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Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into

Cancer and Nutrition (EPIC) study1–3
Theodora Psaltopoulou, Androniki Naska, Philippos Orfanos, Dimitrios Trichopoulos, Theodoros Mountokalakis, and Antonia Trichopoulou
ABSTRACT Background: Diet has been reported to influence arterial blood pressure, and evidence indicates that the Mediterranean diet reduces cardiovascular mortality. Objective: The objective was to examine whether the Mediterranean diet, as an entity, and olive oil, in particular, reduce arterial blood pressure. Design: Arterial blood pressure and several sociodemographic, anthropometric, dietary, physical activity, and clinical variables were recorded at enrollment among participants in the Greek arm of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Of these participants, 20 343 had never received a diagnosis of hypertension and were included in an analysis in which systolic and diastolic blood pressure were regressed on the indicated possible predictors, including a 10-point score that reflects adherence to the Mediterranean diet and, alternatively, the score’s individual components and olive oil. Results: The Mediterranean diet score was significantly inversely associated with both systolic and diastolic blood pressure. Intakes of olive oil, vegetables, and fruit were significantly inversely associated with both systolic and diastolic blood pressure, whereas cereals, meat and meat products, and ethanol intake were positively associated with arterial blood pressure. Mutual adjustment between olive oil and vegetables, which are frequently consumed together, indicated that olive oil has the dominant beneficial effect on arterial blood pressure in this population. Conclusions: Adherence to the Mediterranean diet is inversely associated with arterial blood pressure, even though a beneficial component of the Mediterranean diet score— cereal intake—is positively associated with arterial blood pressure. Olive oil intake, per se, is inversely associated with both systolic and diastolic blood pressure. Am J Clin Nutr 2004;80:1012–18. KEY WORDS Olive oil, Mediterranean diet, arterial blood pressure, European Prospective Investigation into Cancer and Nutrition study, EPIC study, Greece

dietary factors (2, 3). Adoption of the low-saturated fat, plantbased DASH (Dietary Approaches to Stop Hypertension) diet has been advocated together with weight reduction, dietary sodium reduction, enhancement of physical activity, and moderation in alcohol consumption (2). An increase in fruit, vegetable, and fish intakes and a reduction in saturated fat and cholesterol intakes has also been advocated by the European Society of Hypertension (3). The Mediterranean diet has been considered to be a healthy eating pattern ever since Ancel Keys initiated the Seven Countries Study in the 1950s (4, 5). Several studies have indicated that adherence to a Mediterranean diet is associated with a reduction in total and cardiovascular mortality (6-9). High intakes of olive oil are considered a hallmark of the traditional Mediterranean diet, resulting in high intakes of monounsaturated fatty acids and lower intakes of saturated fatty acids. Replacement of saturated with monounsaturated lipids is associated with a considerable reduction in coronary heart disease risk, through a mechanism involving reduction of LDL cholesterol, without a reduction of HDL cholesterol or an increase in triacylglycerols (10). Less is known about the relation of arterial blood pressure with Mediterranean diet or its dominant components. In a cross-sectional study of 2282 residents of the Attica area in Greece (which surrounds and includes the capital city of Athens), it was reported that adherence to a Mediterranean diet increases the likelihood of having the arterial blood pressure controlled (11). To further evaluate the association between a Mediterranean diet and its components and systolic and diastolic blood pressure, we conducted a general population study in a large sample that covers most of the geographic regions of Greece. To avoid problems generated by diet modification subsequent to the diagnosis
From the Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece (TP, AN, PO, DT, and AT); the Department of Epidemiology, Harvard School of Public Health, Boston (DT); and the Hypertension Center, Third University Department of Medicine, Sotiria Hospital, Athens, Greece (TM). 2 Supported by the Europe Against Cancer Program of the European Commission, the Greek Ministry of Health, and the Greek Ministry of Education. 3 Address reprint requests to A Trichopoulou, Department of Hygiene and Epidemiology, School of Medicine, University of Athens, 75 Mikras Asias Street, GR-115 27 Athens, Greece. E-mail: antonia@nut.uoa.gr. Received December 23, 2003. Accepted for publication April 1, 2004.

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Hypertension can result in stroke, myocardial infarction, congestive heart failure, sudden cardiac death, peripheral vascular disease, and renal insufficiency, and yet it is clearly modifiable (1). Guidelines for the management of hypertension emphasize


Am J Clin Nutr 2004;80:1012–18. Printed in USA. © 2004 American Society for Clinical Nutrition

place of residence.0 for WINDOWS 98/95/NT. 6479 (24. were alternatively substituted for the Mediterranean diet score (all of them continuously per SD increment. a value of 1 was given to men whose consumption of ethanol was from 10 to 50 g/d. Specifically. waist-to-hip ratio (continuously. semiquantitative. 20 343 persons were included in the current study. 13). We ascertained diet through a validated.OLIVE OIL. the components of the Mediterranean diet score. prospective study conducted in 22 research centers in 10 European countries and coordinated by the International Agency for Research on Cancer (IARC) to examine the role of dietary. years of schooling (continuously. Briefly. whereas persons whose consumption of these components was above the corresponding median were given a value of 0.1%) were excluded because of missing values for one or more variables used in the present analysis. The study protocol was approved by the ethics committees of IARC and the University of Athens Medical School. EPIC is a multicountry. per SD). Finally. place of residence. Usual dietary intake over the past year was assessed through a validated.2%) of them had already received a diagnosis of hypertension and were also excluded because they may have changed their diet in response to that diagnosis. In all instances. All participants signed an informed consent form before enrollment. Values of 0 to 1 were assigned to each of the 9 indicated components by using the respective sex-specific medians as cutoffs (9).1 cm. A metabolic equivalent index was computed by assigning a multiple of resting metabolic rate (17) to each activity (MET value). and Mediterranean diet score (continuously. systolic and diastolic blood pressures were measured twice. expressed per 10-y increment). RESULTS Downloaded from www.ajcn. The STATA statistical package was used for the analysis (Intercooled Stata 7. Waist and hip circumferences were measured with an inelastic tape and were recorded to the nearest 0. In contrast. In additional models. 2011 The distribution of 8685 men and 11 658 women without a prior diagnosis of hypertension. interviewer-administered foodfrequency questionnaire (14. Thus. BMI (continuously. including total energy intake and physical activity. SUBJECTS AND METHODS Subjects The study sample consisted of volunteers aged 20 – 86 y. which are rarely non. interaction terms of the former 3 variables. per SD). whereas for women the corresponding cutoffs were 5 and 25 g/d (9). and all MET-hour products were summed to give a total daily MET score. legumes. the average time per day spent on household. and years of schooling. Body mass index (BMI) was calculated as weight (in kg) over height squared (in m2). but 1750 of them (6. The averages of the 2 readings for both systolic and diastolic blood pressure were used. and environmental factors in the etiology of cancer and other chronic diseases. TX). persons with a below the median consumption of components with a presumably beneficial effect on overall mortality (vegetables. and fish) were assigned a value of 0. 16). because monounsaturated lipids are consumed in much higher quantities in Greece. SDs were sexspecific. by systolic and diastolic blood . except for ethanol intake). professional. such as age. Thus. expressed per 3 unit increment). biological. and other activities was calculated. After 5 min of rest.org by guest on September 25. energy intake (continuously. For ethanol. 12. Of the remaining 26 822 participants. Urban areas were classified as those having Œ10000 inhabitants and. Inc. WABaum Co. cereals. Standard portion sizes were used for the estimation of consumed quantities (14. extensive food-frequency questionnaire and we controlled in the analysis for several factors with confounding potential. A total of 28572 volunteers were enrolled in the Greek EPIC cohort. As indicated. Professional and leisure time physical activity were assessed by a special section of the lifestyle EPIC questionnaire (13. a 10-point Mediterranean diet scale was constructed. Body weight was measured to the nearest 100 g and height to the nearest 0. and dairy products. rural areas (including semiurban) with 9999 inhabitants (18). lifestyle. fruit. 15). 9). with at least a 2-min interval between the 2 measurements. persons who reported a diagnosis of hypertension at any time in the past or who were using antihypertensive drugs were excluded from the analysis.or low-fat in Greece) were assigned a value of 1. New York). meat products. per SD). who were recruited during a 5-y period (1994 –1999) from around Greece to participate in the Greek component of the EPIC study (European Prospective Investigation into Cancer and Nutrition). A gradient of adherence to the traditional GreekMediterranean diet was constructed on the basis of 9 nutritional components (6. for lipid intake. MEDITERRANEAN DIET. per SD). Participants were seated on a chair with their backs supported and their right arm bared at the level of the heart. expressed per 3-y increment).1 cm. which could take a value from 0 (minimal adherence to the traditional Mediterranean diet) to 9 (maximal adherence to the traditional Mediterranean diet). sporting. persons with a below the median consumption of components with a presumably detrimental effect on overall mortality (meat. the ratio of monounsaturated to saturated lipids instead of the ratio of polyunsaturated to saturated lipids was used. The questionnaire included 150 food items and beverages as well as questions on habitual cooking methods and type of lipids used in cooking. as well as olive oil. STATA Corporation. Details on the design and methods of the EPIC study and the Greek cohort were previously described in detail (9. Anthropometric measurements also followed standard procedures and were taken with subjects wearing light clothing and no shoes. Type of residence was determined according to the population of the area the person was living in. we excluded all persons who reported a diagnosis of hypertension at any time in the past. which represented the amount of energy per kilogram body weight expended during an average day. Time spent on each of the activities was multiplied by the MET value of the activity. Arterial blood pressure measurements were conducted by specially trained physicians with the use of a mercury sphygmomanometer (Baumanometer. 2 at a time. Years of schooling was used as a proxy to socioeconomic status. 15). AND BLOOD PRESSURE 1013 of hypertension. Statistical analysis Systolic and diastolic blood pressure were alternatively regressed on age (continuously. Methods Standard interviewing procedures were used to assess sociodemographic characteristics. sex. College Station. whereas persons with consumption above the median were given a value of 1. physical activity (continuously.

1 24.3 8.6 6.9) 2775 (32.0 7. The beneficial effect is assumed in the indicated range.002  0.07 724 6.9 28. a nutritional factor generally considered to be beneficial to health.1 76. vegetables.001 0. is shown in Table 1. the cutoffs used to calculate the Mediterranean diet score are indicated.8) 140 –149 16 120 373 396 56 6 967 (11.5 212.5 6.6 150.1 139.8 23.7 (n Men 8685) 12.0 95.02  0. 2666 (30.7 222.8) 0 5 34 76 55 22 192 (1.1014 PSALTOPOULOU ET AL TABLE 1 Distribution of 8685 men and 11 658 women without a prior diagnosis of hypertension.3 8.3) 57 (0.0 0. Substituting the various components of the Mediterranean diet score and olive oil for the score in the regression showed that olive oil.7 50.8 — 1.9) 1502 (17.8 1955 35.6 4.67 4.8 All values are x SD.8 0.2 4. The mean ( SD) daily consumption of olive oil and nutritional variables that contribute to the Mediterranean diet score.81 4.0) 3377 (38.6) 4245 (36. As expected.001  0.7%) women had a systolic or diastolic blood pressure that would classify them as probable hypertensives.5 24. The latter variables are potential confounders in the association between qualitative aspects of diet and arterial blood pressure.1 21. Mediterranean diet score. metabolic equivalents. on the indicated predictor variables are shown in Tables 4 and 5.5 372.3) 289 (3. pressure in the Greek EPIC study.3) 209 (1.1) 1976 2699 727 47 1 1 5451 (46. arterial blood pressure declines significantly with increasing educational level and increases significantly with increasing BMI and waist-to-hip ratio.8) 120 –129 112 828 1255 251 14 0 2460 (28.25 0.31 (n Women 11 658) 11. BMI.7 1.1) 19 134 519 369 30 2 1073 (9. Indeed.4 224.9 190.6) 1430 (12.0) Downloaded from www.7 10–50 Women (n x 542.30 1.7 5.4 11 658) Cutoff 1 499.001 0.org by guest on September 25. notwithstanding the absence of a relevant diagnosis.9 15. after control for sociodemographic and anthropometric variables as well as for energy intake and energy expenditure.87 5.7) 2 49 205 280 54 3 593 (5.20 P (two tailed) 0.3) 11658 (100.0) 45 345 857 341 14 1 1603 (13.6 1.9) 130 –139 42 308 831 437 31 1 1650 (19.0) 2170 (18.9 28. In the same table.3 10.7 20. MET.5 83. waist-to-hip ratio. It is worth noting that cereals.7) Total n (%) 685 (7.0 2438 35.3 191. energy intake.8 144. are positively TABLE 3 Daily food consumption in men and women without a prior diagnosis of hypertension in the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study.7 89.0 1.9 1.5 196.08 585 4. .7%) men and 2758 (23.8) 36 (0.5 9. TABLE 2 Sociodemographic and anthropometric characteristics.7 120.8 3. and physical activity expenditure) are shown.09 0.4 61. respectively. by sex.7.8 45.7 356.2) 150 –159 7 50 155 209 65 9 495 (5. In Table 2. 2011 Participants who had a systolic blood pressure 140 mm Hg or a diastolic blood pressure 90 mm Hg and were considered likely to have hypertension.ajcn.9 9.6 26. the Spearman correlation coefficient being 0.8 82. are given in Table 3. and physical activity level in men and women without a prior diagnosis of hypertension in the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. The unusually high consumption of vegetables and the high consumption of olive oil in the Greek population are evident in these data.7 5–25 x 582.7 — 1. The Mediterranean diet score is significantly inversely associated with both systolic and diastolic blood pressure.7) 170 1 3 29 49 50 27 159 (1. 1994 –19991 Variable Age (y) Mediterranean diet score Years of schooling (y) BMI (kg/m2) Waist-to-hip ratio Energy intake (kcal) Physical activity (MET h/d) 1 Mutually adjusted partial regression coefficients of systolic and diastolic blood pressure. representative values of the participants’ age.4) 3568 (30. and variables considered to be predictive of hypertension (ie.7 177. by systolic (SBP) and diastolic (DBP) blood pressure in the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study.7) 8685 (100.0 SD 233.001  0. and fruit are the principal factors that explain the overall effect of the Mediterranean diet on arterial blood pressure. This value is a numerical expression of the tendency in the Greek population to use olive oil for the preparation of vegetable dishes (raw or cooked).6 129. these 2 variables are highly correlated.8 18.2 150.8 22.3) 126 995 1130 172 8 0 2431 (20.9) 2 18 96 145 47 7 315 (2. Values of the sex-specific medians in the Greek EPIC cohort (9).0 377.1) 160 –169 1 11 52 107 70 12 253 (2.1 362.70 4. 1994 –19991 SBP (mm Hg) DBP (mm Hg) Men 69 70–79 80–89 90–99 100–109 110 Total [n (%)] Women 69 70–79 80–89 90–99 100–109 110 Total [n (%)] 1 119 506 1455 682 53 3 2 2701 (31. energy intake.27 50.2 0.9 55.8 19.7 SD 236. 1994 –1999 Men (n Variable Vegetables (g) Legumes (g) Fruit (g) Dairy products (g) Cereals (g) Meat and meat products (g) Fish and seafood (g) Olive oil (g) Monounsaturated: saturated lipids Ethanol (g)2 1 2 8685) Cutoff 1 549.9 212. years of schooling.

45 to 0.001 0.4 ( 0. 0.001 0. In contrast.4.001  0.4 Legumes (per SD)2 Fruit (per SD)2 Dairy products (per SD)2 Cereals (per SD)2 Meat and meat products (per SD)2 Fish and seafood (per SD)2 Olive oil (per SD)2. Both tobacco smoking and dieting for any reason were significantly inversely associated with both systolic and diastolic blood pressure. Because the intakes of vegetables and olive oil are highly correlated and because they are both inversely associated with arterial blood pressure.5.2 ( 0. by adding tobacco smoking among the core variables.08  0. 0. We repeated our analyses by substituting waist circumference for waist-to-hip ratio.4) 0.03  0.5 ( 0.1. We examined the association between arterial blood pressure and a variant of the Mediterranean diet score.001 0.1. and nutritional variables in the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. its components.5. 0.0) 0.ajcn.4) 0.08  0.11  0.8 ( 0.22). 3. 5 Additionally controlled for vegetable intake. 0.0) 0.3.8 ( 1. and nutritional variables in the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study.2 (0. 0.001 0. 0.2. 0.4 ( 0.5 Monounsaturated:saturated lipids (per SD)2 Ethanol (using low intake as baseline)6 Medium High 1 Coefficient (95% CI) 1.3. the indicated food groups were alternatively substituted for the Mediterranean diet score.2) 0.1) 0.001  0. instead of waist-to-hip ratio.5.4 ( 0.1.001  0. MEDITERRANEAN DIET.8.4) 0. we examined whether their apparent effects in Tables 4 and 5 are mutually confounded.001 0. 1994 –19991 Variable Years of schooling (per 3 y) BMI (per SD)2 Waist-to-hip ratio (per SD)2 Energy intake (per SD)2 Physical activity (per SD)2 Mediterranean diet score (per 3 units) Alternative models3 Vegetables (per SD)2. Introduction of both olive oil and vegetables in the models indicated in Tables 4 and 5 showed that the effect of olive oil was not substantially affected by the control for vegetable intake (the partial regression coefficient for systolic blood pressure decreased in absolute terms from 0.44  0. 0.2 ( 0. AND BLOOD PRESSURE TABLE 4 Multiple regression– derived partial regression coefficients of systolic blood pressure on sociodemographic.2) 0. or olive oil on the one hand and systolic or diastolic blood pressure on the other hand.OLIVE OIL.5.4) 0. 1994 –19991 Variable Years of schooling (per 3 y) BMI (per SD)2 Waist-to-hip ratio (per SD)2 Energy intake (per SD)2 Physical activity (per SD)2 Mediterranean diet score (per 3 units) Alternative models3 Vegetables (per SD)2.4. 0. 0.3 ( 0.04 0. per 10 y). again.5 (1.4) P  0.8. or olive oil.7 (0. anthropometric.1.001).1 ( 0. residence (urban versus rural). 0.1.7 (2. associated with both systolic and diastolic blood pressure.2 ( 1. All values were controlled for sex.15  0.84 to 0.2) 0.001  0. 0.2) 0.3.org by guest on September 25. age and residence.2) 0.0) 0. 0.5. anthropometric. the regression coefficient of systolic blood pressure per 3 units of Mediterranean diet score changed from 0. All values were controlled for sex. 0. 0.8 (Table 4) to 1.2 ( 0.1 (2. and interactions between age and sex. the only regression coefficients that were substantially affected were. none of these variables were found to confound the association between Mediterranean diet score. in absolute terms.0.001 coefficient (95% CI) 0.0) 2.001 0. 0.0) P  0.001 0. 1.6) 0. 0.02 0.26 0. residence (urban versus rural).1 ( 0.02  0.4.1 ( 0.4. and sex and residence.8) 0. age and residence. 6 Sex-specific categories (see Table 3).01 ( 0.8 ( 0.2 ( 0.3) 0. 3 In additional models.3) 0. those for BMI.1 ( 0.1)  0. as expected.4.1. The consumption of meat and meat products is significantly positively associated with diastolic blood pressure.2 ( 0.1.2 (0.0) 0.001 Downloaded from www.6 (0.22 0.36 to 0. 2 Per sex-specific SD (see Tables 2 and 3). 0. .2 (Table 5) to 0.001 0. 5 Additionally controlled for vegetable intake. 0.1.1 ( 0.38 0. 3.3. age (continuously.25). 0.4)  0. 0.5. the effect of vegetables was considerably less. and sex and residence. in which a high intake of cereals was considered to be detrimental (value 0) and a low intake of cereals as beneficial (value 1).3 ( 0.6) 2. 0. When waist circumference was controlled for.001  0. its components.01 and for diastolic pressure from 0. whereas no noticeable changes were evident with respect to the regression coefficients for Mediterranean diet score.2) 0.3. 0. 0. 0. 2.5 Monounsaturated:saturated lipids (per SD)2 Ethanol (low intake used as baseline)6 Medium High 1 1015 TABLE 5 Multiple regression– derived partial regression coefficients of diastolic blood pressure on sociodemographic. but. 0.001 0.0. 2 Per sex-specific SD (see Tables 2 and 3).6 (0. 1.2 ( 0.4 (P for both  0.2) 0. 3 In additional models.8) 0.5.1) 0.001  0. 0.6 ( 0. 0.0) 0.95 0.2 ( 0.5 ( 0. n 20 343 persons.001  0.1 ( 0. when olive oil was controlled for (the partial regression coefficient for systolic blood pressure changed from 0.35 to 0. as is a high intake of ethanol.4 ( 0.1 ( 0. 2.83 and for diastolic blood pressure from 0.5.0) 0. 2011 0. 1.68  0.1 ( 0. the indicated food groups were alternatively substituted for the Mediterranean diet score.5) 1. and by controlling for dieting for any reason at the time the subjects were examined.5) 0.67  0. and interactions between age and sex. 0.001 n 20 343 persons. and the regression coefficient of diastolic blood pressure for the same increment changed from 0. 6 Sex-specific categories (see Table 3). age (continuously.4. per 10 y).30 0.7.7 (0. As expected.3) 2.4.01  0. 0. 4 Additionally controlled for olive oil intake.5) 0.2) 0.4 Legumes (per SD)2 Fruit (per SD)2 Dairy products (per SD)2 Cereals (per SD)2 Meat and meat products (per SD)2 Fish and seafood (per SD)2 Olive oil (per SD)2.001 0. whereas the consumption of fish and seafood is significantly inversely associated with systolic blood pressure.1) 0.9) 0. 4 Additionally controlled for olive oil intake.1. 0.0) 0.

9. and the detrimental effect associated with a high intake of ethanol. Olive oil intake per se may be as important as fruit and Downloaded from www. which describe the average change in the systolic and diastolic blood pressure per specified increment in the Mediterranean diet score. whereas meat intake has been reported to increase and fish intake to decrease arterial blood pressure (27. there is wide agreement that a high consumption of alcoholic beverages is positively associated with arterial blood pressure (25. the beneficial effect associated with the intake of fish and seafood (significant with respect to systolic blood pressure). 35). magnesium. olive oil has been compared with sunflower oil. Compatible with the apparent effect of the Mediterranean diet score is the detrimental effect associated with the intake of meat and meat products (significant with respect to diastolic blood pressure). may represent mediating mechanisms of the apparent protective effects of these foods. which enhance nitric oxide concentrations and may help dilate arteries. however. 38). which is enriched in olive oil rather than in other fatty acids and perhaps in some grain products. fruit. general. The fatty acids in olive oil are protected by natural antioxidants (40). is inversely associated with both systolic and diastolic blood pressure. that fish intake is inversely associated with arterial blood pressure (27. is inversely associated with both systolic and diastolic blood pressure. 33. It has been shown that olive oil decreased arterial blood pressure more than did sunflower oil. a synthetic derivative of oleic acid. which could affect arterial stiffness (41-44). are.1016 DISCUSSION PSALTOPOULOU ET AL In a large. considered independently of advice to reduce salt intake (2). The search for mediating processes has mainly focused on the blood lipid profile and mechanisms of thrombogenesis (29. a Mediterranean diet— operationalized in line with the recommendations of Trichopoulou et al (6. such as the DASH diet. a conceivable relation between salt intake and Mediterranean diet could not be evaluated in our study. we found evidence that adherence to a Mediterranean diet. it may be worth examining in future studies the dataderived evidence that cereal intake is positively associated with arterial blood pressure. which is widely recommended in the United States. tocopherols. and waist-to-hip ratio indicate that overt biases were not operating in the study. which is more susceptible to oxidation (45). which is a widely consumed staple food in Greece. Simply put. The strengths of this study were its large sample size. Alemany et al reported that intraperitoneal or oral administration to animals of 2-hydroxyoleic acid. BMI. 49)—was found to be inversely associated with arterial blood pressure (11). In a recent publication. which shares many of the characteristics of the DASH diet. Salt intake is one of the principal dietary components involved in increases in arterial blood pressure. and exclusion of persons with a diagnosis of hypertension. The high content of plant foods in minerals. and its design allowed both the control for a large set of potential confounders and a separate examination of the specific effects of the various components of the Mediterranean diet. Antioxidants tend to inactivate the effects of free radicals and lipid peroxidation. The Mediterranean diet shares many of the characteristics of the DASH diet. are mainly responsible for the apparent protection against hypertension conveyed by the Mediterranean diet. In an epidemiologic study undertaken in Greece. Of the components of the Mediterranean diet. provided that the balance between total energy intake and expenditure is preserved and the dietary pattern is culinary acceptable. reliance on a validated food-frequency questionnaire. which reduces blood pressure. that one of the beneficial components of the Mediterranean diet. In humans. at the population level (19. Dietary recommendations to manage hypertension. The results of the few comprehensive studies that have been conducted to evaluate the association between arterial blood pressure and intake of dairy products suggest an inverse association (36). coverage of a large set of potential confounders. The values of the regression coefficients. vegetables. we found evidence that a Mediterranean diet. Note. whereas the high content of plant foods and olive oil in antioxidants may also contribute to the health of the vascular system (21-24).org by guest on September 25. daily doses of blood pressure medication were reduced by 48% during the olive oil diet and by 4% during the sunflower oil diet. Because. 48. the results of our evaluation of the association of arterial blood pressure with socioeconomic status. A high intake of alcoholic beverages has been consistently associated with high arterial blood pressure (25. Thus. 31. it could be argued that the DASH diet. According to Ferrara et al (47). The current study. are small. is considerably larger. arterial blood pressure is characteristic of all persons. small individual changes are translated into substantial changes in morbidity from hypertension-related diseases. 30) and because salt is frequently added to cereal products. possibly because carbohydrate intake has been linked to several cardiovascular disease risk factors and clinical entities (29. this finding could be attributed to polyphenols.ajcn. In conclusion. including carotenes. A Mediterranean diet is widely regarded as a health-promoting diet. There is considerable evidence that the consumption of fruit and vegetables is inversely associated and the consumption of cereals and meat and meat products is positively associated with arterial blood pressure (20. the latter of which prevents bias that could be introduced from changes in habitual diet in response to the diagnosis of hypertension. 32). could represent an improvement over the classic DASH diet. is actually positively associated with both systolic and diastolic blood pressure. Indeed. an effect that was attributed. 26). induced substantial decreases in arterial blood pressure. 20). but it is difficult to ascertain (50). olive oil was again compared with sunflower oil and was found to reduce the need for daily pharmaceutical antihypertensive treatment. 34). and calcium). at least in part. in terms of both general and cardiovascular mortality (4. particularly bread. however. however. which tend to reduce arterial blood pressure (including potassium. 2011 . to olive oil’s polyphenolic content (21). and phenolic compounds. 37. cereal consumption. In animal experiments. population-based study. Evidence suggests. but does not conclude. mainly systolic blood pressure (46). On the basis of the Greek EPIC data. In contrast. which is the primary monounsaturated fatty acid found in olive oil. it is difficult to argue whether olive oil or monounsaturated lipids in general have differential effects on arterial blood pressure. 39). however. 28). however. The cross-sectional nature of the study was a drawback. 6. and olive oil (as reflected in the high ratio of monounsaturated to saturated lipids). The main difference between the 2 diets is that the Mediterranean diet is high in olive oil (2. Polyphenols are completely absent in sunflower oil. including coronary heart disease and stroke. as operationalized through the Mediterranean diet score. Few studies have examined the relation of olive oil or a Mediterranean diet with arterial blood pressure. 26).

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Gnardellis C. Black HR. Kromhout D.Kyoto and spontaneously hypertensive rats. Trichopoulou A.26(1):155–9. None of the authors declared a conflict of interest. Status and management of hypertension in Greece: role of the adoption of a Mediterranean diet: the Attica study. Primary prevention of hypertension: clinical and public health advisory from the National High Blood Pressure Education Program. PO coordinated the data analysis. Lagiou A. Engler MB. All authors contributed to the writing of the manuscript. Chernichow S. Dubnov G.42(3):319 –28. Plotnick GD. The Seventh Report of the Joint National Committee on Prevention. Mussolino ME. Keys A. et al. Biological activities and metabolic fate of olive oil phenols. Hennekens C. Lasherras C. Trichopoulos D. Diet and overall survival in elderly people. Ascherio A. Appel LJ.6(1):74 –7. Keys AB. 34. 45. Quiles JL.30(1):130 –5. Detection.93(4):124– 8. fish eaters. Visioli F. 7. Rouse IL.26(suppl 1):S118 –27. Katsouyanni K. Free Radic Biol Med 1998. squalene. 26.6(1):27–30.113(suppl 9B):13S–24S. Jauhiainen T. J Hypertens 2003. Molteni LB. Passi S. Reproducibility and validity of an extensive semi-quantitative food frequency questionnaire among Greek school teachers. Roysommuti S.OLIVE OIL. Aravanis C. REFERENCES 1. Food consumption patterns in the 1960s in seven countries. Prospective study of moderate alcohol consumption and risk of hypertension in young women. et al. Martin JL. The postprandial effect of components of the Mediterranean diet on endothelial function. Korpela R. Corretti MC. Reducing risks. Epidemiology 2000. Epidemiologic studies on dietary fats and coronary heart disease. DASH Collaborative Research Group.36(5):1455– 60. Pitsavos CH. Poussa T. Visioli F.24(4):511–21. 289(19):2560 –72. J Am Coll Cardiol 2000. 13. High-risk and population strategies of prevention: ethical considerations. 22. N Engl J Med 1997. Salen P. Kahonen M. J Agric Food Chem 2002. 2. 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Leon AS. Effects of docosahexaenoic acid on vascular pathology and reactivity in hypertension. and hypertension among US women. Quiles JL. Evaluation. Ainsworth BE. Battino M. World Health Organization. Am J Clin Nutr 2003. Chrysohoou C. Svetkey LP. Athens: Parisianos. Crit Rev Food Sci Nutr 2002. Herrera MD.228(3):299 –307. 5. Arch Intern Med 2002.360(9344):1455– 61. The Atherosclerosis Risk in Communities Study. Fish consumption and hypertension incidence in African Americans and whites: the NHANES I Epidemiological Follow-up Study. Whelton PK. Heiss G. Engler MM. Am J Hypertens 2002. 2003 European Society of Hypertension. Monjaud I. 16. Cardiovasc Pharmacol 2003. Cambridge. Rimm EB. Hypertension and blood pressure among meat eaters. Molteni A. Br J Nutr 2001. 33.5(5):645–54. Seppo L. Adherence to a Mediterranean diet and survival in a Greek population. JAMA 2003. Bryant HJ. Int J Epidemiol 1997. 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MA: Harvard University Press.71(4):987–92. 11. Vandongen R. Panagiotakos DB. et al Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (IndoMediterranean Diet Heart Study): a randomised single-blind trial. Vascular influences of calcium supplementation and vitamin D-induced hypercalcemia in NaClhypertensive rats. 23.113(suppl 9B):9S–12S. Clough DL. Rastrelli L. 38. blood pressure. Body mass index in relation to energy intake and expenditure among adults in Greece. 36. et al. Geneva. Clin Exp Hypertens 2003. N Engl J Med 2003. Lancet 2002.21(6):409 –13. Biological properties of olive oil phytochemicals. Margetts BM. dietary fatty acids and vitamin E in lipid peroxidation. Trichopoulou A. vegetarians and vegans in EPIC-Oxford. AND BLOOD PRESSURE 1017 vegetable intakes in the apparent beneficial effect of the Mediterranean diet in the context of arterial blood pressure control. et al. Davey G. 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46. Vogler O. 49. Sacks F. 43(2):249 –54. Hypertension 2004. Teres S.Blazos A.org by guest on September 25. Olive oil and reduced need for antihypertensive medication. Kouris. 2011 . Br J Nutr 2002.ajcn. Downloaded from www. Guida L. 50. et al. Escriba PV. J Cardiovasc Risk 2000.61(suppl): 1402S– 6S. Baamonde C. Law M. Am J Clin Nutr 1995. Arch Intern Med 2000.1018 PSALTOPOULOU ET AL 48. Trichopoulou A. 2-Hydroxyoleic acid: a new hypotensive molecule. Am J Clin Nutr 1995. Mediterranean diet pyramid: a cultural model for healthy eating. Vassilakou T. Marotta T.7(1):5– 8. Raimondi AS.88(1):57– 65. Trichopoulou A. Ferrara LA.160(6):837– 42. or sunflower oils differentially induces oxidative stress in rat liver microsomes. blood pressure and cardiovascular diseases.61(suppl): 1346S–50S. et al. Salt. Dello Russo A. 47. d’ Episcopo L. Diet and survival of elderly Greeks: a link to the past. Willett WC. Benet M. Alemany R.

Boyer J. Because we did not measure quercetin concentrations in our subjects. Murray LJ. et al.com Department of Epidemiology and Public Health Queen’s University Belfast United Kingdom J Maurice Savage David C Watkins Department of Child Health Queen’s University Belfast United Kingdom Madeleine M Rooney Rheumatology Department Musgrave Park Hospital Belfast United Kingdom Colin A Boreham REFERENCES 1. Am J Clin Nutr 2004. and bone mineral density Dear Sir: McGartland et al (1) reported a correlation between a diet high in fruit and bone mineral density.uk Liam J Murray Gordon W Cran Downloaded from www. McGartland CP. Notoya M. Nutr J 2004. et al. fruit consumption. Quercetin suppresses bone resorption by inhibiting the differentiation and activation of osteoclasts. Muraki Y. et al. Liu RH.61:158 –9. we did not specifically mention quercetin in our discussion. Reply to CM Ross Dear Sir: In her response to our article “Fruit and vegetable consumption and bone mineral density: the Northern Ireland Young Hearts Project. with flavonoids as their largest group (1). 1176 Am J Clin Nutr 2005.ac.4:504 –9. Kamel S.65:35– 42.80:1019 –23. Tobe H. Vaya J. et al. 2011 Celia M Ross 36 Ridgewood Circle Wilmington. Phytoestrogens comprise a variety of structurally diverse chemicals. The author had no conflicts of interest to report. In our discussion. Kamel S. Wattel A. Tamir S.81:1176 – 81. Claire P McGartland Paula J Robson Northern Ireland Center for Food and Health University of Ulster Coleraine United Kingdom E-mail: c. Printed in USA. Nakagawa H. The relation between the chemical structure of flavonoids and their estrogen-like activities. important for bone health (2). Robson PJ. Biochem Pharmacol 2003. The authors had no conflicts of interest to report. © 2005 American Society for Clinical Nutrition . et al. 2. Diets high in fruit contain high amounts of flavonoids (2). Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NFkappaB and AP-1. Biosci Biotechnol Biochem 1997. DE 19809 E-mail: celiamaryross@aol.Letters to the Editor Quercetin. 2. Woo JT.mcgartland@qub.11: 1333– 43. Kitamura K. Biol Pharm Bull 2004. Prouillet C. Curr Med Chem 2004.” Ross raises an interesting issue for discussion.ajcn.3:5. Apple phytochemicals and their health benefits. Mentaverri R. Fruit and vegetable consumption and bone mineral density: the Northern Ireland Young Hearts Project. 5. The flavonoid quercetin decreases the differentiation of osteoclast progenitor cells and inhibits the activity of mature osteoclasts (3–5). We thank Ross for her interest in our article and for highlighting the potential role of quercetin in bone health.92:285–95. Quercetin might act together with the alkaline-forming properties of fruit to inhibit osteoclasts and enhance bone mineral density. Wattel A. Their article includes a discussion of how a low pH stimulates osteoclasts and how fruit’s alkalineforming properties influence the body’s acid-base balance. 3. Another mechanism exists that could work in parallel or in synergy with the one proposed by McGartland et al. we stated that phytoestrogens have been identified as being potentially School of Applied Medical Sciences and Sports Studies University of Ulster Jordanstown United Kingdom REFERENCES 1. J Cell Biochem 2004. We agree that the flavonoid quercetin may inhibit osteoclasts and enhance bone mineral density. Bone resorption inhibitors from hop extract. 4. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption.org by guest on September 25.

a connection between vitamin D and pathogenesis of atopic dermatitis is discussed. Penna G. Consequently. did not find an association between type 1 diabetes among the offspring and the prenatal use of multivitamin supplements. In conclusion. 11. it would be premature to state that there is evidence that vitamin D deficiency during pregnancy may be a predisposing factor for the fetus to the development of immunologic diseases. and that this function of vitamin D is likely responsible for the numerous epidemiologic observations that persons who live at higher latitudes. et al. The author had no conflicts of interest to report. At present. Drevon CA. Mayo Clin Proc 2003. Epidemiologic studies have shown that patients with atopic dermatitis have a lower vitamin D intake than do control subjects (6). which leads to suppression of T cell activation. 7. Sandstad B. These investigators. production of interleukin (IL) 10 is stimulated and production of IL-12 inhibited.25-dihydroxyvitamin D3 as pluripotent immunomodulators. Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. Analogs of 1 .25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro. 6. This case-control study (85 cases and 1071 controls) from Norway found that cod liver oil taken during pregnancy was associated with reduced risk of type 1 diabetes in the offspring. Van Etten E. Topical vitamin D3 downregulates IgE-mediated murine biphasic cutaneous reactions. 5. 11). 1. In dendritic cells. but could be due to additional nutritive factors in cod liver oil or other confounding factors. Anton K. Vitamin D deficiency: what a pain it is. such as atopic dermatitis.88:323– 6. Am J Clin Nutr 2004. Department of Dermatology The Saarland University Hospital 66421 Homburg/Saar Germany E-mail: hajrei@uniklinik-saarland. important new immunomodulatory effects of vitamin D analogues have been characterized (4. Effects of 1 . 6. J Cell Biochem 2003. yet none of the studies they cited pertain to pregnancy. Arch Biochem Biophys 2003. including multiple sclerosis and type 1 diabetes (2–5). Vitamin D requirements during pregnancy. 2011 Reply to J Reichrath and K Querings Dear Sir: I appreciate the interest of Reichrath and Querings in my review of vitamin D requirements during pregnancy. Worm M. Minatohara K.25(OH)2D3. Eur J Immunol 2002. Garland FC. hypertension. 9.78:1457–9. including diseases of the immune system. Consequently. J Cell Biochem 2003. Verstuyf A. We would like to add to this discussion an important topic that has become evident recently and that was not addressed by the clinical studies that Specker reviewed: the fact that extrarenal synthesis of 1. CD80. such as atopic dermatitis or autoimmune diseases (4.25(OH)2D3 inhibits maturation and induces a phenotype that promotes tolerance and inhibits immunity after stimulation with antigen (8. J Cell Biochem 2003. Katayama I. which typically contain significant amounts of vitamin D. are at increased risk of not only developing prostate. An estimate of premature cancer mortality in the U.25-dihydroxyvitamin D3 and its analogs on dendritic cell function. Downloaded from www. 7–9). During the past few years. Oral administration of 1. colon. DeLuca HF. Griffin M. T and B lymphocytes. and other autoimmune diseases. 9). In these cells. Heine G.94:1867–75. but also of great importance to guarantee the healthy development of a broad variety of tissues. Mathieu C. due to inadequate doses of solar ultraviolet-B radiation. 1. therefore. Jörg Reichrath Kerstin Querings Bonny Specker . including the immune system. type 1 diabetes. The authors had no conflicts of interest to report. monocytes. It has been shown that various cell types involved in immunologic reactions (eg.S. including the immune system.88:227–33. This association. Uskokovic M. 7).org by guest on September 25. Serum 25hydroxyvitamin D and colon cancer: eight year prospective study. Vitamin D analogues suppress in vitro immunoglobulin E production and immunoglobulin E–mediated cutaneous reactions (10. 8. who are more prone to vitamin D deficiency. Comstock GW. Adorini L. 2. 7. or calcitriol] is of great importance for homeostasis in a multitude of tissues. Bouillon R. breast. a growing body of evidence now clearly indicates that adequate vitamin D concentrations during pregnancy are not only necessary to ensure appropriate maternal responses to the calcium demands of the fetus and neonatal handling of calcium. calcitriol suppresses expression of major histocompatibility complex II molecules and of costimulatory molecules. Although the studies discussed by Reichrath and Querings are intriguing. who carried out a comprehensive review of studies that investigated maternal and neonatal outcomes of vitamin D deficiency or supplementation during pregnancy.25dihydroxyvitamin D3 completely protects NOD mice from insulindependent diabetes mellitus. Eur J Clin Nutr 2000. Nishioka K. and CD86 (8. Yokozeki H.25(OH)2D3 inhibits activation of T cells and induces the generation of CD25 /CD4 regulatory T cells (4. the local synthesis of calcitriol in immune cells is considered to be of great importance for the regulation and control of immune responses. 9). Dietary habits among patients with atopic dermatitis. McCary LC. Giarratana N.25-dihydroxyvitamin D [1. Verlinden L. Those authors noted that there is increasing evidence that vitamin D deficiency during pregnancy may lead to a predisposition to immunologic diseases.LETTERS TO THE EDITOR 1177 Vitamin D deficiency during pregnancy: a risk factor not only for fetal growth and bone metabolism but also for correct development of the fetal immune system? Dear Sir: We read with great interest the excellent article by Specker (1). vitamin D deficiency during pregnancy may represent for the fetus a predisposing factor for the future development of a multitude of diseases not related to fetal growth and bone metabolism. Kumar R. Today.25(OH)2D3 (4. and cardiovascular heart disease but also of developing autoimmune diseases.88:223– 6. Soyland E. Lancet 1989.80(suppl):1740S–7S. 4.2:1176 – 8. Zella JB. However. 3. Grant WB.32:3395– 404. Henz BM. In dendritic cells. including diseases of the immune system. is not likely to be a direct result of maternal vitamin D status. 10. including CD40.ajcn. 9).111:71– 6. Solvoll K.de REFERENCES 1. however. Decallone B. 1 . and Langerhans cells) not only express the vitamin D receptor but also possess the enzymatic machinery (25-hydroxyvitamin D-1 -hydroxylase) for the local synthesis of 1. Garland CF. Holick MF.54:93–7. increasing evidence now indicates that vitamin D deficiency during pregnancy may represent for the fetus a predisposing factor for the future development of a broad variety of diseases. one study was found in the literature that investigated the relation between vitamin D status during pregnancy and the subsequent development of immunologic diseases (1). Cancer 2002.417:77– 80. 7–9). and other solid tumors. Specker B. Int Arch Allergy Immunol 1996.

This was based on similarities in iron absorption when measured by whole-body scintillation counting (22% and 22% from ferritin and ferrous sulfate.edu LETTERS TO THE EDITOR labeled a full range of isoferritins but that isotope incorporation into the more acidic forms was slightly higher (4).43:1093– 8. For instance. It is possible that a lower absorption of ferritin iron may explain the slightly greater (10%) absorption of nonheme iron from extrinsically than from intrinsically labeled foods (5). Skikne et al (4) observed a minor small molecular peak in the Sepharose 6B elution pattern of in vitro. in vivo–labeled ferritin 59Fe was only 36% as well absorbed as was 55Fe from intrinsically labeled soybeans consumed in the same meal (2). an erratum was submitted.6% compared with 2. was clearly distinguishable from. nonheme-iron absorption from a hamburger meal supplemented with 20 mg Fe as ferrous sulfate was 8. The evidence does not support the conclusion that iron absorbed from ferrous sulfate REFERENCE 1. and it is not known whether these techniques alter ferritin isomerization. and the assumption of 80% incorporation of the absorbed isotope into blood was confirmed (9). Using Mössbauer spectroscopy. 4).1% from a 3-mg dose without food. Absorption of iron from ferritin Dear Sir: I would like to comment on the article “Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women. Davila-Hicks et al (1) concluded that iron from ferritin or ferrous sulfate follow different metabolic pathways after absorption.specker@sdstate. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes in the offspring.6% from a 50-mg dose with food. On the other hand. In conclusion. varying 10 –15-fold between subjects (see Figure 1 of reference 9).7) by the erythrocyte incorporation method. in addition to the low iron status of the subjects (8).8% in iron-replete men (11). respectively. SD 57007 E-mail: bonny. but when expressed as the percentage absorbed seem insufficient. Davila-Hicks et al (1) appear to have expressed the blood incorporation as a percentage of the ingested dose.9% from a 50-mg dose without food (4). but this would not necessarily explain the reduced iron bioavailability because the portion that is unlabeled may be less.7.4% (geometric x 1 SE: 6. including results with added ferrous sulfate (9). The greater retention of isotope in the erythrocytes than in the whole body suggests methodologic difficulties.1178 EA Martin Program in Human Nutrition Box 2204 South Dakota State University Brookings. 2011 . It is clear that the in vivo procedure does not uniformly label all of the iron in ferritin.3) by whole-body counting (see data in Figure 1 of reference 9) and 8.8% compared with 24. in vitro labeling results in higher bioavailability regardless of whether the ferritin has first been depleted of iron (1) or not (4). the similar results obtained by Murry-Kolb et al (8) and Sayers et al (10) do not support the hypothesis that the iron from the high-ferritin Tokyo soybean cultivar was more bioavailable than was that from commonly used soybean cultivars.98) (9). On the one hand. This relation alone is sufficient to account for the differences in iron absorption from soybeans cited by Davila-Hicks et al (1): 26% in women with borderline iron deficiency (assuming 80% red blood cell incorporation of absorbed isotope) (8). reports involved procedures to limit the radiolabel incorporation into blood by reducing erythrocyte synthesis or increasing erythrocyte breakdown. expressed as such. Those who have studied ferritin radiolabeled in vivo have concluded that ferritin iron is poorly absorbed and that it is not part of the nonheme pool of dietary iron that is readily exchangeable in and is similarly absorbed from the intestinal lumen (2– 4). but not in all (3). For example. Ambe et al (7) found that the form of ferric iron. their values seem excessive.” by Davila-Hicks et al (1). the blood incorporation method was highly correlated with the whole-body 0. and 2. For instance. These data do not confirm the counting method (R2 finding that iron from ferrous sulfate is more extensively incorporated into blood than is apparent from whole-body counting measurements. With the use of data from individual subjects (n 23). labeled ferritin. which suggests that the ferritin iron content of food is only a minor portion of total food iron. 10. 10.org by guest on September 25. The conclusion indicated in the title is based on measurements of iron absorption from horse spleen ferritin that was radiolabeled in vitro and appears to contrast with the results of others whose studies using ferritin radiolabeled in vivo were not cited (2– 4).8. It is unlikely that horse spleen ferritin labeled with extra phosphorus in vitro (1) is comparable with plant ferritin. 20% in women with iron deficiency (assuming 100% red blood cell incorporation. Note that the blood incorporation data in reference 9 was incorrectly labeled as the incorporation of the ingested rather than of the absorbed isotope dose. The specific method and assumptions used were not delineated. Stene LC. Although physicochemical methods detected only minor alterations in ferritin labeled in vitro (1. absorption of iron is inversely related to body iron stores. It is worth noting that the ferritin iron content of foods has not been widely determined because of the lack of species-specific antibodies as well as the insolubility and possible time-dependent molecular changes that may make ferritin iron less exchangeable (6). horse spleen ferritin than to ferric phytate. we repeatedly obtained similar absorption results between the 2 methods. and 0. Lacking a direct comparison of cultivars with the same subjects.2% compared with 8. see Table 1) but differences in absorption when measured from erythrocyte iron incorporation (27% and 48%). the human absorption results provide a distinguishing bioassay for ferritin labeled in vitro compared with in vivo. Joner G. the in vivo labeling of animal ferritin has in some (2. Davila-Hicks et al (1) proposed that a high absorption of iron from the Tokyo soybean cultivar is partially explained by a high ferritin content of this cultivar.ajcn. After logarithmic transformations of both variables. exchangeable or absorbable.2% from a 3-mg dose with food. representing 95% of the iron in soybeans. Each labeling method has potential problems. the same group further reported that radioiron incorporated into bovine spleen ferritin in vivo was significantly less absorbed than was iron from ferrous sulfate: 3. Ulriksen J. that they proposed to be denatured ferritin.7% compared with 7. and in vitro iron exchange can induce ferritin degradation through Fenton chemistry (6). With the use of commonly used methods (see citations in reference 9) and an assumption of 80% incorporation of the absorbed isotope into blood. Magnus P. not more. 4). the absorption calculation is increased to 25% if red blood cell incorporation is assumed to be 80%) (10).5% (6. 0. but not in vivo. but more similar to. However. 3. Those investigators (4) determined that in vitro procedures Downloaded from www. Skikne et al (4) also found that iron from ferritin radiolabeled in vitro was absorbed similarly to iron from ferrous sulfate. research on iron bioavailability from ferritin labeled in vitro must be interpreted with caution. Diabetologia 2000.

nonheme-iron complexes such as ferrous sulfate and ferric EDTA. We observed a difference for ferritin iron and ferrous sulfate. using EXAFS analysis. Blood 1975. Mechanism of the transition from plant ferritin to phytosiderin. J Clin Invest 1972. 4. Murray-Kolb LE. Mössbauer study of iron in soybean seeds. that the high phosphate mineral content in horse spleen ferritin was similar to that in natural pea ferritin (8) and distinct from that in animal ferritins. For Hunt’s assertion to be correct.usda. phosphate. and hydroxide from liquid to solid in biology remains poorly understood at this time. Beard JL. Layrisse M. which had endogenous iron both in vitro and in vivo. in that study the estimate of the iron:protein ratio in the isolated ferritin was very high. Derman DP. In Hunt’s previous work (10). Welch R. the reality is much more complicated. There were no conflicts of interest. Dassenko SA.org by guest on September 25. Fonzo D. Theil EC. Hunt misunderstood our statement about soybean cultivars. Am J Clin Nutr 2004. The phase transition of calcium. In the 1997 study annotated in Hunt’s letter (7). which suggested the presence of denatured ferritin protein/hemosiderin to which some labeled iron added in vitro may have been adsorbed. Lynch SR. Cook JD. Studies currently in progress will explore the influence.LETTERS TO THE EDITOR follows a metabolic distribution different from that of iron absorbed from ferritin.24:209 –18. iron. Beard JL. Am J Clin Nutr 2004. assuming 80% incorporation and calculating whole-body retention from blood volume estimated from body weight. of the plant ferritin protein on iron absorption. Davila-Hicks P. Walker R. In our recent article. unfortunately.27:228 –33. In addition. 9. We used the conventional approach for estimating whole-body retention from red blood cell (RBC) incorporation. 1179 Janet R Hunt USDA–ARS Grand Forks Human Nutrition Research Center 2420 2nd Avenue N. In contrast with the statement in Hunt’s letter. there is no other solid mineral in humans. Layrisse M. ie. the label was added to ferritin (bovine). which simply indicated that soybeans with more ferritin would likely have a greater proportion of the bean iron in ferritin. Renzy M. the structure of the iron mineral is sensitive to physiologic conditions (4). Bothwell TH. and soya. Iron absorption by heterozygous carriers of the HFE C282Y mutation associated with hemochromatosis. Jacobs P. We previously compared the mineral in pea ferritin with that in horse spleen ferritin reconstituted to have a plant ferritin mineral composition and found. we merely suggested this as a possible explanation for the differences observed.29:18 –24.77:180 – 4.ajcn. Nozaki T. based on the data in the article. With the exception of calcium phosphate minerals. we did not “conclude” that iron from ferritin or ferrous sulfate follow different metabolic pathways after absorption. Cook JD.35:292– 6. Reply to JR Hunt Dear Sir: The comments of Hunt about our recently published article on the absorption of iron from ferritin (1) reflect the confusion that often exists over the consequences of the unique features of ferritin biology and chemistry: a solid mineral inside an organic protein shell. 7. wheat. giving rise to the inappropriately high absorption observed (7). Under the hydroponic. Women with low iron stores absorb iron from soybeans.80:936 – 40.80:924 –31. Lynch SR. Am J Clin Nutr 1984. Zeng H. Further molecular studies at a cellular level are needed to verify this. Further studies are needed to explore this in more detail. in our study. To summarize. Martinez-Torres C. Bovine ferritin iron bioavailability in man. ND 58202 E-mail: jhunt@gfhnrc. These differences between the 2 methods for determining iron absorption may be related to differences in the geometry of the counter when determining radioactivity from a point source (blood) rather than from a whole body. nonnodulating conditions used in the study described (9). the same method was used in the 2 groups of subjects. Am J Clin Nutr 2003. 10. Eur J Clin Invest 1997.51:805–15. Ambe S. This was stated in the text as the well-known “RBC incorporation method for estimating iron absorption” rather than in explicated detail in the Methods. solid mineral in ferritin. Leets I.gov REFERENCES 1. Ferritin iron absorption in man. 5. may have caused confusion. Adding iron to ferritin involves a phase transition that makes full equilibration of exogenous iron very slow (2). The effect of ascorbic acid supplementation on the absorption of iron in maize. In addition. Laboure AM. We did not intend to state that the retention in erythrocytes was greater than that in the whole body. Briat JF. Monsen E. Finally. We obtained a higher absorption using this method than when using whole-body counting. Briefly. Finch CA. Sayers MH. Cook JD. Food iron absorption measured by an extrinsic tag. equilibration is very slow (days to months). All soybean cultivars have a large fraction of the iron in ferritin when grown under field conditions. which. However. Laulhere JP. None of these possibilities would have been detected in the protein analyses described in the article by Hunt. 2011 . et al. we showed an efficient absorption (20 –25%) of ferritin iron in several studies using different analytic methods to Downloaded from www. 8. which suggested a difference in metabolic handling of the 2 types of iron. Iron absorption from ferritin and ferric hydroxide. ferritin protein varies in different tissues or under different physiologic conditions and controls the entry and exit of iron to and from the solid phase (3). PO Box 9034 Grand Forks.ars. J Biol Chem 1989. Scand J Haematol 1982.40:42–7. Martinez-Torres C. Lynch SR. Iron absorption from legumes in humans. because the effect is on the location of the labeled iron in the iron mineral. the work was annotated in our recent paper. a lower value was obtained with the RBC method (calculated from Figure 1 in reference 10) than with whole-body counting. but our own preliminary data from Caco-2 cells (presented at Experimental Biology 2004) support such a scenario. Torrance JD. the nonconserved structural features would have had to dominate the many conserved structural features of ferritin protein in iron absorption. Skikne B. Hunt JR. J Agric Food Chem 1987. Theil EC. However. 11. Lönnerdal B. Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women. 3. The discussion of the causes of the apparent inconsistencies in the results of using isotopically labeled ferritin in iron-absorption experiments appears in our first article on iron absorption from ferritin (5) and again in a recent review (6). The assertion in Hunt’s letter about the plant ferritin mineral in reconstituted horse spleen ferritin is incorrect. we were merely exploring whether the structure of the plant ferritin mineral influenced iron absorption in humans.264:3629 –35. Ambe F. 2. 6. Under physiologic conditions.45:689 –98. et al. the iron in solutions of ferritin— the protein with the solid iron mineral inside—appears to be physically in the same phase as iron in solutions of other nutritional. Br J Hematol 1973. when labeled iron atoms are added to the unlabeled. if any. the percentage of bean iron in ferritin was lower than that in field-grown beans.

CA 94609 Bo Lönnerdal Department of Nutrition University of California One Shields Avenue Davis.109:797– 802. Iron. There was no conflict of interest. Ades PA. Beard JL. Mössbauer spectroscopic studies of human haemosiderin and ferritin. Szulc P. Bell SH. and routine physical activity both at work and during leisure time were shown to positively affect arm and leg muscle masses. Sharp GA.70:91– 6. Marchand F. It is interesting to note that we came to a similar conclusion (2) in regard to healthy white postmenopausal women of a comparable age range (54 –76 y). Harlow C. Bovine ferritin iron bioavailability in man. 3. Moreover. as noted by Szulc et al from self-reported data in their male cohort (1). 3. this investigation indicated that relatively nonstructured. Theil EC. Formation of the ferritin iron mineral occurs in plastids: an x-ray absorption spectroscopy (EXAFS) study. Poulos T. Starling RD. Jin W. Theil EC. solid.27:228 –33. Waldo GS. Poehlman ET. Proc Natl Acad Sci U S A 2003.126: 154 – 60. Purified ferritin and soybean meal can be sources of iron for treating iron deficiency in rats. 4. United Kingdom: Wiley & Sons. gardening. Beard JL. Sayers DE. Earlier. and potassium content of fat-free mass in postmenopausal women. mineral ferritin in vitro or in vivo if the label is added late in bean development.75:314 –20. and housework— can help to maintain muscle mass in elderly men. 6. 2011 REFERENCES 1. Theil EC. Am J Clin Nutr 2004. 5. Iron in ferritin or in salts (ferrous sulfate) is equally available in non-anemic women. eds. Peters TJ. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS study. we suggested that both the iron status of the subjects and the labeling method may have contributed to the apparent inconsistencies among the various studies (5. Huber R. There were no conflicts of interest. including a reduction of abdominal fat. 4. 9. Opening protein pores with chaotropes enhances Fe reduction and chelation of Fe from the ferritin biomineral. Theil EC. Physical activity. and appendicular skeletal muscle mass in older men. household. because the women in our recent study had normal iron status (1). In: Messerschmidt A. practical aspects of the complex relation between physical activity and sarcopenia. Weir MP. Wieghardt K. Roughead ZK.au REFERENCES 1. Although it must be acknowledged that some training and observational studies have failed to confirm a positive effect of these predominantly aerobic types of activity on muscle mass (3. or leisure activity with a combined energy expenditure of Œ5 MJ per fortnight had markedly better muscle mass indexes than did their less active counterparts. which has been shown to be significantly associated with decreased functional status and increased disability and falls in the elderly (6). Fonzo D. Theil EC.100:3653– 8. Habitual physical activity. Now it appears more likely that the apparent inconsistencies among previous studies depend most heavily on poor equilibration of labeled iron with endogenous. Schiaffino S. Lynch SR. Theil EC. Am J Clin Nutr 2002. Annu Rev Nutr 2004. may be useful in preventing sarcopenic obesity. We avoided the problem of equilibration of unlabeled. Function. 11).77:180 – 4. 2) using soybean plants to which the label was added before seed ferritin formation (9. Biochim Biophys Acta 1984.71: 94 –102. Murray-Kolb LE. corrected for body size. Ferritin.ajcn. solid. Women with low iron stores absorb iron from soybeans. Allen BJ. independently of age.org by guest on September 25. Chichester. anabolic hormones. accumulating evidence supports a role for these popular activities in the maintenance of muscle and the provision of other metabolic benefits. Burton JW. Theil EC. Mantoni M. dancing.80:496 –503. Adaptation of iron absorption in men consuming diets with high or low iron bioavailability. Eur J Clin Invest 1997. Dickson DPE. Hunt JR. Am J Clin Nutr 2000. Am J Clin Nutr 2003. Delmas PD.24:327– 43. displayed a notable age-related decline after the age of 60 y. 2. Theil EC. 7. NSW 2065 Australia E-mail: hansenr@med. et al. 2. in both men and women (5). and tennis) to be relatively nonstructured and moderate in intensity (2). Elizabeth C Theil Center for BioIron Children’s Hospital Oakland Research Institute 5700 Martin Luther King Jr Way Oakland. 10. mineral iron in ferritin with added labeled iron in 3 ways: 1) using no label (5). ferritin and nutrition. Wright E.1180 LETTERS TO THE EDITOR measure iron incorporation. Handbook of metalloproteins. 4). swimming. Appendicular skeletal muscle mass. Cook JD. Hansen RD. Evidence for reutilization of nodule iron in soybean seed development. Those women who routinely engaged in work.21:913–27. Klitgaard H. Davila-Hicks P. A curvilinear relation between muscle mass and age was found. The follow-up reports of cohorts such as the MINOS Study subjects should be invaluable in further quantifying these important. floor exercises. Wang Z-H. morphology and .80:936 – 40. CA 95616 E-mail: bllonnerdal@ucdavis.edu Downloaded from www. J Plant Nutr 1998.787:227–36. Liu X. Lönnerdal BL. 2001:771– 81. interviews with these women showed the most common leisure-time activities undertaken (walking.usyd. 8. 9). Plant Physiol 1995. walking. protein intake. Am J Clin Nutr 1999. low-to-moderate intensity activities—including bicycling. Importantly. Ross D Hansen Centre for In Vivo Body Composition Gastrointestinal Investigation Unit (11E) Royal North Shore Hospital St Leonards. with an accelerated decline after 60 – 65 y. gardening. Duboeuf F. J Nutr 1996.edu. Burton JW. and 3) using ferritin from which iron was removed before reconstituting the mineral with labeled iron (1). Skikne B. Am J Clin Nutr 2004. Hormonal and lifestyle determinants of appendicular skeletal muscle mass in men: the MINOS Study Dear Sir: The recent article by Szulc et al (1) identified several lifestyle and hormonal factors as potential determinants of sarcopenia in a large sample of men aged 45– 85 y. Such activities. Gibson JF. 11. Welch R. Briat J-F. this effect was evident throughout the age range studied. therefore.

0 for men and 46. Downloaded from www. The partial regression coefficients of systolic and diastolic blood pressure on SD increments in olive oil intake and the corresponding 95% CIs and P values (reported in Tables 4 and 5 and throughout the text) were unaffected by this error. and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Naska A. Mech Aging Dev 2003. The correct mean ( SD) intakes (in g) were 53. Poehlman ET. Am J Clin Nutr 2004. Baumgartner RN.124:259 – 67. Table 3.8 for women. Trichopoulou A.140:41–54.4 21. 6. Ades PA. although there was no error in the corresponding SDs. Dionne IJ.80:1012– 8.904:437– 48. the mean daily intakes of olive oil by men and women were incorrect. Mountokalakis T. the Mediterranean diet. Acta Physiol Scand 1990. 2011 On page 1014. Impact of cardiovascular fitness and 1181 physical activity level on health outcomes in older persons. Body composition in healthy aging. . 5. Trichopoulos D. Ann N Y Acad Sci 2000.LETTERS TO THE EDITOR protein expression of ageing skeletal muscle: a cross-sectional study of elderly men with different training backgrounds.org by guest on September 25.ajcn. A programming error was responsible for this overestimation. Olive oil. Erratum Psaltopoulou T.6 24. Orfanos P.

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