Food and Nutrition Sciences, 2013, 4, 39-47
http://dx.doi.org/10.4236/fns.2013.47A006 Published Online July 2013 (http://www.scirp.org/journal/fns)
Dietary Fibers and Nutraceuticals for Primary
Cardiovascular Prevention in Children and
Adolescents: A C rit ical Re vie w
Francesco Martino1, Paolo Emilio Puddu2, Giuseppe Pannarale2, Francesco Barillà2
1Lipid Research, Department of Pediatrics and Pediatric Neuropsichiatry, “Sapienza” Università di Roma, Rome, Italy; 2Department
of Cardiovascular, Respiratory, Nefrological, Anesthesiological and Geriatric Sciences, “Sapienza” Università di Roma, Rome, Italy.
Received March 17th, 2013; revised April 18th, 2013; accepted April 25th, 2013
Copyright © 2013 Francesco Martino et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
The roles of dietary fibers and nutraceuticals for primary prevention of cardiovascular disease from childhood are re-
viewed. Nutrition as an epigenetic modifier and the roles of endothelium, risk factors, epidemiological evidence and
Mediterranean diet are critically analysed. Overfeeding in childhood can lead to the development of obesity and/or
atherosclerosis in adult life. In particular, a high intake of nutrients affects the in utero programming with the adverse
consequences of insulin resistance an endothelial dysfunction that lead to early atherosclerosis. Dietary fibers have im-
portant health benefits in childhood and research suggests that they may prevent obesity and lower blood cholesterol
levels with a favourable impact on the risk of future cardiovascular disease incidence. However, it is for further studies
to assess whether also in Southern European Countries, practicing Mediterranean diet as a normal habit, dietary fibers
may contribute to modify the relatively low proportion of hyperlipemia observed in our population.
Keywords: Cholesterol; Hyperlipemia; Childhood; Dietary Fibers; Nutraceuticals; Prev ention
1. Introduction
Numerous epidemiological and clinical studies perform-
ed in recent decades have brought an important con-
tribution in understanding the p athogenesis of atheroscle-
rosis. Although atherosclerosis is clinically manifest in
adulthood, it is well recognized that it develops without
symptoms in the earliest years of life. Fatty streaks, in
fact, containing characteristic deposits of lipids, lipid per-
oxidation products, and white cells (monocytes/macro-
phages), can be observed in the aorta of premature hu-
man fetuses and intimal thickening has been demonstrat-
ed in fetal coronary arteries [1-3]. These early lesions
may develop in advanced atherosclerotic lesions [4-8]
and the progression may be influenced by risk factors
promot i ng in flamm at i on and pl aque rupture [9] .
In the last two decades a number of epidemiological
and experimental studies aimed to understand the path-
ogenesis of atherosclerosis. Increased serum levels of
LDL-cholesterol represent the most important risk factor
for atherosclerotic cardiovascular disease; however, ge-
netic and environmental factors interact in the onset and
progression of the disease. This interaction emphasizes
the key role of epigenetic mechanisms in the pathogene-
sis of early atherosclerosis. Epigenetics refers to a phe-
nomenon of altered phenotypic expression without heri-
table variations in the nucleotide sequence of the DNA.
The most frequent mechanisms in mammals include DNA
methylation and histone modifications, resulting in a
change in chromatin structure and pathway of small non-
coding RNAs. The epigenetic modifications control em-
bryonic development, differentiation, programming and
reprogramming of stem cells. These changes are a bio-
logical response to environmental stressors (obesity, dia-
betes, smoking, etc.) and can be transmitted to the off-
spring influencing their risk of atherosclerosis [10-12].
2. Nutrition and Epigenetics
Nutrition is an important modifier of epigenetic profile,
even before birth [13]. In fact, nutritional imbalances of
the father before conception and of the mother during
pregnancy, may predispose the fetus to the risk of car-
diovascular and metabolic diseases in adulthood. Mater-

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review
40
nal nutrition can affect the epigenetic status of the fetal
genome and can persist into adulthood [10,11]. There are
many studies that suggest that most chronic diseases of
adulthood, such as atherosclerosis, originate from an al-
tered intrauterine growth and development. Among the
classical risk factors for atherosclerosis, obesity and hy-
percholesterolemia seem to have the main role [10-12,
14-16].
2.1. Roles of Endothelium and Risk Factors
Endothelial dysfunction is considered an early stage of
vascular damage and an early event in atherogenesis
[17-19]. Until recently, the understanding of alterations
in pediatric cardiovascular disease was mainly limited to
autopsy studies and pathological findings in adolescents
and young adults died from accidental causes. Recent
advances in non-invasive diagnostic techniques have
made it possible to detect early (anatomical, physiologi-
cal, mechanical, proinflammatory and prothrombotic) ch an-
ges of the vessel wall, which reflects the subclinical ath e-
rosclerosis [20-22]. The first changes of the arterial wall
(intima-media thickening, IMT), can be observed with a
technique of high-resolution ultrasound. IMT, preceding
future clinical cardiovascular events, is considered a mark-
er of systemic atherosclerosis. The arteries most com-
monly examined in adults, are the internal and common
carotid arteries in the proximity of the carotid bulb and
the carotid bulb itself. IMT in adults is associated with
lesions, arteriografically documented, and the presence
of cardiovascular risk factors such as diabetes, obesity
and dyslipidemia.
The flow-mediated dilation (FMD) is the technique of
choice for the study of endothelial function in adults and
children and is the gold standard for research on endo-
thelial function in cardiovascular pathophysiology [23].
It measures the changes in brachial artery diameter in
response to increased shear stress produced by brief is-
chemia mechanics. Moreover, a significant reduction of
FMD associated with increased oxidative stress in chil-
dren with risk factors for cardiovascular disease (CVD)
was demo ns trated [24].
Several experimental and clinical studies have sug-
gested that an increase in oxidative stress represents an
important mechanism which leads to a reduced av ailabil-
ity of endothelial NO in response to cardiovascular risk
factors and, subsequently, promotes the development and
progression of atherosclerosis. These non-invasive tech-
niques have been used in recent years in pediatric age to
investigate the association of the CVD risk factors with
structure and function of th e arterial wall. In particular, it
was noted that IMT correlates positively with levels of
total cholesterol and with BMI [25].
Among the classical risk factors for atherosclerosis,
hypercholesterolemia, and obesity seem to be the main
determinants of early atherosclerosis [6,7,26]. The endo-
thelial dysfunction, assessed by the FMD has been rec-
ognized as a measure of systemic atherosclerosis [27].
The FMD depends on the release of nitric oxide (NO), a
potent vasodilator and anti-aggregating molecule from
the vessel wall [28,29]. Oxidative stress plays an impor-
tant role in the modulation of the bioactivity of NO be-
cause it contributes to its rapid metabolism [29]. Children
and adolescents with hypercholesterolemia and obesity
have increased oxidative stress and impaired FMD [24,
30]. The coexistence of hypercholesterolemia and obesity,
through the endothelial dysfunction and the activation of
NOx2, represents, in addition, a trigger for the early
atherosclerosis [3 1].
2.2. CVD Epidemiology: From Adulthood to
Childhood
The primary prevention of non-communicable chronic
degenerative diseases (such as CVD, cancer, neurode-
generative diseases) and infections should be the “main
goal of modern medicine”. Ancel Keys, about 60 years
ago, was the first investigator to understand the close
correlation between the intake of a cholesterol-rich diet
and CVD [32,33]. The results of the Seven Countries
Study confirmed this intuition show ing that the campaign
to reduce the cholesterol in the United States has signifi-
cantly reduced CVD mortality. The Framingham Heart
Study was the first longitudinal study population that
allowed us to observe the development of cardiovascular
events in relation to a number of variables and to show,
after 10 years, multiple risk facto rs directly related to the
occurrence of CVD events [34]. There is clear-cut evi-
dence that hyperlipidemia, hypertension, obesity, diabe-
tes and smoking are the main risk factors for atheroscle-
rosis and subsequent CVD [34].
Many studies, including the Muscatine Study, the
Bogalusa Heart Study, the Cardiovascular Risk in Young
Finns Study, the Coronary Artery Risk Development in
Young Adults (CARDIA), have demonstrated the track-
ing of cholesterol from childhood to adulthood, the fam-
ily risk factor aggregation and the role of obesity and
hypercholesterolemia in predicting vascular damage in
young adults [35-38]. At present time, the scientific evi-
dence indicates that primary prevention of atherosclero-
sis, related to classical cardiovascular risk factors, should
be implemented as early as possible. Therefore it is nec-
essary to screen healthy children at risk in the setting of a
primary prevention program aimed to non-drug man-
agement: changes in dietary habits (limited intake of ca-
lories, saturated fat and salt, increase in the consump-
tion of fruits, vegetables and fiber) associated with phy-
sical activity.

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review 41
Effective strategies for risk factors reduction in chil-
dren are poorly investigated and only few studies evalu-
ated the role of a healthy diet and individual nutrients. In
fact, a relationship between fruit and vegetable consump-
tion and prevention of atherosclerotic-related disease is
based on observational and epidemiological analysis in
adulthood [39]. Recently it has been observed that an
adolescent population, consuming predominantly vege-
tarian foods, showed significantly better scores of mark-
ers of cardiovascular health and atherosclerotic progres-
sion, including body mass index, waist circumference,
cholesterol/high-density lipoprotein ratio, and low-den-
sity lipoprotein-cholesterol [40].
2.3. Meditarranean Diet: Only for
Mediterranean Countries?
The traditional Mediterranean diet is characterized by: a
high intake of olive oil, fruit, nuts, vegetables and cereals;
a moderate intake of fish and poultry; a low intake of
dairy products, red meat, processed meats and sweets; a
moderate wine consumption during meals [41]. A meta-
analysis of 50 studies (approximately 500,000 individu-
als) suggests that adherence to the Mediterranean diet is
associated with a lower prevalence and progression of
metabolic syndrome (MS). In addition, a greater adher-
ence to this dietary pattern is associated with positive
effects on the individual components of the MS [42].
These results are extremely important for public health,
because this alimentary model can be easily adopted by
all population groups with different traditions and it has
been shown to be more effective in modifying athero-
sclerosis-related risk factors then low-fat diets [43].
In a randomized trial for the primary prevention of
cardiovascular events it was observed that an energy-
unrestricted Mediterranean diet, supplemented with ex-
tra-virgin olive oil or nuts, resulted in a substantial re-
duction in the risk of major cardiovascular events among
high-risk subjects. These results support the benefits of
the Mediterranean diet for the primary prevention of car-
diovascular disease [44]. Using the KIDMED (Mediter-
ranean Diet Quality Index for children and adolescents)
diet score on a population of 622 children Lazarou and
colleagues found a positive correlation between lower
levels of blood pressure and a higher KIDMED score
[45]. Although the increased consumption of dietary fi-
bers (fruits, vegetables, whole grains, legumes) is an im-
portant step in obesity control, dietary fiber supplements
often represent a useful add-on, since lifestyle changes
are difficult to follow after a while and high cholesterol
levels may be resistant to these changes. On the other
hand, different nutraceuticals have been studied for their
ability to reduce cholesterol in hu mans [46]. Dietary sup-
plement has been recognized as a starting point in the
prevention and management of CVD and type 2 diabetes.
Recent data show that about half of the US population
and 70% of older people use every day dietary supple-
ments [47].
3. Dietary Fibers
The American Dietetic Association (ADA) position pa-
per uses ADA’s Evidence Analysis Process and informa-
tion from ADA’s Evidence Analysis Library [48]. Four
topics were included in the evidence analysis for dietary
fibers (DF): cardiovascular disease, gastrointestinal health
and disease, weight control, and diabetes. The Evidence
Analysis Library does not include the topic of dietary
fibers and cancer. The Institute of Medicine defines DF
as the “non-digestible carbohydrates and lignin that are
intrinsic and intact in plants.” [49]. DF are usually di-
vided into 2 major categories based on water solubility
and viscosity. The physical properties of viscous and
non-viscous DF in food determine their physiologic ef-
fects, which in turn are related to their known and po-
tential health benefits [50].
Recently, the National Academy of Sciences (NAS)
proposed a new definition for fiber [49]. The new defini-
tion proposes that total fiber = dietary fiber + functional
fiber. Under this new definition, fiber consists of non-
digestible carbohydrates and lignin (a non-carbohydrate
substance bound to fiber), which are intrinsic and intact
in plants (e.g., gums, cellulose, oat bran, wheat bran),
and functional fiber consists of isolated, non-digestible
carbohydrates that have beneficial physiological effects
in humans. Functional fibers may be extracted or modi-
fied from plants (e.g., resistant starch from green bananas
and cooked, cooled potatoes) or may be derived from
animal sources (e.g., chitin and chitosan found in crab
and lobster shells). Functional fiber also must have a
beneficial physiological effect in humans.
The health benefits of DF are determined, in part, by
their physical attributes, particularly solubility and vis-
cosity. DF can be differentiated by the chemical proper-
ties of their components and the processes used to extract
those component and can be classified as insoluble DF,
which do not dissolve in water, and soluble DF, which
dissolve in water [51,52]. Soluble DF can be further di-
vided into viscous (i.e., gel-forming) or non-viscous types.
The viscous DF in turn, can be totally soluble (oligosac-
charides, prebiotics) or gel forming. Those forming gels
are characterized by their viscosity and fermentability
that vary widely from fiber to fiber and characterize their
action. The viscosity exerts its action at the metabolic-
hormonal level, while the fermentation improves th e for-
mation of short-chain fatty acids (SCFA) and increases
the proliferation of bacteria in healthy colons improving
the trophism [53].

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review
42
Observational studies in adults showed that the con-
sumption of large amounts of DF is associated with
lower rates of CVD, stroke and peripheral vascular dis-
ease and that the main cardiovascular risk factors (hy-
pertension, diabetes, obesity and dyslipidemia) are less
common in subjects with increased consumption of DF
[51].
The known or potential h ealth benefits of DF in child-
hood include: promotion of normal intestinal function
and prevention of gastrointestinal disorders, prevention
and treatment of childhood obesity, reduction of blood
cholesterol, modulation of postprandial hyperglycemia
and glucose intolerance and possible effects on reducing
the risk of future chronic diseases, such as cancer, car-
diovascular disease, and adult-onset diabetes.
A daily total dietary fiber intake from food sources of
at least age plus 5 g for young children up to 14 g/
1000kcal for older children and adolescents is recom-
mended [54]. Recent European guidelines on the man-
agement of dyslipidemias also recommend some nutra-
ceuticals as potentially useful lipid-lowering substances
[55]. As cardiovascular disease prevention needs a life-
course approach, both the tolerability and safety of die-
tary supplements/nutraceuticals used to control plasma
cholesterol levels have to be adequately defined as well
as the risk/benefit ratio of their assumption. A relatively
large number of recent reviews already described the me-
chanism of action and the efficacy of the different nutra-
ceuticals and botanicals with lipid-lowering effects [56-
58].
4. Nutraceuticals and Obesity
Childhood obesity has increased 3-fold in the last 20
years, with potentially long-lasting effects on health.
Childhood obesity affects a consi derable part of the world’s
population across gender and ethnic groups [59]. In Italy,
22.1% of infants are overweight and 10.2% are obese,
with the highest rates in central and southern regions [60].
The reasons for this escalation are not fully determined;
however, sedentary lifestyle and dietary changes in com-
bination with genetic predisposition are probably in-
volved.
Many studies, including the Bogalusa Heart Study,
have convincingly shown that childhood obesity is cor-
related with risk factors for CVD in adulthood, MS and
early development of atherosclerosis [6]. This empha-
sizes the importance of prevention and early management
of obesity in the young, in cluding both dietar y and physi-
cal activity modifications, as well as pharmacologic in-
terventions. Intake of DF is inversely associated with
body weight, body fat, and BMI [61]. DF are capable of
promoting satiation, decreasing the absorption of macro-
nutrients, and altering the secretion of gut hormones [62].
Although the increase of fiber consumption with meals is
an important step to control the obesity, the addition of
fiber supplements should also be considered. Data from
the NHANES III study showed that 13 - 18 years old
boys and girls with a low fiber intake were three to four
times more likely to be overweight compared to those
with higher fiber intake [63].
Glucomannan is a natural gel forming fiber (composed
of beta-1, 4-linked d-glucose and d-mannose) extracted
from Amorphophallus Konjac tubers. There are many
kinds of glucomannan but only the one with high viscos-
ity is effective in the treatment of metabolic disorders,
overweight and obesity. This soluble highly viscous fiber
can promote weight loss and improve lipid and glucose
profile in adults but currently no data on weight loss in
children are available [62,64]. Several other fibers are
marketed as dietary supplements, including use in chil-
dren; however, their weight-lowering effects have not
been studied yet.
5. Nutraceuticals and Hypercholesterolemia
Hypercholesterolemia can be diagnosed in childhood
[65,66] and requires an early management to prevent
future CVD [24,65-67]. Lipid-lowering drugs are not
usually recommended for children since no data are cur-
rently available about long-term effects and safety. The
NCEP recommends that drugs should be administered
only in patients abov e 10 years of age (ideally at pu bertal
Tanner stage II or higher, preferably after onset of men-
ses in girls), and only after failure of an aggressive diet
over a 6 - 12 months period. Therefore, the current man-
agement of children and adolescents with high LDL-
cholesterol includes diet changes and increased physical
activity [68,69].
Dietary changes are the cornerstone for the manage-
ment of children with elevated blood cholesterol levels.
The Expert Panel on Blood Cholesterol Levels in Chil-
dren and Adolescents recommends a dietary intervention
in two steps. The Step-1 diet calls for an average intake
of total fat less than 30% of total calo ries, of saturated fat
of no more than 10% and of dietary cholesterol less than
300 mg per day. If cholesterol reduction is not achieved
after a minimum of 3 months on this diet, the child pro-
gresses to the Step-2 diet, which calls for further reduc-
tion of saturated fat to less than 7% of total calories and
of dietary cholesterol to less than 200 mg per day [70].
However, the dietary changes result in a relatively small
reduction of cholesterol concentrations; nevertheless, these
changes would be difficult to be maintained over a long
period. A low-fat and fiber-rich diet is the first treatment
in all hypercholesterolemic children [71]. The quality of
dietary fiber is important: water-soluble fibers such as
pectin, gums and mixed-linked β-1, 3- and 4-D-glucans

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review 43
have a significant cholesterol-lowering effect [72]. The
high viscosity glucomannan has shown a lipid-lowering
capacity 3 to 5 times greater than that of psyllium, guar
and oat products [73]. This fiber may decrease serum
levels of total cholesterol and LDL-cholesterol without
changes in HDL-cholesterol. Previous studies demon-
strated these positive effects in adults [74,75] and in
children [76,77]. A meta-analysis of 14 studies (N = 531
subjects) showed that glucomannan seems to have bene-
ficial effects on total cholesterol, LDL-cholesterol, trigly-
cerides, body weight, fasting blood glucose but not on
HDL-cholest e r ol or bl o o d pressure [78].
The action of high viscosity glucomannan in decreas-
ing and maintaining the targeted cholesterolemia is also
validated by the European Food Safety Authority (EFSA)
report and many clinical trials [72,74-76,78-80]. Other
nutraceuticals as chromium-polynicotinate and polico-
sanol were investigated in the treatment of lipid disord ers
showing cholesterol-lowering effects [79-81]. Unfortu-
nately, subjects taking high doses of these products ex-
perienced adverse effects. Glucomannan alone or in com-
bination with low-dose chromium-polynicotinate or po-
licosanol was able to significantly reduce total choles-
terol and LDL-cholesterol without changing HDL-cho-
lesterol, triglycerides and glucose. The highest reduction
was obtained in children treated with a combination of
glucomannan and low-dose chromium-polynicotinate and
no adverse effects were reported, however the concomi-
tant use of glucomannan with resistant starch inhibited its
effectiveness [82].
Dietary supplementation with 6 g/day of psylliu m over
6 weeks improves fat distribution and lipid profile (6%
reduction in LDL cholesterol) in a population at risk of
adolescent males. Conversely, psyllium supplementation
did not improve insulin sensitivity [83]. However, Den-
nison et al. found no additional lowering effect of psyl-
lium fiber on total or LDL-cholestertol in children who
were following a low total fat, low saturated fat, and low
cholester ol diet [84].
6. Conclusions
Overfeeding in childhood can lead to th e development of
obesity and/or atherosclerosis in adult life. In particular,
a high intake of nutrients affects the in utero program-
ming with the adverse consequences of insulin resistance
an endothelial dysfunction that lead to early atheroscle-
rosis.
DF have important health benefits in childhood: re-
search suggests that DF may be useful in preventing and
treating obesity and in lowering blood cholesterol levels
with a favourable impact on the risk of future CVD. It
remains for further investigation to assess whether also in
Southern European Countries, practicing Mediterranean
diet as a normal habit, DF may indeed contribute to mod-
ify the relatively low proportion of hyperlipemia ob-
served in our population [85]. Clearly, adequately pow-
ered and controlled trials are needed.
7. Acknowledgements
The continuous efforts and support of Ca. Di. GROUP
S.r.l., Rome, Italy (www.cadigroup.eu) is greatly acknowl-
edged.
REFERENCES
[1] C. Napoli, F. P. D’Armiento, F. P. Mancini, J. L. Witz-
tum, G. Palumbo and W. Palinski, “Fatty Streak Forma-
tion Occurs in Human Fetal Aortas and Is Greatly En-
hanced by Maternal Hypercholesterolemia: Intimal Ac-
cumulation of LDL and Its Oxidation Precede Monocyte
Recruitment into Early Atherosclerotic Lesions,” Journal
Clinical Investigation, Vol. 100, No. 11, 1997, pp. 2680-
2690. doi:10.1172/JCI119813
[2] C. Napoli, J. L. Witztum, F. de Nigris, G. Palumbo, F. P.
D’Armiento and W. Palinski, “Intracranial Arteries of
Human Fetuses Are More Resistant to Hypercholestero-
lemia Induced Fatty Streak Formation than Extracranial
Arteries,” Circulation, Vol. 99, 1999, pp. 2003-2010.
doi:10.1161/01.CIR.99.15.2003
[3] W. Palinski and C. Napoli, “Pathophysiological Events
during Pregnancy Influence the Development of Athero-
sclerosis in Humans,” Trends Cardiovascular Medicine,
Vol. 9, No. 7, 1999, pp. 205-214.
doi:10.1016/S1050-1738(00)00022-0
[4] H. C. Stary, “Evolution and Progression of Atheroscle-
rotic Lesions in Coronary Arteries of Children and Young
Adults,” Arteriosclerosis, Vol. 9, No. 1, 1989, pp. I19-
I32.
[5] Pathobiological Determinants of Atherosclerosis in Youths
(PDAY) Research Group, “Natural History of Aortic and
Coronary Atherosclerotic Lesions in Youth. Findings
from the PDAY Study,” Arteriosclerosis Thrombosis, Vol.
13, 1993, pp. 1291-1298. doi:10.1161/01.ATV.13.9.1291
[6] G. S. Berenson, S. R. Sriniva san, W. Bao, W. P. Newman,
R. E. Tracy and W. A. Wattigney, “Association between
Multiple Cardiovascular Risk Factors and Atherosclerosis
in Children and Young Adults. The Bogalusa Heart Study,”
New England Journal Medicine, Vol. 338, 1998, pp.
1650-1656. doi:10.1056/NEJM199806043382302
[7] C. Napoli, C. K. Glass, J. L. Witztum, R. Deutsch, F. P.
D’Armiento and W. Palinski, “Influence of Maternal Hy-
percholesterolaemia during Pregnancy on Progression of
Early Atherosclerotic Lesions in Childhood: Fate of Early
Lesions in Children (FELIC) Study,” Lancet, Vol. 354,
No. 9186, 1999, pp. 1234-1241.
doi:10.1016/S0140-6736(99)02131-5
[8] H. C. Stary, “Lipid and Macrophage Accumulation in
Arteries of Children and the Development of Atheroscle-
rosis,” American Journal Clinical Nutrition, Vol. 72, No.
5, 2000, pp. 1297S-1306S.

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review
44
[9] R. Ross, “Atherosclerosis, an Inflammatory Disease,”
New England Journal Medicine, Vol. 340, 1999, pp. 115-
126. doi:10.1056/NEJM199901143400207
[10] J. A. Attaman, T. L. Toth, J. Furtado, H. Campos, R.
Hauser and J. E. Chavarro, “Dietary Fat and Semen Qual-
ity among Men Attending a Fertility Clinic,” Human Re-
production, Vol. 27, No. 5, 2012, pp. 1466-1474.
doi:10.1093/humrep/des065
[11] R. Nistala, M. R. Hayden, V. G. DeMarco, E. J. Henrik-
sen, D. T. Lackland and J. R. Sowers, “Prenatal Pro-
gramming and Epigenetics in the Genesis of the Cardio-
renal Syndrome,” Cardiorenal Medicine, Vol. 1, No. 4,
2011, pp. 243-254. doi:10.1159/000332756
[12] J. K. Kim, M. Samaranayake and S. Pradhan, “Epigenetic
Mechanisms in Mammals,” Cellular Molecular Life Sci-
ence, Vol. 66, No. 4, 2009, pp. 596-612.
doi:10.1007/s00018-008-8432-4
[13] B. T. Heijmansa, E. W. Tobia, A. D. Steinb, H. Putterc, G.
J. Blauwd and E. S. Sussere, “Persistent Epigenetic Dif-
ferences Associated with Prenatal Exposure to Famine in
Humans,” Proceedings of the National Academy of Sci-
ences of the United States of America, Vol. 105, No. 44,
2008, pp. 17046-17049. doi:10.1073/pnas.0806560105
[14] V. E. A. Russo, R. A. Martienssen a nd A. D. Riggs, “Epi-
genetic Mechanisms of Gene Regulation,” Cold Spring
Harbor Laboratory Press, Plainview, 1996.
[15] C. Napoli, A. Casamassimi, V. Crudele, T. Infante and C.
Abbondanza, “Kidney and Heart Interactions during Car-
diorenal Syndrome: A Molecular and Clinical Pathogenic
Framework,” Future Cardiology, Vol. 7, No. 4, 2011, pp.
485-497. doi:10.2217/fca.11.24
[16] B. E. Bernstein, A. Meissner and E. S. Lander, “The
Mammalian E pigenome, ” Cell, Vol. 128, No. 4, 2007, pp.
669-681. doi:10.1016/j.cell.2007.01.033
[17] M. Rodriguez-Porcel, L. O. Lerman, J. Herrmann, T. Sa-
wamura, C. Napoli and A. Lerman, “Hypercholesterole-
mia and Hypertension Have Synergistic Deleterious Ef-
fects on Coronary Endothelial Function,” Arteriosclerosis
Thrombosis Vascular Biology, Vol. 23, 2003, pp. 885-891.
doi:10.1161/01.ATV.0000069209.26507.BF
[18] J. C. Fruchart, M. C. Nierman, E. S. Stroes, J. J. Kastelein
and P. Duriez, “New Risk Factors for Atherosclerosis a nd
Patient Risk Assessment,” Circulation, Vol. 109, pp. III15-
III19.
[19] G. K. Hansson, “Inflammation, Atherosclerosis, and Co-
ronary Artery Disease,” New England Journal Medicine,
Vol. 352, 2005, pp. 1685-1695.
doi:10.1056/NEJMra043430
[20] Y. Aggoun, D. Bonnet and D. Sidi, “Arterial Mechanical
Changes in Children with Familial Hypercholesterole-
mia,” Arteriosclerosis Thrombosis Vascular Biology, Vol.
20, 2000, pp. 2070-2075. doi:10.1161/01.ATV.20.9.2070
[21] G. Arcaro, B. M. Zenere and D. Travia, “Non-Invasive
Detection of Early Endothelial Dysfunction in Hypercho-
lesterolaemic Subjects,” Atherosclerosis, Vol. 114, No. 2,
1995, pp. 247-254. doi:10.1016/0021-9150(94)05489-6
[22] M. J. Jarvisalo, L. Jartti and K. Nanto-Salonen, “Increas-
ed Aortic Intima-Me dia Thickness. A Marker of Preclini-
cal Atherosclerosis in High-Risk Children,” Circulation,
Vol. 104, 2001, pp. 2943-2947.
doi:10.1161/hc4901.100522
[23] J. E. Deanfield, J. P. Halcox and T. J. Rabelink, “Endo-
thelial Function and Dysfunction: Testing and Clinical
Relevance,” Circulation, Vol. 115, 2007, pp. 1285-1295.
[24] F. Martino, L. Loffredo, R. Carnevale, V. Sanguigni, E.
Martino and E. Catasca, “Oxidative Stress Is Associated
with Arterial Dysfunction and Enhanced Intima-Media
Thickness in Children with Hypercholesterolemia: The
Potential Role of Nicotinamide -Adenine Di nucleoti de Phos-
phate Oxidase,” Pediatrics, Vol. 122, No. 3, 2008, pp.
e648-e655. doi:10.1542/peds.2008-0735
[25] O. T. Raitakari, M. Juonala and M. Kahonen, “Cardio-
vascular Risk Factors in Childhood and Carotid Artery
Intima-Media Thickness in Adulthood: The Cardiovascu-
lar Risk in Young Finns Study,” Journal American Me-
dical Association, Vol. 290, No. 17, 2003, pp. 2277-2283.
doi:10.1001/jama.290.17.2277
[26] W. P. Newman III, D. S. Freedman, A. W. Voors, P. D.
Gard, S. R. Srinivasan and J. L. Cresanta, “Relation of
Serum Lipoprotein Levels and Systolic Blood Pressure to
Early Atherosclerosis. The Bogalusa Heart Study,” New
England Journal Medicine, Vol. 314, 1986, pp. 138-144.
doi:10.1056/NEJM198601163140302
[27] M. C. Corretti, T. J. Anderson, E. J. Benjamin, D. Celer-
majer, F. Charbonneau and M. A. Creager, “Guidelines
for the Ultrasound Assessment of Endothelial-Dependent
Flow-Mediated Vasodilation of the Brachial Artery: A
Report of the International Brachial Artery Reactivity
Task Force,” Journal American College Cardiology, Vol.
39, No. 2, 2002, pp. 257-265.
doi:10.1016/S0735-1097(01)01746-6
[28] R. Joannides, W. E. Haefeli, L. Linder, V. Richard, E. H.
Bakkali and C. Thuillez, “Nitric Oxide Is Responsible for
Flow-Dependent Dilatation of Human Peripheral Conduit
Arteries in Vivo,” Circulation, Vol. 91, 1995, pp. 1314-
1319. doi:10.1161/01.CIR.91.5.1314
[29] H. Cai and D. G. Harrison, “Endothelial Dysfunction in
Cardiovascular Diseases: The Role of Oxidant Stress,”
Circulation Research, Vol. 87, 2000, pp. 840-846.
doi:10.1161/01.RES.87.10.840
[30] F. Violi, V. Sanguigni, R. Carnevale, A. Plebani, P. Rossi
and A. Finocchi, “Hereditary Deficiency of gp91(phox) Is
Associated with Enhanced Arterial Dilatation: Results of
a Multicenter Study,” Circulation, Vol. 120, 2009, pp.
1616-1622.
doi:10.1161/CIRCULATIONAHA.109.877191
[31] L. Loffredo, F. Martino, R. Carnevale, P. Pignatelli, E.
Catasca, M. L. Perri, C. M. Cala brese, M. M. Palumbo, F.
Baratta, M. Del Ben, F. Angelico and F. Violi, “Obesity
and Hypercholesterolemia Are Associated with NOX2
Generated Oxidative Stress and Arterial Dysfunction,” Jour-
nal Pediatrics, Vol. 161, No. 6, 2012, pp. 1004-1009.
doi:10.1016/j.jpeds.2012.05.042
[32] A. Keys, J. T. Anderson and F. Grande, “Prediction of
Serum-Cholesterol Responses of Man to Changes in Fats
in the Diet,” Lancet, Vol. 273, No. 7003, 1957, pp. 959-
966. doi:10.1016/S0140-6736(57)91998-0

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review 45
[33] M. Mancini and J. Stamler, “Diet for Preventing Cardio-
vascular Diseases: Light from Ancel Keys, Distinguished
Centenarian Scientist,” Nutrition Metabolism Cardiovas-
cular Disease, Vol. 14, No. 1, 2004, pp. 52-57.
doi:10.1016/S0939-4753(04)80047-4
[34] Framingham Heart Study, Framingham, 2013.
http://www.framinghamheartstudy.org
[35] W. P. Newman, D. S. Freedman and A. W. Voors, “Rela-
tion of Serum Lipoprotein Levels and Systolic Blood
Pressure to Early Atherosclerosis. The Bogalusa Heart
Study,” New England Journal Medicine, Vol. 314, 1986,
pp. 138-144. doi:10.1056/NEJM198601163140302
[36] R. M. Lauer and W. R. Clarke, “Use of Cholesterol Mea-
surements in Childhood for the Prediction of Adult Hy-
percholesterolemia. The Muscatine Study,” The Journal
of American Medical Association, Vol. 264, No. 23, 1990,
pp. 3034-3038. doi:10.1001/jama.1990.03450230070031
[37] M. Juonala, J. S. Viikari, T. Ronnemaa, J. Marniemi, A.
Jula and B. M. Loo, “Associations of Dyslipidemias from
Childhood to Adulthood wit h Carotid Intima -Media Thick-
ness, Elasticity, and Brachial Flow-Mediated Dilatation in
Adulthood. The Cardiovascular Risk in Young Finns
Study,” Arteriosclerosis Thrombosis Vascular Biology,
Vol. 28, 2008, pp. 1012-1017.
doi:10.1161/ATVBAHA.108.163329
[38] S. S. Gidding, C. A. McMahan, H. C. McGill, L. A.
Colangelo, P. J. Schreiner and O. D. Williams, “Predic-
tion of Coronary Artery Calcium in Young Adults Using
the Pathobiological Determinants of Atherosclerosis in
Youth (PDAY) Risk Score: The CARDIA Study,” Ar-
chives of Internal Medicine, Vol. 166, No. 21, 2006, pp.
2341-2347. doi:10.1001/archinte.166.21.2341
[39] L. Dauchet, P. Amouyel and J. Dallongeville, “Fruits,
Vegetables and Coronary Heart Disease,” Nature Review
Cardiology, Vol. 6, 2009, pp. 599-608.
[40] R. Grant, A. Bilgin and C. Zeuschner, “The Relative Im-
pact of a Vegetable-Rich Diet on Key Markers of Health
in a Cohort of Australian Adolescents,” Asia Pacific Jour-
nal of Clinical Nutrition, Vol. 17, No. 1, 2008, pp. 107-
118.
[41] W. C. Willett, F. Sacks and A. Trichopoulou, “Mediter-
ranean Diet Pyramid: A Cultural Model for Healthy Eat-
ing,” The American Journal of Clinical Nutrition, Vol. 61,
Suppl. 6, 1995, pp. 1402S-1406S.
[42] C. M. Kastorini, H. J. Milionis, K. Esposito, D. Giugliano,
J. A. Goudevenos and D. B. Panagiotakos, “The Effect of
Mediterranean Diet on Metabolic Syndrome and Its Com-
ponents. A Meta-Analysis of 50 Studies and 534,906 In-
dividuals,” Journal of the American College of Cardiol-
ogy, Vol. 57, No. 11, 2011, pp. 1299-1313.
doi:10.1016/j.jacc.2010.09.073
[43] A. J. Nordmann, K. Suter-Zimmermann, H. C. Bucher, I.
Ihai, K. R. Tuttle and R. Estruch, “Meta-Analysis Com-
paring Mediterranean to Low-Fat Diets for Modification
of Cardiovascular Risk Factors,” The American Journal
of Medicine, Vol. 124, No. 9, 2011, pp. 841-851.
doi:10.1016/j.amjmed.2011.04.024
[44] R. Estruch, E. Ros, J. Salas-Salvadó, M. I. Covas, D.
Corella and F. Arós, “Primary Prevention of Cardiovas-
cular Disease with a Mediterranean Diet,” The New Eng-
land Journal of Medicine, Vol. 368, 2013, pp. 1279-1290.
doi:10.1056/NEJMoa1200303
[45] C. Lazarou, D. B. Panagiotakos and A. L. Matalas, “Li fe-
style Factors Are Determinants of Children’s Blood
Pressure Levels: The CYKIDS Study,” Journal of Human
Hypertension, Vol. 23, No. 7, 2009, pp. 456-463.
[46] A. F. G. Cicero and S. Ertek, “Natural Sources of Anti-
dyslipidaemic Agents: Is There an Evidence-Based Ap-
proach for Their Prescription?” Mediterranean Journal of
Nutrition and Metabolism, Vol. 1, No. 2, 2008, pp. 85-93.
doi:10.1007/s12349-008-0011-6
[47] R. L. Bailey, J. J. Gahche and C. V. Lentino, “Dietary
Supplement Use in the United States, 2003-2006,” The
Journal of Nutrition, Vol. 141, No. 2, 2011, pp. 261-266.
doi:10.3945/jn.110.133025
[48] American Dietetic Association. Fiber Evidence Analysis
Project, “ADA Evidence Analysis Library Web site.
&highlight_fiber&home_1,” 2008.
http://www.adaevidencelibrary.com/topic.cfm?cat_1586
[49] Food and Nutrition Board, Institute of Medicine, “Dietary
Reference Intakes for Energy, Carbohydrates, Fiber, Fat,
Fatty Acids, Cholesterol, Protein, and Amino Acids,” Na-
tional Academies Press, Washington DC, 2005.
[50] M. L. Gurr and N. G. Asp, “Dietary Fibre,” International
Life Science Press, Washington DC, 1994.
[51] J. Anderson, P. Baird, R. Davis, S. Ferreri, M. Knudtson,
and A. Koraym, “Health Benefits of Dietary Fiber,” Nu-
trition Reviews, Vol. 67, No. 4, 2009, pp. 188-205.
doi:10.1111/j.1753-4887.2009.00189.x
[52] C. L. Dikeman and G. C. Fahey, “Viscosity as Related to
Dietary Fiber: A Review,” Critical Review Food Science
Nutrition, Vol. 46, No. 8, 2006, pp. 649-663.
doi:10.1080/10408390500511862
[53] T. Mizutani and T. Mitsuoka, “Effect of Konjac Mannan
on Spontaneous Liver Tumorigenesis and Fecal Flora in
C3H/He Male Mice,” Cancer Letters, Vol. 17, No. 1,
1982, pp. 27-32. doi:10.1016/0304-3835(82)90104-5
[54] Expert Panel on Integrated Guidelines for Cardiovascular
Health and Risk Reduction in Children and Adolescents,
“Expert Panel on Integrated Guidelines for Cardiovascu-
lar Health and Risk Reduction in Children and Adoles-
cents: Summary Report,” Pediatrics, Vol. 128, Suppl. 5,
2011, pp. S213-S256. doi:10.1542/peds.2009-2107C
[55] A. L. Catapano, Z. Reiner, G. de Backer, I. Graham, M. R.
Taskinen and O. Wiklund, “ESC/EAS Guidelines for the
Management of Dyslipidaemias. The Task Force for the
Management of Dyslipidaemias of the European Society
of Cardiology (ESC) and the European Atherosclerosis
Society (EAS),” Atherosclerosis, Vol. 217, Suppl. 1, 2011,
pp. 3-46.
[56] S. Hasani-Ranjbar, N. Nayebi and L. Moradi, “The Effi-
cacy and Safety of Herbal Medicines Used in the Treat-
ment of Hyperlipidemia: A Systematic Review,” Current
Pharmacology Research, Vol. 16, No. 26, 2010, pp.
2935-2947.
[57] M. P. McGowan and S. Proulx, “Nutritional Supplements

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review
46
and Serum Lipids: Does Anything Work?” Current Athe-
rosclerosis Reports, Vol. 11, No. 6, 2009, pp. 470-476.
doi:10.1007/s11883-009-0070-2
[58] J. Y. Kim and O. Kwon, “Culinary Plants and Their Po-
tential Impact on Metabolic Overload,” Annals of the New
York Academy Sciences, Vol. 1229, 2011, pp. 133-139.
doi:10.1111/j.1749-6632.2011.06090.x
[59] Z. B. Yu, S. P. Han, G. Z. Zhu, C. Zhu, X. J. Wang and X.
G. Cao, “Birth Weight and Subsequent Risk of Obesity:
A Systematic Review and Meta-Analysis,” Obesity Re-
views, Vol. 12, No. 7, 2011, pp. 525-542.
doi:10.1111/j.1467-789X.2011.00867.x
[60] OKkio alla SALUTE, “Sintesi Dei Risultati,” 2012.
www.epicentro.iss.it/okkioallasalute/
[61] J. L. Slavin, “Dietary Fiber and Body Weight,” Nutri-
tion, Vol. 21, No. 3, 2005, pp. 411-418.
doi:10.1016/j.nut.2004.08.018
[62] A. L. Rogovik and R. D. Goldman, “Should Weight-Loss
Supplements Be Used for Pediatric Obesity?” Canadian
Family Physician, Vol. 55, No. 3, 2009, pp. 257-259.
[63] P. Samuel, D. R. Keast, C. L. Williams and S. J. Bar-
tholmey, “Dietary Fiber and Its Role in Childhood Obe-
sity,” The FASEB Journal, Vol. 14, 2003, p. A746.
[64] J. Keithley and B. Swanson, “Glucomannan and Obesity:
A Critical Review,” Alternate Therapy Health Medicine,
Vol. 11, No. 6, 2005, pp. 30-34.
[65] C. J. McNeal, T. Dajani, D. Wilson, A. E. Cassidy-
Bushrow and B. Dickerson, “Hypercholesterolemia in Youth:
Opportunities and Obstacles to Prevent Premature Athe-
rosclerotic Cardiovascular Disease,” Current Atheroscle-
rosis Reports, Vol. 12, No. 1, 2010, pp. 20-28.
doi:10.1007/s11883-009-0072-0
[66] S. R. Daniels, F. R. Greer and the Committee on Nutrition,
“Lipid Screening and Cardiovascular Health in Child-
hood,” Pediatrics, Vol. 122, No. 1, 2008, pp. 198-208.
doi:10.1542/peds.2008-1349
[67] L. Iughetti, “Drugs for Children with Hypercholesterole-
mia: Be Cautious,” Journal of Pediatric Endocrinology
and Metabolism, Vol. 22, No. 6, 2009, pp. 483-485.
doi:10.1515/JPEM.2009.22.6.483
[68] L. Iughetti, P. Bruzzi and B. Predieri, “Evaluation and
Management of Hyperlipidemia in Children and Adoles-
cents,” Current Opinion in Pediatrics, Vol. 22, No. 4,
2010, pp. 485-493.
[69] AAP (American Academy of Pediatrics), “Committee on
Nutrition,” Cholesterol in Childhood, 2011.
http://www.aap.org/en-us/about-the-aap/Committees-Cou
ncils-Sections/Pages/Committee-On-Nutrition.aspx
[70] NCEP (National Cholesterol Educational Program), 2013.
http://www.nhlbi.nih.gov/about/ncep/ncep_pd.htm
[71] W. L. Haskell, G. A. Spiller, C. D. Jensen, B. K. Ellis and
J. E. Gates, “Role of Water-Soluble Dietary Fiber in the
Management of Elevated Plasma Cholesterol in Healthy
Subjects,” The American Journal of Cardiology, Vol. 69,
No. 5, 1992, pp. 433-439.
doi:10.1016/0002-9149(92)90980-D
[72] D. J. A. Jenkins, C. W. C. Kendall and V. Vuksan, “Vis-
cous Fibers, Health Claims, and Strategies to Reduce Car-
diovascular Disease Risk,” The American Journal of Cli-
nical Nutrition, Vol. 71, No. 2, 2000, pp. 401-402.
[73] V. Vuksan, J. Sievenpiper and Z. Xu, “Konjac-Mannan
and American Ginsing: Emerging Alternative Therapies
for Type 2 Diabetes Mellitus,” Journal of the American
College of Nutrition, Vol. 20, Suppl. 5, 2001, pp. 370S-
380S.
[74] A. Arvill and L. Bodin, “Effect of Short-Term Ingestion
of Kojac Glucomannan on Serum Cholesterol in Healthy
Men,” The American Journal of Clinical Nutrition, Vol.
61, No. 3, 1995, pp. 585-659.
[75] H. L. Chen, W. H. H. Sheu, T. S. Tai, Y. P. Liaw and Y.
C. Chen, “Konjac Supplement Alleviated Hypercholes-
terolemia and Hyperglycemia in Type 2 Diabetic Subjects.
A randomized Double-Blind Trial,” Journal of the Ameri-
can Collage of Nutrition, Vol. 22, No. 1, 2003, pp. 36-42.
[76] F. Martino, E. Martino, F. Morrone, E. Carnevali, R.
Forcone and T. Niglio, “Effect of Dietary Supplementa-
tion with Glucomannan on Plasma Total Cholesterol and
Low Density Lipoprotein Cholesterol in Hypercholes-
terolemic Children,” Nutrition, Metabolism & Cardio-
vascular Diseases, Vol. 15, No. 3, 2005, pp. 174-180.
doi:10.1016/j.numecd.2004.04.004
[77] C. Stefanutti and F. Mazza, “Multiple Lipid Lowering
Treatment in Pediatric Patients with Hyperlipidemia,”
Medical Chemistry, Vol. 8, No. 6, 2012, pp. 1171-1181.
[78] N. Sood, W. L. Baker and C. I. Coleman, “Effect of Glu-
comannan on Plasma Lipid and Glucose Concentrations,
Body Weight, and Blood Pressure: Systematic Review
and Meta-Analysis,” The American Journal of Clinical
Nutrition, Vol. 88, No. 4, 2008, pp. 1167-1175.
[79] F. Violi, “Nutraceuticals Special Issue,” Cardiovascular
Therapy, Vol. 128, 2010, pp. 185-245,e01-e52.
[80] V. Vuksan, J. L. Sievenpiper, R. Owen, J. A. Swilley, P.
Spadafora and D. J. Jenkins, “Beneficial Effects of Vis-
cous Dietary Fiber from Konjac-Mannan in Subjects with
the Insulin Resistance Syndrome,” Diabetes Care, Vol.
23, No. 1, 2000, pp. 9-14. doi:10.2337/diacare.23.1.9
[81] I. Gouni-Berthold, “Policosanol: Clinical Pharmacology
and Therapeutic Significance of a New Lipid-Lowering
Agent,” American Heart Journal, Vol. 143, No. 2, 2002,
pp. 356-365. doi:10.1067/mhj.2002.119997
[82] F. Martino, P. E. Puddu, G. Pannarale, C. Colantoni, E.
Martino, T. Niglio, C. Zanoni and F Barillà, “Low Dose
Chromium-Polynicotinate or Policosanol Is Effective in
Hypercholesterolemic Children only in Combination with
Glucomannan,” Atherosclerosis, Vol. 228, No. 1, 2013,
pp. 198-202. doi:10.1016/j.atherosclerosis.2013.02.005
[83] M. de Bock, J. G. B. Derraik, C. M. Brennan, J. B. Biggs,
G. C. Smith, D. Cameron-Smith, C. R. Wall and W. S.
Cutfield, “Psyllium Supplementation in Adolescents Im-
proves Fat Distribution and Lipid Profile: A Randomized,
Participant-Blinded, Placebo-Controlled, Crossover Trial,”
PLoS One, Vol. 7, No. 7, 2012, Article ID: e41735.
doi:10.1371/journal.pone.0041735
[84] B. A. Dennison and D. M. Levine, “Randomized, Dou-
ble-Blind, Placebo-Controlled, Two-Period Crossover Cli-

Dietary Fibers and Nutraceuticals for Primary Cardiovascular Prevention
in Children and Adolescents: A Critical Review
47
nical Trial of Psyllium Fiber in Children with Hyper-
cholesterolemia,” The Journal of Pediatrics, Vol. 123, No.
1, 1993, pp. 24-29.
[85] F. Martino, P. E. Puddu, G. Pannarale, C. Colantoni, C.
Zanoni, E. Martino and F. Barillà, “Arterial Blood Pres-
sure and Serum Lipids in a Population of Children and
Adolescents from Southern Italy: The Calabrian Sierras
Community Study (CSCS),” International Journal Car-
dioliology, 2012. doi:10.1016/j.ijcard.2012.11.045