Atherosclerosis disease and its extent in childhood correlate positively with established risk factors, namely obesity, hypercholesterolemia, diabetes mellitus, and hypertension. The safety and efficacy of some dietary interventions to modulate risk factors in childhood are documented by an increasing body of evidence. The present review analyzes nutritional and nutraceutical current strategies addressed to modify some risk factors of atherosclerosis in childhood. In particular, studies concerning nutrients such as fibers, omega-3-fatty acids, vitamin D, antioxidants, and calcium have been evaluated. An overall analysis suggests that some nutraceuticals might represent an attractive tool to lower the development of atherosclerotic-related cardiovascular complication in children. Nevertheless, at this moment, due to the methodological weakness that characterizes the majority of the analyzed studies, nutrients or supplements should not be considered as a therapeutic tool potentially usable for clinical purpose in children at risk for cardiovascular disease.
Atherosclerosis is a disease that begins in childhood; it is mediated by the presence of well-recognized risk factors such as hypercholesterolemia, diabetes mellitus, hypertension, and obesity (see Figure 1). Pathological studies in children and young adults demonstrate that the extent of atherosclerotic vascular change is associated with both the number and the intensity of risk factors . Noninvasive studies, such as those evaluating Intima Media Thickness (IMT) or Flow-Mediated Dilatation (FMD), refer each of the known risk factors measured in childhood to abnormalities of vascular structure and function [2,3]. Moreover, a decrease in intensity of risk factors is associated with improvement in the vascular abnormalities [4,5].
Certain pediatric disease states, such as homozygous hypercholesterolemia, are associated with dramatically accelerated atherosclerosis in the first decade of life . On the contrary, for most children the degree of vascular involvement is minor and the rate of progression is slow. In this setting an appropriate therapeutic preventive approach, with an emphasis on healthy lifestyle and behavior modification, seems to be appropriate [7,8].
This has already been demonstrated in adulthood in which a significant reduction of cardiovascular events (CVE) may be achieved following particular diets or using specific nutrients . It is worthwhile to mention the significant reduction of CVE observed in subjects following the Mediterranean diet  or a diet rich in fruits and vegetables  or the Eskimos diet .
This review will focus on the strength and weakness of the emerging fields of nutrigenomics and nutraceuticals per se or as a component of “antiatherosclerotic diets” as a nonpharmacologic approach potentially usable to modify risk factors for atherosclerosis and to prevent its progression and clinical manifestations in early infancy. The present review is summarized in the following outlines.
• Nutrition and atherosclerosis.
• Atherosclerosis and nutraceuticals.
• Nutraceuticals and Obesity.
• Nutraceuticals and Hypercholesterolemia.
• Nutraceuticals and Diabetes Mellitus.
• Nutraceuticals and Hypertension.
Nutrition and Atherosclerosis
Atherosclerosis is a process that is already detectable in children; autopsy studies performed in children or youths with established risk factors demonstrated a positive association with the presence and extent of atherosclerotic lesions in the aorta and coronary arteries [13,14].
Effective strategies for reducing risk factors for atherosclerosis in children are poorly investigated and only few studies evaluated the role of diet and nutrients. A relationship between fruit and vegetable consumption and prevention of atherosclerotic-related disease is based on observational and epidemiological analysis in adulthood . Recently, it has been observed that adolescent population, consuming predominantly vegetarian foods, showed significantly better scores on markers of cardiovascular health and atherosclerotic progression, including, body mass index (BMI), waist circumference, Cholesterol/High-density lipoprotein (HDL) ratio, and low-density lipoprotein (LDL) .
Although Mediterranean diet and Eskimo diet were proposed to prevent atherosclerosis-related disease in adulthood, just little data concerning children were available.
The Young Finns Study reported complete dietary data from the years 1980, 1986, and 2001 and outcome data from the year 2001 obtained from 785 children and adolescent populations. The study evidenced that a traditional dietary pattern characterized by high consumption of potatoes, butter, sausages, and coffee was associated with higher IMT compared to that measured in subjects following a health-conscious dietary pattern characterized by high consumption of vegetables, legumes and nuts, rye, tea, cheese, and other dairy products . Mediterranean diet is also associated with a reduction of other atherosclerotic-related risk factors such as high blood pressure. Using the KIDMED (Mediterranean Diet Quality Index for children and adolescents) diet score on a population of 622 children (11.7U ± 0.83 years) Lazarou and colleagues found a positive correlation between lower levels of blood pressure and a higher KIDMED score . Fish consumption, typical of the Eskimo diet, can provide substantial amounts of omega-3-fatty acids essential for the maintenance of health (especially brain development during childhood) . To the best of our knowledge, there is still a lack of scientific studies regarding atherosclerotic risk factor prevention for children and preadolescents with the Eskimo diet.
Atherosclerosis and Nutraceuticals
The use of surrogate vascular markers, including biomarkers such as high sensitivity C-reactive protein, cell adhesion molecules, and methylarginines, as well as FMD, IMT, and arterial stiffness could help to develop a better understanding of early pathological vascular changes in youth. They can also facilitate earlier diagnosis of preclinical atherosclerosis and provide an objective measure of the vascular effects of any therapeutic intervention aimed at risk factor modification.
Endothelial adhesion molecules (vascular cell adhesion molecule-1 and InterCellular Adhesion Molecule [ICAM]-1) play a crucial role during the earliest phases of atherogenesis, upregulating leukocyte and monocyte adhesion to the endothelial cell surface and their transendothelial migration .
Polyunsaturated fatty acid (PUFA), especially omega-3-fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from Fish oil appear to have antiinflammatory properties through dietary supplementation in humans, even modulating cardiovascular disease (CVD) risk biomarkers such as LDL cholesterol and cell adhesion molecules .
Although fish consumption can provide substantial amounts of omega-3-fatty acids, dietary intake of fish to obtain an adequate amount of these fatty acids is in general insufficient, and this is especially true for children . Therefore, the interest to develop foods enriched with fish oil is emergent. Such “functional foods” could be an effective way to reduce cardiovascular risk factors without the need for modification of the consumer's dietary habits in childhood . Recently, the effects of a 5-month daily intake of milk enriched with long-chain PUFAs, oleic acid, carbohydrates, vitamins, minerals, and low in saturated fatty acids on several CVD risk biomarkers was studied in a population of healthy children aged 8–14 years. In this randomized double-blind placebo-controlled trial, a total of 107 children of both genders were included. In the enriched dairy drink-supplemented group, adhesion molecules E-selectin and ICAM-1 as well as lymphocyte levels decreased while plasma DHA increased, suggesting that consumption of a milk enriched with fish oil and oleic acid could reduce indices of endothelial cell activation in healthy children .
Endothelial dysfunction is a hallmark of early atherosclerosis and predicts CVE in high-risk cohorts . Oxidative stress is believed to play an important role in that it can influence activity and generation of nitric oxide (NO), a potent vasodilator molecule produced by endothelial cells . This has been recently confirmed by the results of a multicenter study evaluating FMD in patients with hereditary deficiency of gp91phox, the catalytic core of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, including adults and children. The study demonstrated that FMD correlated directly with NO levels and inversely with in vivo indexes of oxidative stress .
Several studies investigated interventions aimed to improve endothelial dysfunction with divergent results. Dietary L-arginine supplementation has been shown to improve endothelial function in the brachial artery of young people with hypercholesterolemia . A second randomized, double-blind, placebo-controlled trial of L-arginine supplementation was conducted in 21 normotensive children with chronic renal failure, a pathology associated with endothelial dysfunction and accelerated atherosclerosis. In this second study, endothelial function was not improved with L-arginine, suggesting that dietary supplementation is not a useful clinical approach in children with chronic renal failure .
Antioxidant vitamins may provide vascular defense against oxidative stress by scavenging free radicals and protecting NO from inactivation [30,31]. Antioxidant administration improves endothelial function of coronary and peripheral vessels in hypercholesterolemic and coronary heart disease (CHD) patients [30,31]. Of interest, a randomized, double-blind, placebo-controlled trial, analyzing the effects of antioxidant vitamins C (500 mg/day) and E (400 IU/day) on FMD in 15 hyperlipidemic children demonstrated that supplementation with antioxidant vitamins is capable of restoring endothelial function in children at high risk for atherosclerosis .
Nutraceuticals and Obesity
Childhood obesity has increased 3-fold in the last 20 years, with potentially long-lasting effects on health. Approximately, 13% of children aged 6–11 years were considered obese by the National Center for Health Statistics survey (1988–1994) . Obesity rates are also rising worldwide, with some European countries reaching the levels seen in North America .
Many factors, including decrease in physical activity and increase in the availability of foods high in fat and sugar, have potentially contributed to the increase in childhood obesity .
Childhood overweight puts children at risk for adulthood obesity [36,37] and similarly at risk for the development of CHD and diabetes later in life . Common risk factors contributing to the development of CVD in overweight children and adolescents include low HDL (≤40 mg/dL), elevated triglycerides (≥110 mg/dL), high blood pressure (≥90th percentile), and impaired glucose tolerance . One recent study demonstrated that children with these risk factors were significantly more likely to have CVD 25 years later as adults compared with their peers .
Intake of dietary fibers is inversely associated with body weight, body fat, and BMI . Fibers are capable of promoting satiation, decreasing the absorption of macronutrients, and altering the secretion of gut hormones . The average fiber intake in North America is less than half of recommended levels. Pashankar et al. studied the role of fibers in child obesity concluding that children with chronic constipation were twice as likely to be obese compared to children without this problem (22.4% vs. 11.7%), and that one contributing factor was a diet with a low intake of dietary fibers . Some studies suggest that fiber supplements, when added to traditional weight-control regimens, result in approximately 2 kg of added weight loss. In a crossover study with obese children, 15 g/day of dietary fiber added to a reduced-calorie diet resulted in greater mean weight loss compared with the nonfiber treatment period .
Although increasing fiber (e.g., fruits, vegetables, whole grains, legumes) consumption with diet is an important step to control the obesity, the addition of fiber supplements should also be considered. Glucomannan, a soluble highly viscous fiber derived from the konjac plant, can promote weight loss and improve lipid and lipoprotein parameters and glycemic status with minimal gastrointestinal side effects in adults but at the moment no data are available concerning weight loss in children . Several other fibers such as Inulin (from chicory root) are sold in many mainstream stores as a supplement, including for use in children; however, its weight-lowering effect have not been studied yet.
Finally, calcium intake is another potential factor that may reduce body weight or weight gain , but this is not certain at present . Observational studies on the association between calcium and/or dairy intake in children and weight and/or body composition yielded inconsistent results. Cross-sectional and case-control studies, in fact, have often found inverse associations [47–49], which were not confirmed in subsequent studies . On the other hand, longitudinal studies have reported an inverse association of calcium intake with body fat measured in children [51–53]. However, Phillips and colleagues reported no association between calcium intake, percentage of body fat, and BMI  whereas Berkey et al. showed BMI gains in children with increasing dairy intakes . Interventional study also provided negative results. Thus, a 1-year randomized calcium and activity trial of 178 children showed that changes in fat mass were not significantly different by activity group or between children randomly assigned to receive calcium or placebo . This evidence has also been confirmed recently by a large meta-analysis that found no statistically significant effects of calcium supplementation on weight loss in children .
Nutraceuticals and Hypercholesterolemia
Among the classic risk factors for atherosclerosis, total cholesterol (TCh) seems to be a major determinant of early atherosclerosis. Accordingly, autopsy studies documented an association between TCh and LDL cholesterol with the extent and severity of atherosclerosis in infants, children, and adolescents . An early increase of cholesterol is also relevant in the progression of atherosclerosis in adults and measurement of LDL in childhood predicts higher IMT in young adults . In children with hypercholesterolemia, early functional and anatomic changes of the arterial wall have been detected . In particular, a significant decrease of FMD has been observed in hypercholesterolemic children, suggesting a role for cholesterol in impairing the NO release by inhibiting endothelial NO and by enhancing oxidative stress as shown by Martino et al. . In a cross-sectional study on 50 hypercholesterolemic and 50 healthy children these authors demonstrated, in fact, that hypercholesterolemic children had reduced FMD and enhanced IMT, which correlated with enhanced urinary isoprostanes and gp91phox platelet expression . In this view, it is attractive to hypothesize that nutritional intervention could either reduce TCh levels or interact with the negative effect of TCh by modulating TCh-related oxidative stress.
Dietary modification is the cornerstone of management for children with elevated blood cholesterol levels . The Expert Panel on Blood Cholesterol Levels in Children 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 calories, 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 progresses to the Step-2 diet, which calls for further reduction of saturated fat to less than 7% of total calories and of dietary cholesterol to less than 200 mg per day . However, the dietary modification results in a relatively small reduction of cholesterol concentrations ; nevertheless, this modification would be difficult to be maintained over a long period .
Lipid-lowering drugs are usually not recommended for children since no data are currently available about long-term effects and safety. In adults, water-soluble fibers have been shown to be effective in reducing cholesterol concentrations . However, the results of the studies that have assessed the effects of fiber supplements on blood lipids in children with dyslipidemia were controversial. Dennison et al.  found no additional lowering effect of psyllium fiber on total or LDL-Ch in children who were following a low total fat, low saturated fat, and low cholesterol diet. On the contrary, Martino et al. found a significant reduction of TCh after 8 weeks of glucomannan supplementation in association with a hypocholesterolemic diet  and Sanchez-Bayle et al. obtained a similar result using wheat bran and pectin as a source of fibers .
Hypercholesterolemia is associated with enhanced levels of oxidative stress from infancy . To modulate cholesterol-related oxidative stress, Cadoner-Franc et al. performed an interventional trial by giving mandarin juice to hypercholesterolemic children. Natural citrus juices contain vitamin C, folate, and carotenoids, as well as some flavonoids that are almost exclusively found in the citrus species, namely flavanone-7–0-glycosides and fully methoxylated flavones , all of which exert antioxidant effects. Hypercholesterolemic children were supplemented for 28 days with 500 mL/day of pure (100%) mandarin juice. At the end of the study, levels of the plasma biomarkers of oxidative stress were significantly decreased but plasma lipids and antibodies to oxidized LDLs remained unchanged suggesting that a regular ingestion of mandarin juice enhances the antioxidant status of hypercholesterolemic children but does not affect LDL oxidation .
Nutraceuticals and Diabetes Mellitus
Type 1 diabetes mellitus (T1DM) is among the most prevalent chronic diseases with onset in childhood. It is linked to genes in the HLA complex on chromosome 6p21 and depends upon an immune-mediated destruction of pancreatic beta cells . The genetic susceptibility is not sufficient to induce the disease, and the environmental triggers of the disease are essentially unknown: nonetheless, early diet is among the strongest candidates, together with viral infections, in initiating the autoimmune process that leads to clinical disease .
The role of nutrients, such as cow milk  as well as other aspects of diet such as the use of fat, proteins, and meat , has been investigated in relation to the development of T1DM. Among the nutritional interventions suggested reducing the risk of developing T1DM, there is evidence concerning vitamin D and omega-3-fatty acids. Accordingly, several studies have focused on the immunomodulatory effects of vitamin D, which may be relevant in the prevention of T1DM . In fact, vitamin D was found to prevent autoimmune diabetes in nonobese diabetic mice  and two epidemiologic studies showed associations between the use of vitamin D supplements in the first year of life and a lower risk of T1DM [74,76].
Long-chain n-3 fatty acids are incorporated into cell membranes and have antiinflammatory properties that may be relevant for the prevention of T1DM, such as decreased expression of HLA class II molecules on activated human monocytes and reduced expression of interleukin 1-beta . The long-chain n-3 fatty acids play an important role in eicosanoid metabolism, and there is evidence for aberrant prostaglandin metabolism in children with T1DM . Cod liver oil is an important source of both vitamin D and the long-chain n-3 fatty acids (DHA and EPA) as shown in the Norwegian population and it was investigated as a protective nutrient . In a case-control study in Norway with 545 cases of childhood-onset T1DM and 1668 population control subjects , the effect of cod liver oil or vitamin D supplementation was analyzed. Use of cod liver oil in the first year of life was associated with a significantly lower risk of developing T1DM. Use of other vitamin D supplements during the first year of life and maternal use of cod liver oil or other vitamin D supplements during pregnancy were not associated with T1DM suggesting a predominant effect of omega-3-fatty acids in the prevention of the disease.
A second larger study is a prospective study of vitamin D supplementation in infants published in 2001 by Hypponen et al. . All 12,055 pregnant women who lived in one of two regions of Northern Finland were enrolled in the study, and 91% of their living children had multiple assessments of vitamin D supplementation during their first year. Compared with children who were not given vitamin D supplements, the relative risk of developing T1DM was only 0.12 among children given vitamin D supplements regularly. Among infants who were given vitamin D, diabetes risk was lower in subjects receiving doses of over 50 μg/day (relative risk 0.14) compared with those receiving doses under 50 μg/day. This large, prospective study provides compelling evidence that vitamin D supplementation of 50 μg/day or more during infancy may reduce the risk for T1DM, at least in very northern areas of the world where sunlight is severely limited during a greater part of the year. A possible explanation for the seemingly contradictory findings of the Hypponen and Stene [76,79] studies is that vitamin D supplements may prevent diabetes only when given in relatively large doses.
A second nutritional approach attempts to block the impact of the early pathogenic inflammatory events associated with the development of T1DM. Diabetes mellitus, in fact, is a typical model of accelerated atherosclerosis associated with the development of endothelial dysfunction and vascular complications that involve both micro- and macrocirculation . Studies suggest that macrophage infiltration and inflammatory cytokine production are early events in the pathogenesis of T1DM . Although several mechanisms have been proposed to explain the diabetic-related impaired endothelial functions , oxidative stress seems to play the main role in diabetic microangiopathy . Chronic hyperglycemia induces increased concentrations of free radicals, hydrogen peroxide, and reactive ketoaldehydes  giving a rationale for treatments with antioxidant such as vitamin E or polyphenols-rich fruit juice.
In a trial published in 2000, 29 diabetic children and 21 controls were supplemented with vitamin E (100 IU/orally) or placebo for 3 months demonstrating that vitamin E supplementation was capable of increasing glutathione (by 9%) and lowering malondialdehyde (by 23%) as well as HbA1c (by 16%) concentrations in diabetic children .
The effect of other antioxidants such as blueberry was also analyzed in a population of type 1 diabetic children. Two months of blueberry juice supplementation to diabetic children enhanced the erythrocyte superoxide dismutase activity and reduced the levels of glycated hemoglobin . Unfortunately, studies concerning antioxidant supplementation lack information about the effect of treatment on endothelial function.
Nutraceuticals and Hypertension
Blood pressure in adulthood has a strong influence on risk of CHD and stroke . It has been postulated that factors operating in early life, influence the development of high blood pressure in adulthood, and that nutrition early in life may influence subsequent blood pressure [87,88].
Taittonen et al. had linked breast-feeding in infancy to lower blood pressure during childhood; the authors showed that children who were breast-fed for at least 3 months had lower systolic and diastolic blood pressures in later childhood and adolescence compared to those children who were formula-fed .
Considerable interest has been shown in the role of omega-3-fatty acids, which is a fundamental component of maternal milk. Several studies in adults with hypertension have shown that an increased dietary intake of omega-3-fatty acids is associated with lower blood pressure . Preterm infants and some term infants may not be able to synthesize enough omega-3-fatty acids during their first weeks of life to meet demand, and therefore infants fed with formula without supplementation may be relatively deficient in omega-3-fatty acids, compared with breast-fed infants.
In a multicenter randomized controlled trial, Forsyth et al.  analyzed whether supplementation of infant formula milk with omega-3-fatty acids influences blood pressure in later childhood. Seventy-one children in the omega-3-fatty acids supplementation group and 76 children in the nonsupplementation group were enrolled. The omega-3-fatty acids group had significantly lower mean blood pressure and diastolic blood pressure than the nonsupplementation group.
Calcium adjunction was also suggested to play a role in blood pressure modulation in childhood, as increased dietary calcium intake has been associated with lower blood pressure among children, adults, and pregnant women . The effect seems to be more evident among individuals with low habitual calcium intake . Experimental and observational studies in humans and animals have reported an association between maternal calcium intake during pregnancy and blood pressure in the offspring , but others have not . These findings follow a large body of evidence indicating that blood pressure levels in childhood and young adulthood are influenced by factors operating early in life  and are associated with later CVD and mortality . By contrast, a recent large study investigating systolic blood pressure in 1173 mother–child pairs from the same cohort reported no association between maternal calcium intake during the first or second trimester of pregnancy and child blood pressure at age 3 years .
The foundations for CVD in adults lay in childhood and are accelerated by the presence of risk factors, such as obesity, dyslipidemia, diabetes, and hypertension (see Figure 1). Children and adolescents were once considered to be at low risk, but with the growing health concerns related to sedentary lifestyle and poor diet, cardiovascular screening as well as strategies directed toward prevention of vascular disease in these populations, including exercise and dietary interventions, may be needed earlier.
In this review, we have analyzed some of the current nutritional and nutraceutical strategies aimed at modifying cardiovascular risk factors associated with atherosclerotic disease in childhood (see Figure 1). Several evidence suggest that many of the risk factors for vascular disease can be reduced by early nutritional intervention. Studies concerning obesity, hypercholesterolemia, and diabetes are attractive and of potential interest; nevertheless, methodological weakness related to the study design, sample size, and follow-up duration, as well as the lack of clear-cut mechanistic insights, preclude definite conclusion.
At this moment, any nutrient or supplement, even if attractive, should not be considered as a unique therapeutic tool potentially usable for clinical purpose in children at risk of cardiovascular disease.