Asgary 2018

Journal of the American College of Nutrition
ISSN: 0731-5724 (Print) 1541-1087 (Online) Journal homepage: http://www.tandfonline.com/loi/uacn20
Functional Food and Cardiovascular Disease

Prevention and Treatment: A Review
Sedigheh Asgary, Ali Rastqar & Mahtab Keshvari
To cite this article: Sedigheh Asgary, Ali Rastqar & Mahtab Keshvari (2018): Functional Food and
Cardiovascular Disease Prevention and Treatment: A Review, Journal of the American College of
Nutrition, DOI: 10.1080/07315724.2017.1410867
To link to this article: https://doi.org/10.1080/07315724.2017.1410867
Published online: 12 Mar 2018.
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JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
https://doi.org/10.1080/07315724.2017.1410867
Functional Food and Cardiovascular Disease Prevention and Treatment: A Review

Sedigheh Asgarya, Ali Rastqarb,c, and Mahtab Keshvaria
a
Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; bDepartment of
Psychiatry and Neuroscience, Universite Laval, Quebec, Quebec, Canada; cResearch Center of University Affiliated Quebec Mental Health Institute,
Quebec, Quebec, Canada
ABSTRACT ARTICLE HISTORY

Cardiovascular disease (CVD) is now the leading cause of death globally and is a growing health concern. Received 10 October 2017
Lifestyle factors, including nutrition, play an important role in the etiology and treatment of CVD. Accepted 26 November 2017
Functional foods based on their basic nutritional functions can decrease the risk of many chronic diseases KEYWORDS
and have some physiological benefits. They contain physiologically active components either from plant Cardiovascular disease;
or animal sources, marketed with the claim of their ability to reduce heart disease risk, focusing primarily functional foods; nutrition
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
Chronic diseases will cause $17.3 trillion of cumulative
Cardiovascular disease (CVD) has been a major cause of death economic loss from 2011 to 2030 in field of health care
around the world (1). Although CVD mortality has decreased expenditures, diminished productivity, and lost capital in
in most high-income countries, trends are increasing in most worldwide (6). Due to these health and economic burdens,
low- and middle-income countries (2). CVD accounts for 46% diet-related illnesses are among the leading priorities of our
of total deaths in Europe (3) and creates high socioeconomic time.
burdens, costing up to $320 billion annually in the USA (4), “Let food be thy medicine and medicine be thy food.” This
and costs associated with CVD are substantial (5) and predicted quote, attributed to Hippocrates, reflects the age-old desire of
to increase (6). There is no exception for Asian countries: CVD people to heal or even prevent diseases with certain foods. The
ranks second in mortality causes in South Korea (7) and term “functional food,” coined in Japan and the USA in the
explains 25% for all-cause death in Japan (8). Many of these 1970s, refers to foodstuffs fortified with different probiotics or
deaths could be avoided by addressing modifiable behavioral microorganisms, natural or processed food that contains
risk factors, such as smoking, diet, and exercise (9). known biologically active compounds, and the specific health-
Although the cardiovascular risk factors (Table 1) have promoting benefits of which must be sufficiently scientifically
been widely investigated, dietary factors are also important substantiated (12). The food industry has started to market
in the incidence of CVD but have been less widespread products with a “functional food” label. Although the benefits
investigated (10). of some functional food constituents may be perceived to
The evidence linking nutrition in early life to health in enhance short-term well-being, the benefits are generally
adulthood now forms a cornerstone of health promotion and related to the long-term mitigation of certain diseases.
public health nutrition programs globally. A report recog- These products contain physiologically active components
nized and promoted the importance of fetal and early-life either from plant or animal sources and are able to reduce heart
nutrition and its relationship with lifelong health. This disease risk, focusing primarily on established risk factors, such
experiment reported compelling evidence of role of early-life as diabetes, hypertension, and blood lipid level. It is believed
nutrition in setting the risk of conditions such as coronary that functional foods exert their cardioprotective effects mainly
heart disease, type 2 diabetes, osteoporosis, asthma, lung dis- through antioxidant actions and blood lipid level–lowering
ease, and some types of cancer (11). effects (Table 2).
CONTACT Mahtab Keshvari Mahtabkeshvari87@yahoo.com Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of
Medical Sciences, Isfahan, Iran.
© 2018 American College of Nutrition
2 S. ASGARY ET AL.
Table 1. Cardiovascular risk factors. (17). This paper will review the effect of individual bioactive
Category Examples
dietary compounds on cardiovascular protection.
Vegetable and fruit fiber (with pectin), herbs and spices, nut,
Nonmodifiable risk factors Age legume, whole grains, chocolate, coffee and tea, fish oil, and soy
Male gender
Family history/genotype proteins have blood lipid level–lowering effects in humans,
Race through both inhibition of fat absorption and suppression of
Hypertension cholesterol synthesis (18). Kulkarni et al. have reported that the
Metabolic risk factors Hyperlipidemia
Diabetes mellitus higher intake of folate, antioxidant vitamins, whole grains, and
Metabolic syndrome phytochemicals can abolish the deleterious vascular effects in
Obesity/overweight the heart (19). A significant cardiovascular benefit of phyto-
Diet
Lifestyle risk factors Smoking chemicals (flavonoids flavanols, anthocyanins), vitamins
Physical activity (ascorbate, tocopherol), and minerals (selenium, magnesium)
Elevated homocysteine level in foods (14,15) is thought to be the capability of scavenging
Novel risk factors Elevated lipoprotein (a) level
Small dense LDL-C free radicals produced during atherogenesis.
Elevated inflammatory markers levels
Elevated hemostatic factors levels
Metabolic syndrome Methods for review
HIV
Renal disease An extensive search was performed in PubMed, ScienceDirect,
Scopus, and Google Scholar to identify clinical studies on the
association between functional foods and cardiovascular dis-
Epidemiological studies have demonstrated the association ease published from inception up to September 26, 2017.
between cardiovascular health and certain dietary patterns Search terms were (“Functional foods ” OR “Phytoprotective”
(13–16). Research on the cardioprotective potential of dietary OR “Dietary factors” OR “Pomegranate” OR “Citrus” OR
components can help in the development of functional foods “Apples” OR “Tomato” OR “Watermelon” OR “Berries” OR
Table 2. Potential cardiovascular protective effects of functional foods (25).

Functional foods Bioactive compounds Potential mechanism
Nuts Tocopherols, omega-3 fatty acids Lowering blood cholesterol

Legumes Fiber and polyphenols
Fruits and vegetables Fiber (pectin)
Fish oil Omega-3 fatty acids Inhibition of LDL-C oxidation
Whole grains Fiber and phytochemicals
Soy proteins Genistein and daidzein
Dark chocolate Flavonoid
Herbs and spices Flavonoids and polyphenols
Fish Omega-3 fatty acids
Green leafy vegetables, fruits Carotenoids
Fruits and vegetables Vitamin C
Tomato Lycopene
Green tea Tea polyphenols
Soy proteins Genistein, daidzein, and glycitein
Pomegranate Polyphenols
Herbs and spices Flavonoids and polyphenols
Fish oil Omega-3 fatty acids Lowering blood triglycerides
Fish oil Omega-3 fatty acids Decreasing blood pressure
Legumes Fiber
Whole grains Fiber and phytochemicals
Citrus Ascorbic acid
Pomegranate Polyphenols
Green and black teas Tea polyphenols
Grapes Grape polyphenols
Tomatoes Lycopene Antioxidant action
Green leafy vegetables fruits Carotenoids
Soy proteins Genistein and daidzein
Green and black teas Tea polyphenols
Grapes Anthocyanins, catechins, cyanidins, flavonols, myricetin, and quercetin
Herbs and spices Flavonoids and polyphenols Endothelial function
Nuts Polyphenols
Grapes Anthocyanins, catechins, cyanidins, and flavonols, myricetin, and quercetin
Grapes Anthocyanins, catechins, cyanidins, and flavonols, Platelet aggregation
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION 3
“Grape” OR “Pumpkin” OR “Herbs” and “Spices” OR “Saffron” as flavonoids, condensed tannins (proanthocyanidins), and
OR “Nigella sativa” OR “Curcuma” OR “Cinnamon” OR “Nut” hydrolysable tannins (ellagitannins and gallotannins) (28).
OR “Legume” OR “Whole grains” OR” Chocolate” OR “Coffee Pomegranate consumption has been described to decrease blood
and tea” OR “Fish oil “OR “Soy Proteins”) AND (“Cardiovas- pressure and positively affect cardiovascular risk factors in sev-
cular disease”). The search was performed in titles and abstracts eral clinical studies (14,15,20,29,30), as outlined in Table 3.
and was restricted to articles published in English language. All In patients with carotid artery stenosis who consumed pome-
titles, abstracts, and full texts of potentially relevant studies granate juice (50 mL/day), the results indicated a significant
were assessed for eligibility. Papers were excluded if (1) data on reduction in systolic blood pressure (SBP), but not diastolic blood
exposure (Functional foods) or outcome (Cardiovascular dis- pressure )DBP(, starting from 1 month after starting supplemen-
ease) were not reported; (2) no data were reported on the rela- tation and generally decreasing up to month 12 (equivalent to
tionship between exposure and outcome; (3) if the effect of 12% decrement). However, no further decline was observed
fruit or derived preparations, e.g., juice, extract, vinegar, etc., when supplementation was continued for another 2 years (31).
could not be identified (e.g., weight loss studies that focused on After 1 year’s consumption of pomegranate juice, there was
flavonoids, anthocyanidins, or fruits and vegetables); and (4) a 30% decline in carotid intima-media thickness and the
nonoriginal studies. 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
Vegetable and fruit
90% and 95%, respectively (31).
There is a substantial amount of evidence that nutrients con- Pomegranate juice is an affluent source of polyphenols with
tained in vegetables and fruits have beneficial effects on CVD high antioxidative potential. Moreover, its antiatherogenic,
risk (16,20). As nutritional imbalance is a risk factor for CVD, antihypertensive, and anti-inflammatory effects have been
the American Heart Association (AHA) encourages adequate shown in human studies (15,20). Pomegranate can induce its
intake of fruits and vegetables (21). In return, inadequate con- beneficial effects through its various metabolites. The antioxi-
sumption of vegetables and fruits has been associated with dant and antiatherosclerotic potentials of pomegranate are
higher rate of CVD (22). The benefits of vegetable and fruit mainly relevant to the high polyphenol concentrations in
intake appear to be dose related. In addition, rate of vegetable pomegranate fruit, such as ellagitannins and hydrolysable tan-
and fruit intake has been associated with lower CVD risk (23). nins. Cyclooxygenase 1 (COX-1) and COX-2 enzymes and
The mechanisms of protective effects by which vegetables interleukin 1b (IL-1b) activity can be inhibited by pomegranate
and fruits exert their effects are not completely clear. But there fruit extract (32).
is some evidence on anti-inflammatory and antioxidant effects It is suggested that pomegranate can antagonize the stimula-
of bioactive nutrient. Among the possible explanations for tion of mRNA of matrix metalloproteinase 9 (MMP-9) in a
these beneficial effects, reduction susceptibility of low-density human monocytic cell line (THP-1) monocytes. The whole
lipoprotein cholesterol (LDL-C) particles to oxidation has been fruit and compounds inhibit tumor necrosis factor (TNF)-
found (24). Several bioactive components in vegetables and induced metalloproteinase (MMP-9) promoter activity. Uroli-
fruits such as magnesium, fiber, vitamin C, carotenoids, and thins are metabolites that are metabolized by the human intes-
potassium act synergistically or antagonistically to promote a tinal microflora. These compounds decreased MMP-9
holistic beneficial effect. Potassium also has a protective role in secretion and mRNA levels induced by TNF. It is suggested
the incidence of CVD because it has an inverse association that ellagitannins are responsible for the control of excessive
between dietary intake of vegetables and fruits and blood pres- production of MMP-9, which could result in decreased produc-
sure (25). The totality of evidence supports current dietary tion of the noxious cytokine TNF. TNF cytokines promote
guidelines to increase vegetable and fruit consumption to at nuclear factor kappa B (NF-kB) binding to target sequences
least b-glucan from oats and barley, fiber from flaxseed and while inducing transcription of several genes such as the MMP-
psyllium, and soluble fiber including pectins from apples and 9 gene. Ellagitannins prevent NF-kB promoter activity by
citrus fruits are known to lower LDL-C (26). blocking NF-kB–driven transcription and affecting the entire
cytokine cascade. Ellagitannins inhibit the activation of inflam-
matory pathways such as mitogen-activated protein kinases
Pomegranate
(MAPKs) (32). Pomegranate can induce its beneficial effects
The pomegranate (Punica granatum L., family Punicaceae) is through the influence of its various bioavailable constituents
used in several systems of medicine for a variety of ailments. In and metabolites on gene expression. Although many in vitro,
Ayurvedic medicine, the pomegranate is considered as “a phar- animal, and clinical trials have been carried out to examine and
macy unto itself” and it is able to improve the arterial tone, to prove the therapeutic effects of these compounds, further
treat aphthae, diarrhea, and ulcers, and also it has antimicrobial human trials and studies are necessary to understand the thera-
effects (2,10). The fruit can be divided into 3 parts: the seeds peutic potentials of pomegranate (32).
(3%) and the juice (30%) representing about a third of the fruit
weight, and the peels characterized by membrane internal net-
Citrus
works (27), which contain different chemical components that
have demonstrated beneficial cardiovascular effects; therefore, The genus Citrus L. of the family Rutaceae includes several
this fruit has emerged as an alternative medical management. important fruits such as oranges, mandarins, limes, lemons,
Pomegranate includes several kinds of phytochemicals, such sour orange, and grapefruits (33).
4
Table 3. Epidemiological evidence, clinical trials, or meta-analyses of beneficial effects of functional foods and cardiovascular disease.
Functional foods Type and duration of study Number of subjects enrolled Dietary intervention Outcomes Reference
Pomegranate Randomized Hypertensive patients 10 Pomegranate juice consumption (50 mL, 1.5 mmol of Decrease SBP, reduction in serum ACE activity (14)
total polyphenols per day, for 2 weeks)
Randomized, double-blind, parallel trial 290 men and women at moderate risk for 240 mL/day of pomegranate juice for 18 months Reduce HDL, cholesterol, TG/HDL-C, TC/HDL-C, and apolipoprotein (15)
coronary heart disease B100
Randomized, placebo-controlled 20 hypertensive subjects 150 mL/day of pomegranate juice for 2 weeks Improve endothelial function by decreasing serum concentrations (20, 248)
S. ASGARY ET AL.
of VCAM-1
Randomized 22 diabetic type 2 patients with 40 g pomegranate juice, 8 weeks Reduce LDL-C/HDL-C ratio, TC/HDL-C ratio, LDL-C, and TC (30)
hyperlipidemia
Randomized, placebo-controlled parallel 51 healthy adults 330 mL/day pomegranate juice ,4 weeks Decrease SBP and DBP (249)
trial
Randomized, controlled, crossover 19 young, healthy men 237 mL of pomegranate extract, 15 minutes before a Prevent postprandial SBP (250)
high-fat meal
Randomized, placebo-controlled, double- 45 patients with coronary heart disease 240 mL/day pomegranate juice for 3 months Stress-induced ischemia decreased (251)
blind
Citrus Randomized, placebo-controlled 22 healthy volunteers 500 mL commercial and fresh orange juice, 4 weeks Consumption of both juices decreased VCAM, hs-CRP, and E- (40, 41)
selectin but increased Apo A-1. SBP and DBP were significantly
decreased
Cohort study 20,024 participants Citrus fruits/juice Reduction in risk of ischemic stroke (252)
Randomized controlled trial 74 overweight adults Grapefruit, for 6 weeks Decrease in TC, LDL (253)
Placebo-controlled, randomized, double- 80 osteoarthritis patients Citrus extracts capsules (370 mg each) twice daily Reductions in TG and LDL, increase in HDL (254)
blind
Randomized, placebo-controlled, single- 19 nondiabetic subjects 500 mL red orange juice per day Improved endothelial function, decreased hs-CRP, IL-6, and TNF-a (255)
blind, crossover
Randomized, controlled, double-masked, 49 healthy, male volunteers Whole orange: 452.8 mg Impairments in FMD (256)
crossover
Apples Randomized, double-blind, placebo- 71 subjects with a body mass index 600 mg apple polyphenol extract, 12 weeks Decrease of serum TC and LDL-C (257)
controlled
Randomized, double-blind, placebo- 28 subjects with normal cholesterol level, 375 mL apple juice or 340 g complete apple No significant difference was observed in serum levels of TC, LDL- (258)
controlled for 6 weeks C, HDL-C, and Apo B and insignificant increase was observed in
fasting TG level
Randomized, placebo-controlled 49 hypercholesterolemic women 300 g apple for 12 weeks Increased TG and decreased TC (259)
Randomized, placebo-controlled 110 hypercholesterolemic subjects 720 mL apple juice for 6–12 weeks TC and TG increased (54)
Crossover trial 25 healthy men and women 375 mL commercial apple juice or 340-g-cored fresh Did not affect fasting lipid measurements, but apple juice was (260)
apple each day for 6 weeks associated with a significant increase in lag time of copper-
induced LDL oxidation and a slight reduction in conjugated
diene production
Lycopene Randomized controlled trial 72 cardiovascular disease and healthy 7 mg lycopene for 2 months Blood pressure, arterial stiffness, and lipid and hs-CRP levels were (261)
volunteers unchanged. Lower LDL improved endothelial function
Single-blind, placebo-controlled trial Forty patients with grade 1 hypertension 250 mg Decrease SBP and DBP, No changes lipid parameters (262)
Lyc-O-Mato, for 4 weeks
Randomized (exposure sequence), single- 19 healthy subjects 70 g tomato paste containing 33.3 mg of lycopene Increase in FMD, decrease total oxidative status (263)
blind (operator), crossover design
Randomized, crossover, controlled 40 healthy subjects 7.0 g of raw tomatoes—3.5 g of tomato sauce, 3.5 g of Decreased TC, TG and several cellular and plasma inflammatory (264)
tomato sauce with refined olive biomarkers, and increased plasma HDL and IL-10
oil/kg of body weight, for 6 h concentrations
Berries Clinical trial 23 healthy volunteers 500 g of strawberries for 1 month. Decrease activated platelets, improves plasma lipid profile, (79)
biomarkers of antioxidant status, antihemolytic defenses, and
platelet function
Randomized dose-response 60 volunteers with abdominal adiposity and 25–50 g freeze-dried strawberries for 12 weeks Lowering serum TCL and LDL (265)
controlled trial elevated serum lipids
Randomized double-blind placebo- 105 hyperlipidemic patients 350 mg of Vaccinium arctostaphylos fruit capsule every Reduced TC, TG, and LDL-C but increased HDL-C (266)
controlled clinical trial 8 hours for 2 months
Grapes Randomized trial 87 patients undergoing elective and isolated 100 mg grape seed extract, every 6 hours, orally Antioxidative effects and reduced deleterious effects of (267)
coronary bypass surgery cardiopulmonary bypass during coronary artery bypass grafting
surgery
Randomized, double-blind, 2-arm, parallel, 36 subjects with prehypertension 300 mg/day grape seed extract (150 mg) twice daily Improve BP, supporting the use of grape seed extract as a (268)
placebo-controlled trial, 12-week, in for 6 weeks functional ingredient in a low-energy beverage for BP control
middle-aged adults
Randomized, double-blind, placebo- 134 healthy individuals, 500 mL/day polyphenol-rich juice based on red grapes, Reduced SBP (269)
controlled trial cherries, chokeberries, and bilberries of 12 weeks
Randomized trial 69 patients with hypercholesterolemia 500 g whole fruit of red grapes of either Condori red Increased total antioxidant capacity, decreased TC and LDL-C, no (270)
grapes or Shahroodi white grapes daily, for 8 weeks change in blood glucose, TG, or HDL-C
Double-blind, placebo-controlled, 50 subjects with prehypertension and mild 400 mg red grape cell powder, for 12 weeks Improvement of FMD, decrease in lipid peroxidation, decreased (89)
randomized study hypertension diastolic BP
Randomized, double-blind, placebo- 91 women menopause status, Grape seed extract tablets containing either low-dose Improving the physical and psychological symptoms of menopause (271)
controlled pilot study (100 mg/day) or high-dose (200 mg/day) while increasing muscle mass and reducing blood pressure in
proanthocyanidin, for 8 weeks middle-aged women
Pumpkin Clinical trials 35 postmenopausal women Pumpkin seed oil Increase HDL, decrease DBP (272)
Saffron Randomized, placebo-controlled clinical 105 subjects with metabolic syndrome 100 mg/day saffron, for 12 weeks The efficacy of saffron in the improvement of some markers of (273)
trial autoimmunity HSPs in patients with metabolic syndrome
Clinical trials 20 human subjects 50 mg of saffron dissolved in 100 mL of milk was The significant fall in LOS indicates the potential of saffron as an (274)
administered twice a day antioxidant
Garlic Randomized, double-blind, placebo- 19 patients taking statin therapy AGE/placebo, AGE: 4 mL, 1 year CAC progression: 7.5% reduction (275)
controlled
Randomized, double-blind, placebo- 79 patients with uncontrollable AGE/placebo, AGE: 240/480/960 mg b.i.d., 12 weeks Antihypertensive: 11.8 mm Hg SBP decrease (276)
controlled hypertension
Randomized, double-blind, crossover 34 normal healthy adults AGE/placebo, AGE: 2.4–7.2 g/day t.i.d., 44 weeks Antiplatelet aggregation and adhesion (277)
Randomized 65 Asymptomatic patients with CAC >30% AGE C vitamin B12 C folic acid C vitamin B6 C L- CAC progression: 65% reduction (278)
arginine/placebo, AGE: 250 mg, 1 year
Randomized, double-blind, placebo- 65 Intermediate CAD risk patients with CAC AGE C vitamin B12 C folic acid C vitamin B6 C L- CAC progression: 29% reduction, LDL-C (125)
controlled >30% arginine/placebo, AGE: 250 mg, 1 year
Randomized, double-blind, placebo- 65 intermediate CVD risk firefighters AGE C Co Q10/placebo, AGE: 1200 mg, 1 year CAC progression: 3.99% reduction antiinflammatory; 7.67% (279)
controlled decreased CRP
Randomized, double-blind, placebo- 65 asymptomatic firefighters with CAC AGE C Co Q10/placebo, AGE: 300 mg, 1 year Improved vascular reactivity: 1.2 m/s decreased PWV anti- (280)
controlled >20% inflammatory; 1.31 g/L decreased CRP
Randomized, double-blind, placebo- Weeks Weeks Antihypertensive: 10.2 mm Hg SBP decrease (276)
controlled
Randomized, single-blind, placebo- 150 hyperlipidemic patients Garlic powder tablets/anethum/placebo enteric-coated TC: 12.1% reduction; LDL-C: (123)
controlled garlic powered tablets: 400 mg garlic C 1 mg allicin 17.3% reduction
b.i.d., 6 weeks
Randomized, double-blind, placebo- 84 newly diagnosed mildly to moderately TR garlic tablets, low-dose/TR garlic tablets, high-dose/ Antihypertensive Allicor: 7 mm Hg SBP decrease and 3.8 mm Hg (281)
controlled hypertensive patients garlic tablets/placebo TR garlic tablets (Allicor): 600 DBP decrease; Kwai: 7 mm Hg SBP decrease
or 2400 mg b.i.d.; Kwai: 900 mg daily, 8 weeks
Randomized, double-blind, placebo- 51 CAD patients TR garlic tablets/placebo TR garlic tablets: 150 mg/d b.i. LDL-C reduction: males, 32.9 mg/dL females, 27.3 mg/dL (124)
controlled d., 12 weeks
Nigella sativa Randomized controlled clinical trial 90 obese women 3 g per day Nigella sativa oil, for 8 weeks Decline triglycerides and VLDL. NS oil concurrent with a low-calorie (282)
diet can reduce cardiometabolic risk factors in obese women
Randomized, double-blind, placebo- 158 dyslipidemia patients 500 mg black seed and garlic, for 8 weeks Reduction in non-HDL, triglycerides, LDL, and TC (283)
controlled,
Randomized, double-blind, placebo- 70 healthy volunteers 2.5–5 mL N. sativa oil 2 times a day, for 8 weeks Lowers SBP and DBP without any adverse effects (284)
controlled clinical trial
Randomized, double-blind, placebo- 119 hypertensive patients 100 and 200 mg of Nigella sativa extract twice a day, Reduced both SBP and DBP (136)
controlled trial for 8 weeks
Curcuma Randomized, Placebo-controlled, double- 40 nonalcoholic fatty liver disease 500 mg/ day curcumin, for 8 weeks Reduction in liver fat content, body mass index, and serum levels (285)
blind of TC, LDL, TG, aspartate aminotransferase, alanine
aminotransferase, glucose, and glycated hemoglobin
compared with the placebo group
Randomized double-blind placebo- 117 subjects with with metabolic syndrome 1g curcumin, for 8 weeks Improved serum SOD activities and reduced MDA and CRP (286)
controlled trial, concentrations
Randomized controlled trial 50 metabolic syndrome Curcuminoids (C3 complex 1000 mg/day; n D 50) or Reducing serum LDL-C, non-HDL-C, TC, TG, and Lp(a) and elevating (287)
placebo for 8 weeks HDL-C concentrations
(Continued on next page)

5
6
Table 3. (Continued )
Functional foods Type and duration of study Number of subjects enrolled Dietary intervention Outcomes Reference
Cinnamon Single-blind, randomized crossover study 9 healthy, young subjects 3 g cinnamon or placebo 3 g cinnamon did not alter the postprandial response to a high-fat (288)
test meal. No evidence was found to support the use of 3 g
cinnamon supplementation for the prevention or treatment of
metabolic disease
Randomized 59 with type 2 diabetes 1200 mg/day cinnamon or matched placebo, for 12 Change-from-baseline SBP was a function of regression to the (289)
S. ASGARY ET AL.
weeks mean rather than a treatment-associated change

Beetroot Double-blind, randomized crossover study 30 patients (left ventricular ejection fraction 70 mL beetroot juice for 9 days Low- and high-intensity constant-load cardiopulmonary exercise (290)
40%) tests were performed with noninvasive measurements of
central hemodynamics (stroke volume, heart rate, and cardiac
output via impedance cardiography), arterial blood pressure,
pulmonary oxygen uptake, quadriceps muscle oxygenation
(near-infrared spectroscopy), and blood lactate concentration
Randomized, double-blind, placebo- 69 patients with hypercholesterolemia 250 mL beetroot juice, for 6 weeks Improves vascular function in hypercholesterolemic patients, (291)
controlled parallel study increase in the FMD, improvement in the aortic pulse wave
velocity, reduction in platelet-monocyte aggregates, reductions
in stimulated (ex vivo) P-selectin expression
Double-blind, placebo-controlled, 9 patients with heart failure 11.2 mmol, beetroot juice, 2 hours later Increases in peak knee extensor power, well tolerated and (292)
randomized crossover enhanced NO bioavailability and muscle power in patients with
systolic heart failure
Controlled, randomized crossover 24 hypertensive subjects 250 mL of raw beet juice and 250 g cooked beet FMD, increased, but SBP and DBP, ICAM-1, VCAM-1, hs-CRP, (293)
interleukin-6, E-selectin, and TNF-a, decreased
Randomized, placebo-controlled, double- 27 hypertensive 70 mL nitrate-rich beetroot juice, for 1 week Increase in plasma nitrite and nitrate, However, no differences in (294)
blind crossover trial home blood pressure and 24-hour ambulatory blood pressure
were observed with 1-week intake of nitrate-rich beetroot juice
in comparison with the placebo
Nuts Randomized crossover 72 participants 30 g/day of either raw or dry roasted, lightly salted Consumption of dry form decreases LDL, TG; consuming both (295)
hazelnuts for 28 days forms of hazelnuts significantly improved HDL-C and Apo A1,
TC/HDL-C ratio, and SBP
Clinical trial 30 hypertensive women Nuts (1350 g walnuts, 675 g hazelnuts, and 675 g Changes in eNOS, caveolin 2 and endothelin-1 receptor gene (296)
almonds), for 3 months expression
Randomized, crossover, controlled 30 type 2 diabetes Pistachios for 4 weeks Decrees TC, TC/HDL, LDL, TG (297)
Randomized, controlled, crossover, 15 healthy overweight or obese men A peanut meal containing 3 ounces (85 g) ground Decreased FMD, LDL, TG (298)
postprandial peanuts (1198 kcal; 40.0% carbohydrate, 47.7% fat,
19.4% saturated fat, 13.2% protein)
Randomized crossover trial, double-blind, 91 hypertensive and dyslipidemic subjects 13 g Brazil nut, for 12 weeks Increased plasma selenium, plasma glutathione peroxidase, (299)
placebo-controlled reduced oxidized-LDL levels
Legumes Randomized, controlled crossover trial 64 middle-aged men who had undergone Egumeen-riched (1.5 servings/1000 kcal) for 4 weeks Decreases TC, LDL, TC/HDL-C, and LDL-C/HDL-C (300)
colonoscopies
Randomized crossover clinical trial 26 first-degree relatives of patients with (50.73 § 7.10 g/day) legumes during habitual diet, No significant effect on anthropometric measurements, glycemic (301)
diabetes for 6 weeks indices, and lipid profiles
Whole grains Double-blind, randomized, controlled 40 overweight or obese Whole grains or refined grains (50 g/1000 kcal in each Decreases in DBP after the whole-grain diet, reductions in body (302)
crossover trial diet), for 8 weeks weight, fat loss, systolic blood pressure, total cholesterol, and
LDL-C were observed during both diet periods
Prospective study 182 women postmenopausal women with Mean whole-grain intake was 9.6 (SE 0.6) servings per Plasma alkylresorcinol concentrations were significantly correlated (303)
coronary artery disease week with dietary whole grains
Randomized clinical trial 61 metabolic syndrome 12-week diet based on whole-grain products decreased postprandial insulin and TG (304)
A randomized crossover intervention 46 overweight women 58 g/day whole-grain barley kernels, for 4 weeks Decreased TC/LDL, TC/HDL, DBP, Apo B (305)
Chocolate Randomized control trial 92 hypertensive 50 g of dark chocolate, for 8 weeks Significantly larger increase in vitamin C, carotenoids, and (306)
epicatechin
Clinical study 22 mild hypertensive 49 g/day of dark chocolate, for 8 weeks No significant effect on blood pressure or other cardiovascular risk (307)
factors during a reduced snack period.
Open-label, randomized, controlled trial 79 patients with hypertension 30 g/day of dark chocolate, dehydrated red apple and Finally, C-reactive protein plasma levels were reduced significantly (308)
green tea, for 6 months in all groups independently of the applied treatment. It was
concluded that the addition of flavonoids to pharmacological
antihypertensive therapy shows additional benefits on BP, lipid
profile, leptin, obesity, and inflammation
Blinded, randomized, controlled crossover 21 patients with symptomatic (Fontaine 50 g dark chocolate or 50 g white chocolate, for 7 days No effect on endothelial and microvascular function in patients (309)
trial; tests were done in each patient stage II) peripheral artery disease with symptomatic PAD
on 2 single days, with an interval of 7
days
Randomized, placebo-controlled crossover 30 overweight adults 37 g/day of dark chocolate, for 4 weeks The high-flavanol cocoa and dark chocolate treatment was (310)
study associated with enhanced vasodilation in both conduit and
resistance arteries and was accompanied by significant
reductions in arterial stiffness in women
Double-blind, randomized, placebo- 20 patients with heart failure 40 g a chocolate bar, for 4 weeks Flavanol-rich chocolate acutely improves vascular function in (311)
controlled trial patients with heart failure
Randomized, open-label, blinded 102 patients with prehypertension/stage 1 6 or 25 g/day of flavanol-rich dark chocolate, for 3 Reduction blood pressure (BP) (312)
hypertension months
Coffee and tea Cohort Study 33,638 healthy women free of cardiovascular Caffeine intakes across increasing quintiles of caffeine Elevated caffeine consumption was not associated with an (313)
disease and atrial fibrillation at baseline intake were 22, 135, 285, 402, and 656 mg/day, increased risk of incident AF
respectively
Double-blind, randomized placebo, and 20 healthy young 300 mg caffeine Increased SBP and DBP, but did not alter heart rate (314)
active drug study
Randomized, double-blind 75 healthy men Black tea for 6 weeks Reduces platelet activation and plasma C-reactive protein in (315)
healthy men
Randomized controlled intervention 171 healthy nonsmokers Caffeine, given as tablets or as strong coffee Both tea and coffee were potentially beneficial in decreasing (316)
postprandial falls in SBP, but coffee drinking may increase
fasting DBP in untreated hypertensives
Clinical trial 10 healthy, male coffee or tea drinkers Dose of caffeine (125 mg) on 2 separate days after Cardiovascular effects of caffeine may persist throughout the day (317)
overnight abstinence, for 2 hours with repeated administration of moderate amounts of caffeine
Fish oil Randomized, double-blind, placebo- 48 coronary artery disease Omega-3 fatty acid supplement (720 mg Increased serum irisin, decreased serum hs-CRP and LDL-C, not (318)
controlled trial eicosapentaenoic acid plus 480 mg result in any significant changes in anthropometric
docosahexaenoic acid) for 8 weeks measurements, blood pressure, serum lipids except for serum
LDL, fasting blood glucose, body composition, or serum insulin
level
Randomized controlled trial 103 mother-infant pairs Maternal fish oil intake (1.5 g/day n-3 LCPUFA), 13 years Decrease DBP (319)
Randomized, double-blind, placebo- 145 patients with psoriatic arthritis 3 g of marine n-3 polyunsaturated fatty acids, for Increase in RR intervals and decrease in heart rate, blood pressure, (320)
controlled trial 24 weeks and PWV. Central blood pressure did not change
Soy proteins Dose-response randomized controlled trial 20 moderately elevated blood pressure, 6 50 g/day soy protein Reduced brachial DBP, did not improve ex vivo cholesterol efflux, (321)
weeks macrovascular function, or other blood markers of CVD risk
Open-label, controlled, crossover clinical 147 peri- and postmenopausal women 500 mL per day soy drink for 12 weeks Reduced climacteric symptoms, improved health-related quality (322)
trial life
Randomized, double-blind controlled trial 242 hypercholesterolemic adults 25 g soy protein for 6 weeks Reduced LDL, no significant treatment effects on total or HDL-C, (323)
TG, CRP, homeostatic model assessment of insulin resistance,
blood pressure, or the Framingham 10-year CHD risk score
Randomized, placebo-controlled, double- 102 participants on novel CVD risk factors 40 g of soybean protein supplement, 8 weeks Reduce E-selectin and no changes in ICAM-1, VCAM-1, (324)
blind, 3-phase crossover trial thrombomodulin, and adipocytokines (high-molecular-weight
adiponectin, leptin, resistin)
Note. SBP D systolic blood pressure; DBP D diastolic blood pressure; HDL-C D high-density lipoprotein cholesterol; VLDL D very-low-density lipoprotein; LDL-C D low-density lipoprotein cholesterol; ICAM-1 D intracellular adhesion
molecule 1; VCAM-1 D vascular cell adhesion molecule 1; TG D triglycerides; TC D total cholesterol; hs-CRP D high-sensitivity C-reactive protein; Apo A D apolipoprotein-A; ACE D angiotensin-converting enzyme; FMD D flow-
mediated dilation; IL-6 D interleukine-6; TNF D tumor necrosis factor; AGE D aged garlic extract; b.id. D twice daily; CAC D coronary artery calcification; CAD, coronary artery disease; Co Q10 D coenzyme Q10; Lp(a) D lipoprotein
(a).
7
8 S. ASGARY ET AL.
The health benefits of citrus fruit have mainly been attrib- flavonoids, and dietary fiber (47). Most apple flavonoids,
uted to the presence of bioactive compounds, such as phenolics namely, quercetin and epicatechin, are found in the skin of
(e.g., flavanone glycosides, hydroxycinnamic acids) (34), vita- apples (48).
min C (35), and carotenoids (36); naringin, naringenin, nobeli- Apples contain nutritionally important phytochemicals,
tin, narirutin, and hesperidin are the most important although the amount and type vary greatly, depending on
flavonoids thus far isolated from citrus fruits (37). which part of the apple is consumed. In general, the apple peel
Epidemiological evidence and clinical and preclinical studies is abundant in phytochemicals, whereas apple flesh is not, and
suggest that flavanones present in the Citrus genus positively unripe apples are richer in polyphenols than ripe apples.
influence cardiometabolic parameters, preventing cardiovascu- Extracting apples for their juice causes a substantial loss of
lar disease (38,39). Consumption of citrus fruits or their juice polyphenols.
has been associated with a reduction in cardiovascular events, Apple flavonoids may have beneficial effects on blood pres-
suggesting that intake of flavonoids found specifically in citrus sure, vascular function, and blood lipid levels, but the quantity
fruits may be cardioprotective (40,41). For example, drinking 1 administered is the key to determining the level of the effects
glass of grapefruit juice per day has been demonstrated to lower (49–51). This quantity is, in turn, highly dependent on the vari-
the risk of stroke in men by 25% (42), and intake of grapefruit ety of apple, the part of the apple (skin or flesh), and the food
was associated with a significant reduction in mortality due to matrix, that is, how the apple is consumed (aqueous, lyophi-
coronary heart disease (16). A meta-analysis of 3 randomized lized, juice, or extract). It appears that apple polyphenol
clinical trials, including 233 patients, demonstrated a correla- extracts give the best effects, followed by consumption of whole
tion between grapefruit intake and a reduction in blood pres- apple with skins. It has been shown that a minimum period of
sure. Although grapefruit intake does not significantly reduce 4 weeks of consumption is necessary for the appearance of
body weight, it was responsible for a small, but significant, observable effects (52).
reduction in the systolic blood pressure and waist circumfer- More specifically, positive effects of apples may come from
ence in overweight and obese adults. The authors speculated their potential to lowering cholesterol: plasma and liver choles-
that such beneficial effects can be related to naringin, which is terol levels drop significantly after eating lyophilized apples
in considering great among meta in grapefruit (43). In larger (53). Moreover, cholesterol excretion increases in the feces of
studies, intake of citrus fruits (6–7 times/week) in Japanese sub- rats that were fed apples, suggesting that the dietary fiber and/
jects (10,623 participants: 4147 men and 6476 women) was or polyphenols that exist in apples may reduce dietary choles-
inversely associated with CVD events, particularly ischemic terol absorption (53).
stroke (22). Similarly, after 14 years of follow-up in the Nurses’ Intake of apple (300 g golden apple per day for 8 weeks)
Health Study (69,622 women), high flavanone intake through a in hyperlipidemic and overweight men was inversely associ-
combination of consumption of orange and grapefruit juices ated with CVD events, particularly ischemic stroke. In this
and fruits was associated with a 19% lower risk of ischemic study, the golden apple increased the serum levels of very-
stroke (22). Moreover, Wang and colleagues published a sys- low-density lipoprotein (VLDL) and triglycerides (TG) but
tematic review and meta-analysis of prospective cohort studies, had no effect on total cholesterol (TC), LDL-C, high-density
which demonstrated that flavonoid consumption, especially of lipoprotein cholesterol (HDL-C), LDL/HDL ratio, lipopro-
flavanones, was associated with a decreased risk of cardiovascu- tein A, and apoprotein B (ApoB); these effects can be due
lar disease (44). to the increase of fructose intake, the low value of polyphe-
Epidemiological evidence and clinical studies demonstrate nol in this type of apple and thereby the diminishing of
that citrus fruits significantly reduce the incidence of cardiovas- fiber and polyphenol synergy, the low number of subjects,
cular disease risk, and preclinical investigations highlight cellu- and insufficient duration of the study (53).
lar and subcellular targets that are responsible for these In a study of hypercholesterolemic subjects consuming apple
beneficial effects (45). There has been special attention on eval- juice together with gum Arabic and pectin (by a ratio of 4:1),
uating intracellular pathways involved in direct cardiovascular the mean serum levels of TC and TG increased by 3.5% and
and cardiometabolic effects mediated by naringenin, hespere- 28.5%, respectively, during the 12 weeks, whereas HDL-C and
tin, and eriodictyol or their glycosylated derivatives. Although LDL-C levels showed no significant difference. During the
some mechanisms of action remain unclear and bioavailability washout period, TC mean level had a significant increase of
problems should to be solved, the current evidence supports 2.4%. Finally, the hypothesis of serum cholesterol reduction by
the use of a functional food approach with citrus fruits to pre- apple juice consumption was rejected in this study (54).
vent and cure several aspects of cardiovascular disease (45), as Therefore, daily intake of apple with low polyphenol can-
outlined in Table 3. not 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
Apples
been selected from the general population. The polyphenol
Apples (Malus pumila, family Rosaceae) are one of the most levels present in golden apple, red apple, and Granny Smith
commonly consumed fruits in the human diet, contributing a apple were calculated to be 485, 620 and 835 mL/kg fresh
large percentage of phenolic consumption in the USA and are apple fruit weight, respectively, and the polyphenol received
the third highest contributor of dietary flavonoids in the Neth- daily by the intervention group from a 300-g golden apple
erlands (46) Apples are among the most frequently consumed was less than from red apple and Granny Smith apple by
fruits and a rich source of phytochemicals such as polyphenols, 1.3 and 1.7 times, respectively (55).
Apple juice (300 mL) extracted from Golden Delicious or nitric oxide level in coronary arteries (62), inhibition of the
Catarina apples in Brazil was consumed by 9 healthy, normal mevalonate pathway of cholesterol biosynthesis (63), improve-
weight women, aged 21–27 years (56). Antioxidant capacity, ment of endothelial function, and attenuation of inflammatory
based on ferric-reducing antioxidant power (FRAP) and oxida- damage (64), as well as improvements in lipoprotein profiles
tion of 2,29-azino-bis(3-ethylbenthiazoline-6-sulfonic acid), and their turnover (62) in different animal models of CVD.
was significantly increased within 1 hour of consuming each These changes may represent a molecular basis for lycopene
juice, ranging from 4.2% to 10.6% over baseline and compared action in CVD.
with water. Nonspecific biomarkers of lipid peroxidation in Watermelon (Citrullus lanatus, family Cucurbitaceae) is a
serum, such as hydroperoxides, were reduced comparably by potential source of lycopene. Lycopene contents of red-fleshed
both juices and were inversely correlated with serum antioxi- watermelon are almost 40% higher than in tomato, i.e., 4.81
dant capacity. Interestingly, however, serum uric acid and vita- and 3.03 mg/100 g, respectively (65). The distinctive aroma of
min C each increased by 11%, but only the former was watermelon is imparted by medium- and short-chain fatty
correlated with serum antioxidant capacity and inversely asso- acids along with geranial, b-ionone, and neral. Its consumption
ciated with lipid peroxidation (56). Twenty-six elderly men and has been escalated owing to rich nutritional profile and allied
women (>60 years) were randomly assigned to drink health benefits. It is effective in reducing the extent of cardio-
250 mL/day of either freshly prepared pomegranate juice or vascular disorders (66).
commercial apple juice. After 4 weeks, plasma concentrations The watermelon is also helpful to lessen some other meta-
of malondialdehyde were decreased in both groups, and only bolic syndromes owing to vitamin A, B6, C, magnesium, and
pomegranate juice increased FRAP and reduced carbonyl con- potassium. These along with lycopene are health-promoting
tent in plasma compared with baseline (57). functional ingredients are associated with reduced risk of car-
The large volume of apple juice and the 10–15 minute intake diovascular disorders. Heart attacks, ischemic strokes, and ath-
period may limit the generalization of these findings; such erosclerosis are faced through the oxidation of low-density
reports underscore the importance of determining which bioac- lipoproteins and their curing has been observed though high
tive components mediate antioxidant effects, particularly in the consumption of lycopene (67). Consumption of watermelon is
absence of a rise in presumed antioxidants (phenolic com- more advantageous because watermelon’s lycopene is readily
pounds) in plasma or serum in these subjects. Measures of the and rapidly available (68,69).
rate and lag time of copper-induced LDL-C oxidation are used A comprehensive meta-analysis suggests that high intake or
as surrogate markers of antioxidant capacity in plasma, sug- high serum concentration of lycopene is associated with signifi-
gesting a potential effect on components in the blood (Table 3). cant reductions in the risk of stroke (26%), mortality (37%),
and CVDs (14%) (70). Evidence from epidemiological and clin-
ical studies suggests a possible correlation between serum anti-
Plant lycopene
oxidant levels and cardiovascular disease risk. High plasma
Lycopene is a polyunsaturated hydrocarbon phytochemical concentrations of lycopene have been associated with reduced
present in red fruit and vegetables (tomatoes, watermelons, prevalence of cardiovascular disease.
grape, papayas, red peppers, etc.) and belongs to the tetrater-
pene carotenoid family (58). Tomato (Solanum lycopersicum L.,
Berries
family Solanaceae)-based products represent an essential ele-
ment of the Mediterranean diet, which motivates many In everyday language, a berry is a small, pulpy, and often edible
researchers to search for the link between lycopene consump- fruit. Common examples are strawberries, raspberries, blueber-
tion and occurrence of CVD. The direct role of lycopene in pre- ries, and red- and blackcurrants (71). Berries are fruits that are
vention of CVD has been shown by many epidemiological rich both in nutritive compounds, including minerals, vitamins,
studies. As has been recently confirmed in the Framingham and dietary fiber, and in nonnutritive elements, especially poly-
Heart Offspring Study (23), there is a strong inverse relation phenolic phytochemicals (phenolic acids flavonoids, tannins,
between lycopene intake and incidence of myocardial infarc- and lignans) (72,73).
tion, angina pectoris, and coronary insufficiency. Low plasma In the past few years, research on polyphenols has consider-
lycopene levels were reported by many researchers in hyperten- ably increased, and because of the involvement of oxidative
sion, myocardial infarction, stroke, and atherosclerosis. Less stress in the onset and development of degenerative diseases,
convincing results and a more complex landscape emerge great attention has been paid to their antioxidant properties.
when the data from interventional studies on lycopene intake Previously, polyphenols’ antioxidant capacity was the most
in CVD patients are analyzed. There are multiple conflicting known and accepted mechanism, through which they are able
reports on how lycopene administration affects the progression to scavenge free radicals or limit their formation (74).
of CVD and its outcomes. However, there is a certain degree of Evidence suggests that the addition of polyphenol-rich
reproducibility in scientific reports describing the reduction of foods in the diet may improve CVD risk factors, inhibiting
cholesterol (LDL-C and total), up-regulation of HDL-C (47), inflammation and platelet aggregation and ameliorating
decrease in carotid artery intima-media thickness (52), and endothelial function, plasma lipid profile, and free radical
lowering of both plasma markers of oxidative damage (60) and scavenging (75,76).
postprandial oxidative stress (61) in patients treated with lyco- In dyslipidemic subjects, anthocyanin consumption (about
pene. There are multiple and reproducible reports describing 160 mg twice daily for 12 weeks) was found to increase HDL-C
normalization of endothelial nitric oxide synthase activity and concentration and to decrease LDL-C concentration and
10 S. ASGARY ET AL.
cholesteryl ester transfer protein activity in plasma (77). Simi- cardiac dysfunction. Therefore, experimental models appear to
larly, Cassidy et al. demonstrated that, in young or middle-aged support the premise that PPAR-a agonism is beneficial for the
women, a reduced risk for myocardial infarction was associated heart, whereas the effects of PPAR-g agonism appear to vary
with elevated anthocyanin intake (78). Another study showed (84). In humans, increased plasma TNF-a is associated with
that the daily consumption of 500 g of strawberries for 1 month heart failure trajectory (86). Cardiac TGF-b is up-regulated by
in young healthy volunteers was associated with a general elevated work load and provokes the hypertrophic and proin-
improvement of the serum lipid profile of the subjects, through flammatory cardiac gene expression (87). Herrington and col-
a reduction of total cholesterol, LDL-C, and triglyceride levels, leagues assessed the effect of muscadine grape seed
indicating that some of the constituents of the fruit, such as supplementation on endothelial function and cardiovascular
vitamin C and anthocyanins, may favorably affect the plasma risk factors in subjects with increased cardiovascular risk (88).
lipid profile (79) (Table 3). In a double-blind, randomized crossover trial, there was no evi-
dence that 4 weeks of daily supplementation with muscadine
grape seed improved endothelial function measured by brachial
Grapes
flow-mediated dilatation (FMD). However, there was clear evi-
Grape (Vitis vinifera L., family Vitaceae) is the most valuable dence that this supplement produced an increase in resting bra-
fruit in the world. Remarkably, over 1600 compounds have chial diameter. Increase in resting diameter was not
been identified in grapes, including resveratrol, lycopene, quer- accompanied by a reduction in blood pressure or changes in
cetin, melatonin, and other potent antioxidants (80). Many of other plasma markers of cardiovascular risk, including plasma
these agents are associated with health-beneficial properties, lipids and C-reactive protein (88). The finding of no effect on
and several of them have been shown to have synergistic/addi- FMD was unexpected, in light of the antioxidant and other
tive effects. Thus, although the individual ingredients, such as properties of the muscadine seed polyphenolics. It is possible
resveratrol, have been shown to have limited in vivo bioavail- that the whole muscadine grape could have better efficacy than
ability, the overall collective antioxidant content of whole grape seed-alone polyphenolics. Interestingly, in another study, Vais-
is likely to be very high owing to the coexistence of catechins, man and Niv also examined blood pressure, FMD, and oxida-
procyanidins, flavonols, and anthocyanins (80). tive stress in subjects with prehypertension and mild
Grapes and resveratrol have been linked closely with heart hypertension. This study showed that red grape powder con-
health. Seymour et al. have reported a reduction of heart failure sumption was associated with an improvement of FMD, endo-
pathogenesis with the administration of grape powder– thelial function, diastolic blood pressure, and oxidative stress,
enriched diets in Dahl salt-sensitive (Dahl-SS) rats, a model of without any adverse effects (89). In a recent study, Zunino and
salt-sensitive hypertension and diastolic dysfunction (81). In colleagues assessed the effects of dietary grapes on blood lipid
this study, grape powder (3.0% per weight; for 18 weeks) profiles, plasma inflammatory marker concentrations, and
administration (1) lowered blood pressure; (2) improved car- immune cell function in a randomized, double-blind crossover
diac function; (3) reduced systemic inflammation, cardiac study in 24 obese human subjects (90). This study suggested
hypertrophy, cardiac fibrosis, and oxidative damage; and (4) that dietary grapes may induce beneficial alterations in poten-
increased cardiac glutathione (81). tially atherogenic lipid subfractions associated with an
In addition, grape feeding enhanced cardiac peroxisome increased risk of obesity related disease, such as cardiovascular
proliferator–activating receptor (PPAR-a and PPAR-g) DNA diseases (90). In this study, dietary grape powder supplementa-
binding activity but reduced NF-kB DNA binding activity, tion (46 g grape powder in 240 mL of water, 2 times per day for
reduced cardiac TNF-a and transforming growth factor b 3 weeks, representing 4 servings of grapes/day) was found to
(TGF-b) protein expression, increased IkB-a expression, and (1) reduce plasma concentrations of large LDL-C and large
reduced cardiac fibrosis, suggesting cardioprotective properties LDL particles, and (2) increase production of IL-1b and IL-6 in
of grape powder (82). The findings of these studies support the supernatants from lipopolysaccharide-activated peripheral
efficacy of grape-enriched diets against hypertension-associated blood cells (PBMCs) (90). In another study, Barona et al. evalu-
cardiac pathology, specifically for older patients, as salt-sensi- ated the effects of grape consumption on inflammation and
tive hypertension is common in the aged population (82). oxidation in metabolic syndrome–affected men: 11 men with
NF-kB is well known in that apoptosis is involved in the high triglycerides and low HDL and 13 men with no dyslipide-
pathology of heart failure, myocardial infarction, and cardio- mia (91). Grape consumption showed favorable responses by
myopathy (83). Studies with PPAR agonists confirm the inverse increasing IL-10 and adiponectin, 2 anti-inflammatory cyto-
association of PPAR activity with NF-kB activity. In Dahl-SS kines, in nondyslipidemic subjects. In addition, inducible nitric
rats, PPAR-a agonist fibrate inhibited cardiac hypertrophy and oxide synthase (iNOS) expression was higher in PBMCs from
hemodynamic dysfunction and improved survival (84). Fibrate nondyslipidemic individuals (91). Why grape consumption did
treatment also decreased NF-kB activity and the expression of not provide benefits to men with dyslipidemia may be the sub-
NF-kB–related target genes. In stroke-prone, spontaneously ject of future research. In a separate study, Barona et al. also
hypertensive rats, PPAR-g agonist pioglitazone reduced cardiac demonstrated that daily consumption of grape powder for
NF-kB activity, cardiac fibrosis, and expression of NF-kB– 30 days significantly potentiated vasodilation, decreased circu-
related transcripts such as TNF-a (85). PPAR-a activation lating cell adhesion molecules (CAMs), and reduced blood
dose-dependently improved cardiac output, myocardial con- pressure, resulting in improved vascular function in men with
tractility, and diastolic relaxation and reduced cardiac hyper- metabolic syndrome (92). In another recent study, Zern and
trophy and fibrosis. However, PPAR-g activation exacerbated colleagues found that grape powder supplementation (36 g
daily for 4 weeks) resulted in improvement of plasma lipid lev- Saffron

els, inflammatory cytokines, and oxidative stress in 24 pre- and
Saffron is a spice obtained from the stigmas of the flower
20 postmenopausal women, suggesting possible beneficial
of Crocus sativus L., family Iridaceae, which is widely cultivated
effects for coronary heart disease in women (93) (Table 3).
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
Pumpkin
which the most powerful ones are crocin, crocetin, and safranal
Pumpkin (Cucurbita pepo L., family Cucurbitaceae) is a round (110–112).
fruit with smooth, slightly ribbed skin, and deep yellow to Considerable interest has been shown in saffron supplemen-
orange color. It is famous for its edible seeds that are low-fat tation as a potential cure for dyslipidemiic (113), antinocicep-
and protein-rich (94). The second most important part is its tive, anti-inflammatory, and antioxidant effects (114,115).
fruit. The immature fruit is cooked as a vegetable, whereas the Saffron also offers protective effects against cardiovascular dis-
mature fruit is sweet and used to make confectionery and bev- ease (116), atherosclerosis, and other diseases (117,118). In
erages. The fruit has a good b-carotene content and has a mod- fact, saffron supplement attenuated reperfusion-induced fatal
erate content of carbohydrates, vitamins, and minerals. ventricular fibrillations in ischemic rat hearts (119). Similarly,
Pumpkin seeds are used for extract for an edible oil, which is crocetin reportedly reduced the infarct size of ischemic rat
rich in oleic acid (95). myocardium and significantly attenuated apoptosis within the
Pumpkin has been accepted as beneficial to health because it cardiac tissues. Furthermore, saffron was shown to reduce iso-
contains various biologically active components, such as poly- proterenol-induced injuries in rat hearts and to attenuate histo-
saccharides, para-aminobenzoic acid, fixed oils, sterols, pro- logical changes of the myocardium (120,121) (Table 3).
teins, 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) Garlic
and useful amounts of the essential fatty acid, linoleic acid, and
Garlic (Allium sativum L.) has been used as a food and medici-
remarkably high proportions of essential amino acids (100).
nal herb for thousands of years. Asia is one of the origin centers
Pumpkin is a well-known edible plant; most parts of this
of Allium genus, especially garlic (Allium sativum L.), onion
plant are also used in traditional medicine around the world
(Allium cepa L.), and Chinese chive (Allium tuberosum) (122).
(96). Oxidative stress has been considered as a hallmark of vari-
The vast majority of studies have been conducted with the use
ous chronic diseases and their complications such as diabetes,
of cell culture (in vitro) or animals (in vivo) and clinical studies
obesity, CVD, and cancer. It is a condition of potentially harm-
that investigate whether garlic intake may provide protection
ful imbalance between the level of prooxidants and antioxidants
against cardiovascular disease.
in favor of the former (101). Various extracts of pumpkin have
The Allium genus is rich in sulfur compounds, steroidal sap-
potential antioxidant activity, which might play an important
onins, flavonoids, and so on, which have anticancer, antioxi-
role in prediabetics, diabetics, and individuals with vascular
dant, anti-platelet aggregation, antiatherosclerosis, and
injury (102,103). Xia and Wang demonstrated that pumpkin
antimicrobial activities. It also lowers blood lipids and blood
fruit has an important antioxidant role for its cytoprotective
glucose levels. S-alk(en)yl-l-cysteine sulfoxides are cysteine-
(cell-protecting) action in streptozotocin-induced diabetic ani-
derived secondary metabolites highly accumulated in the genus
mals (104). Pumpkin seeds have a high content of vitamin E
Allium (122).
(tocopherol; an antioxidant), and pumpkin seed oil has been
Clinical studies showed garlic’s effects on atherosclerotic risk
considered to provide a significant source of vitamin E in Japa-
factors, as outlined in Table 3. All studies were randomized,
nese diets (105). Chang reported that pumpkin extract admin-
double-blind, placebo-controlled that used either garlic powder
istration significantly increased the serous and hepatic activities
or aged garlic extract (AGE). Three of these trials examined
of superoxide dismutase and glutathione peroxidase in mice
garlic’s lipid-lowering effects. Hyperlipidemic patients (123)
and reduced the concentration of malonaldehyde (106).
and patients with coronary artery disease (CAD) (124,125)
Pumpkin is an edible food that can be included in our daily
showed a reduction in total cholesterol, LDL-C, and TG in
diet that can give various health benefits to improve our overall
response to daily garlic intake. Similar findings were observed
health. Pumpkin has various effects beneficial to health, such as
in a study of healthy male long-distance runners (126). Zhang
antidiabetic, anticarcinogenic, antioxidant, and antimicrobial
et al. found that although there was no effect of garlic on cho-
potential (107) (Table 3).
lesterol in normal male subjects, garlic did lower total choles-
terol and increase HDL-C in female subjects, suggesting a
potential gender effect (127). The data summarized in a review
Herbs and spices
study point out that major mechanism and many functional
The use of herbs and spices enhances the flavor and palatability components derived from the Allium genus, especially garlic
of food and reduces the requirement to salt or fat. In addition, and onion, exert potent effects in preventing chronic diseases
herbs are a natural source of phytochemicals, including flavo- (128).. Although functional components in alliums for prevent-
noids and polyphenols. These compounds are potent antioxi- ing and treating chronic diseases seen complicated task, the
dants and can inhibit lipid peroxidation as well as suppress development of functional foods may still open new beginning
cholesterol synthesis (108). for therapeutic interventions (128).
12 S. ASGARY ET AL.
Based on the current available literature, garlic has shown (diferuloylmethane) is a polyphenol responsible for the yellow
favorable effects on several clinically relevant risk factors that color of turmeric, a curry spice. The yellow-pigmented fraction
not only help prognosticate but can alter management strate- of turmeric contains curcuminoids, which are chemically
gies for patients in the primary prevention of ischemic heart related to its principal ingredient, curcumin (140). Curcumin
disease. One of the challenges of studying the effects of garlic is has antioxidant, anti-inflammatory, antiviral, and antifungal
the standardization of the preparation or active ingredient. actions. Studies have shown that curcumin is not toxic to
Kyolic brand aged garlic extract has shown the most consistent humans (141).
results, because the product is standardized to a certain level of Studies have demonstrated the effects of curcumin on the
N-acetylcysteine before packaging. Nonetheless, numerous tri- serum cholesterol and lipid peroxide levels (142). After curcu-
als and meta-analyses have shown favorable effects from garlic min administration (500 mg/day) for 7 days to 10 healthy vol-
on well-accepted risk factors such as hypertension and hyper- unteers, a significant decrease were observed in the serum lipid
cholesterolemia (129). SBP and DBP have been shown to be peroxides, increase in the serum HDL-C, and decrease in the
reduced by 7–16 and 5–9 mm Hg, respectively, compared with total serum cholesterol (33%, 29%, and 12%, respectively)
placebo. TC has been shown to be reduced by 7.4–29.8 mg/dL (143). Similarly, another study in patients with atherosclerosis
(129) (Table 3). 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 metabo-
Nigella sativa
lism principally contributes to the pathogenesis of atherosclero-
Nigella sativa L. is a small shrub and annual flowering plant that sis, these observations suggest the potentially protective role of
belongs to the family Ranunculaceae. It bears white, yellow, pink, curcumin in atherosclerotic diseases (142).
and purplish delicate flowers containing 5–10 petals (130). The therapeutic effects of curcumin have been extensively
Chemical composition of N. sativa is very diverse and con- investigated, particularly in the treatment of anti-inflammatory
sists of range of different components, including carbohydrates, diseases (144–146). In addition, curcumin is well tolerated
proteins, fats, oils, fiber, vitamins, minerals (Cu, Fe, P, Zn, etc.), when taken at doses as high as 12 g/day and has low toxicity
and many other biologically active compounds (131). and low cost (147). Evidence has shown that curcumin has a
It is estimated that N. sativa consumption (1 g powder per potential role in the protection against many cardiovascular
day for a period of 60 days) resulted significant reduction in diseases. The antioxidant effects of curcumin have been consid-
LDL-C and triglyceride levels and increase in HDL-C level in erably shown to decrease Adriamycin-induced cardiotoxicity
hypercholesterolemic patients (132). Another study also (148) and may prevent diabetic cardiovascular complications
reported similar results on the hypercholesterolemic patients in (149). The antithrombotic (150), antiproliferative (151), and
whom N. sativa consumption was found to be associated with anti-inflammatory effects of curcumin and the effect of curcu-
lowering of LDl-C level; thus, it is helpful in normalization of min in decreasing the serum cholesterol level may protect
lipid profile in patients with heart problems (133-135). against the pathological changes seen in atherosclerosis (142).
The study in patients with mild hypertension designed to Furthermore, curcumin can prevent atrial and venticular
assess the effect of N. sativa on blood pressure shows that N. arrhythmias, possibly via correcting of calcium homeostasis
sativa extract consumption favorably affects the elevated blood (152,153). Since the last decade, there are several ongoing trials
pressure (136). Qidwai et al. reported similar results that N. sat- on the preventive effects of curcumin on various cancers (154)
iva seeds have favorable effect on the high blood pressure (137). (Table 3).
Different preparations of N. sativa, including seed powder
(100 mg to 20 g daily), seed oil (20–800 mg daily), thymoqui-
Cinnamon
none (3.5–20 mg daily), and seed extract (methanolic extract
especially), were shown to reduce plasma levels of total choles- Cinnamon (Cinnamomum verum, family Lauraceae) has
terol, LDL-C, and triglycerides, but the effect on HDL-C was been used as a spice in daily life without any side effects.
not significant. N. sativa and thymoquinone have been reported Several reports have dealt with the many properties of cin-
to be safe and well tolerated with no severe adverse effect. In namon in the forms of bark, bark powder, essential oils, fla-
clinical trials, N. sativa was found to be effective when added as vonoids, phenolic compounds, and isolated components.
adjunct to standard antihyperlipidemic and antidiabetic medi- Each of these properties plays a key role in the advance-
cations. Lipid-modifying effect of N. sativa could be attributed ment of human health (155,156).
to the inhibition of intestinal cholesterol absorption, decreased Cinnamon compounds are cinnamic acid, cinnamate, and
hepatic cholesterol synthesis, and up-regulation of LDL recep- cinnamaldehyde, an abundant essential oil (157). The spicy
tors (138) (Table 3). 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).
Curcuma
Different flavonoids isolated from cinnamon have free-radi-
Curcuma longa L. (belonging to the family Zingiberaceae) is a cal-scavenging activities and antioxidant and anti-inflamma-
vegetatively propagated, polyploid crop cultivated mostly in tory properties (159).
Southeast Asia, commonly known as “Indian saffron” and One of the active components isolated from C. cassia (2-
“Golden spice.” Turmeric is widely used as a spice, natural food methoxycinnamaldehyde [2-MCA]) decreases the expression
dye, and preservative in Asian countries (139). Curcumin of vascular cell adhesion molecule 1 (VCAM-1) (160).
A recent study reported the potential effects of 2 com- Studies reported a significant improvement in FMD and cir-
pounds, cinnamic acid and cinnamic aldehyde, isolated from C. culating NO pool following consumption of a standardized
cassia against myocardial ischemia, representing that cinnamon mixed meal coadministered with 140 mL beetroot juice (equiv-
also has potential effects in cardiovascular disease treatment alent to 500 mg dietary nitrate) (172,180).
(161). Numerous studies have reported the defensive effects of Asgary et al. compared the effects of raw beetroot juice and
cinnamaldehyde on the cardiovascular system (161,162). Cin- cooked beetroot on blood pressure, FMD, lipid profile, and
namophilin mainly inhibits thromboxane receptor–mediated inflammatory markers in hypertensive individuals. Twenty-
vascular smooth muscle cell proliferation and can have the four hypertensive subjects aged 25–68 years were randomly
potential for use in the prevention of vascular diseases and ath- assigned to raw beet juice or cooked beets both for 2 weeks,
erosclerosis (163). intermittent by a 2-week washout period, in a crossover,
The administration of cinnamon has positive effect on the unblinded, non-placebo-controlled design. Results showed a
lipid profile in mice. It reduced plasma triglycerides but significant improvement of FMD and significant reduction in
increased the HDL-C levels (164). Another study showed an blood pressure and inflammatory cytokines following con-
attenuation in triglycerides, low-density lipoproteins, and the sumption of either of the preparations. Between-groups com-
total cholesterol in rats after administration of C. cassia powder parisons showed that raw beetroot juice was more effective
(15%) for 35 days (165). Additionally, cinnamon oils reduced than cooked beetroot in increasing of FMD and reducing high-
the cholesterol levels in broiler chickens (166). El-Bassossy et al. sensitivity C-reactive protein (hs-CRP) and TNF-a. The
reported that the administration of cinnamon at 1, 3, and 6 g authors concluded that both preparations of beetroot are effec-
doses per day caused a lessening in serum total cholesterol, tri- tive in improving blood pressure, endothelial function, and sys-
glyceride, LDL-C, and glucose levels in humans (167) (Table 3). temic 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
Beetroot
the treatment of tumors of intestine, breast, stomach, and
Beetroot (Beta vulgaris L.) belongs to the Chenopodiaceae fam- uterus (181). It has been reported that consumption of beet leaf
ily and is originally from temperate climate regions (168). This improves antioxidant capacity, reduces lipid peroxidation, and
plant contains biologically active phytochemicals, including enhances glutathione levels (182) (Table 3).
betalains (e.g., betacyanins and betaxanthins), flavonoids, poly-
phenols, and dietary nitrate (169). Dietary nitrate and nitrite
Nuts
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. Nuts are a specific kind of fruit characterized by a hard shell
suggested that nitrite, a known vasodilator, has an indirect and dry seed. Nuts are considered as one of the most nutri-
effect in promoting vascular NO synthesis (173). tional foods because they contain high amounts of vegetable
Mechanistically, vascular dysfunction is characterized by a protein and unsaturated fatty acids. Nuts rich in dietary fiber,
reduced bioavailability of the endothelium-derived vasoprotec- vitamins (folic acid, niacin, tocopherols, and vitamin B6), min-
tive molecule NO. NO is a vasodilator associated with anti- erals (calcium, magnesium, and potassium), and many other
platelet, anti-inflammatory, and antiproliferative effects that bioactive constituents such as phytosterols and phenolic com-
underlie its critical role in sustaining cardiovascular health pounds (183).
(174). The dysfunction of the conventional L-arginine/NO syn- Nuts are complex foods containing cholesterol-lowering
thase pathway and enhanced scavenging of NO underlie the mono- and polyunsaturated fatty acids, several antioxidant poly-
reduced bioavailability in individuals at risk of CVD, including phenols, soluble fiber, and arginine (a precursor to the vasodilator
those with hypercholesterolemia (174), which is a phenomenon nitric oxide) (184,185). Postprandial vascular reactivity is charac-
reflected by impaired FMD responses. Thus, approaches that terized by increased expression of proinflammatory cytokines
might restore this lost NO have obvious therapeutic potential. and CAMs and decreased bioavailability of nitric oxide (186). It
Absorbed nitrate is concentrated in the salivary gland and is not surprising that the evidence supporting the cardioprotective
subsequently reduced to nitrite by symbiotic oral bacteria; a effects of diets high in nuts is healthy, as multiple mechanisms
portion of the nitrite is then absorbed and found in plasma work together to decrease risk. Prospective data from the Physi-
(175). In the USA, dietary intake of nitrate is approximately cians’ Health Study (187) indicated reduced risk of sudden car-
40–100 mg/day, with 85% from vegetable sources (176). diac death associated with nut consumption originally perceived
Studies reported that administration of beetroot juice, approx- as being unhealthy because of their high-fat content.
imately 3 hours after ingestion of a dietary nitrate load (500 mL Nut consumption was shown to have beneficial effects on
of beetroot juice), has a BP-lowering effect in healthy volunteers several CVD risk factors, including lowering LDL-C (188) and
(177). Similarly, Hobbs et al. showed that consumption of 200 g ameliorating endothelial function (189). Furthermore, nutrients
of bread containing 100 g beetroot increases endothelium-inde- contained in nuts may also modify specific processes related to
pendent vasodilation and lowers DBP in healthy subjects (178). cancer development such as the regulation of cell differentia-
Additionally, results of a recent meta-analysis indicated a signifi- tion and proliferation, reduction of tumor initiation or promo-
cant reduction in SBP (¡4.4 mm Hg, 95% confidence interval tion, DNA protection, and regulation of immunological and
[CI]: ¡5.9 to ¡2.8) and a trend toward reducing of DBP inflammatory responses (190). Four recent meta-analyses
(¡1.1 mm Hg, 95% CI: ¡2.2 to 0.1) as a result of inorganic showed that higher consumption of nuts was associated with
nitrate and beetroot juice supplementation in adults (179). reduced risk of coronary artery disease and hypertension (191).
14 S. ASGARY ET AL.
Epidemiological investigations have consistently shown that and Australia (200). Additionally, evidence from experimental
frequent nut consumption reduces coronary heart disease research indicates that cholesterol-lowering effect of legumes
(CHD) risk. Studies showed that the mean CHD risk was 37% maybe due to the combined effects of numerous bioactive com-
lower among subjects who consumed 4 or more servings of ponents, such as protein, phytosterols, and soluble and insolu-
nuts a week compared with those who seldom or never ate ble fiber (201). An interventional trial has shown that lupin
nuts, with a mean reduction of 8.3% for each incremental serv- kernel flour added to bread has also a positive effect on blood
ing per week of nuts consumed (192). According to scientific pressure: both the fiber and the protein were suggested to be
data documenting the beneficial advantages of nut consump- responsible (202).
tion, the US Food and Drug Administration (FDA) issued a
qualified health claim in 2003 stating that eating 43 g/day (1.5
Whole grains
oz/day) of specific nuts (such as almonds, hazelnuts, pecans,
pistachios, walnuts, and peanuts) may reduce CHD risk. Several healthy ingredients of the Mediterranean diet, including
Although many mechanisms by which nuts perform this CHD polyunsaturated fat products, legumes, whole grains, and vege-
protective effect have been postulated, their lipid-lowering tables and fruits, have functional properties that may protect
properties have been studied extensively (193). against type 2 diabetes (203). They were also shown to reduce
In 2015, Grosso et al. pooled individual primary data from the risk of coronary events, especially in high-risk persons
25 nut consumption trials conducted in 7 countries into a sys- (204).
tematic review. In that review, the data extracted among 583 Studies in the early 1970s have shown that whole grains have
men and women with normolipidemia and hypercholesterol- the potential protective role. Whole-grain products contain
emia who were not taking lipid-lowering medications, with a intact grain kernels rich in fiber and trace nutrients. They are
mean daily consumption of 67 g of nuts. Results demonstrated nutritionally more important because they contain phytopro-
the effects of nut consumption were dose related, and different tective substances that might work synergistically to reduce car-
types of nuts had similar effects on blood lipid profile levels. diovascular risk (205). Based on the results of the prospective
Nut consumption improved blood lipid profile levels in a dose- Iowa Women’s Health Study, cereal fiber had different associa-
related manner, especially among subjects with higher LDL-C tions with total mortality, because it depends on whether the
or with lower body mass index (BMI) (194). fiber came from foods that contained primarily whole grain or
In a study, the assignment for 24 weeks on a low-calorie diet refined grain (206). Whole grains exert their protective effects
enriched with 84 g/day of almonds was associated with an 11% on CVD risk via returning of blood pressure and plasma lipid
reduction in SBP compared with a low-calorie diet enriched levels to normal range and decreasing inflammation (207,208).
with complex carbohydrates (195). Whole grains have a reduced glycemic response following
Other studies on walnut-enriched diets reported improved ingestion compared with refined grains, (i.e., a little effect on
FMD in comparison with control diets without walnuts postprandial blood glucose rising). The reduction of postpran-
(186,196). Using a crossover design, Ros et al. studied the effect dial glucose surge is associated with reduced reactive oxygen
of walnut consumption for 4 weeks on vascular reactivity in generation, inflammation, and CVD risk after a meal ingestion
hypercholesterolemic patients. The authors showed a signifi- (209).
cant improvement in FMD after the consumption of 40– A meta-analysis based on 7 qualifying prospective cohort
65 g/day of a walnut supplement (186). In a crossover study studies focused on whole-grain consumption and cardiovascu-
conducted in type 2 diabetic patients, a walnut-enriched ad libi- lar outcomes reported that the inverse association between die-
tum diet for 4 weeks also improved FMD compared with the tary whole grains and incident CVD was strong and consistent
same diet without walnuts (196). Finally, using a crossover across trials (207).
design in an acute study, the effect of walnut consumption on Threapleton et al. in a systematic review study in 2013
postprandial FMD was studied after 2 high-fat meal sequences pooled individual primary data from 22 cohort study publica-
(separated by 1 week) to which 25 g of olive oil or 40 g of wal- tions that met inclusion criteria and reported total dietary fiber
nuts were added. In this study, the authors showed that, in intake, fiber subtypes, or fiber from food sources and primary
comparison with olive oil, walnuts reversed the impairment of events of cardiovascular disease or coronary heart disease (risk
FMD associated with a fatty meal (197). 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
Legumes
by fiber type or source emphasizes the need for a better under-
Legumes are complex foods rich in soluble fiber and polyphenols, standing of action of fiber components (210).
as well as folic acid. Legumes are also rich in protein, complex In a systematic review study on 2013, the authors pooled
carbohydrates, fiber, and various micronutrients (e.g., phyto- individual primary data from 45 studies (64 publications), and
chemicals) (198). Controlled trials have shown beneficial effects after meta-analysis, results showed that whole-grain intake is
of the consumption of nuts and legumes on 5 risk factors of associated with a reduced risk of coronary heart disease, cardio-
CVD (198), and a recent trial in high-risk adults showed that fol- vascular disease, and total cancer, and mortality from all causes,
lowing advice to consume a Mediterranean diet supplemented respiratory diseases, infectious diseases, diabetes, and all non-
with nuts significantly reduced CVD events by 30% (199). cardiovascular, noncancer causes. These findings support die-
Legumes were the only food group predictive of survival tary guidelines, that intake of whole grain can reduce the risk of
among 5 long-lived elderly cohorts in Japan, Sweden, Greece, chronic diseases and premature mortality (211).
Chocolate coffee seems to offer some health benefits too. It can be a good
choice for those who experience uncomfortable effects from
Cocoa is a flavonoid-rich food that has been investigated for its
caffeine stimulation. Drinkers of caffeinated coffee in particular
possible role in the prevention of CVD (212,213). In healthy
might be advised to ensure adequate calcium consumption
adults, drinking flavonoid-rich cocoa may improve NO-depen-
from dietary sources to guard against potential adverse out-
dent vasorelaxation and flow-mediated dilation in the brachial
comes related to bone health (220).
arteries (214). Administration of dark chocolate in essential
Green tea consumption appears to protect from CVD (221),
hypertensives reduced ambulatory serum LDL-C levels and
but results are again inconsistent. It has been reported in a
blood pressure, whereas white chocolate had no effect (215).
meta-analysis that the incidence of myocardial infarction
Also, there was a clear decrease of the blood cholesterol levels
among individuals who consumed 3 cups of tea daily was not
as well as a significant rise of HDL-C in addition to a marked
statistically significant, and there has been large variability
decrease of circulating oxidized LDL (216).
across studies (222). There were regional differences in this
A systematic review of the literature of observational studies
meta-analysis, with increasing tea consumption associated with
for effects of chocolate, cocoa, and flavan-3-ols on cardiovascu-
an increased risk for CHD in the United Kingdom and for
lar health pooled 42 acute or short-term chronic (18 week)
stroke in Australia, whereas the risk decreased in other regions,
randomized controlled trials (RCTs). Effects on insulin resis-
particularly in continental Europe. The hypothesis that addi-
tance index (homeostatic model assessment: insulin resistance
tion of milk to tea (as typically done in United Kingdom and
[HOMA-IR]) and FMD remained stable to sensitivity analyses.
Australia) abolishes its plasma antioxidant potential may only
Results of this study showed reductions in DBP and mean arte-
partially explain these geographic differences.
rial pressure and marginally significant effects on LDL and
A meta-analysis of tea consumption in relation to stroke,
HDL-C. Chocolate or cocoa improved FMD regardless of the
myocardial infarction, and all coronary heart disease is based
dose consumed, whereas doses 50 mg epicatechin/day resulted
on 10 cohort studies and 7 case-control studies (222). The inci-
in greater effects on SBP and DBP. GRADE (Grading of Rec-
dence rate of myocardial infarction is estimated to decrease by
ommendations, Assessment, Development, and Evaluation), a
11% with an increase in tea consumption of 3 cups per day
tool to assess quality of evidence and strength of recommenda-
(fixed-effects relative risk estimate D 0.89, 95% CI: 0.79, 1.01)
tions, suggested low- to moderate-quality evidence of beneficial
(1 cup D 237 mL) (222). However, evidence of bias toward
effects, with no suggestion of negative effects. Also [xxx] consis-
preferential publication of smaller studies that suggest protec-
tent acute and chronic benefits of chocolate or cocoa on FMD
tive effects urges caution in interpreting this result. The geo-
and previously unreported promising effects on insulin and
graphic region where the studies were conducted appeared to
HOMA-IR More experimental are needed to appear the poten-
explain much of the heterogeneity among coronary heart dis-
tial cardiovascular benefits of cocoa flavan-3-ols (217)
ease, myocardial infarction, and probably stroke results. With
(Table 3).
increasing tea consumption, the risk increased for coronary
heart disease in the United Kingdom and for stroke in Aus-
tralia, whereas the risk decreased in other regions, particularly
Coffee and tea
in continental Europe (222) (Table 3).
Coffee and tea, after water, are the most widely consumed bev-
erages in the world, and are the principal source of caffeine
Fish oil
intake among adults. The biological effects of coffee and tea
may be substantial and are not limited to the actions of caffeine. People with a high intake of dietary fish and fish oil supple-
The active constituents of coffee, diterpenes (such as kahweol ments have a low rate of CVD (223). Although fish per se con-
and cafestol), are apparently responsible for cardioprotective tains various nutrients with potentially favorable effects on
effect. Coffee has hundreds of biologically active compounds, health, attention has been particularly focused on the omega-3
and the health benefits of chronic coffee intake are wide rang- (n-3) fatty acids. Omega-3 fatty acids also include the plant-
ing, because consumption of coffee may diminish the risk of derived docosahexaenoic acid (DHA; 22:6 n-3), eicosapentae-
hypertension (218). A dose-response decrease in cardiovascular noic acid (EPA; 20:5 n-3), and a-linolenic acid (ALA; 18: 3 n-
risk and heart disease mortality was reported for a daily caffeine 3). Both DHA and EPA are found in oily fish. Despite the
intake in patients with type 2 diabetes (219). established beneficial effect of fatty fish consumption on CHD,
It seems that intake of 2–3 cups of coffee per day is safe. the species and amount of fish consumed, as well as the prepa-
However, most of the data on coffee’s health effects are based ration method, have an impact on CHD risk (223). The con-
on observational data, with very few randomized, controlled comitance of low amounts of n-3 fatty acids in our average diet
studies, and association does not prove causation. In addition, and the need for prolonged administration for prevention and
the possible advantage of regular consumption of coffee has to treatment has led to the development of selected preparations.
be weighed against potential risks, which are mostly related to These should combine acceptability and adequate bioavailabil-
its high caffeine content (220). ity of their relatively low contents of n-3 fatty acids. These fatty
The currently available evidence on cardiovascular (CV) acids are therefore being incorporated into a number of com-
effects related to habitual coffee consumption is largely reassur- mercially available, natural foods that, due to rather their struc-
ing. Coffee can be as part of a healthy diet for those with tural features, appear to be particularly suited as efficient fatty
increased CV risk or CV disease. Although many of coffee’s acid vehicles (224). Furthermore, some environmental contam-
benefits probably derive from its caffeine content, decaffeinated inants found in certain fish, for example, polychlorinated
16 S. ASGARY ET AL.
biphenyls, dioxins, and methylmercury, may diminish the amino acids, which makes it nutritionally equivalent to animal
health benefits of fish-derived n-3 fatty acids (224).There are protein but with lower fat associated and no cholesterol (232).
some suggested potential mechanisms for the CVD protective Soy also represents the richest source of isoflavones (a type of
effects of n-3 fatty acids, including anti-inflammatory, antiar- phytoestrogen that belongs to the flavonoids group) in the
rhythmic, and antithrombotic effects and decreasing of heart human diet. Soy proteins and isoflavones have received much
rate, BP, and plasma triglycerides improved endothelial func- attention in relation to their potential biological activities (233).
tion effects (224). Fish ingestion has been related to a reduced The proteomic investigations of the profile changes in the
risk for myocardial infarction, which may be related to benefi- human serum as response of food enriched in soy extract con-
cial effects of EPA and DHA on plaque stability (probably sumption (yogurt and soy pudding with an intake of 60 mg/day
related to the content of inflammatory cells) and modulation of of isoflavones for 2 weeks) by young women led to a beneficial
endothelial function (225). modulation of the level of a number of serum proteins. Nine
EPA and DHA have also been shown to decrease LDL oxi- proteins with modified concentrations were identified following
dative susceptibility in postmenopausal women, which could soy isoflavone consumption by functional food intake. Particu-
help to reduce the risk of CVD (226). Fish oil supplements larly, the apolipoprotein E (important in the lipid metabolism)
have favorable effects on lipid profile and blood pressure and ceruloplasmin (a copper-carrying protein) contents signifi-
(227,228). A meta-analysis of 65 studies demonstrated that n-3 cantly increased, whereas a-1-acid glycoprotein (an immuno-
fatty acids lowered triglyceride levels to baseline levels in a modulating molecule) decreased (234). The nature of the
dose-dependent manner (229). proteins identified in the serum suggests that the consumption
A meta-analysis from 11 published articles, including more of the soy isoflavones as part of functional foods may modulate
than 5000 participants, demonstrated that fish oil supplementa- the lipid metabolism, the response to oxidative stress, and the
tion was not associated with reduced risks for gestational diabetes immunomodulation on vascular protection. Other proteomic
mellitus (GDM), pregnancy-induced hypertension (PIH), and research carried out on menopausal women consuming isofla-
preeclampsia (PE). No statistically significant heterogeneity was vones (50 mg/day for 8 weeks by cereal bars enriched with soy
detected for the comparison of each outcome. The effects of fish extracts) showed an increase of the metabolic profile in mono-
oil on these gestational complications were consistent between nuclear blood cells on the expression of the proteins linked to
women with low-risk and high-risk pregnancies. Gestational sup- the anti-inflammatory response (235).
plementation with fish oil during the second or third trimester of Postmenopausal women with a diet low in saturated
pregnancy is not associated with reduced risks for GDM, PIH, or fat and cholesterol (the National Cholesterol Education
PE. Other possible benefits of fish oil supplementation during Program Step I diet) consumed 40 g/day of soy protein for 6
pregnancy warrant further evaluation (230). months. These women had significantly better blood lipid
A meta-analysis of randomized controlled trials from 7 trials profiles (average changes from baseline: 8.2% decrease in
showed that levels of tumor necrosis factor a (TNF-a) and non–HDL-C and a 4.4% increase in HDL-C) after duration
interleukin 1 and interleukin 6 (IL-1 and IL-6) were signifi- consumption (236). In other experiments, HDL significantly
cantly decreased after fish oil supplementation; however, hs- increased 7% from baseline with consumption of 32 g soy
CRP, soluble intracellular adhesion molecular 1 (ICAM-1), and protein for 4 weeks as soymilk in both women and men with
vascular cell adhesion molecular 1 (VCAM-1) were not signifi- hypercholesterolemia (237). Crouse et al. reported reductions
cantly affected. Meta-regression and subgroup analysis results of 4% and 6% in total and LDL cholesterol, respectively, in
suggested that the difference in dose of fish oil and follow-up hypercholesterolemic individuals consuming 25 g soy protein
duration might influence the effects of fish oil on TNF-a and for 9 weeks (238).
IL-6. Greater reduction of these 2 markers might be achieved in Thus, 20–50 g soy protein/day improved blood lipid levels
patients who take a higher dose (over 1000 mg/day) or for a (1.5%–4.5%) in mildly hypercholesterolemic persons (239).
longer duration (over 4 months) of fish oil (230). The FDA recently published its final ruling on a food-labeling
The large heterogeneity within studies with n-3 fatty acid health claim for soy protein and cholesterol reduction stating
supplementation for the response to triglycerides is likely to be that 25 g/day of soy protein, as part of a diet low in saturated
attributable to genetic variability within the study population. fat and cholesterol, may reduce the risk of heart disease (240)
Furthermore, more studies are needed to determine whether (Table 3).
specific genotypes exist that may benefit to a greater extent
from n-3 fatty acids for hypotriglycerolemic effects. Clinical
Discussion
studies also need to determine whether the reduction in CVD
risk factors is due to EPA, DHA, or the combination of both Functional components of food can be applied in the treatment
and the dosage of the effective components (223) (Table 3). and prevention of chronic diseases; they include nonstarchy
carbohydrates (dietary fiber, resistant starch, and fucoidan),
antioxidants (organosulfur compounds, polyphenols, carote-
Soy proteins
noids, tocopherols, tocotrienols, phytosterols, and isoflavones),
Soy products have been part of Eastern countries’ diets for cen- unsaturated fatty acids, bioactive peptides, sterols, and phytoes-
turies, and nowadays they are increasingly becoming important trogens (13).
in the Western diets as related to the use of soy-based products In recent years, the consumption of polyphenols has become
and functional foods enriched in soy extracts (231). The soy- common in the treatment of various diseases, including chronic
bean contains 35%–40% of proteins containing all essential and neurodegenerative conditions, as well as CVD (241).
Advances in flavonoid research have included substantial prog- concentrations of total cholesterol and LDL-C. The most stud-
ress in the identification of the biological activities of these ied effect of plant sterols is their inhibition of intestinal absorp-
compounds, especially in the area of activities that may act in tion of cholesterol. Plant sterols are more hydrophobic than
the prevention of CVD (242). Several areas of investigation cholesterol; thus, they can competitively reduce the absorption
appear promising and may have substantial health effects. Poly- of micellar cholesterol. In addition, the plant sterols can reduce
phenols may have several antiatherosclerotic activities, includ- the rate of cholesterol esterification in the enterocyte (affecting
ing anti-inflammatory, antioxidant, antiproliferative, and the activity of acyl coenzyme A [CoA]:cholesterol acyltransfer-
antiplatelet activities. Cholesterol-lowering and antihyperten- ase), thus reducing the amount of cholesterol exported into the
sive effects appear minimal for the polyphenols. Bioactive com- blood in the chylomicrons formed. The inhibition of choles-
pounds found in some plants are potent antioxidants that may terol absorption produces an increase in the synthesis of LDL
affect initial steps in the development of atherosclerosis receptor, which increases the elimination of LDL and also the
through the prevention of LDL oxidation, blockage of LDL-C IDL from the circulation, and given that these are the precur-
uptake by macrophages, and prevention of foam cell formation. sors of LDL-C, this decreases in addition its production without
The antioxidant activity of polyphenols may occur through sev- affecting triacylglyceride and HDL-C concentrations. There are
eral mechanisms, including scavenging of reactive oxygen/ no conclusive data regarding the effect of plant sterols on the
nitrogen species, chelation of metals, inhibition of propagation bile metabolism, although some studies suggest that they pro-
reactions in lipid peroxidation, and sparing of LDL-associated duce an increase in the excretion of bile acids, whereas other
antioxidants (242). studies suggest that there is no effect (243,246).
There are several studies showing the antiplatelet effect of Chronic inflammation is typical in vascular endothelial dys-
bioactive compounds both in vivo and in vitro. A possible pro- function, triggered by the activation of certain factors such as
posed mechanism is the preferential inhibition of COX-1 and nuclear factor (NF)-kB, which is functionally dependent on the
COX-2, because of the balance of prostaglandins synthesized cellular redox state. In this context, tumor necrosis factor
by 2 isoforms of the COX enzyme regulates vascular homeosta- (TNF)-a activates NF-kB signaling transduction, which is con-
sis (243). Under certain conditions, the inactivation of COX-1 sidered to be involved in the pathogenic of atherosclerosis
by resveratrol as a bioactive compound is irreversible, and the (246,247). Thereby, functional foods also act as inhibitors NF-
platelets are unable to synthesize new proteins, which implies kB and NF-kB–dependent mediators.
that a fleeting exposure to resveratrol may have effects in vivo Vasodilation is a process to increase blood flow through
(human platelet renewal time is 10 days) (244). endothelial cells, which release vasodilators such as prostacyclin
The vasodilation ability of bioactive compounds has been and NO, which have great influence on vascular tone. Endothe-
attributed to their ability to stimulate Ca2C and KC channels, lium cells also release molecules that inhibit NO function called
and to improve of nitric oxide (NO) signaling in endothelium. vasoconstrictor molecules, such as endothelin-1 (ET-1) and
This last activity is due to the inhibition of the activity of angiotensin-2. The bioactive compounds also have inhibitory
NADH/NADPH oxidase, allowing a reduction in the superox- action on vasodilators (246).
ide basal production, and consequently a decrease in the inacti-
vation of NO. In vivo, bioactive compounds increase the
Conclusion
expression of endothelial nitric oxide synthase (eNOS) and
inducible nitric oxide synthase (iNOS). Therefore, bioactive The bioactive compounds found in some plants produce posi-
compounds increase the NO concentration through an increase tive effects that have been used in the medicinal field as potent
of the expression of NOS and decreases inactivation by free new drugs for the treatment of several diseases, including CVD.
radicals (243). This review showed that this fact remains true for the use of
Bioactive or functional peptides are defined as amino acid functional foods as potent drugs for the prevention of CVD
sequences of inactive precursor protein inside carrying out cer- due to inhibition of the inflammatory process, prevention of
tain biological activities after its release by chemical or enzy- endothelial dysfunction, and vasodilator production. Therefore,
matic hydrolysis. Usually, the released peptides during the the major proposed mechanisms of action of fruits/vegetable
industrial food processing or during gastrointestinal digestion extracts or isolated components are antioxidant action (captur-
are small (3–20 amino acids). The described main effects of the ing free radicals).
bioactive peptides on the cardiovascular system are those relat- The mechanisms responsible for the beneficial effects of
ing to their antithrombotic and antihypertensive activities functional foods on the cardiovascular system are multiple and
(245). remain somewhat unclear, although, in general, the available
The most studied antihypertensive activity of bioactive pep- clinical and preclinical studies suggest a positive correlation
tides is the inhibition of the activity of ACE (angiotensin-con- between their intake and a significant reduction in the cardio-
verting enzyme) (243). vascular risk factors. However, such evidence is satisfactory to
Sterols are compounds associated with variable proportion confer vegetables and fruits with an interesting functional food
of lipids, between 0.2% and 2%. Their basic structure is the value in the context of the spread of cardiovascular disease in
cyclopentanophenanthrene condensed 4-cycle system. Sterols Western countries and its high impact on the quality of life of
are compounds that can be free or esterified with fatty acids, patients. Indeed, to date, cardiovascular drugs represent the
mainly saturated fatty acids. There is a large amount of experi- most commonly used category in the world, and although there
mental evidence that demonstrated that the plant sterols have are large-scale pharmacological treatments, cardiovascular
an important hypocholesterolemic effect, reducing both the diseases are the most widespread, consuming a high level of
18 S. ASGARY ET AL.
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Journal of the American College of Nutrition

ISSN: 0731-5724 (Print) 1541-1087 (Online) Journal homepage: http://www.tandfonline.com/loi/uacn20

Functional Food and Cardiovascular Disease

Sedigheh Asgary, Ali Rastqar & Mahtab Keshvari

To link to this article: https://doi.org/10.1080/07315724.2017.1410867

Published online: 12 Mar 2018.

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Functional Food and Cardiovascular Disease Prevention and Treatment: A Review

ABSTRACT ARTICLE HISTORY

Table 2. Potential cardiovascular protective effects of functional foods (25).

Nuts Tocopherols, omega-3 fatty acids Lowering blood cholesterol

(Continued on next page)

weeks mean rather than a treatment-associated change

daily for 4 weeks) resulted in improvement of plasma lipid lev- Saffron

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