumes, especially soy foods, was associated with lower BP levels.

Abstract P395: Color of Fruits, Vegetables and Blood Pressure: The INTERMAP Study

Background: The color of the edible portion of fruits and vegetables, reflecting the presence of pigmented phytochemicals, may be used as an indicator of their nutrient profile. Previous cohort and intervention studies have documented beneficial associations of fruits and vegetables with blood pressure (BP). However, whether the color of fruits and vegetables is associated with BP is unknown. Methods: We used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) on 4,680 men and women ages 40-59 years from Japan, China, United Kingdom, and United States. During four visits, eight BP measurements and four 24-hr dietary recalls were completed. Fruits and vegetables were categorized in 4 color groups: green, orange/yellow, red/purple, and white. BP regression coefficients per 2SD higher intake were estimated using multivariable linear regression models. To estimate overall associations, country-specific regression coefficients were pooled, weighted by inverse of their variance. Adjustments were for age, gender, sample, intake of total energy and alcohol, 24-hr urinary sodium excretion, smoking, education, dietary supplement use, adherence to any special diet, history of cardiovascular diseases or diabetes, family history of hypertension, use of medication (antihypertensive, cardiovascular or for diabetes), body mass index, and intake of low-fat dairy, fibre-rich grain products, red and processed meats, fish and shellfish, and mutually for other fruit and vegetable color groups. Results: Average daily fruit plus vegetable intakes (g/1000 kcal) was 183 in the total population, varying from 129 in the United Kingdom to 222 in China. White fruits and vegetables contributed 32% of total fruit and vegetable intake, orange/yellow 27%, green 26%, and red/purple 15%. Fruit and vegetable color groups were weakly related to each other, partial r values ranged from 0.08 for green with red/purple to 0.15 for white with orange/yellow. Fruit and vegetable color groups were highly correlated with dietary and urinary potassium; highest correlation coefficients were for white fruits and vegetables (r=0.46 for dietary and r=0.26 for urinary potassium). Green fruits and vegetables were also highly related to beta-carotene (r=0.40) and dietary fiber (r=0.40), orange fruits and vegetables to vitamin C (r=0.59), and white fruits and vegetables to dietary fibre (r=0.49). Green fruit and vegetable intake higher by 90 g/1000 kcal was associated with a systolic BP difference of -1.19 mm Hg (P&lt;0.05). Green fruits and vegetables comprised mainly green vegetables including: cabbages (52%), lettuces (21%), dark leafy (10%), and a heterogeneous group (17%). Other fruit and vegetable color groups and total fruits plus vegetables were not associated with BP. Conclusion: Higher intake of green fruits and vegetables may contribute to lower systolic BP.

Characteristics of hypertension in Chinese and their relevance for the choice of antihypertensive drugs

According to the 4th National Nutrition and Health Survey in 2002, the prevalence of hypertension in China was 18.8%. Despite that, the treatment rate among hypertensive patients was 82%, the control rate remained low in persons with hypertension (6%), because of the low awareness in general (30%) and the low control rate among treated hypertensive patients (25%). One of the major reasons for the increasing prevalence of hypertension is unbalance of dietary sodium and potassium intakes. In the International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP), Chinese, compared with American, British, and Japanese populations, had highest dietary sodium intakes and lowest potassium intakes, leading to a two to three times higher sodium/potassium ratio. High dietary sodium intakes may change the circadian rhythm of 24 h blood pressure, which is characterized by a higher night-time blood pressure. Indeed, the prevalence of isolated night-time hypertension, defined as a night-time blood pressure of at least 120 mmHg systolic or 70 mmHg diastolic and a daytime systolic/diastolic blood pressure less than 135/85 mmHg, was higher in Chinese than in Europeans. The complications of hypertension are also different across ethnicities, being mainly stroke instead of myocardial infarction in Chinese. Blood pressure lowering provides more protection against stroke than myocardial infarction, and calcium channel blockers provide more protection against stroke than other classes of antihypertensive drugs. Current Chinese hypertension guidelines recommend calcium channel blockers as the first of the five classes of antihypertensive drugs for stage 1 and low-risk hypertension.

A Nutrient-Wide Association Study on Blood Pressure

A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations.

Food and nutrient intakes and their associations with lower BMI in middle-aged US adults: the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP)

Clinical trial data show that reduction in total energy intake enhances weight loss regardless of the macronutrient composition of the diet. Few studies have documented dietary patterns or nutrient intakes that favor leanness [BMI (in kg/m²) ≤25] in free-living populations. This investigation examined associations of usual energy, food, and nutrient intakes with BMI among US participants of the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP). The INTERMAP is an international cross-sectional study of dietary factors and blood pressure in men and women (ages 40-59 y) that includes 8 US population samples. The present study included data from 1794 Americans who were not consuming a special diet and who provided four 24-h dietary recalls and 2 timed 24-h urine collections. Multivariable linear regression with the residual method was used to adjust for energy intake; sex-specific associations were assessed for dietary intakes and urinary excretions with BMI adjusted for potential confounders including physical activity. Lower energy intake was associated with lower BMI in both sexes. Univariately, higher intakes of fresh fruit, pasta, and rice and lower intakes of meat were associated with lower BMI; these associations were attenuated in multivariable analyses. Lower urinary sodium and intakes of total and animal protein, dietary cholesterol, saturated fats, and heme iron and higher urinary potassium and intakes of carbohydrates, dietary fiber, and magnesium were associated with lower BMI in both sexes. The consumption of foods higher in nutrient-dense carbohydrate and lower in animal protein and saturated fat is associated with lower total energy intakes, more favorable micronutrient intakes, and lower BMI.

413 A NUTRIENT WIDE ASSOCIATION STUDY ON BLOOD PRESSURE

Background: Epidemiological studies often test relationships of single nutrients with disease or examine food patterns e.g. the Mediterranean diet. A nutrient-wide approach is useful to test associations between nutrients (derived from both foods and supplements) and blood pressure (BP), with proper adjustment for multiple comparisons. Methods: Data from 4,680 participants ages 40–59 in the International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. NHANES cohorts of 1999–2000 to 2005–2006 were used for external validation. We performed multiple linear regression analyses associating each of 87 nutrients and urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (False Discovery Rate<5% in training, p < 0.05 for internal and external validation). Results: Among the validated nutrients (False Discovery Rate<5% in training, p < 0.05 for internal and external validation), alcohol was directly associated, while dietary phosphorus, magnesium, folacin, and riboflavin were inversely associated with systolic and diastolic BP. In addition, sodium to potassium ratio were directly and dietary fiber, iron, thiamin, and copper were inversely associated with systolic BP. Inclusion of nutrient intake from supplements in addition to food intake of nutrients did not alter the aforementioned associations for fiber, phosphorus and magnesium intake and attenuated the associations between folacin, thiamin and riboflavin intake with BP. Conclusion: Our analysis highlights previously unstudied or unconfirmed associations between B vitamins, minerals and BP, and offers a systematic unbiased approach to the evaluation and validation of other important nutrient-BP associations.

1106 INVERSE ASSOCIATIONS OF GUT MICROBIAL DERIVED CO-METABOLITES WITH BLOOD PRESSURE

Background: The gut microbiome has been implicated in blood pressure (BP) variation and cardiovascular disease. Methods: Eight random population samples, 2,000 Americans ages 40–59 in the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP); eight BP measurements at four visits; 24-h urinary sodium, potassium excretion, and most abundant urinary gut microbial co-metabolites, measured by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) from two 24-h collections per individual. Associations between gut microbial metabolites and BP assessed by multiple linear regression. Results: 24-h urinary hippurate, 4-cresylsulphate (4CS) and phenylacetylglutamine (PAG) were inversely associated with diastolic BP (P = 0.002 to P = 9.2 x 10–5 for 4CS), as was the 4CS/PAG ratio (P = 0.01 to P = 1.9 x 10–6); regression coefficients per 2 SD difference ranged from -1.03 to -1.99 mm Hg for the 4CS/PAG ratio (Table). Results for systolic BP were also inverse, though not all significant. Table. Estimated mean differences in diastolic BP (mm Hg) per 2 standard deviation (SD) higher excretion of UPLC-MS/MS derived gut microbial metabolites. INTERMAP US samples, men and women combined* (N = 2,000)Interpretation: Both phenylalanine and tyrosine can be converted to the potent vasopressors β-phenylethylamine and tyramine, respectively, by bacterial putrefaction processes in the distal colon; PAG and 4CS are in related, directionally opposite, pathways, but non-vasoactive. Their inverse associations with BP may reflect activity of competing putrefactive microbial pathways away from sympathomimetic amine production. Gut microbial co-metabolism may have a role in BP regulation.

183 FRUIT (RAW, TOTAL), FRUIT JUICE INTAKE AND BLOOD PRESSURE

Background: Epidemiological evidence suggests that fruit intake prevents cardiovascular diseases through blood pressure (BP) lowering effects. Relatively little is known about relationships between raw fruit and fruit juice with BP. Methods: Cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) were evaluated in 4,680 men and women, ages 40-59 years from Japan, China, United Kingdom, and United States. During 4 visits, blood pressure was measured 8 times and dietary intake assessed by four 24-hour recalls. Associations between intake of total fruit (including raw fruit and fruit juice), raw fruit and fruit juice with BP were estimated using multivariable linear regression. Results: Mean fruit intakes (g/1000 kcal) were 63.3 in Japan, 68.0 in China, 88.8 in UK, and 108.2 in US. In contrast to minimal fruit juice intake in Asian countries, fruit juice contributed more to total fruit intake in the US (50%) than in UK (30%). Fruit juice intake alone was not related to BP. Total fruit and raw fruit intake (+100 g/1000 kcal) were inversely related to systolic BP, -0.96 mmHg (P ≤ 0.001) and -1.23 mmHg (P ≤ 0.001), but did not remain statistically significant after adjustment for dietary and lifestyle confounders. Participants in highest quartile of total and especially raw fruit intake had lower SBP levels (-1.1 mmHg, Ptrend: 0.09) compared with lowest quartile, but was not statistically significant. Inclusion of height and weight to the model further attenuated associations. Conclusion: Higher intake of especially raw fruit, but not fruit juice, may modestly contribute to beneficial BP levels.

Diet, Nutrients, and the Prevention of Hypertension

A large part of blood pressure variation among individuals cannot be explained by known nutritional and dietary factors, and thus, many studies are in progress. We reviewed recent observational and interventional studies investigating the relationship of dietary and nutritional factors to blood pressure in human populations. During the past few years, a cross-sectional study of large-scale international populations, the INTERMAP (International Study of Macro/Micronutrients and Blood Pressure), reported the favorable effects of several nutrients, including minerals (phosphorus, calcium, magnesium, and non-heme iron), glutamic acid, n-6 and n-3 polyunsaturated fatty acids, and starch, and reduced intake of cholesterol, glucose, and fructose. Observational and interventional studies also showed new evidence suggesting unfavorable effects resulting from higher intakes of red meat, fructose, and sugar-sweetened beverages, and favorable effects resulting from higher intake of lactotripeptides and polyphenol-rich dark chocolate. For the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, further evidence on blood pressure–lowering effects and other favorable outcomes has accumulated. These new findings should be established by further studies for the future update of dietary guidelines to prevent and manage hypertension.

Nutrient and food intakes of middle-aged adults at low risk of cardiovascular disease: the international study of macro-/micronutrients and blood pressure (INTERMAP)

Individuals with favorable levels of readily measured cardiovascular disease (CVD) risk factors (low risk, LR) experience low long-term rates of CVD mortality and greater longevity. The purpose of the current study was to compare nutrient/food intakes of LR participants with participants not LR in the INTERMAP study. Men and women (40-59 years) from 17 population samples in four countries (China, Japan, UK, US) provided four 24-h dietary recalls and two timed 24-h urine collections. LR was defined as meeting all of the following CVD risk criteria: systolic/diastolic blood pressure (BP) ≤ 120/ ≤ 80 mmHg; no drug treatment for high BP, hyperlipidemia, or CVD; non-smoking; BMI <25.0 kg/m(2) (US, UK) or <23.0 kg/m(2) (China, Japan); alcohol consumption <26.0 g/day (men)/<13.0 g/day (women); and no history of diabetes or CVD. Multivariate logistic regression was used to examine associations of nutrient/food intakes with LR. LR individuals reported higher intake of vegetable protein, fiber, magnesium, non-heme iron, potassium; lower energy intake; lower intake of cholesterol, saturated fatty acids, animal protein; and lower 24-h urinary sodium compared with individuals not LR. With regard to foods, LR individuals reported higher intake of fruits, vegetables, grains, pasta/rice, fish; lower intakes of meats, processed meats, high-fat dairy, and sugar-sweetened beverages than individuals not LR. Lower energy intake and differential intake of multiple specific nutrients and foods are characteristic of individuals at low risk for developing CVD. Identification of dietary habits associated with LR is important for further development of public health efforts aimed at reduction/prevention of CVD.

Relationship of dietary cholesterol to blood pressure: the INTERMAP study.

A direct relationship of dietary cholesterol to blood pressure of men has been reported in a few observational studies from the USA. It is not clear whether this association prevails consistently, for example, in populations with varied dietary habits, across ethnic groups, and sexes. Cross-sectional data from the International Study of Macro/Micro-nutrients and Blood Pressure (INTERMAP) were used to assess relations of dietary cholesterol intake to blood pressure in men and women from four countries. Data include 83 nutrients from four multipass 24-h dietary recalls and two-timed 24-h urine collections; eight blood pressure readings, and questionnaire data, for 4680 participants ages 40-59 years from 17 population samples in Japan, People's Republic of China, UK, and USA. With sequential models to control for multiple possible confounders (dietary, other), linear regression analyses showed that dietary cholesterol was directly related to SBP for all participants and for nonhypertensive individuals, but not to DBP. With adjustment for 12 variables, estimated SBP differences with 2SD for higher cholesterol intake (131.0 mg/1000 kcal) were 0.9 mmHg (P < 0.05) for all participants and 1.1 mmHg (P < 0.01) for nonhypertensive individuals, findings attenuated with addition of height and weight to the model. INTERMAP found a low-order, positive relationship of dietary cholesterol intake to SBP with control for multiple possible confounders. Reduction of dietary cholesterol intake may contribute to prevention and control of adverse blood pressure levels in general populations.