Functional Food and Cardiovascular Disease Prevention and Treatment: A Review

Sedigheh Asgarya, Ali Rastqarb,c, and Mahtab Keshvaria

ABSTRACT
Cardiovascular disease (CVD) is now the leading cause of death globally and is a growing
health concern. Lifestyle factors, including nutrition, play an important role in the etiology and
treatment of CVD. Functional foods based on their basic nutritional functions can decrease the
risk of many chronic diseases and have some physiological benefits. They contain
physiologically active components either from plant or animal sources, marketed with the claim
of their ability to reduce heart disease risk, focusing primarily on established risk factors, which
are hyperlipidemia, diabetes, metabolic syndrome, obesity/overweight, elevated lipoprotein A
level, small dense low-density lipoprotein cholesterol (LDL-C), and elevated inflammatory
marker levels. Functional foods are suspected to exert their cardioprotective effects mainly
through blood lipid profile level and improve hypertension control, endothelial function, platelet
aggregation, and antioxidant actions. Clinical and epidemiological observations indicate that
vegetable and fruit fiber, nuts and seeds, sea foods, coffee, tea, and dark chocolate have
cardioprotective potential in humans, as well whole-grain products containing intact grain
kernels rich in fiber and trace nutrients. They are nutritionally more important because they
contain phytoprotective substances that might work synergistically to reduce cardiovascular risk.
This review will focus on the reciprocal interaction between functional foods and the potential
link to cardiovascular health and the possible mechanisms of action.

Introduction
Cardiovascular disease (CVD) has been a major cause of death around the world. Although
CVD mortality has decreased in most high-income countries, trends are increasing in most low-
and middle-income countries. CVD accounts for 46% of total deaths in Europe and creates high
socioeconomic burdens, costing up to $320 billion annually in the USA, and costs associated
with CVD are substantial and predicted to increase. There is no exception for Asian countries:
CVD ranks second in mortality causes in South Korea and explains 25% for all-cause death in
Japan. Many of these deaths could be avoided by addressing modifiable behavioral risk factors,
such as smoking, diet, and exercise.
Although the cardiovascular risk factors (Table 1) have been widely investigated, dietary
factors are also important in the incidence of CVD but have been less widespread investigated.
The evidence linking nutrition in early life to health in adulthood now forms a cornerstone
of health promotion and public health nutrition programs globally. A report recognized and
promoted the importance of fetal and early-life nutrition and its relationship with lifelong health.
This experiment reported compelling evidence of role of early-life nutrition in setting the risk of
conditions such as coronary heart disease, type 2 diabetes, osteoporosis, asthma, lung disease,
and some types of cancer.
Chronic diseases will cause $17.3 trillion of cumulative economic loss from 2011 to 2030
in field of health care expenditures, diminished productivity, and lost capital in worldwide. Due
to these health and economic burdens, diet-related illnesses are among the leading priorities of
our time.

“Let food be thy medicine and medicine be thy food.” This quote, attributed to
Hippocrates, reflects the age old desire of people to heal or even prevent diseases with certain
foods. The term “functional food,” coined in Japan and the USA in the 1970s, refers to
foodstuffs fortified with different probiotics or microorganisms, natural or processed food that
contains known biologically active compounds, and the specific health promoting benefits of
which must be sufficiently scientifically substantiated. The food industry has started to market
products with a “functional food” label. Although the benefits of some functional food
constituents may be perceived to enhance short term well being, the benefits are generally related
to the long-term mitigation of certain diseases.
These products contain physiologically active components either from plant or animal
sources and are able to reduce heart disease risk, focusing primarily on established risk factors,
such as diabetes, hypertension, and blood lipid level. It is believed that functional foods exert
their cardioprotective effects mainly through antioxidant actions and blood lipid level lowering
effects (Table 2).
Epidemiological studies have demonstrated the association between cardiovascular health
and certain dietary patterns (13–16). Research on the cardioprotective potential of dietary
components can help in the development of functional foods (17). This paper will review the
effect of individual bioactive dietary compounds on cardiovascular protection.
Vegetable and fruit fiber (with pectin), herbs and spices, nut, legume, whole grains,
chocolate, coffee and tea, fish oil, and soy proteins have blood lipid level lowering effects in
humans, through both inhibition of fat absorption and suppression of cholesterol synthesis (18).
Kulkarni et al. have reported that the higher intake of folate, antioxidant vitamins, whole grains,
and phytochemicals can abolish the deleterious vascular effects in the heart (19). A significant
cardiovascular benefit of phytochemicals (flavonoids flavanols, anthocyanins), vitamins
(ascorbate, tocopherol), and minerals (selenium, magnesium) in foods (14,15) is thought to be
the capability of scavenging free radicals produced during atherogenesis.

Methods for review

An extensive search was performed in PubMed, ScienceDirect, Scopus, and Google
Scholar to identify clinical studies on the association between functional foods and
cardiovascular disease published from inception up to September 26, 2017. Search terms were
(“Functional foods ” OR “Phytoprotective” OR “Dietary factors” OR “Pomegranate” OR
“Citrus” OR “Apples” OR “Tomato” OR “Watermelon” OR “Berries” OR “Grape” OR
“Pumpkin” OR “Herbs” and “Spices” OR “Saffron” OR “Nigella sativa” OR “Curcuma” OR
“Cinnamon” OR “Nut” OR “Legume” OR “Whole grains” OR” Chocolate” OR “Coffee and tea”
OR “Fish oil “OR “Soy Proteins”) AND (“Cardiovascular disease”). The search was performed
in titles and abstracts and was restricted to articles published in English language.
All titles, abstracts, and full texts of potentially relevant studies were assessed for
eligibility. Papers were excluded if (1) data on exposure (Functional foods) or outcome
(Cardiovascular disease) were not reported; (2) no data were reported on the relationship
between exposure and outcome; (3) if the effect of fruit or derived preparations, e.g., juice,
extract, vinegar, etc., could not be identified (e.g., weight loss studies that focused on flavonoids,
anthocyanidins, or fruits and vegetables); and (4) nonoriginal studies.

Vegetable and fruit

 There is a substantial amount of evidence that nutrients contained in vegetables and fruits
have beneficial effects on CVD risk (16,20). As nutritional imbalance is a risk factor for CVD,
the American Heart Association (AHA) encourages adequate intake of fruits and vegetables (21).
In return, inadequate consumption of vegetables and fruits has been associated with higher rate
of CVD (22). The benefits of vegetable and fruit intake appear to be dose related. In addition,
rate of vegetable and fruit intake has been associated with lower CVD risk (23).
The mechanisms of protective effects by which vegetables and fruits exert their effects
are not completely clear. But there is some evidence on anti-inflammatory and antioxidant
effects of bioactive nutrient. Among the possible explanations for these beneficial effects,
reduction susceptibility of low-density lipoprotein cholesterol (LDL-C) particles to oxidation
has been found (24). Several bioactive components in vegetables and fruits such as magnesium,
fiber, vitamin C, carotenoids, and potassium act synergistically or antagonistically to promote a
holistic beneficial effect. Potassium also has a protective role in the incidence of CVD because it
has an inverse association between dietary intake of vegetables and fruits and blood pressure
(25). The totality of evidence supports current dietary guidelines to increase vegetable and fruit
consumption to at least b-glucan from oats and barley, fiber from flaxseed and psyllium, and
soluble fiber including pectins from apples and citrus fruits are known to lower LDL-C (26).

Pomegranate
The pomegranate (Punica granatum L., family Punicaceae) is used in several systems of
medicine for a variety of ailments. In Ayurvedic medicine, the pomegranate is considered as “a
pharmacy unto itself” and it is able to improve the arterial tone, to treat aphthae, diarrhea, and
ulcers, and also it has antimicrobial effects (2,10). The fruit can be divided into 3 parts: the seeds
(3%) and the juice (30%) representing about a third of the fruit weight, and the peels
characterized by membrane internal networks (27), which contain different chemical components
that have demonstrated beneficial cardiovascular effects; therefore, this fruit has emerged as an
alternative medical management. Pomegranate includes several kinds of phytochemicals, such as
flavonoids, condensed tannins (proanthocyanidins), and hydrolysable tannins (ellagitannins and
gallotannins) (28). Pomegranate consumption has been described to decrease blood pressure and
positively affect cardiovascular risk factors in several clinical studies (14,15,20,29,30), as
outlined in Table 3.
In patients with carotid artery stenosis who consumed pomegranate juice (50 mL/day),
the results indicated a significant reduction in systolic blood pressure (SBP), but not diastolic
blood pressure )DBP(, starting from 1 month after starting supplementation and generally
decreasing up to month 12 (equivalent to 12% decrement). However, no further decline was
observed when supplementation was continued for another 2 years (31).
After 1 year’s consumption of pomegranate juice, there was a 30% decline in carotid
intima-media thickness and the patients showed 83% increase in serum paraoxonase 1 (PON 1)
activity, whereas both serum LDL-C basal oxidative state and LDL-C susceptibility to copper
ion significantly decreased, by 90% and 95%, respectively (31).

Pomegranate juice is an affluent source of polyphenols with high antioxidative potential.

Moreover, its antiatherogenic, antihypertensive, and anti-inflammatory effects have been shown
in human studies (15,20). Pomegranate can induce its beneficial effects through its various
metabolites. The antioxidant and antiatherosclerotic potentials of pomegranate are mainly
relevant to the high polyphenol concentrations in pomegranate fruit, such as ellagitannins and
hydrolysable tannins. Cyclooxygenase 1 (COX-1) and COX-2 enzymes and interleukin 1b (IL-
1b) activity can be inhibited by pomegranate fruit extract (32).
It is suggested that pomegranate can antagonize the stimulation of mRNA of matrix
metalloproteinase 9 (MMP-9) in a human monocytic cell line (THP-1) monocytes. The whole
fruit and compounds inhibit tumor necrosis factor (TNF) induced metalloproteinase (MMP-9)
promoter activity. Urolithins are metabolites that are metabolized by the human intestinal
microflora. These compounds decreased MMP-9 secretion and mRNA levels induced by TNF. It
is suggested that ellagitannins are responsible for the control of excessive production of MMP-9,
which could result in decreased production of the noxious cytokine TNF.
TNF cytokines promote nuclear factor kappa B (NF-kB) binding to target sequences
while inducing transcription of several genes such as the MMP- 9 gene. Ellagitannins prevent
NF-kB promoter activity by blocking NF-kB–driven transcription and affecting the entire
cytokine cascade. Ellagitannins inhibit the activation of inflammatory pathways such as mitogen-
activated protein kinases (MAPKs) (32).
Pomegranate can induce its beneficial effects through the influence of its various
bioavailable constituents
and metabolites on gene expression. Although many in vitro, animal, and clinical trials have
been carried out to examine and prove the therapeutic effects of these compounds, further human
trials and studies are necessary to understand the therapeutic potentials of pomegranate (32).

Citrus
The genus Citrus L. of the family Rutaceae includes several important fruits such as
oranges, mandarins, limes, lemons, sour orange, and grapefruits (33).
The health benefits of citrus fruit have mainly been attributed to the presence of bioactive
compounds, such as phenolics (e.g., flavanone glycosides, hydroxycinnamic acids) (34), vitamin
C (35), and carotenoids (36); naringin, naringenin, nobelitin, narirutin, and hesperidin are the
most important flavonoids thus far isolated from citrus fruits (37).
Epidemiological evidence and clinical and preclinical studies suggest that flavanones
present in the Citrus genus positively influence cardiometabolic parameters, preventing
cardiovascular disease (38,39). Consumption of citrus fruits or their juice has been associated
with a reduction in cardiovascular events, suggesting that intake of flavonoids found specifically
in citrus fruits may be cardioprotective (40,41). For example, drinking 1 glass of grapefruit juice
per day has been demonstrated to lower the risk of stroke in men by 25% (42), and intake of
grapefruit was associated with a significant reduction in mortality due to coronary heart disease
(16).
A meta analysis of 3 randomized clinical trials, including 233 patients, demonstrated a
correlation between grapefruit intake and a reduction in blood pressure. Although grapefruit
intake does not significantly reduce body weight, it was responsible for a small, but significant,
reduction in the systolic blood pressure and waist circumference in overweight and obese adults.
The authors speculated that such beneficial effects can be related to naringin, which is in
considering great among meta in grapefruit (43). In larger studies, intake of citrus fruits (6–7
times/week) in Japanese subjects (10,623 participants: 4147 men and 6476 women) was
inversely associated with CVD events, particularly ischemic stroke (22).
 Similarly, after 14 years of follow-up in the Nurses Health Study (69,622 women), high
flavanone intake through a combination of consumption of orange and grapefruit juices and
fruits was associated with a 19% lower risk of ischemic stroke (22). Moreover, Wang and
colleagues published a systematic review and meta-analysis of prospective cohort studies, which
demonstrated that flavonoid consumption, especially of flavanones, was associated with a
decreased risk of cardiovascular disease (44).
Epidemiological evidence and clinical studies demonstrate that citrus fruits significantly
reduce the incidence of cardiovascular disease risk, and preclinical investigations highlight
cellular and subcellular targets that are responsible for these beneficial effects (45). There has
been special attention on evaluating intracellular pathways involved in direct cardiovascular and
cardiometabolic effects mediated by naringenin, hesperetin, and eriodictyol or their glycosylated
derivatives. Although some mechanisms of action remain unclear and bioavailability problems
should to be solved, the current evidence supports the use of a functional food approach with
citrus fruits to prevent and cure several aspects of cardiovascular disease (45), as outlined in
Table 3.

Apples
Apples (Malus pumila, family Rosaceae) are one of the most commonly consumed fruits
in the human diet, contributing a large percentage of phenolic consumption in the USA and are
the third highest contributor of dietary flavonoids in the Netherlands (46) Apples are among the
most frequently consumed fruits and a rich source of phytochemicals such as polyphenols,
flavonoids, and dietary fiber (47). Most apple flavonoids, namely, quercetin and epicatechin, are
found in the skin of apples (48).
Apples contain nutritionally important phytochemicals, although the amount and type
vary greatly, depending on which part of the apple is consumed. In general, the apple peel is
abundant in phytochemicals, whereas apple flesh is not, and unripe apples are richer in
polyphenols than ripe apples. Extracting apples for their juice causes a substantial loss of
polyphenols.
Apple flavonoids may have beneficial effects on blood pressure, vascular function, and
blood lipid levels, but the quantity administered is the key to determining the level of the effects
(49–51). This quantity is, in turn, highly dependent on the variety of apple, the part of the apple
(skin or flesh), and the food matrix, that is, how the apple is consumed (aqueous, lyophilized,
juice, or extract). It appears that apple polyphenol extracts give the best effects, followed by
consumption of whole apple with skins. It has been shown that a minimum period of 4 weeks of
consumption is necessary for the appearance of observable effects (52).
More specifically, positive effects of apples may come from their potential to lowering
cholesterol: plasma and liver cholesterol levels drop significantly after eating lyophilized apples
(53). Moreover, cholesterol excretion increases in the feces of rats that were fed apples,
suggesting that the dietary fiber and/ or polyphenols that exist in apples may reduce dietary
cholesterol absorption (53).
Intake of apple (300 g golden apple per day for 8 weeks) in hyperlipidemic and
overweight men was inversely associated with CVD events, particularly ischemic stroke. In this
study, the golden apple increased the serum levels of verylow density lipoprotein (VLDL) and
triglycerides (TG) but had no effect on total cholesterol (TC), LDL-C, high density lipoprotein
cholesterol (HDL-C), LDL/HDL ratio, lipoprotein A, and apoprotein B (ApoB); these effects can
be due to the increase of fructose intake, the low value of polyphenol in this type of apple and
thereby the diminishing of fiber and polyphenol synergy, the low number of subjects, and
insufficient duration of the study (53).
In a study of hypercholesterolemic subjects consuming apple juice together with gum
Arabic and pectin (by a ratio of 4:1), the mean serum levels of TC and TG increased by 3.5%
and 28.5%, respectively, during the 12 weeks, whereas HDL-C and LDL-C levels showed no
significant difference. During the washout period, TC mean level had a significant increase of
2.4%. Finally, the hypothesis of serum cholesterol reduction by apple juice consumption was
rejected in this study (54).
Therefore, daily intake of apple with low polyphenol cannot have positive and significant
effect on the level of lipid profile. Although in similar studies whereby significant effect has
been observed, the target society has generally been selected from the general population. The
polyphenol levels present in golden apple, red apple, and Granny Smith apple were calculated to
be 485, 620 and 835 mL/kg fresh apple fruit weight, respectively, and the polyphenol received
daily by the intervention group from a 300-g golden apple was less than from red apple and
Granny Smith apple by 1.3 and 1.7 times, respectively (55).
Apple juice (300 mL) extracted from Golden Delicious or Catarina apples in Brazil was
consumed by 9 healthy, normal weight women, aged 21–27 years (56). Antioxidant capacity,
based on ferric reducing antioxidant power (FRAP) and oxidation of 2,29-azino-bis(3-
ethylbenthiazoline-6-sulfonic acid), was significantly increased within 1 hour of consuming each
juice, ranging from 4.2% to 10.6% over baseline and compared with water.
Nonspecific biomarkers of lipid peroxidation in serum, such as hydroperoxides, were
reduced comparably by both juices and were inversely correlated with serum antioxidant
capacity. Interestingly, however, serum uric acid and vitamin C each increased by 11%, but only
the former was correlated with serum antioxidant capacity and inversely associated with lipid
peroxidation (56). Twenty-six elderly men and women (>60 years) were randomly assigned to
drink 250 mL/day of either freshly prepared pomegranate juice or commercial apple juice. After
4 weeks, plasma concentrations of malondialdehyde were decreased in both groups, and only
pomegranate juice increased FRAP and reduced carbonyl content in plasma compared with
baseline (57).
The large volume of apple juice and the 10–15 minute intake period may limit the
generalization of these findings; such reports underscore the importance of determining which
bioactive components mediate antioxidant effects, particularly in the absence of a rise in
presumed antioxidants (phenolic compounds) in plasma or serum in these subjects. Measures of
the rate and lag time of copper-induced LDL-C oxidation are used as surrogate markers of
antioxidant capacity in plasma, suggesting a potential effect on components in the blood (Table
3).

Plant lycopene
Lycopene is a polyunsaturated hydrocarbon phytochemical present in red fruit and
vegetables (tomatoes, watermelons, grape, papayas, red peppers, etc.) and belongs to the
tetraterpene carotenoid family (58). Tomato (Solanum lycopersicum L., family Solanaceae)-
based products represent an essential element of the Mediterranean diet, which motivates many
researchers to search for the link between lycopene consumption and occurrence of CVD.
Low plasma lycopene levels were reported by many researchers in hypertension,
myocardial infarction, stroke, and atherosclerosis. Less convincing results and a more complex
landscape emerge when the data from interventional studies on lycopene intake in CVD patients
are analyzed. There are multiple conflicting reports on how lycopene administration affects the
progression of CVD and its outcomes.
However, there is a certain degree of reproducibility in scientific reports describing the
reduction of cholesterol (LDL-C and total), up-regulation of HDL-C (47), decrease in carotid
artery intima-media thickness (52), and lowering of both plasma markers of oxidative damage
(60) and postprandial oxidative stress (61) in patients treated with lycopene. There are multiple
and reproducible reports describing normalization of endothelial nitric oxide synthase activity
and nitric oxide level in coronary arteries (62), inhibition of the mevalonate pathway of
cholesterol biosynthesis (63), improvement of endothelial function, and attenuation of
inflammatory damage (64), as well as improvements in lipoprotein profiles and their turnover
(62) in different animal models of CVD. These changes may represent a molecular basis for
lycopene action in CVD.
Watermelon (Citrullus lanatus, family Cucurbitaceae) is a potential source of lycopene.
Lycopene contents of red-fleshed watermelon are almost 40% higher than in tomato, i.e., 4.81
and 3.03 mg/100 g, respectively (65). The distinctive aroma of watermelon is imparted by
medium and short chain fatty acids along with geranial, b-ionone, and neral. Its consumption has
been escalated owing to rich nutritional profile and allied health benefits. It is effective in
reducing the extent of cardiovascular disorders (66).
The watermelon is also helpful to lessen some other metabolic syndromes owing to
vitamin A, B6, C, magnesium, and potassium. These along with lycopene are health-promoting
functional ingredients are associated with reduced risk of cardiovascular disorders. Heart attacks,
ischemic strokes, and atherosclerosis are faced through the oxidation of low-density lipoproteins
and their curing has been observed though high consumption of lycopene (67). Consumption of
watermelon is more advantageous because watermelon’s lycopene is readily and rapidly
available (68,69).
A comprehensive meta-analysis suggests that high intake or high serum concentration of
lycopene is associated with significant reductions in the risk of stroke (26%), mortality (37%),
and CVDs (14%) (70). Evidence from epidemiological and clinical studies suggests a possible
correlation between serum antioxidant levels and cardiovascular disease risk. High plasma
concentrations of lycopene have been associated with reduced prevalence of cardiovascular
disease.

Berries
In everyday language, a berry is a small, pulpy, and often edible fruit. Common examples
are strawberries, raspberries, blueberries, and red and blackcurrants (71). Berries are fruits that
are rich both in nutritive compounds, including minerals, vitamins, and dietary fiber, and in
nonnutritive elements, especially polyphenolic phytochemicals (phenolic acids flavonoids,
tannins, and lignans) (72,73).
In the past few years, research on polyphenols has considerably increased, and because of
the involvement of oxidative stress in the onset and development of degenerative diseases, great
attention has been paid to their antioxidant properties. Previously, polyphenols’ antioxidant
capacity was the most known and accepted mechanism, through which they are able to scavenge
free radicals or limit their formation (74).
Evidence suggests that the addition of polyphenol-rich foods in the diet may improve
CVD risk factors, inhibiting inflammation and platelet aggregation and ameliorating endothelial
function, plasma lipid profile, and free radical scavenging (75,76).
 In dyslipidemic subjects, anthocyanin consumption (about 160 mg twice daily for 12
weeks) was found to increase HDL-C concentration and to decrease LDL-C concentration and
cholesteryl ester transfer protein activity in plasma (77). Similarly, Cassidy et al. demonstrated
that, in young or middle-aged women, a reduced risk for myocardial infarction was associated
with elevated anthocyanin intake (78). Another study showed that the daily consumption of 500
g of strawberries for 1 month in young healthy volunteers was associated with a general
improvement of the serum lipid profile of the subjects, through a reduction of total cholesterol,
LDL-C, and triglyceride levels, indicating that some of the constituents of the fruit, such as
vitamin C and anthocyanins, may favorably affect the plasma lipid profile (79) (Table 3).

Grapes
Grape (Vitis vinifera L., family Vitaceae) is the most valuable fruit in the world.
Remarkably, over 1600 compounds have been identified in grapes, including resveratrol,
lycopene, quercetin, melatonin, and other potent antioxidants (80). Many of these agents are
associated with health-beneficial properties, and several of them have been shown to have
synergistic/additive effects. Thus, although the individual ingredients, such as resveratrol, have
been shown to have limited in vivo bioavailability, the overall collective antioxidant content of
whole grape is likely to be very high owing to the coexistence of catechins, procyanidins,
flavonols, and anthocyanins (80).

Grapes and resveratrol have been linked closely with heart health. Seymour et al. have
reported a reduction of heart failure pathogenesis with the administration of grape powder
enriched diets in Dahl salt-sensitive (Dahl-SS) rats, a model of salt-sensitive hypertension and
diastolic dysfunction (81). In this study, grape powder (3.0% per weight; for 18 weeks)
administration (1) lowered blood pressure; (2) improved cardiac function; (3) reduced systemic
inflammation, cardiac hypertrophy, cardiac fibrosis, and oxidative damage; and (4) increased
cardiac glutathione (81).
In addition, grape feeding enhanced cardiac peroxisome proliferator activating receptor
(PPAR-a and PPAR-g) DNA binding activity but reduced NF-kB DNA binding activity, reduced
cardiac TNF-a and transforming growth factor b (TGF-b) protein expression, increased IkB-a
expression, and reduced cardiac fibrosis, suggesting cardioprotective properties of grape powder
(82). The findings of these studies support the efficacy of grape-enriched diets against
hypertension-associated cardiac pathology, specifically for older patients, as salt-sensitive
hypertension is common in the aged population (82).
NF-kB is well known in that apoptosis is involved in the pathology of heart failure,
myocardial infarction, and cardiomyopathy (83). Studies with PPAR agonists confirm the
inverse association of PPAR activity with NF-kB activity. In Dahl-SS rats, PPAR-a agonist
fibrate inhibited cardiac hypertrophy and hemodynamic dysfunction and improved survival (84).
Fibrate treatment also decreased NF-kB activity and the expression of NF-kB–related target
genes. In stroke-prone, spontaneously hypertensive rats, PPAR-g agonist pioglitazone reduced
cardiac NF-kB activity, cardiac fibrosis, and expression of NF-kB related transcripts such as
TNF-a (85). PPAR-a activation Dose dependently improved cardiac output, myocardial
contractility, and diastolic relaxation and reduced cardiac hypertrophy and fibrosis. However,
PPAR-g activation exacerbated cardiac dysfunction.
Therefore, experimental models appear to support the premise that PPAR-a agonism is
beneficial for the heart, whereas the effects of PPAR-g agonism appear to vary (84). In humans,
increased plasma TNF-a is associated with heart failure trajectory (86). Cardiac TGF-b is up-
regulated by elevated work load and provokes the hypertrophic and proinflammatory cardiac
gene expression (87). Herrington and colleagues assessed the effect of muscadine grape seed
supplementation on endothelial function and cardiovascular risk factors in subjects with
increased cardiovascular risk (88).
In a double-blind, randomized crossover trial, there was no evidence that 4 weeks of daily
supplementation with muscadine grape seed improved endothelial function measured by brachial
flow-mediated dilatation (FMD). However, there was clear evidence that this supplement
produced an increase in resting brachial diameter. Increase in resting diameter was not
accompanied by a reduction in blood pressure or changes in other plasma markers of
cardiovascular risk, including plasma lipids and C-reactive protein (88).
The finding of no effect on FMD was unexpected, in light of the antioxidant and other
properties of the muscadine seed polyphenolics. It is possible that the whole muscadine grape
could have better efficacy than seed-alone polyphenolics. Interestingly, in another study,
Vaisman and Niv also examined blood pressure, FMD, and oxidative stress in subjects with
prehypertension and mild hypertension. This study showed that red grape powder consumption
was associated with an improvement of FMD, endothelial function, diastolic blood pressure, and
oxidative stress, without any adverse effects (89).
In a recent study, Zunino and colleagues assessed the effects of dietary grapes on blood
lipid profiles, plasma inflammatory marker concentrations, and immune cell function in a
randomized, double-blind crossover study in 24 obese human subjects (90). This study suggested
that dietary grapes may induce beneficial alterations in potentially atherogenic lipid subfractions
associated with an increased risk of obesity related disease, such as cardiovascular diseases (90).
In this study, dietary grape powder supplementation (46 g grape powder in 240 mL of
water, 2 times per day for 3 weeks, representing 4 servings of grapes/day) was found to (1)
reduce plasma concentrations of large LDL-C and large LDL particles, and (2) increase
production of IL-1b and IL-6 in supernatants from lipopolysaccharide-activated peripheral blood
cells (PBMCs) (90).
In another study, Barona et al. evaluated the effects of grape consumption on
inflammation and oxidation in metabolic syndrome–affected men: 11 men with high
triglycerides and low HDL and 13 men with no dyslipidemia (91). Grape consumption showed
favorable responses by increasing IL-10 and adiponectin, 2 anti inflammatory cytokines, in
nondyslipidemic subjects. In addition, inducible nitric oxide synthase (iNOS) expression was
higher in PBMCs from nondyslipidemic individuals (91).
Why grape consumption did not provide benefits to men with dyslipidemia may be the
subject of future research. In a separate study, Barona et al. also demonstrated that daily
consumption of grape powder for 30 days significantly potentiated vasodilation, decreased
circulating cell adhesion molecules (CAMs), and reduced blood pressure, resulting in improved
vascular function in men with metabolic syndrome (92). In another recent study, Zern and
colleagues found that grape powder supplementation (36 g daily for 4 weeks) resulted in
improvement of plasma lipid levels, inflammatory cytokines, and oxidative stress in 24 pre- and
20 postmenopausal women, suggesting possible beneficial effects for coronary heart disease in
women (93) (Table 3).
 Pumpkin
Pumpkin (Cucurbita pepo L., family Cucurbitaceae) is a round fruit with smooth, slightly
ribbed skin, and deep yellow to orange color. It is famous for its edible seeds that are low fat and
protein rich (94). The second most important part is its fruit. The immature fruit is cooked as a
vegetable, whereas the mature fruit is sweet and used to make confectionery and beverages. The
fruit has a good b-carotene content and has a moderate content of carbohydrates, vitamins, and
minerals. Pumpkin seeds are used for extract for an edible oil, which is rich in oleic acid (95).
Pumpkin has been accepted as beneficial to health because it contains various
biologically active components, such as polysaccharides, para-aminobenzoic acid, fixed oils,
sterols, proteins, and peptides (96,97). The fruits are a good source of carotenoids and g-
aminobutyric acid (98). Pumpkin seeds (Cucurbita spp.) are valued for their high protein content
(99) and useful amounts of the essential fatty acid, linoleic acid, and remarkably high proportions
of essential amino acids (100).
Pumpkin is a well-known edible plant; most parts of this plant are also used in traditional
medicine around the world (96). Oxidative stress has been considered as a hallmark of various
chronic diseases and their complications such as diabetes, obesity, CVD, and cancer. It is a
condition of potentially harmful imbalance between the level of prooxidants and antioxidants in
favor of the former (101). Various extracts of pumpkin have potential antioxidant activity, which
might play an important role in prediabetics, diabetics, and individuals with vascular injury
(102,103).
Xia and Wang demonstrated that pumpkin fruit has an important antioxidant role for its
cytoprotective (cell-protecting) action in streptozotocin-induced diabetic animals (104). Pumpkin
seeds have a high content of vitamin E (tocopherol; an antioxidant), and pumpkin seed oil has
been considered to provide a significant source of vitamin E in Japanese diets (105). Chang
reported that pumpkin extract administration significantly increased the serous and hepatic
activities of superoxide dismutase and glutathione peroxidase in mice and reduced the
concentration of malonaldehyde (106).
Pumpkin is an edible food that can be included in our daily diet that can give various
health benefits to improve our overall health. Pumpkin has various effects beneficial to health,
such as antidiabetic, anticarcinogenic, antioxidant, and antimicrobial potential (107) (Table 3).

Herbs and spices

The use of herbs and spices enhances the flavor and palatability of food and reduces the
requirement to salt or fat. In addition, herbs are a natural source of phytochemicals, including
flavonoids and polyphenols. These compounds are potent antioxidants and can inhibit lipid
peroxidation as well as suppress cholesterol synthesis (108).

Saffron
Saffron is a spice obtained from the stigmas of the flower of Crocus sativus L., family Iridaceae, which is
widely cultivated in Iran and other countries such as India and Greece. Saffron has been used to treat more than 90
diseases (109). Saffron is a natural antioxidant with various active compounds out of which the most powerful ones
are crocin, crocetin, and safranal (110–112).
Considerable interest has been shown in saffron supplementation as a potential cure for dyslipidemiic
(113), antinociceptive, anti-inflammatory, and antioxidant effects (114,115). Saffron also offers protective effects
against cardiovascular disease (116), atherosclerosis, and other diseases (117,118). In fact, saffron supplement
attenuated reperfusion-induced fatal ventricular fibrillations in ischemic rat hearts (119). Similarly, crocetin
reportedly reduced the infarct size of ischemic rat myocardium and significantly attenuated apoptosis within the
cardiac tissues. Furthermore, saffron was shown to reduce isoproterenol induced injuries in rat hearts and to
attenuate histological changes of the myocardium (120,121) (Table 3).

Garlic
Garlic (Allium sativum L.) has been used as a food and medicinal herb for thousands of years. Asia is one
of the origin centers of Allium genus, especially garlic (Allium sativum L.), onion (Allium cepa L.), and Chinese
chive (Allium tuberosum) (122). The vast majority of studies have been conducted with the use of cell culture (in
vitro) or animals (in vivo) and clinical studies that investigate whether garlic intake may provide protection against
cardiovascular disease.
The Allium genus is rich in sulfur compounds, steroidal saponins, flavonoids, and so on, which have
anticancer, antioxidant, anti-platelet aggregation, antiatherosclerosis, and antimicrobial activities. It also lowers
blood lipids and blood glucose levels. S-alk(en)yl-l-cysteine sulfoxides are cysteinederived secondary metabolites
highly accumulated in the genus Allium (122).
Clinical studies showed garlic’s effects on atherosclerotic risk factors, as outlined in Table 3. All studies
were randomized, double blind, placebo-controlled that used either garlic powder or aged garlic extract (AGE).
Three of these trials examined garlic’s lipid-lowering effects. Hyperlipidemic patients (123) and patients with
coronary artery disease (CAD) (124,125) showed a reduction in total cholesterol, LDL-C, and TG in response to
daily garlic intake.
Similar findings were observed in a study of healthy male long-distance runners (126). Zhang
et al. found that although there was no effect of garlic on cholesterol in normal male subjects, garlic did lower total
cholesterol and increase HDL-C in female subjects, suggesting a potential gender effect (127).
The data summarized in a review study point out that major mechanism and many functional components
derived from the Allium genus, especially garlic and onion, exert potent effects in preventing chronic diseases
(128).. Although functional components in alliums for preventing and treating chronic diseases seen complicated
task, the development of functional foods may still open new beginning for therapeutic interventions (128).
Based on the current available literature, garlic has shown favorable effects on several clinically relevant
risk factors that not only help prognosticate but can alter management strategies for patients in the primary
prevention of ischemic heart disease. One of the challenges of studying the effects of garlic is the standardization of
the preparation or active ingredient.
Kyolic brand aged garlic extract has shown the most consistent results, because the product is standardized
to a certain level of N-acetylcysteine before packaging. Nonetheless, numerous trials and meta analyses have shown
favorable effects from garlic on well accepted risk factors such as hypertension and hypercholesterolemia
(129). SBP and DBP have been shown to be reduced by 7–16 and 5–9 mm Hg, respectively, compared with
placebo. TC has been shown to be reduced by 7.4–29.8 mg/dL (129) (Table 3).

Nigella sativa
Nigella sativa L. is a small shrub and annual flowering plant that belongs to the family Ranunculaceae. It
bears white, yellow, pink, and purplish delicate flowers containing 5–10 petals (130).
Chemical composition of N. sativa is very diverse and consists of range of different components, including
carbohydrates, proteins, fats, oils, fiber, vitamins, minerals (Cu, Fe, P, Zn, etc.), and many other biologically active
compounds (131).
It is estimated that N. sativa consumption (1 g powder per day for a period of 60 days) resulted significant
reduction in LDL-C and triglyceride levels and increase in HDL-C level in hypercholesterolemic patients (132).
Another study also reported similar results on the hypercholesterolemic patients in whom N. sativa consumption was
found to be associated with lowering of LDl-C level; thus, it is helpful in normalization of lipid profile in patients
with heart problems (133-135).
The study in patients with mild hypertension designed to assess the effect of N. sativa on blood pressure
shows that N. sativa extract consumption favorably affects the elevated blood pressure (136). Qidwai et al. reported
similar results that N. sativa seeds have favorable effect on the high blood pressure (137).
Different preparations of N. sativa, including seed powder (100 mg to 20 g daily), seed oil (20–800 mg
daily), thymoquinone (3.5–20 mg daily), and seed extract (methanolic extract especially), were shown to reduce
plasma levels of total cholesterol, LDL-C, and triglycerides, but the effect on HDL-C was not significant. N. sativa
and thymoquinone have been reported to be safe and well tolerated with no severe adverse effect. In
clinical trials, N. sativa was found to be effective when added as adjunct to standard antihyperlipidemic and
antidiabetic medications. Lipid-modifying effect of N. sativa could be attributed to the inhibition of intestinal
cholesterol absorption, decreased hepatic cholesterol synthesis, and up-regulation of LDL receptors (138) (Table 3).
 Curcuma
Curcuma longa L. (belonging to the family Zingiberaceae) is a vegetatively propagated, polyploid crop
cultivated mostly in Southeast Asia, commonly known as “Indian saffron” and “Golden spice.” Turmeric is widely
used as a spice, natural food dye, and preservative in Asian countries (139). Curcumin (diferuloylmethane) is a
polyphenol responsible for the yellow color of turmeric, a curry spice. The yellow-pigmented fraction of turmeric
contains curcuminoids, which are chemically related to its principal ingredient, curcumin (140). Curcumin
has antioxidant, anti-inflammatory, antiviral, and antifungal actions. Studies have shown that curcumin is not toxic
to humans (141).
Studies have demonstrated the effects of curcumin on the serum cholesterol and lipid peroxide levels (142).
After curcumin administration (500 mg/day) for 7 days to 10 healthy volunteers, a significant decrease were
observed in the serum lipid peroxides, increase in the serum HDL-C, and decrease in the total serum cholesterol
(33%, 29%, and 12%, respectively) (143)
Similarly, another study in patients with atherosclerosis showed that 10 mg of curcumin given twice a day for
28 days significantly decrease the serum LDL-C levels and increased the serum HDL levels (142). Since the
abnormal lipid metabolism principally contributes to the pathogenesis of atherosclerosis, these observations suggest
The potentially protective role of curcumin in atherosclerotic diseases (142).
The therapeutic effects of curcumin have been extensively investigated, particularly in the treatment of anti-
inflammatory diseases (144–146). In addition, curcumin is well tolerated when taken at doses as high as 12 g/day
and has low toxicity and low cost (147).
Evidence has shown that curcumin has a potential role in the protection against many cardiovascular
diseases. The antioxidant effects of curcumin have been considerably shown to decrease Adriamycin-induced
cardiotoxicity (148) and may prevent diabetic cardiovascular complications (149). The antithrombotic (150),
antiproliferative (151), and anti-inflammatory effects of curcumin and the effect of curcumin in decreasing the serum
cholesterol level may protect against the pathological changes seen in atherosclerosis (142). Furthermore, curcumin
can prevent atrial and ventricular arrhythmias, possibly via correcting of calcium homeostasis (152,153). Since the
last decade, there are several ongoing trials on the preventive effects of curcumin on various cancers (154) (Table 3).

Cinnamon
Cinnamon (Cinnamomum verum, family Lauraceae) has been used as a spice in daily life without any side
effects. Several reports have dealt with the many properties of cinnamon in the forms of bark, bark powder, essential
oils, flavonoids, phenolic compounds, and isolated components. Each of these properties plays a key role in the
advancement of human health (155,156).
Cinnamon compounds are cinnamic acid, cinnamate, and cinnamaldehyde, an abundant essential oil (157).
The spicy taste and fragrance are due to the presence of cinnamaldehyde and occur due to the absorption of oxygen.
As cinnamon ages, it darkens in color, improving the resinous compounds (158).
Different flavonoids isolated from cinnamon have free radical scavenging activities and antioxidant and anti
inflammatory properties (159).
One of the active components isolated from C. cassia (2- methoxycinnamaldehyde [2-MCA]) decreases the
expression of vascular cell adhesion molecule 1 (VCAM-1) (160).
A recent study reported the potential effects of 2 compounds, cinnamic acid and cinnamic aldehyde, isolated from C.
cassia against myocardial ischemia, representing that cinnamon also has potential effects in cardiovascular disease
treatment (161). Numerous studies have reported the defensive effects of cinnamaldehyde on the cardiovascular
system (161,162). Cinnamophilin mainly inhibits thromboxane receptor mediated vascular smooth muscle cell
proliferation and can have the potential for use in the prevention of vascular diseases and atherosclerosis (163).
The administration of cinnamon has positive effect on the lipid profile in mice. It reduced plasma
triglycerides but increased the HDL-C levels (164). Another study showed an attenuation in triglycerides, low-
density lipoproteins, and the total cholesterol in rats after administration of C. cassia powder (15%) for 35 days
(165). Additionally, cinnamon oils reduced the cholesterol levels in broiler chickens (166). El-Bassossy et al.
reported that the administration of cinnamon at 1, 3, and 6 g doses per day caused a lessening in serum total
cholesterol, triglyceride, LDL-C, and glucose levels in humans (167) (Table 3).

Beetroot
Beetroot (Beta vulgaris L.) belongs to the Chenopodiaceae family and is originally from temperate climate
regions (168). This plant contains biologically active phytochemicals, including betalains (e.g., betacyanins and
betaxanthins), flavonoids, polyphenols, and dietary nitrate (169). Dietary nitrate and nitrite serve as a nitric oxide
(NO) sources (170). NO has a vital role in the regulation of vascular tone and BP (171,172). Cao et al. suggested
that nitrite, a known vasodilator, has an indirect effect in promoting vascular NO synthesis (173).
Mechanistically, vascular dysfunction is characterized by a reduced bioavailability of the endothelium-derived
vasoprotective molecule NO. NO is a vasodilator associated with antiplatelet, anti-inflammatory, and
antiproliferative effects that underlie its critical role in sustaining cardiovascular health (174). The dysfunction of the
conventional L-arginine/NO synthase pathway and enhanced scavenging of NO underlie the reduced bioavailability
in individuals at risk of CVD, including those with hypercholesterolemia (174), which is a phenomenon reflected by
impaired FMD responses. Thus, approaches that might restore this lost NO have obvious therapeutic potential.
Absorbed nitrate is concentrated in the salivary gland and subsequently reduced to nitrite by symbiotic oral
bacteria a portion of the nitrite is then absorbed and found in plasma (175). In the USA, dietary intake of nitrate is
approximately 40–100 mg/day, with 85% from vegetable sources (176).
Studies reported that administration of beetroot juice, approximately 3 hours after ingestion of a dietary nitrate
load (500 mL of beetroot juice), has a BP-lowering effect in healthy volunteers (177). Similarly, Hobbs et al.
showed that consumption of 200 g of bread containing 100 g beetroot increases endothelium-independent
vasodilation and lowers DBP in healthy subjects (178). Additionally, results of a recent meta-analysis indicated a
significant reduction in SBP (¡4.4 mm Hg, 95% confidence interval [CI]: ¡5.9 to ¡2.8) and a trend toward reducing of
DBP (¡1.1 mm Hg, 95% CI: ¡2.2 to 0.1) as a result of inorganic nitrate and beetroot juice supplementation in adults
(179).
Studies reported a significant improvement in FMD and circulating NO pool following consumption of a
standardized mixed meal coadministered with 140 mL beetroot juice (equivalent to 500 mg dietary nitrate)
(172,180).
Asgary et al. compared the effects of raw beetroot juice and cooked beetroot on blood pressure, FMD, lipid
profile, and inflammatory markers in hypertensive individuals. Twentyfour hypertensive subjects aged 25–68 years
were randomly assigned to raw beet juice or cooked beets both for 2 weeks, intermittent by a 2-week washout
period, in a crossover, unblinded, non-placebo-controlled design.
Results showed a significant improvement of FMD and significant reduction in blood pressure and
inflammatory cytokines following consumption of either of the preparations. Between-groups comparisons
showed that raw beetroot juice was more effective than cooked beetroot in increasing of FMD and reducing
highsensitivity C-reactive protein (hs-CRP) and TNF-a. The authors concluded that both preparations of beetroot are
effective in improving blood pressure, endothelial function, and systemic inflammation, and that raw beetroot juice
has a greater effect versus cooked beetroot on the latter 2 factors (172).
Beetroot has a long ethnopharmacological background in the treatment of tumors of intestine, breast, stomach,
and uterus (181). It has been reported that consumption of beet leaf improves antioxidant capacity, reduces lipid
peroxidation, and enhances glutathione levels (182) (Table 3).

Nuts
Nuts are a specific kind of fruit characterized by a hard shell and dry seed. Nuts are considered as one of the most
nutritional foods because they contain high amounts of vegetable protein and unsaturated fatty acids. Nuts rich in
dietary fiber, vitamins (folic acid, niacin, tocopherols, and vitamin B 6), minerals (calcium, magnesium, and
potassium), and many other bioactive constituents such as phytosterols and phenolic compounds (183).

Nuts are complex foods containing cholesterol lowering mono and polyunsaturated fatty acids, several
antioxidant polyphenols, soluble fiber, and arginine (a precursor to the vasodilator nitric oxide) (184,185).
Postprandial vascular reactivity is characterized by increased expression of proinflammatory cytokines and CAMs
and decreased bioavailability of nitric oxide (186). It is not surprising that the evidence supporting the
cardioprotective effects of diets high in nuts is healthy, as multiple mechanisms work together to decrease risk.
Prospective data from the Physicians Health Study (187) indicated reduced risk of sudden cardiac death associated
with nut consumption originally perceived as being unhealthy because of their high-fat content.

Nut consumption was shown to have beneficial effects on several CVD risk factors, including lowering LDL-C
(188) and ameliorating endothelial function (189). Furthermore, nutrients contained in nuts may also modify specific
processes related to cancer development such as the regulation of cell differentiation and proliferation, reduction of
tumor initiation or promotion, DNA protection, and regulation of immunological and inflammatory responses (190).
Four recent meta-analyses showed that higher consumption of nuts was associated with reduced risk of coronary
artery disease and hypertension (191).
 Epidemiological investigations have consistently shown that frequent nut consumption reduces coronary heart
disease (CHD) risk. Studies showed that the mean CHD risk was 37% lower among subjects who consumed 4 or
more servings of nuts a week compared with those who seldom or never ate nuts, with a mean reduction of 8.3% for
each incremental serving per week of nuts consumed (192). According to scientific data documenting the beneficial
advantages of nut consumption, the US Food and Drug Administration (FDA) issued a qualified health claim in
2003 stating that eating 43 g/day (1.5 oz/day) of specific nuts (such as almonds, hazelnuts, pecans,
pistachios, walnuts, and peanuts) may reduce CHD risk. Although many mechanisms by which nuts perform this
CHD protective effect have been postulated, their lipid-lowering properties have been studied extensively (193).
In 2015, Grosso et al. pooled individual primary data from 25 nut consumption trials conducted in 7 countries
into a systematic review. In that review, the data extracted among 583 men and women with normolipidemia and
hypercholesterolemia who were not taking lipid lowering medications, with a mean daily consumption of 67 g of
nuts. Results demonstrated the effects of nut consumption were dose related, and different types of nuts had similar
effects on blood lipid profile levels. Nut consumption improved blood lipid profile levels in a doserelated manner,
especially among subjects with higher LDL-C or with lower body mass index (BMI) (194).
In a study, the assignment for 24 weeks on a low-calorie diet enriched with 84 g/day of almonds was associated
with an 11% reduction in SBP compared with a low-calorie diet enriched with complex carbohydrates (195).

Other studies on walnut-enriched diets reported improved FMD in comparison with control diets without
walnuts (186,196). Using a crossover design, Ros et al. studied the effect of walnut consumption for 4 weeks on
vascular reactivity in hypercholesterolemic patients. The authors showed a significant improvement in FMD after the
consumption of 40–65 g/day of a walnut supplement (186). In a crossover study conducted in type 2 diabetic
patients, a walnut-enriched ad libitum diet for 4 weeks also improved FMD compared with the same diet without
walnuts (196). Finally, using a crossover design in an acute study, the effect of walnut consumption on
postprandial FMD was studied after 2 high-fat meal sequences (separated by 1 week) to which 25 g of olive oil or 40
g of walnuts were added. In this study, the authors showed that, in comparison with olive oil, walnuts reversed the
impairment of FMD associated with a fatty meal (197).

Legumes
Legumes are complex foods rich in soluble fiber and polyphenols, as well as folic acid. Legumes are also rich
in protein, complex carbohydrates, fiber, and various micronutrients (e.g., phytochemicals) (198). Controlled trials
have shown beneficial effects of the consumption of nuts and legumes on 5 risk factors of CVD (198), and a recent
trial in high-risk adults showed that following advice to consume a Mediterranean diet supplemented with nuts
significantly reduced CVD events by 30% (199).
Legumes were the only food group predictive of survival among 5 long-lived elderly cohorts in Japan,
Sweden, Greece, and Australia (200). Additionally, evidence from experimental research indicates that cholesterol-
lowering effect of legumes maybe due to the combined effects of numerous bioactive components, such as protein,
phytosterols, and soluble and insoluble fiber (201). An interventional trial has shown that lupin kernel flour added to
bread has also a positive effect on blood pressure: both the fiber and the protein were suggested to be responsible
(202).

Whole grains
Several healthy ingredients of the Mediterranean diet, including polyunsaturated fat products, legumes, whole
grains, and vegetables and fruits, have functional properties that may protect against type 2 diabetes (203). They
were also shown to reduce the risk of coronary events, especially in high-risk persons (204).
Studies in the early 1970s have shown that whole grains have the potential protective role. Whole-grain
products contain intact grain kernels rich in fiber and trace nutrients. They are nutritionally more important because
they contain phytoprotective substances that might work synergistically to reduce cardiovascular risk (205). Based
on the results of the prospective Iowa Women’s Health Study, cereal fiber had different associations
with total mortality, because it depends on whether the fiber came from foods that contained primarily whole grain
or refined grain (206).
Whole grains exert their protective effects on CVD risk via returning of blood pressure and plasma lipid
levels to normal range and decreasing inflammation (207,208). Whole grains have a reduced glycemic response
following ingestion compared with refined grains, (i.e., a little effect on postprandial blood glucose rising). The
reduction of postprandial glucose surge is associated with reduced reactive oxygen generation, inflammation, and
CVD risk after a meal ingestion (209).
 A meta analysis based on 7 qualifying prospective cohort studies focused on whole-grain consumption and
cardiovascular outcomes reported that the inverse association between dietary whole grains and incident CVD was
strong and consistent across trials (207).
Threapleton et al. in a systematic review study in 2013 pooled individual primary data from 22 cohort study
publications that met inclusion criteria and reported total dietary fiber intake, fiber subtypes, or fiber from food
sources and primary events of cardiovascular disease or coronary heart disease (risk ratio 0.91 per 7 g/day). Greater
dietary fiber intake has direct association with a lower risk of both cardiovascular disease and coronary heart disease.
The differing strengths of association by fiber type or source emphasizes the need for a better understanding of
action of fiber components (210).
In a systematic review study on 2013, the authors pooled individual primary data from 45 studies (64
publications), and after meta analysis, results showed that whole grain intake is associated with a reduced risk of
coronary heart disease, cardiovascular disease, and total cancer, and mortality from all causes, respiratory diseases,
infectious diseases, diabetes, and all noncardiovascular, noncancer causes. These findings support dietary guidelines,
that intake of whole grain can reduce the risk of chronic diseases and premature mortality (211).

Chocolate
Cocoa is a flavonoid rich food that has been investigated for its possible role in the prevention of CVD
(212,213). In healthy adults, drinking flavonoid-rich cocoa may improve NO dependent vasorelaxation and flow-
mediated dilation in the brachial arteries (214). Administration of dark chocolate in essential hypertensives reduced
ambulatory serum LDL-C levels and blood pressure, whereas white chocolate had no effect (215). Also, there was a
clear decrease of the blood cholesterol levels as well as a significant rise of HDL-C in addition to a marked decrease
of circulating oxidized LDL (216).

A systematic review of the literature of observational studies for effects of chocolate, cocoa, and flavan-3-ols
on cardiovascular health pooled 42 acute or short-term chronic ( kurang lebih 18 week) randomized controlled
trials (RCTs). Effects on insulin resistance index (homeostatic model assessment: insulin resistance
[HOMA-IR]) and FMD remained stable to sensitivity analyses. Results of this study showed reductions in DBP and
mean arterial pressure and marginally significant effects on LDL and HDL-C.

Chocolate or cocoa improved FMD regardless of the dose consumed, whereas doses 50 mg epicatechin/day
resulted in greater effects on SBP and DBP. GRADE (Grading of Recommendations, Assessment, Development,
and Evaluation), a tool to assess quality of evidence and strength of recommendations, suggested low- to moderate
quality evidence of beneficial effects, with no suggestion of negative effects. Also [xxx] consistent acute and chronic
benefits of chocolate or cocoa on FMD and previously unreported promising effects on insulin and HOMA-IR More
experimental are needed to appear the potential cardiovascular benefits of cocoa flavan-3-ols (217) (Table 3).

Coffee and tea

Coffee and tea, after water, are the most widely consumed beverages in the world, and are the principal
source of caffeine intake among adults. The biological effects of coffee and tea may be substantial and are not
limited to the actions of caffeine. The active constituents of coffee, diterpenes (such as kahweol and cafestol), are
apparently responsible for cardioprotective effect. Coffee has hundreds of biologically active compounds, and the
health benefits of chronic coffee intake are wide ranging, because consumption of coffee may diminish the risk of
hypertension (218). A dose-response decrease in cardiovascular risk and heart disease mortality was reported for a
daily caffeine intake in patients with type 2 diabetes (219).

It seems that intake of 2–3 cups of coffee per day is safe. However, most of the data on coffee’s health effects
are based on observational data, with very few randomized, controlled studies, and association does not prove
causation. In addition, the possible advantage of regular consumption of coffee has to be weighed against potential
risks, which are mostly related to its high caffeine content (220).

The currently available evidence on cardiovascular (CV) effects related to habitual coffee consumption is
largely reassuring. Coffee can be as part of a healthy diet for those with increased CV risk or CV disease. Although
many of coffee’s benefits probably derive from its caffeine content, decaffeinated coffee seems to offer some health
benefits too. It can be a good choice for those who experience uncomfortable effects from caffeine stimulation.
Drinkers of caffeinated coffee in particular might be advised to ensure adequate calcium consumption from dietary
sources to guard against potential adverse outcomes related to bone health (220).
 Green tea consumption appears to protect from CVD (221), but results are again inconsistent. It has been
reported in a meta analysis that the incidence of myocardial infarction among individuals who consumed 3 cups of
tea daily was not statistically significant, and there has been large variability across studies (222). There were
regional differences in this meta analysis, with increasing tea consumption associated with an increased risk for
CHD in the United Kingdom and for stroke in Australia, whereas the risk decreased in other regions, particularly in
continental Europe. The hypothesis that addition of milk to tea (as typically done in United Kingdom and Australia)
abolishes its plasma antioxidant potential may only partially explain these geographic differences.

A meta analysis of tea consumption in relation to stroke, myocardial infarction, and all coronary heart disease
is based on 10 cohort studies and 7 case-control studies (222). The incidence rate of myocardial infarction is
estimated to decrease by 11% with an increase in tea consumption of 3 cups per day (fixed-effects relative risk
estimate D 0.89, 95% CI: 0.79, 1.01) (1 cup D 237 mL) (222).

However, evidence of bias toward preferential publication of smaller studies that suggest protective effects
urges caution in interpreting this result. The geographic region where the studies were conducted appeared to
explain much of the heterogeneity among coronary heart disease, myocardial infarction, and probably stroke results.
With increasing tea consumption, the risk increased for coronary heart disease in the United Kingdom and for stroke
in Australia, whereas the risk decreased in other regions, particularly in continental Europe (222) (Table 3).

Fish oil
People with a high intake of dietary fish and fish oil supplements have a low rate of CVD (223). Although fish
per se contains various nutrients with potentially favorable effects on health, attention has been particularly focused
on the omega-3 (n-3) fatty acids. Omega-3 fatty acids also include the plantderived docosahexaenoic acid (DHA;
22:6 n-3), eicosapentaenoic acid (EPA; 20:5 n-3), and a-linolenic acid (ALA; 18: 3 n- 3).

Both DHA and EPA are found in oily fish. Despite the established beneficial effect of fatty fish consumption
on CHD, the species and amount of fish consumed, as well as the preparation method, have an impact on CHD risk
(223). The concomitance of low amounts of n-3 fatty acids in our average diet and the need for prolonged
administration for prevention and treatment has led to the development of selected preparations. These should
combine acceptability and adequate bioavailability of their relatively low contents of n-3 fatty acids.

Both DHA and EPA are found in oily fish. Despite the established beneficial effect of fatty fish consumption
on CHD, the species and amount of fish consumed, as well as the preparation method, have an impact on CHD risk
(223). The concomitance of low amounts of n-3 fatty acids in our average diet and the need for prolonged
administration for prevention and treatment has led to the development of selected preparations.These should
combine acceptability and adequate bioavailability of their relatively low contents of n-3 fatty acids.

These fatty acids are therefore being incorporated into a number of commercially available, natural foods
that, due to rather their structural features, appear to be particularly suited as efficient fatty acid vehicles (224).
Furthermore, some environmental contaminants found in certain fish, for example, polychlorinated biphenyls,
dioxins, and methylmercury, may diminish the health benefits of fish-derived n-3 fatty acids (224).There are some
suggested potential mechanisms for the CVD protective effects of n-3 fatty acids, including anti-inflammatory,
antiarrhythmic, and antithrombotic effects and decreasing of heart rate, BP, and plasma triglycerides improved
endothelial function effects (224). Fish ingestion has been related to a reduced risk for myocardial infarction, which
may be related to beneficial effects of EPA and DHA on plaque stability (probably related to the content of
inflammatory cells) and modulation of endothelial function (225).

EPA and DHA have also been shown to decrease LDL oxidative susceptibility in postmenopausal women,
which could help to reduce the risk of CVD (226). Fish oil supplements have favorable effects on lipid profile and
blood pressure (227,228). A meta-analysis of 65 studies demonstrated that n-3 fatty acids lowered triglyceride levels
to baseline levels in a dose dependent manner (229).

A meta-analysis from 11 published articles, including more than 5000 participants, demonstrated that fish oil
supplementation was not associated with reduced risks for gestational diabetes mellitus (GDM), pregnancy-induced
hypertension (PIH), and preeclampsia (PE). No statistically significant heterogeneity was detected for the
comparison of each outcome. The effects of fish oil on these gestational complications were consistent between
women with low-risk and high-risk pregnancies. Gestational supplementation with fish oil during the second or third
trimester of pregnancy is not associated with reduced risks for GDM, PIH, or PE. Other possible benefits of fish oil
supplementation during pregnancy warrant further evaluation (230).

A meta-analysis of randomized controlled trials from 7 trials showed that levels of tumor necrosis factor a
(TNF-a) and interleukin 1 and interleukin 6 (IL-1 and IL-6) were significantly decreased after fish oil
supplementation; however, hs- CRP, soluble intracellular adhesion molecular 1 (ICAM-1), and vascular cell
adhesion molecular 1 (VCAM-1) were not significantly affected. Meta-regression and subgroup analysis results
suggested that the difference in dose of fish oil and follow-up duration might influence the effects of fish oil on TNF-
a and IL-6. Greater reduction of these 2 markers might be achieved in patients who take a higher dose (over 1000
mg/day) or for a longer duration (over 4 months) of fish oil (230).

The large heterogeneity within studies with n-3 fatty acid supplementation for the response to triglycerides is
likely to be attributable to genetic variability within the study population. Furthermore, more studies are needed to
determine whether specific genotypes exist that may benefit to a greater extent from n-3 fatty acids for
hypotriglycerolemic effects. Clinical studies also need to determine whether the reduction in CVD risk factors is due
to EPA, DHA, or the combination of both and the dosage of the effective components (223) (Table 3).

Soy proteins
Soy products have been part of Eastern countries’ diets for centuries, and nowadays they are increasingly
becoming important in the Western diets as related to the use of soy-based products and functional foods enriched in
soy extracts (231). The soybean contains 35%–40% of proteins containing all essential amino acids, which makes it
nutritionally equivalent to animal protein but with lower fat associated and no cholesterol (232). Soy also represents
the richest source of isoflavones (a type of phytoestrogen that belongs to the flavonoids group) in the human diet.
Soy proteins and isoflavones have received much attention in relation to their potential biological activities (233).

The proteomic investigations of the profile changes in the human serum as response of food enriched in soy
extract consumption (yogurt and soy pudding with an intake of 60 mg/day of isoflavones for 2 weeks) by young
women led to a beneficial modulation of the level of a number of serum proteins. Nine proteins with modified
concentrations were identified following soy isoflavone consumption by functional food intake. Particularly, the
apolipoprotein E (important in the lipid metabolism) and ceruloplasmin (a copper-carrying protein) contents
significantly increased, whereas a-1-acid glycoprotein (an immunomodulating molecule) decreased (234).

The nature of the proteins identified in the serum suggests that the consumption of the soy isoflavones as part of
functional foods may modulate the lipid metabolism, the response to oxidative stress, and the immunomodulation on
vascular protection. Other proteomic research carried out on menopausal women consuming isoflavones (50 mg/day
for 8 weeks by cereal bars enriched with soy extracts) showed an increase of the metabolic profile in mononuclear
blood cells on the expression of the proteins linked to the anti inflammatory response (235).

Postmenopausal women with a diet low in saturated fat and cholesterol (the National Cholesterol Education
Program Step I diet) consumed 40 g/day of soy protein for 6 months. These women had significantly better blood
lipid profiles (average changes from baseline: 8.2% decrease in non–HDL-C and a 4.4% increase in HDL-C) after
duration consumption (236). In other experiments, HDL significantly increased 7% from baseline with consumption
of 32 g soy protein for 4 weeks as soymilk in both women and men with hypercholesterolemia (237). Crouse et al.
reported reductions of 4% and 6% in total and LDL cholesterol, respectively, in hypercholesterolemic individuals
consuming 25 g soy protein for 9 weeks (238).

Thus, 20–50 g soy protein/day improved blood lipid levels (1.5%–4.5%) in mildly hypercholesterolemic
persons (239). The FDA recently published its final ruling on a food-labeling health claim for soy protein and
cholesterol reduction stating that 25 g/day of soy protein, as part of a diet low in saturated fat and cholesterol, may
reduce the risk of heart disease (240) (Table 3).
 Discussion
Functional components of food can be applied in the treatment and prevention of chronic diseases; they include
nonstarchy carbohydrates (dietary fiber, resistant starch, and fucoidan), antioxidants (organosulfur compounds,
polyphenols, carotenoids, tocopherols, tocotrienols, phytosterols, and isoflavones), unsaturated fatty acids, bioactive
peptides, sterols, and phytoestrogens (13).

In recent years, the consumption of polyphenols has become common in the treatment of various diseases,
including chronic and neurodegenerative conditions, as well as CVD (241).

Advances in flavonoid research have included substantial progress in the identification of the biological
activities of these compounds, especially in the area of activities that may act in the prevention of CVD (242).
Several areas of investigation appear promising and may have substantial health effects. Polyphenols may have
several antiatherosclerotic activities, including anti-inflammatory, antioxidant, antiproliferative, and antiplatelet
activities. Cholesterol-lowering and antihypertensive effects appear minimal for the polyphenols. Bioactive
compounds found in some plants are potent antioxidants that may affect initial steps in the development of
atherosclerosis through the prevention of LDL oxidation, blockage of LDL-C uptake by macrophages, and
prevention of foam cell formation. The antioxidant activity of polyphenols may occur through several mechanisms,
including scavenging of reactive oxygen/ nitrogen species, chelation of metals, inhibition of propagation reactions in
lipid peroxidation, and sparing of LDL-associated antioxidants (242).

There are several studies showing the antiplatelet effect of bioactive compounds both in vivo and in vitro. A
possible proposed mechanism is the preferential inhibition of COX-1 and COX-2, because of the balance of
prostaglandins synthesized by 2 isoforms of the COX enzyme regulates vascular homeostasis (243). Under certain
conditions, the inactivation of COX-1 by resveratrol as a bioactive compound is irreversible, and the platelets are
unable to synthesize new proteins, which implies that a fleeting exposure to resveratrol may have effects in vivo
(human platelet renewal time is 10 days) (244).

The vasodilation ability of bioactive compounds has been attributed to their ability to stimulate Ca2C and KC
channels, and to improve of nitric oxide (NO) signaling in endothelium. This last activity is due to the inhibition of
the activity of NADH/NADPH oxidase, allowing a reduction in the superoxide basal production, and consequently a
decrease in the inactivation of NO. In vivo, bioactive compounds increase the expression of endothelial nitric oxide
synthase (eNOS) and inducible nitric oxide synthase (iNOS). Therefore, bioactive compounds increase the NO
concentration through an increase of the expression of NOS and decreases inactivation by free radicals (243).

Bioactive or functional peptides are defined as amino acid sequences of inactive precursor protein inside
carrying out certain biological activities after its release by chemical or enzymatic hydrolysis. Usually, the released
peptides during the industrial food processing or during gastrointestinal digestion are small (3–20 amino acids). The
described main effects of the bioactive peptides on the cardiovascular system are those relating to their
antithrombotic and antihypertensive activities (245).

The most studied antihypertensive activity of bioactive peptides is the inhibition of the activity of ACE
(angiotensin-converting enzyme) (243).

Sterols are compounds associated with variable proportion of lipids, between 0.2% and 2%. Their basic
structure is the cyclopentanophenanthrene condensed 4-cycle system. Sterols are compounds that can be free or
esterified with fatty acids, mainly saturated fatty acids. There is a large amount of experimental evidence that
demonstrated that the plant sterols have an important hypocholesterolemic effect, reducing both the concentrations
of total cholesterol and LDL-C.
The most studied effect of plant sterols is their inhibition of intestinal absorption of cholesterol. Plant sterols
are more hydrophobic than cholesterol; thus, they can competitively reduce the absorption of micellar cholesterol. In
addition, the plant sterols can reduce the rate of cholesterol esterification in the enterocyte (affecting the activity of
acyl coenzyme A [CoA]:cholesterol acyltransferase), thus reducing the amount of cholesterol exported into the
blood in the chylomicrons formed. The inhibition of cholesterol absorption produces an increase in the synthesis of
LDL receptor, which increases the elimination of LDL and also the IDL from the circulation, and given that these
are the precursors of LDL-C, this decreases in addition its production without affecting triacylglyceride and HDL-C
concentrations. There are no conclusive data regarding the effect of plant sterols on the bile metabolism, although
some studies suggest that they produce an increase in the excretion of bile acids, whereas other studies suggest that
there is no effect (243,246).

Chronic inflammation is typical in vascular endothelial dysfunction, triggered by the activation of certain
factors such as nuclear factor (NF)-kB, which is functionally dependent on the cellular redox state. In this context,
tumor necrosis factor (TNF)-a activates NF-kB signaling transduction, which is considered to be involved in the
pathogenic of atherosclerosis (246,247). Thereby, functional foods also act as inhibitors NFkB and NF-kB–
dependent mediators.

Vasodilation is a process to increase blood flow through endothelial cells, which release vasodilators such as
prostacyclin and NO, which have great influence on vascular tone. Endothelium cells also release molecules that
inhibit NO function called vasoconstrictor molecules, such as endothelin-1 (ET-1) and angiotensin-2. The bioactive
compounds also have inhibitory action on vasodilators (246).

Conclusion
The bioactive compounds found in some plants produce positive effects that have been used in the medicinal
field as potent new drugs for the treatment of several diseases, including CVD. This review showed that this fact
remains true for the use of functional foods as potent drugs for the prevention of CVD due to inhibition of the
inflammatory process, prevention of endothelial dysfunction, and vasodilator production. Therefore, the major
proposed mechanisms of action of fruits/vegetable extracts or isolated components are antioxidant action (capturing
free radicals).

The mechanisms responsible for the beneficial effects of functional foods on the cardiovascular system are
multiple and remain somewhat unclear, although, in general, the available clinical and preclinical studies suggest a
positive correlation between their intake and a significant reduction in the cardiovascular risk factors. However, such
evidence is satisfactory to confer vegetables and fruits with an interesting functional food value in the context of the
spread of cardiovascular disease in Western countries and its high impact on the quality of life ofpatients. Indeed, to
date, cardiovascular drugs represent the most commonly used category in the world, and although there are large-
scale pharmacological treatments, cardiovascular diseases are the most widespread, consuming a high level of
therapeutic resources and affecting health significantly.
Furthermore, their prevalence is expected to rise, particularly in Western countries, because of obesity and
the aging population. A functional food approach, such as with vegetables and fruits, aimed at preventing and curing
several aspects of cardiovascular diseases, could be very useful.