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LETTERS TO THE EDITOR

preventing chronic diseases. However, careful methods should be

adopted to avoid incorrect conclusions.
Neither of the authors had a conflict of interest.

Ahmad Esmaillzadeh
Leila Azadbakht
Department of Human Nutrition
School of Nutrition and Food Technology
Shaheed Behshti University of Medical Sciences
PO Box 19816-19573
Tehran
Iran
E-mail: esmaillzadeh@yahoo.ca

REFERENCES

Neither of the authors had a personal or financial conflict of interest.

Katherine Esposito
Dario Giugliano

Whole-grain intake cools down inflammation

Dear Sir:
We read with interest the study of Sahyoun et al (1) reporting a
lower prevalence of the metabolic syndrome and a reduced risk of
cardiovascular disease (CVD) mortality in older people consuming
diets high in whole-grain foods. Although these results are for the
most part confirmatory, adding to the existing evidence that wholegrain intake may confer protection against the metabolic syndrome
and CVD risk, the message about the healthy benefits conferred by
increasing whole-grain intake in an older population is important.
One problem with the study is the use of body mass index (BMI) as
a measure of waist circumference. BMI may be not equivalent to
waist, either in terms of measurement (cm) or in predicting CV risk.
The recent data from the INTERHEART Study (2) clearly showed
that, worldwide, waist is superior to BMI in relation to the risk of
myocardial infarction. Therefore, the results of Sahyoun et al must
be viewed with caution, because their report does not specify how
many subjects with abdominal obesity (men with BMI 31 and

Division of Metabolic Diseases

University of Naples SUN
Piazza L Miraglia 2
80138 Naples
Italy
E-mail: dario.giugliano@unina2.it

REFERENCES
1. Sahyoun NR, Jacques PF, Zhang ZL, Juan W, McKeown NM. Wholegrain intake is inversely associated with the metabolic syndrome and
mortality in older adults. Am J Clin Nutr 2006;83:124 31.
2. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27 000 participants
from 52 countries: a case-control study. Lancet 2005;366:1640 9.
3. King DE, Egan BM, Geesey ME. Relation of dietary fat, fiber to elevation of C-reactive protein. Am J Cardiol 2003;92:13359.
4. Qi L, Rimm E, Liu S, Rifai N, Hu FB. Dietary glycemic index, glycemic
load, cereal fiber, and plasma adiponectin concentration in diabetic men.
Diabetes Care 2005;28:1022 8.
5. Esposito K, Nappo F, Giugliano F, et al. Meal modulation of circulating

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1. Sahyoun NR, Jacques PF, Zhang XL, Juan W, McKeown NM. Wholegrain intake is inversely associated with the metabolic syndrome and
mortality in older adults. Am J Clin Nutr 2006;83:124 31.
2. Jacobs DR Jr, Gallaher DD. Whole grain intake and cardiovascular
disease: a review. Curr Atheroscler Rep 2004;6:41523.
3. Johansson L, Soluoll K, Bjorneboe GEA, Drevon CA. Under- and overreporting of energy intake related to weight status and lifestyle in a
nationwide sample. Am J Clin Nutr 1998;68:266 74.
4. Lafay L, Mennen L, Basdevant A, et al. Does energy intake underreporting involve all kinds of food or only specific food items? Results
from the Fleurbaix Laventie Ville Sante (FLVS) study. Int J Obes Relat
Metab Disord 2000;24:1500 6.
5. Esmaillzadeh A, Mirmiran P, Azizi F. Whole-grain consumption and the
metabolic syndrome: a favorable association in Tehranian adults. Eur
J Clin Nutr 2005;59:353 62.
6. Mirmiran P, Esmaillzadeh A, Azizi F. Dairy consumption and body mass
index: an inverse relationship. Int J Obes Relat Metab Disord 2005;29:
11521.
7. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi F. Dairy consumption
is inversely associated with the prevalence of the metabolic syndrome in
Tehranian adults. Am J Clin Nutr 2005;82:52330.
8. Willett WC. Nutritional epidemiology. 2nd ed. New York: Oxford University Press, 1998.

women with BMI 27) escaped evaluation or what was the frequency of abdominal obesity (with BMI used as a surrogate measure) in the definition of the syndrome.
Among the biologically plausible mechanisms of the beneficial
effects of whole-grain intake on CVD risk, the authors failed to
include inflammation. Recent evidence suggests that inflammation
may be an important mediator in the association between the consumption of dietary fiber, one important constituent of whole-grain
foods, and CVD. In a nationally representative sample of 4900 adults
aged 40 65 y, the likelihood of elevation of C-reactive protein
(CRP) was significantly lower in subjects in the highest fiber quartile
than in those in the lowest quartile (odds ratio: 0.51; 95% CI: 0.27,
0.95), regardless of age and BMI (3). A cross-sectional analysis of
780 diabetic men from the Health Professionals Follow-up Study
(4) showed that high intakes of cereal fiber were associated with
higher plasma concentrations of adiponectin, an insulin-sensitizing
adipocytokine with anti-inflammatory properties. Meal modulation
of circulating inflammatory and anti-inflammatory cytokines may
also play a role in the detrimental or beneficial effects of different
types of carbohydrates. For instance, the fiber content of a highcarbohydrate meal may influence plasma concentrations of adiponectin and interleukin 18 (IL-18): the greater the quantity of fiber
in the load, the greater the inhibition of plasma IL-18 and the stimulation of adiponectin (5). IL-18 is a potent proinflammatory cytokine that may be important in the process of plaque destabilization
and hence in predicting cardiovascular death in patients with
acute coronary syndromes (6). It is interesting that, in the study by
Sahyoun et al, fasting glucose concentrations decreased across increasing quartile categories of whole-grain intake, a finding consistent with a proinflammatory effect of increasing glucose concentrations (7). Increased consumption of high-density and low-quality
foods, such as those rich in refined grains and poor in natural antioxidants and fiber, may cause an activation of the innate immune
system, most likely by excessive production of proinflammatory cytokines associated with a reduced production of anti-inflammatory cytokines. This imbalance may favor the generation of an inflammatory
milieu, which in turn may predispose susceptible persons to a greater
incidence of the metabolic syndrome (8).

LETTERS TO THE EDITOR

interleukin 18 and adiponectin concentrations in healthy subjects and in
patients with type 2 diabetes mellitus. Am J Clin Nutr 2003;78:1135 40.
6. Blankemberg S, Tiret L, Bickel C, et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation
2002;106:24 30.
7. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002;106:206772.
8. Esposito K, Giugliano D. Diet and inflammation: a link to metabolic and
cardiovascular diseases. Eur Heart J 2006;27:1520.

Reply to A Esmaillzadeh and L Azadbakht and to

K Esposito and D Giugliano
Dear Sir:

for all metabolic risk factors, metabolic syndrome, and CVD mortality. Because none of these interactions were significant, we combined the data for men and women to increase the statistical power
of the study. Moreover, as we reported, we controlled for other
dietary factors, such as fruit and vegetables and dairy products, but
the results remained essentially unchanged. Therefore, we did not
retain those factors in our final statistical models.
Esmaillzadeh and Azadbakht stated that the use of the 3-d diet
records is a major weakness of our study. Clearly, the debate over the
best dietary assessment method to use in observational studies is
ongoing (9). All methods of collecting dietary data have inherent
problems. Although no data are available from which to compare the
relative capacity of different dietary methods to capture whole-grain
food intake, we believe that the diet records may present an advantage over the food-frequency questionnaire in measurement of
whole-grain foods. Because the open-ended format of the diet record
includes a greater amount of detail, its use can capture sources of
whole grains that are not listed or that may be grouped with refinedgrain foods on a food-frequency questionnaire. In addition, the 3-d
diet record was more quantitative, because portion sizes were
weighed or measured by using household utensils provided by the
study.
Finally, Esmaillzadeh and Azadbakht questioned our finding that
elderly men are consuming more whole grains than are women. This
finding is likely a consequence of the use of the diet records rather
than a food-frequency questionnaire for assessing whole-grain intake, because the former can capture intake in a more quantitative
manner. According to Table 1 in our article, the fourth quartile of
both whole- and refined-grain distribution includes fewer women;
that difference is a consequence of the higher energy intake among
men. The whole-grain to refined-grain intake ratio across the quartiles of whole grain is higher in women (ie, 0.11, 0.37, 0.74, and 2.12)
than in men (ie, 0.07, 0.24, 0.56, and 1.33).
We agree with Esposito and Giugliano that waist circumference is a better measure for defining abdominal adiposity than is
BMI, but unfortunately, waist circumference was not measured in
these elderly persons. In our study, 17 of 179 men (9.5%) and 125
of 356 women (35.1%) had elevated BMI. The use of BMI rather
than waist circumference may have underestimated the number of
people with abdominal adiposity, particularly men, which potentially led to a modest misclassification of the metabolic syndrome. In that case, the true association may have been stronger
than the one we observed.
We thank Esposito and Giugliano for highlighting the potential
inflammatory role that diets rich in whole-grain foods may play in
reducing CVD risk. Indeed, diets rich in whole grains have been
hypothesized to play a role in preventing CVD through various
potential mechanisms, including body weight, glycemic control,
plasma lipids, and inflammation. It is interesting that only recently
has whole-grain intake been examined in relation to markers of
inflammation (10, 11). A cross-sectional study in 938 healthy
middle-aged persons found no significant association between
whole-grain intake and several markers of inflammation, including
concentrations of C-reactive protein, fibrinogen, and interleukin 6
(10). In contrast, whole-grain intake was significantly associated
with lower concentrations of C-reactive protein and tumor necrosis
factor- receptor 2 in 902 diabetic women (11). At present, the effect
of whole-grain foods on inflammation should be established in different populations and also in clinical studies.
Our study of whole grains, metabolic risk factors, and CVD mortality was conducted in self-selected elderly volunteers more than 2
decades ago (7). As the first study to relate whole-grain intake to
metabolic risk factors and mortality in healthy elderly, it provided

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We thank Drs Esmaillzadeh and Azadbakht and Drs Esposito and

Giugliano for their interest in our study and for their comments.
Prospective studies that used detailed dietary assessment, long-term
follow-up, and control of multiple confounding factors found that
whole grains are associated with lower risk of cardiovascular disease
(CVD; 1, 2), type 2 diabetes mellitus (3, 4), and prevalence of
metabolic syndrome (5, 6). To our knowledge, our study was the first
to examine whole-grain intake in a sample of healthy elderly and to
relate that intake to metabolic risk factors and mortality (7).
Esmaillzadeh and Azadbakht expressed concern that our subjects
were not randomly selected. We share this concern, and we acknowledged in our report that our study population was not representative
of the elderly and stated that, therefore, further studies in this agegroup were needed to confirm our findings. Esmaillzadeh and
Azabakht also indicated a concern about an increase in underreporting of energy intake with age. The extent to which there is underreporting of calories among older US adults is not known because of
paucity of such data. The work that Esmaillzadeh and Azadbakht cite
as evidence of increased underreporting of energy with age is based
on a food-frequency questionnaire used in a Norwegian population
(8). We used 3-d diet records in the current study, so it is not clear that
this finding would pertain to our study. Moreover, we made an
attempt in our study to reduce the potential for underreporting by
having a trained dietitian instruct participants in keeping a food
record and follow up with each subject in a face-to-face interview to
probe for food items that may have been missed and to obtain brand
names of foods.
In response to the question about categorization of foods as whole
or refined grain, we, as stated in our report, used the US Department
of Agriculture Pyramid Servings Database, which provides information on food-group classification. The total number of grain servings per 100 g food was based on the 3-d food record. That total
number of grain servings was classified into whole-grain servings
and non-whole-grain servings according to the proportion of the
grain ingredients in the food that were whole grain and nonwhole
grain as determined in the database. In our study population, wholewheat, rye, and pumpernickel breads contributed 53%, cold cereals
contributed 19%, hot cereals contributed 16%, and crackers and
snacks contributed 6% of the whole-grain intake.
Esmaillzadeh and Azadbakht inquired about the possibility of an
interaction between sex and whole-grain intake and confounding by
other foods. In separate models, 2-way interactions between sex and
whole- and refined-grain intakes were tested in regression models

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