Curr Cardiol Rep (2015) 17: 39
DOI 10.1007/s11886-015-0593-9
DIABETES AND CARDIOVASCULAR DISEASE (S MALIK, SECTION EDITOR)
Impact of Functional Foods on Prevention of Cardiovascular
Disease and Diabetes
Geeta Sikand 1 & Penny Kris-Etherton 2 & Nancy Mariam Boulos 3
Published online: 22 April 2015
# Springer Science+Business Media New York 2015
Abstract A healthy dietary pattern is a cornerstone for the pre-
vention and treatment of cardiovascular disease (CVD) and type
2 diabetes (T2DM). Compelling scientific evidence has shown
many health effects of individual foods (including herbs and
spices), beverages, and their constituent nutrients and bioactive
components on risk of chronic disease and associated risk fac-
tors. The focus of functional foods research that is reviewed
herein has been on assessing the health effects and underlying
mechanisms of action of fruits and vegetables, whole grains,
dairy products including fermented products, legumes, nuts,
green tea, spices, olive oil, seafood, red wine, herbs, and spices.
The unique health benefits of these functional foods have been
the basis for recommending their inclusion in a healthy dietary
pattern. A better understanding of strategies for optimally includ-
ing functional foods in a healthy dietary pattern will confer great-
er benefits on the prevention and treatment of CVD and T2DM.
Keywords Functional foods . Cardiovascular disease
prevention . Type 2 diabetes prevention
Introduction
Cardiovascular disease (CVD) is the leading cause of morbid-
ity and mortality globally. Coronary artery disease (CAD)
This article is part of the Topical Collection on Diabetes and
Cardiovascular Disease
* Geeta Sikand
gsikand@uci.edu
1
Department of Medicine/Cardiology Division, University of
California Irvine School of Medicine, 101 City Drive South,
City Tower, Suite 400, Orange, CA 92868-4080, USA
2
Department of Nutritional Sciences, Penn State University,
319 Chandlee Lab, University Park, PA 16802, USA
3
Heart Disease Prevention Program, Division of Cardiology, C240
Medical Sciences, University of California, Irvine, CA 92697-4079,
USA
accounts for the most deaths in individuals with type 2 diabe-
tes mellitus (T2DM). Presently, 347 million individuals glob-
ally have diabetes and by 2030 diabetes will be the seventh
leading cause of death worldwide [1].
There are many factors that contribute to the develop-
ment of CVD, CAD, and T2DM. Systemic inflammation
is one factor that plays an important role in the develop-
ment and progression of CVD, T2DM, and other chronic
diseases. Chronic stimulation of inflammatory mediators
leads to sustained vascular reactivity, insulin resistance,
and dyslipidemia. Functional foods may modulate the bi-
ological processes that regulate lipid metabolism.
Dyslipidemia is common in patients with T2DM, and the
high frequency of CAD in diabetic patients is attributed to
the abnormalities of lipid metabolism. Optimization of se-
rum lipids has been shown to reduce CVD risk including
T2DM, obesity, and metabolic syndrome (MetS).
Functional foods have been shown to lower LDL-C nd
triglycerides and increase HDL-C [2, 3].
All foods are considered to be functional foods because
they provide energy and nutrients that are essential for
life. However, a growing body of evidence supports the
role of specific food components in the prevention of
CVD and T2DM. Foods containing bioactive components
are referred to as Bfunctional foods^ [4•]. This article will
summarize the role of functional foods including whole
grains, fruits, vegetables, legumes, dairy, fish, green tea,
olive oil, dark chocolate, garlic, cinnamon, turmeric, fenu-
greek, and red wine in the prevention of CVD and
T2DM. The benefits, the mechanisms of action, and the
role of functional foods in the diet will be discussed. In
addition, the practical application of including functional
foods in a healthy dietary pattern will be discussed.
Definition of Functional Foods
Functional foods remain undefined under current US food
regulations despite providing a health benefit beyond the
39 Page 2 of 16
traditional nutrients including reduced risk of disease upon
consumption [5••]. The Academy of Nutrition and Dietetics
(AND) position paper states BFunctional foods are whole
foods along with fortified, enriched or enhanced foods that
have a potentially beneficial effect on health when consumed
as part of a varied diet on a regular basis at effective levels
based on significant standards of evidence^ [4•]. The
International Food Information Council (IFIC) defines func-
tional foods as BFoods or dietary components that may pro-
vide a health benefit beyond basic nutrition and may play a
role in reducing or minimizing the risk of certain diseases and
other health conditions^ [6].
Functional Food Regulations
In the USA, foods are regulated by the Food and Drug
Administration (FDA) under the Federal, Food, Drug, and
Cosmetic Act of 1938. There is definition of functional foods.
However, the Nutrition Labeling and Education Act of 1990
includes both conventional foods and foods for special dietary
use [4•].
Four categories of claims can be used by food manufac-
turers on food labels to communicate health information to
consumers. These include the following [7]:
& Nutrient content claims
& Structure/function claims
& Health claims
& Qualified health claims
According to the Nutrition Labeling and Education
Act, a product is allowed to bear a health claim after
extensive review of the scientific evidence submitted to
the FDA [8]. The FDA permits all four types of claims
on functional foods if the claim meets the defined
criteria outlined for each claim [9]. Such claims are
authorized based on significant scientific agreement or
on an authoritative statement from a scientific body of
the US Government or the National Academy of
Sciences [10].
Table 1 shows the dietary components that are authorized
for a qualified health claim for cardiovascular disease includ-
ing the specific language for the claim and the level of scien-
tific evidence [4•].
New Findings on Functional Foods and their
Bioactive Effects in Conventional Foods Containing
Natural Bioactive Food Components
Table 2 lists the bioactive components of conventional foods
and their benefits for prevention of CVD and T2DM.
Curr Cardiol Rep (2015) 17: 39
Whole Grains
Whole grains including rye, oats, barley, and whole wheat
have protective effects against obesity, T2DM, cardiovas-
cular disease, hypertension, metabolic syndrome, and var-
ious cancers [11]. Functional components in whole grains
include non-digestible complex polysaccharides, e.g., solu-
ble and insoluble fibers, inulin, beta-glucan, and resistant
starches. Additional bioactive components in whole grains
include carotenoids, phytates, phytoestrogens, phenolic
acids (ferulic acids, vanilic acid, caffeic acid, syringic acid,
P-cumaric acid), and tocopherols [12, 13]. Whole grains
increase secretion of glucagon like peptide 1GLP-1, pep-
tide tyrosine tyrosine PYY, and decrease secretion of
ghrelin leading to increased satiety and decreased energy
intake, improved pancreatic beta cell function and insulin
secretion [5••, 14, 15].
The American Society for Nutrition Position paper
states there is moderate evidence, defined as evidence ob-
tained from multiple, well-designed, conducted, and con-
trolled prospective cohort studies with adequate and rele-
vant measures that gave similar results for all populations
or evidence from a well-conducted meta-analysis of pro-
spective cohort studies from different populations that con-
sumption of foods rich in cereal fiber or mixtures of
whole grains and bran is associated with a reduced risk
of obesity (level of evidence: B/C), T2DM (level of evi-
dence: B), or CVD (level of evidence: B) [16].
The 2010 Dietary Guidelines Advisory Committee con-
cluded that a moderate body of evidence from large prospec-
tive cohort studies shows that whole grain intake, which in-
cludes cereal fiber, protects against cardiovascular disease.
Limited evidence shows that consumption of whole grains is
associated with a reduced incidence of T2DM in large pro-
spective cohort studies. Moderate evidence shows that intake
of whole grains and grain fiber is associated with lower body
weight [17].
The Nurses’ Health Study reported 852 all-cause deaths
and 295 CVD deaths among 7822 women with T2DM.
After adjustment for age, the highest vs. the lowest quin-
tiles of dietary whole grain, cereal fiber, bran, and germ
were associated with 16 to 31 % lower all-cause mortality.
After further adjustment for lifestyle and dietary risk fac-
tors, only bran intake was significant (P for trend 0.01).
The multivariate relative risks across bran intake were 1.0
(reference), 0.94 (0.75 to 1.18), 0.80 (0.64 to 1.01), 0.82
(0.65 to 1.04), and 0.72 (0.56 to 0.92). Similarly, bran
intake was inversely associated with CVD-specific mortal-
ity (P for trend 0.04). The relative risks across the quin-
tiles of bran intake were 1.0 (reference), 0.95 (0.66 to
1.38), 0.80 (0.55 to 1.16), 0.76 (0.51 to 1.14), and 0.65
(0.43 to 0.99). Similar results were observed for added
bran alone [18].
Table 1 Qualified health claims for cardiovascular disease in terms of dietary component, qualifying source, language, and claim level
Dietary component(s)
Folic acid, vitamins B-6 and B-12
Almonds, hazelnuts, some pine nuts,
peanuts, pecans pistachios
Walnuts
n-3 fatty acids
Monounsaturated fat from olive oil
Unsaturated fatty acids from canola oil
Corn oil and corn oil- containing products
B, C, and D level claims correspond, respectively, to moderate, low, and lowest level of scientific evidence. (With permission from: Position of the Academy of Nutrition and Dietetics: Functional Foods J
Acad Nutr Diet 2013;113:1096–1103) [4•]
FDA Food and Drug Adminstration, CHD coronary heart disease, EPA eicosapentaenoic acid, DHA docosahexaenoic acid
Qualifying source
Supplements containing vitamin B-6, B-12,
and/or folic acid
Whole or chopped nuts
Whole or chopped walnuts
Fish, other conventional foods, supplements
Salad dressings, vegetable oil, olive oil-containing
food, shortenings
Canola oil, vegetable oil spreads, dressings for salads,
shortenings, canola oil-containing foods
Qualified health claim language Claim level
As part of a well-balanced diet that is low in saturated fat and cholesterol, B
folic acid, and vitamins B-6 and B-12 may reduce the risk of vascular
disease. The FDA evaluated the above claim and found that, while it is
known that diets low in saturated fat and cholesterol reduce the risk of
Curr Cardiol Rep (2015) 17: 39
heart disease and other vascular diseases, the evidence in support of the
above claim is inconclusive
Scientific evidence suggests but does not prove that eating 1.5 oz per day B
of most nuts such as [name of specific nut] as part of a diet low in
saturated fat and cholesterol may reduce the risk of heart disease. [See
nutrition information for fat content]
Supportive but not conclusive research shows that eating 1.5 oz per day of B
walnuts, as part of a low saturated fat and low cholesterol diet and not
resulting in increased caloric intake, may reduce the risk of CHD. [See
nutrition information for fat and calorie content]
Supportive but not conclusive research shows that consumption of EPA B
and DHA n-3 fatty acids may reduce the risk of CHD. One serving of
[name of the food] provides [x] grams of EPA and DHA n-3 fatty acids.
[See nutrition information for total fat, saturated fat, and cholesterol
content]
Limited and not conclusive scientific evidence suggests that eating about 2 C
tbsp (23 g) of olive oil daily may reduce the risk of CHD due to the
monounsaturated fat in olive oil. To achieve this possible benefit, olive
oil is to replace a similar amount of saturated fat and not increase the
total number of calories you eat in a day. One serving of this product
contains [x] grams of olive oil
Limited and not conclusive scientific evidence suggests that eating about 1 C
1/2 tbsp (19 g) of canola oil daily may reduce the risk of CHD due to
the unsaturated fat content in canola oil. To achieve this possible benefit,
canola oil is to replace a similar amount of saturated fat and not increase
the total number of calories you eat in a day. One serving of this product
contains [x] grams of canola oil
Very limited and preliminary scientific evidence suggests that eating about D
1 tbsp (16 g) of corn oil daily may reduce the risk of heart disease due to
the unsaturated fat content in corn oil. The FDA concludes that there is
little scientific evidence supporting this claim. To achieve this possible
benefit, corn oil is to replace a similar amount of saturated fat and not
increase the total number of calories you eat in a day. One serving of this
product contains [x] grams of corn oil.
Page 3 of 16 39
Table 2 Phytochemical/bioactive components and benefits for CVD and T2DM prevention

Functional food item Phytochemical/Bioactive components Functionality References

Barley Beta Glucan Hypolipidemic, antioxidant, anti-inflammatory, increase satiety, [5••, 11–18]
39 Page 4 of 16

and decrease energy intake

Oats Beta Glucan, antioxidants, carotenoids, phytic acid, phenolic Reduce postprandial glycemia, improve glycemic, insulinemic, [5••, 11–18]
acids (hydroxycinnamic acid, caffeic acid, ferulic acid, and lipidemic response in persons with diabetes or prediabetes,
flavonoids, phytosterol) increase satiety, and decrease energy intake
Rye Phenolic acids, tannins, benzoic acid, phenylalanine Decrease carbohydrate absorption, stimulate insulin from beta [5••, 11–18]
cells, increase satiety, and decrease energy intake
Whole wheata Dietary fiber, magnesium (main cofactor of enzymes associated Increase satiety, decrease energy intake, improves postprandial [5••, 11–18]
with glucose metabolism and insulin secretion), potassium, glycemic response, glycosylated hemoglobin, dyslipidemia,
phenolic acid, alfa tocopherols, carotenoids and antioxidants. and CVD risk factors in patients with diabetes
Berries, cranberry, blackberry, Flavonoids (anthocyanins, anthocyanidins and ellagitannins in Blood pressure reduction, reduces pro-inflammatory markers and [19]
black raspberry, blueberry, skin and flesh) adhesion molecules, improves serum lipid profiles
red raspberry, strawberries
Citrus fruits (oranges, grapefruits) Flavonoids (eriodictyol, naringin, hesperidin) Anti-ischemic, antithrombotic antioxidant, vaso-relaxant, [19, 23]
improve endothelial function, blood pressure, lipid profile
Tomato and its by products Flavonoids (lycopenes) Antioxidant and hypolipidemic [22]
Red apple, apple peel, apple and Flavonoids (quercetin and epicatechin in apple skins) Improves blood pressure, vascular function and blood lipid levels [19]
its by products
Grapes Phenolic acids, stilbenes, anthocyanins, and proanthocyanidins Antioxidant activity, suppressing platelet aggregation, lowering [19, 28]
(Phytochemical composition varies among different varieties) cholesterol
Pomegranate Juice, peels, and Flavonoids (Anthocyanins) cyanidin, delphinidin, malvidin, Anti-atherosclerotic, anti-hypertensive, antioxidant, and [19, 29, 30]
fruit extracts pelargonidin, petunidin, peonidin, catechins, tannins anti-inflammatory
Spinach Flavonoid (Flavones): Lutein, betaine, violaxanthin, opioid Augment nitric oxide status, enhance endothelial function, and [19, 31]
peptides (rubisculins), P-cumaric acid, ferulic acid lower blood pressure
Legumes: Peas, Lentils, Beans linoleic acid, alfa linolenic acid, isoflavones (daidzein, genistein, Prevent dyslipidemia, lowered LDL-C in hypercholesterolemic [2, 19, 33–40, 50]
glycitein), phenolic compounds, saponins, and phytic acid; subjects without changing HDL-C
polyphenols (pelargonidin, cyanidin, delphinidin and
malvidin)
Soybeans Phenolic compounds, phytoestrogens (genistein, daidzein, Decrease blood pressure, improve dyslipidemia, glycemic [19, 38–49]
glycitein) control, insulin sensitivity, antioxidant, and anti-inflammatory
Nuts: Almonds, hazelnuts, Proteins, bioactive peptides, functional fatty acids e.g., mono and Attenuate postprandial oxidative stress and inflammatory [5••, 50–59, 60•]
macadamias, peanuts, polyunsaturated, fiber, phytosterols, polyphenols, tocopherols processes, improve dyslipidemia, decrease lipid
pistachios, walnuts and other antioxidant vitamins atherogenecity, improve insulin resistance, decrease all-cause
and CVD mortality
Green tea Polysaccharides, flavonoids including catechins (flavan-3-ols Cardioprotective effects including hypolidemic, anti- [61–64]
contain epigallocatechin-3-gallate (EGCG 50–80 %)), thrombogenic, antidiabetic, anti-inflammatory, antioxidant,
epicatechin 3-gallate (ECG), epigallocatechin (EGC) antihypertensive, antiprolifertive
epicatechin (EC) and catechin.
Chocolate Catechins, epicatechins, procyanidin Hypotensive, antioxidant, anti-inflammatory, lowers insulin [65–69, 70]
resistance, improves insulin sensitivity, improves vascular
endothelial function via activation of nitric oxide
Despite benefits there is a lack of well-designed clinical studies
demonstrating CV benefit. The high caloric and high sugar
content of chocolate, particularly of some less pure forms,
Curr Cardiol Rep (2015) 17: 39
Table 2 (continued)

Functional food item Phytochemical/Bioactive components Functionality References

should be considered before recommending uncontrolled

consumption
Garlic Thiosulfinate (including allicin) Cardiovascular benefit in humans is controversial. Modest but [70–73]
significant decrease in platelet aggregation
Cinnamon Flavones {cinnamaldehyde and trans-cinnamaldehyde (Cin)} Improves insulin sensitivity, glucose, lipids, antioxidants, [74–77]
inflammation, blood pressure and body weight
Curr Cardiol Rep (2015) 17: 39

Hypoglycemic effects with some results conflicting. Current data

insufficient to recommend cinnamon for a medical condition
Turmeric Flavones (curcuminoids) Anti-inflammatory effects through mediation at both the gene and [78]
protein levels. Supplements not recommended due to paucity
of long term research
Fenugreek Alkaloids, saponins, flavones Glycemic control, possibly via delaying gastric emptying, [77–81]
slowing carbohydrate absorption, and increased insulin
sensitivity of the tissues, reportedly elevating
glucose-dependent insulin secretion
Dairy Calcium, phosphorus, potassium, vitamin D Decrease risk of CVD; reductions in blood pressure [83, 84]
Probiotics / yogurt E. faecium and L. reuteri Decreases LDL-C [96]
Olive oil Polyphenols Decrease CVD risk, CV mortality, CV events and stroke [105, 106]
Red wine Polyphenols, resveratrol CVD risk reduction [107]
Fish and seafood Omega-3 fatty acids, high quality protein, B vitamins, vitamins A Lower risk of CHD, CHD death, arrhythmic deaths, ischemic [113, 114, 116]
and D, and phosphorus, potassium, selenium stroke, heart failure
a
Moderate evidence defined as evidence obtained from multiple, well-designed, conducted, and controlled prospective cohort studies with adequate and relevant measures that gave similar results for all
populations or evidence from a well-conducted meta-analysis of prospective cohort studies from different populations [16]
Page 5 of 16 39
39 Page 6 of 16
Fruits and Vegetables
Fruits and vegetables are rich in many phytochemicals, solu-
ble and insoluble fiber, vitamins, and minerals. These are im-
portant components of all cardio-protective dietary patterns.
Most fruits and vegetables are good sources of fiber (soluble
and insoluble), vitamins, and minerals [19]. Based on clinical
trials and meta-analyses, fruits and vegetables are associated
with reduced risk of CVD, diabetes, obesity, and metabolic
syndrome [20, 21]. Improvements were noted in Hb A1C and
triglyceride (TG) levels, antioxidants, oxidative stress and in-
flammatory markers, diabetic retinopathy, and risk of carotid
atherosclerosis with fruits and vegetables intake [19, 22–31].
Legumes
Legumes elicit protective effects against obesity, diabetes, and
CVD [5••, 32, 33].
Legumes include peas, beans, lentils, peanuts, and soy-
beans. Legumes are sources of plant protein, non-digestible
carbohydrates (dietary fiber, resistance starches, oligosaccha-
rides), bioactive compounds including linoleic acid, alpha-
linolenic acid, isoflavones (daidzein, genistein, glycitein),
phenolic compounds, saponins, and phytic acid, and some
polyphenols including pelargonidin, cyanidin, delphinidin,
and malvidin [34]. Beans are high in dietary fiber, phytate,
n-3 fatty acids, antioxidants, and phenolic compounds; they
have a hypoglycemic effect via inhibition of alpha-amylase
and beta-glucosidase activity that is similar to that of anti-
diabetic drugs [35–37].
Pinto, dark red kidney and black beans were associated
with improved dyslipidemia, postprandial glycemic responses
and weight management in T2DM patients [38, 39]. Lupin
protein (35 g/day) extracted from the legume lupin lowered
LDL-C by 8.6 % without lowering HDL-C when compared to
casein [40].
Soybeans
The anti-diabetic effects of soybean are mainly attributable to
the interactions with estrogen receptors (ER) by soy flavones,
which selectively bind to both the ER alpha and ER beta. ER
alpha is the key modulator of glucose and lipid metabolism
and regulates insulin biosynthesis and secretion and beta cell
survival [41]. Soy protein (median of 30 g/day) has favorable
effects on dyslipidemia (a 4 to 5.5 % decrease in LDL-C, a
3.2 % increase in HDL-C, and a 10 % reduction in triglycer-
ides) [42]. Soy protein may be of benefit to kidney patients
with diabetes [43]. However, the effects of soy protein on
glycemic control and insulin sensitivity remain uncertain
[44, 45]. Soybeans have been shown to induce insulin sensi-
tivity and improve lipid homeostasis via activation of perox-
isome proliferator-activated receptor (PPAR) and liver X
Curr Cardiol Rep (2015) 17: 39
receptors and inhibition of the sterol regulatory element bind-
ing protein-1c [46].
Soybeans uniquely inhibit 3-hydroxy-3 methylglutaryl
CoA reductase, a key enzyme involved in cholesterol biosyn-
thesis. The presence of beta conglycinin in soy beans leads to
anti-atherogenic effect via regulation of lipogenesis, decreased
lipogenic enzyme activity, and inhibition of fatty acid biosyn-
thesis in liver and facilitates fatty acid beta oxidation.
Soybeans have antioxidant, anti-inflammatory, and hypoten-
sive effects [47].
Two meta-analyses have examined the effect of soy protein
and LDL-C lowering. The first included 20 parallel studies
and 23 crossover studies. Soy protein consumption of 30 g/
day was associated with a 5.5 % reduction in LDL-C in par-
allel studies and 4.2 % reduction in crossover studies. HDL-C
was 3.2 % higher in parallel studies and TG was decreased by
10.7 % [48]. The second meta-analysis was based on 30 stud-
ies in 2013 participants. The inclusion of modest amounts of
soy protein (25 g) in the daily diet of adults with normal or
mild hypercholesterolemia resulted in a 6 % reduction in
LDL-C and 7.7 mg/dL decrease in TG [49].
Nuts Including Almonds, Hazelnuts, Macadamias,
Peanuts, Pistachios, and Walnuts
A recent review concluded that tree nuts and peanuts improve
glycemic control and reduce risk of CVD in patients with
T2DM [5••]. As an isocaloric substitute for foods high in
saturated fats, nuts increase the proportion of unsaturated fats
and decrease CVD risk. The 2010 Dietary Guidelines
Advisory Committee concluded Bthere is moderate evidence
that consumption of unsalted peanuts and tree nuts, specifical-
ly walnuts, almonds, and pistachios, in the context of a nutri-
tionally adequate diet and when total calorie intake is held
constant, has a favorable impact on cardiovascular disease risk
factors, particularly serum lipid levels^ [17].
In a recent meta-analysis [50], nut consumption was asso-
ciated with a decreased risk of incident ischemic heart disease
(IHD) and diabetes. Consumption of nuts was inversely asso-
ciated with fatal IHD (six studies; 6749 events; RR per four
servings weekly, 28.4 g; 0.76; 95 % confidence interval (CI)
0.69, 0.84; I2 =28 %) and inversely associated with nonfatal
IHD (four studies; 2101 events; RR per four servings weekly,
28.4 g; 0.78; 95 % CI 0.67, 0.92; I2 =0 %) [50].
Nuts are a source of plant proteins, bioactive peptides, un-
saturated fatty acids, e.g., mono and polyunsaturated, fiber,
phytosterols, polyphenols, tocopherols, and other antioxidant
vitamins [51]. The antioxidant effect of nuts is attributed to the
presence of alpha and gama tocopherol, phenolic acid, mela-
tonin, oleic acid, and selenium [52]. In patients with T2DM,
nuts improve postprandial glycemic response post-
consumption of high carbohydrate meals in T2DM, attenuate
postprandial oxidative stress and inflammation, optimize
Curr Cardiol Rep (2015) 17: 39
dyslipidemia, decrease lipid atherogenecity, and improve in-
sulin sensitivity [53, 54].
Habitual intake of nuts in an isocaloric diet may help with
weight management of patients with diabetes due to their ther-
mogenic effects, induction of satiety, decreased dietary fat
absorption, and increased fat excretion. Furthermore, the bio-
active components of nuts may help with appetite modulation
and possibly regulate appetite neurotransmitters and adipose
tissue metabolism. Nuts may decrease proliferation and differ-
entiation of adipocytes, inhibit lipogenesis, and induce fatty
acid beta-oxidation [55, 56].
Nuts lower inflammation by decreasing hs C-reactive pro-
tein (hs CRP), interleukin 6 (pro-inflammatory cytokine), and
fibrinogen and by increasing adiponectin (anti-inflammatory
cytokine from adipose tissue). Dietary patterns high in nuts are
associated with lower inflammatory CV risk markers, e.g.,
intercellular adhesion molecule 1 and vascular cell adhesion
molecule [57, 58]. Nuts exhibit a beneficial effect on the en-
dothelium due to a high content of L-arginine, a main precur-
sor of nitric oxide along with antioxidants and polyphenols
that potentiate this effect [59].
Based on two cohort studies [60•], namely, (1) 76,464
women (Nurses’ Health Study) and (2) 42,498 men (Health
Professionals Study), the frequency of nut consumption was
inversely associated with total and all-cause mortality includ-
ing heart disease independent of others predictors of death.
Pooled multivariate hazard ratios for all-cause mortality
among those who ate nuts versus those who did not were
0.93 (95 % confidence interval (CI), 0.90 to 0.96) for the
consumption of nuts less than once per week, 0.89 (95 %
CI, 0.86 to 0.93) for once per week, 0.87 (95 % CI, 0.83–
0.90) for two to four times per week, 0.85 (95 % CI, 0.79 to
0.91) for five or six times per week, and 0.80 (95 % CI, 0.73 to
0.86) for seven or more times per week (P<0.0001 for trend).
Similar associations were also observed between nut con-
sumption and deaths due to heart disease, cancer, and respira-
tory disease [60•].
Green Tea
Epidemiological, clinical, and experimental evidence supports
the role of green tea in preventing CVD [2]. A meta-analysis
of five studies on green tea showed a significant association
between highest green tea consumption and a decrease in risk
of CAD specifically one cup per day was associated with a
10 % reduction in CAD risk [61]. However, another meta-
analysis of 13 studies on black tea was not associated with a
reduction in CAD risk [61].
Green tea contains polysaccharides and polyphenols in-
cluding catechins especially epigallocatechin-3-gallate
(EGCG) exert cardio protective effects through multiple
mechanisms including antioxidant, anti-hypertensive, anti-in-
flammatory, anti-proliferative, antithrombogenic, and
Page 7 of 16 39
hypolipidemic and anti-diabetic effects. Tea catechins are fla-
vonoids that contain EGCG (50–80 %), epicatechin 3-gallate
(ECG), epigallocatechin (EGC), epicatechin (EC), and cate-
chin. In black tea, 50 % of catechins convert to theaflavins and
thearubegins [2, 61, 62].
In a study that investigated the effects of a catechin-rich
green tea diet on postprandial hyperglycemia in postmeno-
pausal women, postprandial glucose concentrations were
3 % lower than in the control group, there was no effect on
reactive oxygen metabolites after meals, and serum postpran-
dial thioredoxin concentrations were higher in the catechin-
rich group compared to the control group. This study sug-
gested that acute ingestion of catechin-rich green tea provides
benefits for postprandial glucose and redox homeostasis
among postmenopausal women [63].
In both in vivo and in vitro studies, green tea polyphenols
removed endothelial hyper-permeability in the aortas of male
Wistar rats fed a high fat diet and in bovine aortic endothelial
cells fed a high glucose diet attributed to the decrease in reac-
tive oxygen species (ROS) production due to the downregu-
lation of nicotinamide adenine dinuceotide phosphate
(NADPH) oxidase pathway [64].
Dark Chocolate
Cocoa polyphenols are rich in catechins, epicatechins, and
procyanidins which exert antioxidant and anti-inflammatory
effects by scavenging of ROS, Fe2+, and Cu+chelation, inhi-
bition of key enzymes, and promoting antioxidant defenses.
Strong evidence supports consumption of polyphenol-rich co-
coa products could contribute to CVD prevention. Due to their
tricyclic structure, flavonoids scavenge ROS and upregulate
antioxidant defenses to improve endothelial hyper permeability
[65]. Dietary flavonols in cocoa may also lower insulin resis-
tance and reduce risk for T2D due to antioxidant effects [66].
Dietary flavonols exert an antioxidant, antihypertensive,
anti-inflammatory, anti-atherogenic, and anti-thrombotic ef-
fect and also improve insulin sensitivity, vascular endothelial
function, and activation of nitric oxide. Results of a meta-
analysis of seven observational studies showed a positive as-
sociation between higher levels of chocolate consumption and
the risk of CVD. The highest levels of chocolate consumption
were associated with an adjusted lower risk for CVD (RR=
0.63 (95 % CI 0.44–0.90)) and a 29 % reduced risk of stroke
compared with the lowest levels. Results were confounded as
majority of the studies did not adjust for socioeconomic fac-
tors [67]. Several studies indicated the inability to distinguish
between milk and dark chocolate as a limitation. In the
European Union, the minimum amount of cocoa solids re-
quired in dark chocolate is 35 % and in the USA, it is 15 %
[67]. Dietary flavanols may also improve endothelial function
and lower blood pressure by causing vasodilation in the pe-
ripheral vasculature and in the brain [68]. Despite this array of
39 Page 8 of 16
benefits, there is a lack of well-designed clinical studies dem-
onstrating a CV benefit of chocolate. The high caloric and
high sugar content of chocolate, particularly of some less pure
forms, should be considered before recommending uncon-
trolled consumption [69].
Garlic
Garlic is an organosulfur compound high in thiosulfinate in-
cluding allicin, which is the active phenolic component of
garlic. Garlic has been associated with beneficial cardiovascu-
lar effects due to allicin formed when allin comes in contact
with the allinase enzyme when raw garlic is chopped, crushed,
or consumed [70]. In animal trials, garlic was found to be
hypolipidemic [71]. In humans, the impact of garlic on lipids
has been controversial. In a meta-analysis of 13 trials, garlic
had no significant effect on optimization of lipids or blood
pressure versus placebo [72]. The effect of garlic on throm-
botic risk was modest compared to placebo. However, a sig-
nificant decrease in platelet aggregation versus placebo was
noted [73]. In a study of 65 participants with a coronary artery
calcium (CAC) score >10 at baseline, aged garlic extract
(AGE) and coenzyme Q10 (CoQ10) were shown to signifi-
cantly lower CAC progression [74]. At 1-year follow-up,
mean CAC progression was significantly lower in AGE+
CoQ10 (32±6 vs. 58±8, P=0.01) than placebo. Similarly,
CRP was significantly decreased in AGE+CoQ10 compared
with placebo (−0.12±0.24 vs. 0.91±0.56 mg/L, P<0.05).
After adjustment for age, gender, conventional cardiac risk
factors, and statin therapy, AGE+CoQ10 was associated with
3.99-fold (95 % 1.3–12.2, P=0.01) lack of CAC progression
compared with the placebo [74].
Cinnamon
Cinnamon contains cinnamaldehyde and trans-cinnamaldehyde
(Cin), which may play a role in the prevention of T2DM and
CVD. Several studies have demonstrated that cinnamon im-
proved insulin resistance, hyperglycemia, hyperlipidemia, in-
flammation, antioxidant activity, weight reduction, and a reduc-
tion in glycation of proteins [75]. In a trial of 109 patients being
treated for T2DM, cinnamon lowered hemoglobin A1c com-
pared with usual care [76]. However, due to conflicting results,
current data is insufficient to recommend cinnamon for a med-
ical condition but its utility in T2DM is the most desirable area
of research at this time [77, 78].
Turmeric
Turmeric is a spice that has been used in number of traditional
systems of medicine in Asia. The anti-inflammatory proper-
ties of turmeric are attributed to curcuminoids (bioactive poly-
phenols). Systemic inflammation measured by C reactive
Curr Cardiol Rep (2015) 17: 39
protein (CRP) is pivotal in the pathogenesis of atherosclerosis
and CVD [78].
A meta-analysis [79] of six trials comprising of 172 subjects
in the curcuminoid group and 170 subjects in the placebo group
showed curcuminoids were associated with a significant reduc-
tion in circulating CRP levels (mean difference=−6.44 mg/L;
95 % CI −10.77—2.11; P=0.004). This effect was maintained
in those who used high bioavailability turmeric preparations
and supplemented for ≥4 weeks. Curcuminoids provide anti-
inflammatory effects through mediation at both the gene and
protein levels. Several in vitro and in vivo studies have dem-
onstrated the possibility of a cardio protective effect related to
curcuminoids, such as protection against development of car-
diac hypertrophy. However, duration of the trials was short with
only two studies ≥8 weeks. For supplementation, the author
concluded that more research with long-term treatment dura-
tion is needed [79].
Fenugreek
Fenugreek seeds are commonly consumed in seasonings,
pickles, and curry powder in the daily diet in Asia, Africa,
and Mediterranean countries. It is a fiber-rich plant commonly
used for glycemic control in Asia. Research has shown that
fenugreek seeds exhibit antioxidant and anti-inflammatory ac-
tivities attributed to the polyphenolic compounds. Steroidal
saponins in fenugreek seeds are associated with
hyperinsulinemia and decrease plasma total cholesterol [80].
In a meta-analysis of eight trials on fenugreek consumption
in patients with T2DM, significant reductions in fasting blood
glucose (−0.96 mmol/L), 2-h blood glucose (−2.19 mmol/L;
seven trials), and A1c levels (−0.85 %; three trials) were noted
with medium to high doses of fenugreek seed powder (>5 g/
day) [79]. The reduction in blood sugar by fenugreek seeds is
attributed to the presence of oligosaccharides that may act as
glucosidase inhibitors and prevent rapid absorption of mono-
saccharides [81].
A daily dose of 5–100 g of fenugreek seed powder is asso-
ciated with improved fasting blood sugar, postprandial glu-
cose, and HbA1c levels in patients with T2DM. Fenugreek
delays gastric emptying, slowing carbohydrate absorption and
improved tissue insulin sensitivity [78, 82].
Dairy Products
Several meta-analyses of prospective studies have examined
the relationships between dairy consumption, defined as milk
(whole, semi-skimmed, fat-free), cheese, butter, cream, yo-
gurt, and ice cream and the relative risks for CVD, including
CHD and stroke. A comprehensive review of the literature
conducted by Elwood et al. [83] included several meta-
analyses of the relationship between milk and dairy food con-
sumption and risk of cardiovascular disease. Results of the
Curr Cardiol Rep (2015) 17: 39
meta-analyses suggest a reduction in risk in the subjects with
the highest dairy consumption relative to those with the lowest
intake by 13 % for all-cause deaths (RR=0.87, 0.77, 0.98), by
8 % for ischemic heart disease (RR=0.92, 0.80, 0.99) and by
21 % for stroke (RR=0.79, 0.68, 0.91) [83].
Similarly, a dose-response meta-analysis of over 600,000
multi-ethnic adults reported an inverse association between
milk intake and CVD risk, with a 6 % decreased risk associ-
ated with each 200 ml/day of milk consumed [84]. In a pro-
spective cohort study (n=26,445) examining the association
between intake of milk, cheese, cream and butter, and inci-
dence of CVD, total dairy consumption was associated with a
12 % decreased risk of CVD (HR=0.88, 0.77, 1.02 P=0.05).
Among the specific dairy products, a statistically significant
inverse relationship was observed only for fermented milk
(yogurt and cultured sour cream) comparing the highest
(200–300 g/day) versus the lowest (0 g/day) intakes. There
was no association for either milk (full fat or low fat) or butter
and incidence of CVD. This is important based on the com-
monly accepted nutrition strategy of reducing saturated fat
intake to reduce CVD risk [85].
Other studies also have concluded that fat-containing dairy
foods do not increase CVD risk despite their saturated fat
content. For example, in a prospective cohort study of
Swedish adults, 33,636 women were followed for 11.6 years
to examine the association between total, as well as specific,
dairy food intakes and incidence of myocardial infarction (MI)
[86]. When the highest quintile was compared with the lowest
quintile, total dairy food intake was associated with a 23 %
decreased incidence of MI [HR 0.77 (95 % CI 0.63, 0.95,
P<0.05)]. Among specific dairy food products, a 26 % de-
creased incidence of MI [HR 0.74 (95 % CI 0.60, 0.91,
P<0.01)] was observed in highest versus lowest quintile of
cheese intake, while a 17 % reduction in incidence of MI [HR
0.83 (95 % CI 0.68, 1.01, P=0.03)] was observed when com-
paring the highest versus lowest quintile of full fat cheese [86].
A few studies have evaluated associations between bio-
markers of dairy fat and incidence of CVD [87] examined
the potential association of dairy fat (phospholipid 15:0,
trans-16:1n-7, and 14:0) on incident total CVD and CHD in
the Multi-Ethnic Study of Atherosclerosis (MESA). After ad-
justment for demographic, lifestyle, and dietary confounders,
a higher intake of dairy fat (15:0) was associated with a 19 %
lower CVD risk (HR [95 % CI] 0.81 [0.68 to 0.98]) and 26 %
lower CHD risk (0.74 [0.60 to 0.92]). No association was
found for s phospholipid 14:0 and trans-16:1n-7 [87].
Probiotics and Yogurt
Yogurt is a complex functional food produced by the probiotic
bacterial fermentation of milk. The World Health
Organization defines probiotics as live microorganisms
which, when administered in adequate amounts, confer a
Page 9 of 16 39
health benefit on the host. The cardiovascular benefits of yo-
gurt were first investigated in the 1970s when Mann and
Spoerry reported a hypocholesterolemic effect of fermented
milk in Maasai tribesman [88].
Subsequently, several studies have been conducted to clar-
ify the role of fermented dairy products and probiotics on this
relationship. Animal studies have demonstrated the
cholesterol-lowering activity of fermented dairy products with
probiotics. However, human clinical studies using various
probiotics have yielded mixed results, with some studies find-
ing no effect [89–91] while others have identified a significant
cholesterol-lowering effect [92–94].
Two meta-analyses have examined the effect of probiotic
consumption on CHD. In the meta-analysis by Guo et al.
[95], they evaluated the LDL-C- and total cholesterol (TC)-
lowering properties of 10 different probiotic strains. The anal-
ysis included 13 randomized, controlled trials in subjects with
normal and high cholesterol levels. Results from a study of 485
subjects found that, when compared with placebo, probiotic
consumption significantly lowered LDL-C by 4.9 mg/dL
(P<0.01), TC by 6.4 mg/dL (P<0.001), and TG by 3.95 mg/
dL (P <0.05) but had no effect on HDL-C (0.11 mg/dL,
P>0.05). The authors concluded that probiotics Bhave benefi-
cial effects on TC and LDL-C in subjects with high, borderline
high and normal cholesterol levels.^ However, this meta-
analysis is limited by the lack of investigation of the effects
of specific probiotic strains on blood lipids [95].
In a second meta-analysis of five double blind, randomized
controlled trials using the specific probiotic strain
Enterococcus faecium in milk products, [96] Agerholm-
Larsen et al. found a significant decrease in LDL-C and TC
by 5 and 4 % versus placebo, respectively (P<0.05 for both).
The analysis included a total of 400 males and females with
different baseline cholesterol levels. However, the outcomes
from the individual randomized placebo controlled studies
were mixed with some showing a lowering and others
reporting no effect, particularly beyond 3 months [96].
Most recently, DiRienzo [97] reviewed an additional 26
clinical studies including multiple probiotic strains and
found that both E. faecium and Lactobacillus reuteri
lowered LDL-C when compared with placebo. The evidence
for L. reuteri was based on the significant findings of two
multicenter trials, which demonstrated that L. reuteri provid-
ed in either yogurt or capsule form was found to be most
cardioprotective by significantly lowering LDL-C, TC, and
inflammatory markers when compared with the placebo.
The proposed mechanism of action for these probiotics is
thought to be via a reduction in cholesterol absorption as a
result of deconjugation of bile salts in the small intestine due
to bile salt hydroxylase activity. Thus, it was concluded that
both L. reuteri (8.9–11.6 %) and E. faecium (5 %) lowered
LDL-C. Of note is that E. faecium does not have GRAS
status whereas L. reuteri does [97].
39 Page 10 of 16
Olive Oil
Previous meta-analyses of cohort studies reported inconsistent
results of MUFA on coronary heart disease (CHD). In a pooled
analysis of 11 cohort studies, Jakobsen et al. [98•] observed that
replacement of SFA by MUFA marginally increased the risk of
coronary events, whereas there were no significant benefits on
coronary death. However, these results are in contrast with an-
other meta-analysis of cohort studies, where Mente et al. [99]
reported a significant inverse correlation between MUFA (but
not PUFA) rich diets and risk of coronary events [99].
Skeaff and Miller [100] did not observe any association of
MUFA-rich diets with relative CHD events and death.
Similarly, the recent meta-analysis by Chowdhury et al.
[101] including nine cohort studies found no significant asso-
ciations between MUFA intake, circulating MUFA and risk of
CHD. Schwingshackl and Hoffmann [102] summarized the
available evidence regarding MUFA and CVD risk. They con-
cluded that the evidence from long-term prospective cohort
studies provides mixed results about associations of MUFA
with risk of CHD. One explanation for these inconclusive
findings might be for reasons that may pertain to the food
source(s) of MUFA (i.e., animal products) and/or the lack of
control for trans fat in the analyses [102].
For example, results from the PREDIMED trial [103•]
demonstrated significant beneficial effects of experimental di-
ets high in MUFA (from either extra-virgin olive oil, 50 g/day
or mixed nuts, 30 g/day) on major CVD events (a composite
of MI, stroke, or death from cardiovascular causes) in individ-
uals at high cardiovascular risk when compared to a lower-fat
diet. In a recently published follow-up study of 7216 men and
women in the PREDIMED trial, Guasch-Ferre et al. reported
the occurrence of 277 cardiovascular events and 323 deaths.
In this report, participants in the highest energy-adjusted tertile
of baseline total olive oil and extra-virgin olive oil consump-
tion had 35 % (HR 0.65; 95 % CI 0.47, 0.89) and 39 % (HR
0.61; 95 % CI 0.44, 0.85) cardiovascular disease risk reduc-
tion, respectively, compared to the reference. Higher baseline
total olive oil consumption was associated with a 48 % (HR
0.52; 95 % CI 0.29, 0.93) reduced risk of cardiovascular mor-
tality. For each 10 g/day increase in extra-virgin olive oil con-
sumption, cardiovascular disease and mortality risk decreased
by 10 and 7 %, respectively [103•].
It is believed that extra virgin olive oil may provide the
greatest benefit to the Mediterranean diet as it also was found
to be associated with a 26 % reduced risk of all-cause mortal-
ity in the Spanish branch of the EPIC study [104].
Another important study [105] on olive oil consumption is
the Three-City study from France in which the association
with incident stroke was examined in 7625 men and women
after a 5-year follow-up. Compared to those who never used
olive oil, those who used it for both cooking and salad dress-
ing had a 41 % lower risk of stroke [105].
Curr Cardiol Rep (2015) 17: 39
Two meta-analyses have been published recently that exam-
ined the association between olive oil and the risk of CHD. The
meta-analysis conducted by Martinz-Gonzalez [106] consisted
of 101,460 participants (CHD) and 38,673 (stroke). All studies
were conducted in Mediterranean countries. Olive oil con-
sumption was measured via FFQ across all studies. The analy-
sis identified no significant association between olive oil con-
sumption and risk of CHD. A random-effects model assessing
CHD as an outcome showed a relative risk of 0.73 (95 % CI
0.44, 1.21) in case-control studies and 0.96 (95 % CI 0.78,
1.18) in cohort studies following a 25-g increase in olive oil
consumption. Three trials (two cohort studies and the PRED
IMED trial) showed a significantly reduced risk of stroke that
was associated with the consumption of olive oil. For the cohort
studies assessing stroke, a 25 g/day in olive oil consumption
was associated with a combined RR for stroke of 0.76 (95 % CI
0.67, 0.86; P<0.001). The change was negligible when includ-
ing the PREDIMED trial in the model. The random-effects
model combining all cardiovascular events (CHD and stroke)
had a RR of 0.82 (95 % CI 0.70, 0.96) [106].
The meta-analysis [107] conducted by Schwingshackl and
Hoffmann included a total of 32 cohort studies and 841,211
participants. Their results indicate an overall risk reduction of
all-cause mortality (11 %), cardiovascular mortality (12 %),
cardiovascular events (9 %), and stroke (17 %) when compar-
ing the top versus bottom tertile of intakes when MUFA, olive
oil, oleic acid, and the MUFA/SFA ratio were combined. In
subgroup analyses, only olive oil appeared to be associated
with reduced risk since significant associations were only
found between higher intakes of olive oil and reduced risk
of all-cause mortality (RR 0.77, 95 % CI 0.71, 0.84;
P<0.001), cardiovascular events (RR 0.72, 95 % CI 0.57,
0.91; P=0.007), and stroke (RR 0.60, 95 % CI 0.47, 0.77,
P<0.001), respectively [107].
In contrast, subgroup analysis for MUFA (of mixed plant
and animal origin) did not show any significant risk reduction
for all-cause mortality [107].
Red Wine
There is strong epidemiologic evidence that light to moderate
consumption (one to two drinks per day) of alcoholic bever-
ages reduces mortality from all causes and also lessens cardio-
vascular risk with higher intakes being associated with in-
creased cardiovascular risk.
A two-part meta-analysis [108] of 26 studies (13 wine, 13
beer) conducted by Di Castelnuovo et al. identified an inverse
association between light to moderate red wine consumption
and fatal and nonfatal cardiovascular events. For all 13 studies
(5 prospective cohort and 8 case-control studies with a total of
209,418 participants) that compared moderate wine drinkers
(one to two drinks per day) with non-drinkers and heavy or
binge drinkers, moderate wine drinking was associated with a
Curr Cardiol Rep (2015) 17: 39
significant decrease in cardiovascular events after 2 to 24 years
of follow-up (RR=0.68; 95 % CI, 0.59, 0.77) [108]. The second
part of the meta-analysis (7 prospective cohort and 3 case-
control studies) with 176,042 participants, provided evidence
to support a J-shaped dose-response relationship between wine
intake and cardiovascular risk reduction. That is, a statistically
significant inverse association was found as wine intake in-
creased to 150 mL/day (5 oz.). Beer drinking also produced
significant risk reductions although at an extent lower than that
observed with wine. A significant inverse association was ap-
parent when only CHD was considered but, unlike wine, it did
not reach statistical significance when CVD events or cardio-
vascular mortality were individually evaluated [108].
The benefits of red wine are thought to be in part due to the
high polyphenol content, which confers antioxidant, anti-in-
flammatory, and antiplatelet activities. Indeed, multiple small,
randomized controlled trials have found that red wine demon-
strated superior improvements in insulin resistance, lipid pro-
files, and endothelial function compared with other alcoholic
beverages [109]. Thus, for red wine, both the alcohol and
polyphenolic components seem to contribute to its beneficial
effects. In a small prospective clinical study, Chiva-Blanch
et al. [110] found that daily consumption of 275 mL/day
(9 oz.) of dealcoholized red wine decreased systolic and dia-
stolic blood pressure by increasing nitric oxide levels in the
vasculature. This finding is in agreement with previous studies
showing that the vasodilator effects of red wine may be me-
diated by the polyphenolic compounds [110].
Krnic et al. [111] compared the effects of three alcoholic
beverages (red wine, beer, and vodka) on oxidative stress.
While all three beverages provided protection against
oxygen-induced increase in arterial stiffness, only red wine
provided protection against oxidative stress. In addition, stud-
ies comparing red and white wine highlight the greater effects
of red wine on cardiovascular protection [111].
Much of the evidence has focused on the phenolic com-
pound resveratrol as being responsible for the beneficial ef-
fects of red wine, since it has been shown to enhance nitrogen
oxide synthase expression, yet the effect of red wine cannot be
explained by resveratrol alone. It seems more likely, based on
resveratrol’s low bioavailability that many of the effects of red
wine are attributable to the combination of other polyphenolic
compounds found in red wine.
In a meta-analysis [112] assessing the benefits of wine,
beer, and spirits consumption on the incidence of cardiovas-
cular events, the investigators compared 11 studies. They
found a similar J-shaped curve between wine and beer con-
sumption and the incidence of fatal and non-fatal cardiovas-
cular events (with a maximum protection at 25 g alcohol/day).
However, this association was not observed when considering
liquors or spirits, likely due to different drinking patterns of
these individuals compared to those observed for wine and
beers consumers [112].
Page 11 of 16 39
Fish and Seafood
Since the landmark discovery made by Bang, Dyerberg,
and Sinclair in 1980 that consumption of long-chain ome-
ga-3 fatty acids (n-3 FA), i.e., eicosapentanoic acid (EPA)
and docosahexaenoic acid (DHA), was related to a re-
duced rate of ischemic heart disease in Greenland
Eskimos compared with a Danish population, a great deal
of subsequent research has been conducted that has eval-
uated the cardiovascular health benefits and the underlying
mechanisms of action [113]. In 2006, Mozaffarian and
Rimm [114] conducted a comprehensive analysis of pro-
spective cohort studies and randomized controlled trials of
fish intake, n-3 FA, and human health. They reported that
modest consumption (250–500 mg/day) of EPA+DHA
was associated with a lower risk of coronary heart disease
(CHD) death. Between 0 and 205 mg/day was associated
with a 14.6 % decreased risk of CHD death, and between
250 and 500 mg/day risk was decreased by 25 %. In
2013, Mozaffarian et al. [115] reported benefits of plasma
phospholipid n-3 FA levels with cardiovascular mortality
and incident cardiovascular diseases (CVD). Increasing
plasma phospholipid n-3 FA levels (from the first quintile
to the fifth) was associated with decreased total CVD
mortality (−35 %), CHD deaths (−40 %), arrhythmic
deaths (−48 %), fatal and non-fatal CHD (−28 %), and
ischemic stroke (−37 %), P<0.05 for all [114]. Wu et al.
2012 [115] reported that circulating total long-chain n-3
FA and DHA were associated with a lower risk of inci-
dent atrial fibrillation (−29 % for EPA+DPA+DHA and
−23 % for DHA; P<0.01 for both) [116]. In a meta-
analysis of 176,441 subjects from seven prospective stud-
ies, Djousse et al. [117] reported a decreased relative risk
for heart failure comparing the highest to the lowest fish
intake (−15 %) along with marine n-3 FA intake (−14 %;
P<0.05 for both). Collectively, the epidemiologic research
to date clearly demonstrates a beneficial relationship be-
tween fish or fish oil intake and CHD mortality, including
CHD death, as well as sudden death. There is growing
evidence for benefits on ischemic stroke and atrial fibril-
lation, as well as congestive heart failure.
More recent controlled clinical trials have not demonstrated
benefits of n-3 FA in patients with heart disease. Prior to the
more recent trials, the GISSI Prevenzione Study that was pub-
lished in 2002 [118] with 11,300 post-myocardial infarct pa-
tients who were given 850 mg of EPA+DHA per day for
3.5 years reported a 28 % reduction in total mortality (P=
0.027) and a 47 % decrease in sudden death (P=0.0136). In
the Japan EPA Lipid Intervention Study [119], there was a
benefit of EPA in an entire cohort of patients at risk for
CVD or in a secondary prevention cohort with the disease
(−19 % for both). In this study, 18,645 participants were given
statin plus EPA (1.8 g/day) and followed for 5 years. In
39 Page 12 of 16
contrast, several more recent studies have not shown benefits
of EPA+DHA in high-risk CVD patients [120]. The reasons
for this include the following: studies were underpowered and
participants were given low-dose supplementation, as well as
state-of-the-art pharmacotherapy for their heart disease. While
t h e d e b a t e c o n t i n u e s a b o u t w h e t h e r n - 3 FA a r e
cardioprotective, current guidance supports consumption of
250–500 mg/day of EPA+DHA for heart health (USDA)
[121]. In addition, many organizations have recommended
two servings of fish (preferably oily) per week.
Fish and seafood are a source of lean protein and B vita-
mins (B-6, B-12, biotin, and niacin). Vitamin A is found main-
ly in fish liver oils, but some fattier fish like mackerel and
herring can be a good source of vitamin D and vitamin A.
Most seafood is a good source of minerals such as phospho-
rus, potassium, and selenium. Some shellfish, such as clams
and oysters, also are a good source of iron, zinc, and other
trace minerals. Canned fish with edible bones, such as salmon
or sardines, are also rich in calcium.
Practical Application
The impact of functional foods in the prevention of T2DM
and CVD is significant.
Flavonoids come in greater than 8000 chemical structures
and are partly responsible for the protective effects of
cardioprotective dietary patterns rich in vegetables, fruits,
beans, lentils, nuts, seeds, and whole grains. Evidence sup-
ports that a modest long-term consumption of flavonoids
could prevent CVD and T2DM although they are not essential
for short-term well-being [122, 123]. Strong evidence shows
that cardio-protective dietary patterns that have greater impact
on all cause and cardiovascular mortality include the DASH
dietary pattern (Dietary Approaches to Stop Hypertension),
the Mediterranean Style Dietary Pattern, the HEI (Healthy
Eating Index) dietary pattern by the USDA, and the AHEI
(Alternate Healthy Eating Index) food pattern by the
American Heart Association [124].
Recently published guidelines such as the 2015 Dietary
Guidelines for American Committee (DGAC) Report
[125], the lifestyle management guidelines from the
International Atherosclerosis Society [126], the American
Heart Association/American College of Cardiology [127],
the National Lipid Association [128], the American
Diabetes Association [129], and the Obesity Society
[130] recommend consumption of whole food dietary pat-
terns that include increased intake of vegetables, fruits,
legumes, and whole grains; low-fat dairy products, poultry,
fish, non-tropical vegetable oils, and nuts; and limit intake
of saturated fats, sweets, sugar-sweetened beverages, salt
and red meats; and avoid trans-fat and achievement of a
healthy body weight [125–130]. These evidence-based
Curr Cardiol Rep (2015) 17: 39
guidelines recommend referral to a registered dietitian nu-
tritionist (RDN) for in-depth nutrition counseling including
a personalized cardio-protective dietary pattern to prevent
CVD risk and T2D [126–130].
With growing recognition of the many food bioac-
tives and their health benefits, there are many fortified
food products in the marketplace that feature the nutri-
ents and the bioactive components for health benefits.
For example, there are many new sterol/stanol-fortified
foods that are designed to lower cholesterol levels.
Other examples include fiber-fortified foods, probiotics,
and omega-3 fatty acid-fortified foods. In addition, there
are many new products entering the marketplace that are
due to advances in plant and animal breeding tech-
niques, as well as genetically enhanced foods that have
been modified to increase nutrients and bioactives of
interest. Relative to the latter, it will be important to
communicate to the public what the safety and benefits
of foods are that are produced by biotechnology. Given
the pressing need to increase the production of foods
that provide health benefits, it will be important to get
consumer support for new foods in the market that have
been produced using advances in science.
Conclusion
Functional foods can have marked effects in the preven-
tion of CVD and T2DM. Beneficial effects are attribut-
ed to the functional components of different foods on
risk markers related to the initiation and progression of
cardio-metabolic diseases. Ingestion of fatty fish rich in
eicosapentaenoic (EPA) and docosahexaenoic (DHA)
acids could lead to a reduction in inflammatory stimuli
and CVD risk. Consumption of fruits and vegetables,
whole grains, dairy products including fermented prod-
ucts, legumes, nuts, green tea, spices, olive oil, red
wine, herbs, and spices would be expected to decrease
CVD and T2DM risk via multiple mechanisms. As ad-
vances are made in science, it is probable that further
modifications of our food supply can be attained that
further promote health.
Compliance with Ethics Guidelines
Conflict of Interest Geeta Sikand, Penny Kris-Etherton, and Nancy
Mariam Boulos declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Curr Cardiol Rep (2015) 17: 39
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Papers of particular interest, published recently, have been
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