Download Cardioprotective Effect of Nutraceuticals — The Emerging Evidences

Proc Indian Natn Sci Acad 79 No. 4 December 2013, Spl. Issue, Part B, pp. 985-996
Printed in India.
Review Article
Cardioprotective Effect of Nutraceuticals — The Emerging Evidences
M CHOUDHARY* and V TOMER*
*Department of Food and Nutrition, College of Home Science, Punjab Agricultural University, Ludhiana
141 004, India
(Received 01 May 2013; Revised 03 October 2013; Accepted 17 October 2013)
Nutraceuticals are medicinal foods that play a role in maintaining well being, enhancing health, modulating immunity and
thereby preventing as well as treating specific diseases. Thus the field of nutraceuticals can be envisioned as one of the
missing blocks in the health benefit of an individual. More than any other disease, the etiology of cardiovascular disease
reveals many risk factors that are amenable to nutraceutical intervention. Nutraceuticals hold promise in clinical therapy
as they have the potential to significantly reduce the risk of side effects associated with chemotherapy along with reducing
the global health care cost. In whole, nutraceutical has led to the new era of medicine and health, in which the food
industry has become a research oriented sector. In this review, an attempt has been made to summarize some of the recent
research findings on nutraceuticals that have beneficial effects on the heart and have cardioprotective effects.
Key Words: Cardiovascular Diseases; Plant Fibers; Omega-3 Fatty Acids; Soy Protein
1. Introduction
Nutrition is a fundamental need. Various risk factors
related to health result from an imbalance in nutrition
(Kota et al. 2013). Together, these factors contribute
to more than 40 percent of deaths and 30 percent of
the overall disease burden in developing countries.
The nature of India’s nutrition concerns are three
folds — on one hand is the undernourished population
(380 million) with majority having inadequate
purchasing power to even consume a diet sufficient
in calories, let alone take sufficient nutrients (Ramaraj
and Chellappa 2008). On the other hand is the huge
population (570 million) that is nourished in calorie
intake but not in terms of nutrient intake. This
segment would typically include lower middle to
upper class population with sufficient purchasing
power but probably low awareness about their
nutrient requirements, leading to unmet condition
specific needs in addition to foundation needs. In fact,
there are 340 million in our population (30% in urban
and 34% in rural areas) who consume more than
recommended number of calories with higher than
recommended levels of dietary fats and could be the
largest contributor in making India the future
cardiovascular and diabetes capital of the world
(Vaidya and Devasagayam 2007). The third
population segment (80 million) is one which
consumes nutrients and calories more than the norm
due to their enhanced physical requirement because
of their chosen lifestyles and interest areas (Misra
and Khurana 2008, Van Gaal et al. 2006).
Many of the factors affecting nutrition related
concerns are irreversible that have led to natural
sources of nutrients being consumed in insufficient
quantities. Hence, the requirement of external
intervention, that can supplement diet to help prevent
nutrition-related disorders and promote wellness over
treatment of illness, has become critical. Such
products are collectively called as “nutraceuticals”
(Rajasekaran et al. 2008). With the ever increasing
*Authors for Correspondence: E-mail: [email protected], [email protected]
M Choudhary and V Tomer
986
epidemic of obesity, diabetes and hypertension among
young adults, the risk of mortality and morbidity due
to cardiovascular disease is gradually increasing.
Nutraceutical supplements can provide valid alternate
to patients who are intolerant to statins or patients
preferring alternative treatments (Ramaraj and
Chellappa 2008, Misra and Khurana 2008). The
combination of a lipid lowering diet and scientifically
proven nutraceutical supplements can significantly
reduce low density lipoprotein (LDL) cholesterol,
increase LDL particle size, decreased LDL particle
number decreased triglycerides and increased high
density lipoprotein (HDL) particles. In addition, they
address lipid induced vascular damage by suppressing
inflammation, oxidative stress and immune response
leading to additional anti-hypertension, anti-diabetic
properties (Kota et al. 2013). So, the present article
is an attempt to review the evidence in support of
different nutraceuticals and their cardioprotective
effects.
2. Current Scenario of Cardiovascular Diseases
Cardiovascular disease (CVD) due to atherosclerosis
is the leading cause of morbidity and mortality all
over the world. According to World Health
Organization, an estimated 17.3 million people died
from CVDs in 2008, representing 30 percent of all
global deaths. Of these deaths, an estimated 7.3
million were due to coronary heart disease and 6.2
million were due to stroke. Over 80 percent of CVD
deaths take place in low- and middle-income
countries. It is projected that almost 23.6 million
people will die from CVDs by 2030 (WHO 2012).
Cardiovascular diseases have assumed epidemic
proportions in India as well. Rapid westernization in
India has ignited a rapid escalation of lifestyle related
diseases, making the country the global capital for
diabetes and heart disease. The Global Burden of
Diseases (GBD) study reported the estimated
mortality from coronary heart disease (CHD) in India
at 1.6 million in the year 2000. A total of nearly 64
million cases of CVD are likely in the year 2015, of
which nearly 61 million would be CHD cases (the
remaining would include stroke, rheumatic heart
disease and congenital heart diseases). Deaths from
this group of diseases are likely to amount to be a
staggering 3.4 million. Coronary heart disease is
more prevalent in Indian urban populations and there
is a clear declining gradient in its prevalence from
semi-urban to rural populations. Epidemiological
studies show a sizeable burden of CHD in adult rural
(3-5%) and urban (7-10%) populations. Thus, of the
30 million patients with CHD in India, there would
be 14 million of them are in urban and 16 million in
rural areas. In India about 50 per cent of CHD-related
deaths occur in people younger than 70 years
compared with only 22 per cent in the West.
Extrapolation of these numbers estimates the burden
of CHD in India to be more than 32 million patients
(Shah and Mathur 2010).
3. Nutraceuticals
About 2000 years ago, Hippocrates correctly
emphasized “Let food be your medicine and medicine
be your food”. Currently there is an increased global
interest due to the recognition that “nutraceuticals”
play a major role in health enhancement. The term
“Nutraceutical” was coined by combining the terms
“Nutrition” and “Pharmaceutical” in 1989 by Dr
Stephen DeFelice, Chairman of the Foundation for
Innovation in Medicine (Ghodake et al. 2011)
“Nutraceutical” is a marketing term developed for
nutritional supplement that is sold with the intent to
treat or prevent disease and thus has no regulatory
definition (Brower 1998). Hence a “nutraceutical” is
any substance that may be considered a food or part
of a food and provides medical or health benefits,
encompassing, prevention and treatment of diseases.
Such products may range from isolated nutrients,
dietary supplements and diets to genetically
engineered “designer” foods, herbal products and
processed foods such as cereals, soups and beverages.
Presently over 470 nutraceutical and functional food
products are available with documented health
benefits (Zeisel 1999).
4. Current Status of Nutraceuticals in CVD
Majority of the CVD are preventable and
controllable. It was reported that low intake of fruits
and vegetables is associated with a high mortality in
Cardioprotective Effect of Nutraceuticals — The Emerging Evidences
cardiovascular disease (Moller and Kaufman 2005,
Zimmet et al 2005). Many research studies have
identified a protective role for a diet rich in fruits
and vegetables against CVD (Ramaraj and Chellappa
2008). This apart, nutraceuticals in the form of
antioxidants, dietary fibers, omega-3 polyunsaturated
fatty acids (n-3 PUFAs), vitamins, and minerals are
recommended together with physical exercise for
prevention and treatment of CVD. The role of various
nutraceuticals in preventing CVD has been discussed
below:
4.1 Coenzyme Q10 (Ubiquinone)
Coenzyme Q10 (CoQ10) is a potent lipid phase
antioxidant, free radical scavenger, co-factor and
coenzyme in mitochondrial energy production and
oxidative phosphorylation that regenerates vitamins
E, C, and A, inhibits oxidation of LDL, membrane
phospholipids, DNA, mitochondrial proteins, lipids,
reduces total cholesterol (TC), and triglycerides (TG),
raises HDL-C, improves insulin sensitivity, reduces
fasting, random and postprandial glucose, lowers BP
and protects the myocardium from ischemic
reperfusion injury (Digiesi et al. 1990, Digiesi et al.
1992, Morisco et al. 1993, Yokoyama et al. 1996,
Kontush et al. 1997, Langsjoen and Langsjoen 1999,
Singh et al. 1999). Serum levels of CoQ10 decrease
with age and are lower in patients with diseases
characterized by oxidative stress such as
hypertension, CHD, hyperlipidemia, DM,
atherosclerosis, and in those who are involved in
aerobic training, patients on total parenteral nutrition
(TPN), those with hyperthyroidism and patients who
take statin drugs (Digiesi et al. 1990, Kontush et al.
1997). There is a high correlation of CoQ10
deficiency and hypertension. Enzymatic assays
showed a deficiency of CoQ10 in 39 percent of 59
patients with essential hypertension versus only 6
percent deficiency in controls (p < 0.01). Most foods
contain minimal CoQ10, which is primarily found in
meat and seafood.
Supplements are needed to maintain normal
serum levels in many of these disease states and in
some patients taking statin drugs for hyperlipidemia
(Enster and Dallner 1995). Hydroxymethylglutaryl
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coenzyme A reductase inhibitors (statins), first-line
agents for lowering cholesterol levels to prevent
cardiovascular disease, are some of the most
commonly prescribed medications (Sewright et al.
2007, Radcliffe and Campbell 2008). However, statin
therapy carries a risk of myopathy, which can range
from muscle aches to rhabdomyolysis (Sewright et
al. 2007, Radcliffe and Campbell 2008). Statins
inhibit the synthesis of cholesterol by reducing the
production of mevalonate, a precursor of both
cholesterol and CoQ10. Since both cholesterol and
CoQ10 are produced by the same pathway, it is not
surprising that statins have been reported to reduce
serum and muscle CoQ10 levels (Lamperti et al.
2005, Päivä et al. 2005). Nonetheless, researchers
have also hypothesized that a reduction in CoQ10
levels in muscle tissue causes mitochondrial
dysfunction, which could increase the risk of
statininduced myopathy (Young et al. 2007), and
some believe that treatment with CoQ10 may reduce
myalgic symptoms and allow patients to remain on
statin therapy (Radcliffe and Campbell 2008).
Researchers have investigated the potential of
CoQ10 supplementation to reduce or prevent statininduced myopathy. Caso et al. (2007) performed a
small pilot study in 32 patients to determine if CoQ10
supplementation would improve myalgic symptoms
in patients treated with statins. In this double-blind,
randomized trial, patients received either CoQ10 100
mg/day or vitamin E 400 IU/day for 30 days. The
statins were atorvastatin (Lipitor) 10 mg or 20 mg,
lovastatin 40 mg, pravastatin 40 mg, and simvastatin
10, 20, 40, and 80 mg. After 30 days of treatment
with CoQ10, the pain intensity had decreased
significantly from baseline (P < .001). In contrast,
no change in pain intensity from baseline was noted
in patients receiving vitamin E. Also, the interference
of pain with daily activities significantly improved
with CoQ10 (P < .02), whereas vitamin E did not
have a significant impact on this. Similarly, Littlefield
et al. (2013) also concluded that CoQ10
supplementation at a dose of between 30 and 200 mg
daily might benefit those patients suffering from
statin-induced myopathy with no noted side effects.
In contrast, a recent study found no significant effects
M Choudhary and V Tomer
988
on statin-induced myopathy in patients supplemented
with 400 mg Q10 and 200 ìg selenium per day for 12
weeks as compared to control group (Bogsrud et al.
2013).
Coenzyme Q10 has also been postulated to
improve functional status in congestive heart failure
(CHF). Several randomized controlled trials have
examined the effects of CoQ10 on CHF with
inconclusive results (Soja and Mortensen 1997,
Fotino et al. 2013, Stocker and Macdonald 2013).
Morisco et al. 1993 studied the influence of CoQ10
long-term treatment on patients with chronic CHF
(New York Heart Association functional class III and
IV) receiving conventional treatment for heart failure.
They were randomly assigned to receive either
placebo (n = 322, mean age 67 years, range 30-88
years) or CoQ10 (n = 319, mean age 67 years, range
26-89 years) at the dosage of 2 mg/kg per day in a 1year double-blind trial. The results demonstrated that
the addition of CoQ10 to conventional therapy
significantly reduced hospitalization for worsening
of heart failure and the incidence of serious
complications in patients with chronic CHF.
Similarly, Fotino et al. (2013) also found that
supplementation with CoQ10 at a dose = 100 mg per
day resulted in a net change of 3.67 percent in the
ejection fraction (EF) and -0.30 New York Heart
Association (NYHA) functional classification in
patients with CHF.
4.2 Curcumin
It is the bioactive component of tumeric (Curcuma
longa). Curcumin exhibits anticarcinogenic,
antiinflammatory, antioxidative, antiinfectious,
hypoglycemic, and hypocholesterolemic activities as
well as activities blocking TNF, vascular endothelial
growth factor (VEGF), and epithelial growth factor
(EGF) (Olszanecki et al. 2005). Curcumin increases
the LDL receptor, slightly increases HMG-CoA
reductase, and farnesyl diphosphate synthatase;
increases SREBP genes and downregulates
peroxisome proliferator activated receptor (PPAR),
CD 36 FA translocase, and FA binding protein 1 and
stimulates hepatic cholesterol-7 -hydroxylase, which
increases the rate of cholesterol catabolism, liver X
receptor (LXR) expression (Peschel et al. 2007).
Curcumin increases hepatic superoxide dismutase
(SOD) and glutathione peroxidase (GSHPX) leading
to reduced oxidation of LDL-C. Curcumin may
aggravate bleeding in patients taking anticoagulants.
Curcumin has protective effect against alcohol and
PUFA induced hyperlipidemia. A significant decrease
in serum lipid peroxides (33%), increase in HDLC
(29%), and decrease in total serum cholesterol
(11.6%) were noted (Soni and Kuttan 1992). It is
recommended that patients consume about 500 mg
of high quality curcumin (turmeric extracts) per day.
4.3 Flavonoids
Recent interest in phenolic compounds in general,
and flavonoids in particular, has increased greatly
owing to their antioxidant capacity and their possible
beneficial implications in human health (Schroeter
et al. 2002). These include the treatment and
prevention of cancer, cardiovascular disease and other
pathological disorders (Rice-Evans 2001). Flavonoids
block the angiotensin-converting enzyme (ACE) that
raises blood pressure; by blocking the “suicide”
enzyme cyclooxygenase that breaks down
prostaglandins, they prevent platelet stickiness and
hence platelet aggregation. Flavonoids also protect
the vascular system and strengthen the tiny capillaries
that carry oxygen and essential nutrients to all cells.
Flavonoids are widely distributed in onion, endives,
cruciferous vegetables, black grapes, red wine,
grapefruits, apples, cherries and berries (Hollman et
al. 1996). Flavanoids in plants available as flavones
(containing the flavonoid apigenin found in
chamomile); flavanones (hesperidin-citrus fruits;
silybin-milk thistle flavonols (tea: quercetin,
kaempferol and rutin grapefruit; rutinbuckwheat;
ginkgo flavonglycosides - ginkgo), (Majoa 2005) play
a major role in curing the cardiovascular diseases
(Cook and Samman 1996, Hollman et al. 1999).
A recent study by Davison et al. (2008),
investigated the effects of cocoa flavanols and regular
exercise in overweight and obese adults. They showed
that, compared to low-flavanol, high-flavanol cocoa
acutely increased flow mediated dilation (FMD) by
2.4% (P < 0.01) and chronically (over 12 weeks; P <
Cardioprotective Effect of Nutraceuticals — The Emerging Evidences
0.01) by 1.6%. Further, flavanol-rich cocoa intake
reduced insulin resistance by 0.31% (P < 0.05),
diastolic blood pressure by 1.6 mmHg and mean
arterial blood pressure by 1.2 mm Hg (P < 0.05). In
addition, with regard to tea flavanols, an early study
by Duffy et al (2001) showed that short- as well as
long-term black tea consumption reversed endothelial
vasomotor dysfunction in patients with coronary
artery disease. Accordingly, one research study
(Grassi et al. 2009) reported that black tea (containing
increasing doses of flavonoids but very similar of
caffeine) ingestion dose-dependently improved
endothelial function. Black tea increased FMD from
7.8 percent (control) to 9.0, 9.1, 9.6 and 10.3 percent
after the different flavonoid doses, respectively (p =
0.0001). Of interest, even 100 mg/day (less than 1
cup of tea) increased FMD compared with control (p
= 0.0113). Furthermore, FMD after 800 mg/day was
significantly higher than control (p < 0.0001) but also
higher than 100 mg/day (p = 0.0121) and 200 mg/
day (p = 0.0275) administration.
Many of the biological activities of flavonoids
are attributed to their antioxidant properties and free
radical scavenging capabilities. One of the most
actively studied properties of flavonoids is their
protection against oxidative stress (Rice-Evans 2001,
Polovka et al. 2003, Zhao et al. 2000). For example,
flavonoids are ideal scavengers of peroxyl radicals
due to their favourable reduction potentials relative
to alkyl peroxyl radicals and thus, in principle, they
are effective inhibitors of lipid peroxidation. Of
particular importance is the hydrogen (electron)
donating ability of a flavonoid molecule which acts
to scavenge a reactive radical species, and is primarily
associated with the presence of a B-ring catechol
group (dihydroxylated B-ring) (Schroeter et al. 2002).
Hanneken et al. (2006) have conducted a study to
determine whether specific dietary (fisetin, luteolin,
quercetin, eriodictyol, baicalein, galangin and EGCG)
and synthetic (3,6-dihydroxy flavonol and 3,7
dihydroxy flavonol) flavonoids can protect human
retinal pigment epithelial (RPE) cells from oxidativestress-induced death. The results identify a select
group of flavonoids that protect RPE cells from
oxidative-stress-induced death with a high degree of
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potency and low toxicity. Many of these flavonoids
also induce the expression of phase-2 detoxification
proteins which could function to provide additional
protection against oxidative stress. This select group
of flavonoids and the foods that contain high levels
of these compounds may have some clinical benefit
for patients with retinal diseases associated with
oxidative stress.
Recent investigations have demonstrated that
polyphenolic catechins inhibit breast cancer cell
proliferation and tumor growth. Flavonoids block the
enzymes that produce estrogen, thus reducing the risk
of estrogen-induced cancers. Zhang et al. (2004)
conducted to evaluate the effects of 20 naturally
occurring flavonoids on the cellular accumulation and
cytotoxicity of mitoxantrone in both breast cancer
resistance protein (BCRP)-overexpressing and
BCRP-negative human cell lines. BCRPoverexpressing and BCRP-negative human breast
cancer cells (MCF-7) and large cell lung carcinoma
cells (NCI-H460) were used in these studies. Many
of the tested flavonoids (50 microM) increased
mitoxantrone accumulation in BCRP-overexpressing
cells, completely reversing mitoxantrone resistance,
with no effect on the corresponding BCRP-negative
cells, indicating that these flavonoids are BCRP
inhibitors. The effects of these flavonoids on the
cellular accumulation and cytotoxicity of
mitoxantrone were flavonoid concentration
dependent, and significant changes were produced
at concentrations lower than 10 microM for most of
the flavonoids. Chrysin and biochanin A were the
most potent BCRP inhibitors, producing significant
increases in mitoxantrone accumulation at
concentrations of 0.5 or 1.0 microM and in
mitoxantrone cytotoxicity at a concentration of 2.5
microM. Flavonoid glycosides had no effects on the
BCRP-mediated transport of mitoxantrone. Hui et al
(2013) also suggested the chemopreventive effects
of flavonoids on carcinogenesis and revealed that
intake of flavonols and flavones, but not other
flavonoid subclasses or total flavonoids, was
associated with a decreased risk of breast cancer,
especially among post-menopausal women.
M Choudhary and V Tomer
990
4.4 Garlic
4.6 Nuts
Allicin is the active ingredient formed through action
of alliinase enzymes on alliin. It decreases intestinal
cholesterol absorption, inhibits enzymes of
cholesterol synthesis including HMG-CoA reductase
(Nijjar et al. 2010). At doses of 600-900 mg/day of
allicin and ajoene, there is 9-12 percent reduction in
TC and LDL-C (Houston et al. 2009). Raw garlic,
powdered garlic supplement, and aged garlic extract
supplement are equally efficacious. Garlic may have
other protective effects with regard to CVD, such as
reduced blood pressure and platelet inhibition,
fibrinolytic activity, reduction in oxidized LDL, and
coronary artery calcification (Houston et al. 2009).
Based on recent evidence garlic are not reasonably
effective on the lipid profile.
Nuts are a good source of mono- and poly-unsaturated
fatty acids, and they also contain dietary fiber,
phytosterols, and polyphenols. Almonds, walnuts,
hazelnuts, and pistachios have shown reductions in
LDL-C. Increased nut consumption is associated with
reduced risk of CHD (Maki et al. 2010). Consumption
of moderate quantities of walnuts decreases LDL-C
by 18.2 mg/dl (Rajaram et al. 2001). One percent
reductions in LDL-C for walnuts, pecans, peanuts,
macadamias, and pistachios would be achieved with
daily intakes of 4, 11, 4, 10, and 4 g, respectively
(Rajaram et al. 2001). In a recent meta-analysis, diets
supplemented with walnuts resulted in a 6.7 percent
greater decrease in LDL-C (Sabate et al. 2005). They
can be part of a successful low-carbohydrate weightloss program (Foster et al. 2003). Consumption of
28 g of unsalted nuts daily is recommended to
enhance LDL-C lowering and decrease CVD risk
(Kris-Etherton et al. 2001).
4.5 Green Tea
Green tea and its active ingredient, E gallate (EGCG)
reduce fasting and postprandial cholesterol levels
leading to reductions in atherosclerotic CVD
(Tokunaga et al. 2002). EGCG reduces
gastrointestinal cholesterol absorption by interfering
with the emulsification, digestion and micellar
solubilization of lipids, upregulates hepatic LDL
receptor, stimulates FA synthase and paroxonase,
inhibits HMG-CoA reductase, stimulates
mitochondrial energy expenditure, and reduces LDL
oxidation (Tokunaga et al. 2002). EGCG also
decreases Apo B lipoprotein secretion from cells,
mimics the action of insulin, improves endothelial
dysfunction, and decreases body fat (Houston et al.
2009). It reduced total serum glucose and LDL-C,
TGs, and free FAs and increased HDL in diabetic
rats, reduced myocardial levels of lipids, and
improved myocardial function (Anandh et al. 2006).
Two cups of green tea/day in humans reduced serum
LDL-C by 13 mg%, increased plasma total
antioxidant activity, decreased plasma peroxides, and
decreased DNA oxidative damage in lymphocytes
(Erba et al 2005). A meta-analysis showed that EGCG
at 224-674 mg/day reduced TC and LDL-C by 7.2
and 2.19 mg/dl, respectively, (Yu et al. 2006) with
no changes in HDL or TG. The recommended dose is
standardized EGCG extract of 500-700 mg/day.
4.7 Omega-3 Fatty Acids
Long-chain -3 PUFAs such as eicosapentanoic acid
(EPA) and docosahexanoic acid (DHA) (22:6) are
bioactive components in oily fish. Omega-3 PUFAs
alter eicosanoid biosynthesis which affects signaling,
alter membrane fluidity which influences enzymatic
reactions and receptor binding, and directly activate
transcription factors which regulate genes affecting
hyperlipidemia and inflammation. Omega-3 PUFAs
cellular membranes influence membrane fluidity,
which is important for cognitive development.
Omega-3 fatty acids are increasingly being used in
the management of cardiovascular disease as these
reduce platelet aggregation, blood viscosity, plasma
levels of fibrinogen, PF4, and -thromboglobulin and
also increase capillary flow (Semplicini and Valle
1994). In view of this, Weitz et al. (2010) found that
that fish oil, in clinically used doses (typically 4 g/d
of eicosapentaenoic acid and docosahexaenoic acid)
reduce high triglycerides. Kromhout et al. (2011) also
found that an average intake of 223 mg EPA plus 149
mg DHA and/or 1.9 g ALA exerted a protective effect
against ventricular arrhythmia-related events in
postmyocardial infarction patients with diabetes.
Cardioprotective Effect of Nutraceuticals — The Emerging Evidences
Experimental data suggest that long chain n-3
polyunsaturated fatty acids found in fish have
antiarrhythmic properties, and a randomized trial
suggested that dietary supplements of n-3 fatty acids
may reduce the risk of sudden death among survivors
of myocardial infarction. Whether long-chain n-3
fatty acids are also associated with the risk of sudden
death in those without a history of cardiovascular
disease is unknown.
In the Nurses’ Health Study and Physicians’
health study there was a lower risk of CHD and
sudden death with -3 PUFA intake (Hu et al. 2002,
Albert et al. 2002, Zhao et al. 2009). Kottke et al.
(2006) found that raising median n-3 fatty acid levels
would be expected to lower total mortality by 6.4
percent. Similarly, Geelen et al. (2005) concluded
that supplementation with 1.5 g n-3 fatty acids/d from
fish decreased heart rate by 2.1 beats/min in selected
patients, a significant decrease that predicts a lower
risk of sudden death. Further, a recent study
conducted by Mozaffarian (2008) recommended that
consumption of fish or fish oil (1-2 servings/wk of
oily fish, or approximately 250 mg/d of EPA+DHA)
substantially reduced the risk of CHD death and
sudden cardiac death by 36 percent. Each 20-g/day
increase in fish consumption leads to 7 percent
reduction in fatal CHD (Albert et al. 2002). The Diet
and Reinfarction Trial (DART) demonstrated 29
percent decrease in mortality in men postMI. The
Kuppio Heart Study reported 44 percent reduction in
CHD (Houston et al. 2009). Research studies have
proved that one small serving of fish per week would
reduce the risk of nonfatal Myocardial infarction by
27 percent and death from CVD by 17 percent. Each
additional serving would decrease the risk of death
by a further 3.9 percent and would reduce the risk of
stroke by 12 percent. Overall, current data provide
strong concordant evidence that n-3 PUFA are
bioactive compounds that reduce risk of cardiac
death. National and international guidelines have
converged on consistent recommendations for the
general population to consume at least 250 mg/day
of long-chain n-3 PUFA or at least 2 servings/week
of oily fish (Mozaffarian 2011).
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4.8 Plant Fibers
Dietary fibers of plant origin are resistant to digestion.
They are water soluble and structural. Soluble fiber
is found in oats, psyllium, pectin, flaxseed, barley,
and guar gum. The structural fibers such as cellulose,
lignins, and wheat bran are insoluble. Fiber rich diets
are associated with reduced CHD risk (Bazzano et
al. 2003). Soluble fibers physically bind to bile acids
during the intraluminal formation of micelles, entrap
cholesterol resulting in lowered cholesterol
absorption. This leads to increased bile acid synthesis,
reduced hepatic cholesterol, upregulated LDL
receptors, and increased LDL clearance (Brown et
al. 1999). They also increase intraluminal viscosity
and slow macronutrient absorption (Leinonen et al.
2000) and increase satiety leading to lower energy
intake (Blundell and Burley 1987). Insoluble fiber
does not have any effect on LDL-C, unless it replaces
foods supplying saturated fats and cholesterol (KrisEtherton et al. 1988). Ingestion of soluble fibers 210 g/day leads to 5-7 percent reduction in LDL-C
(Brown et al. 1999). There is 12 percent and 19
percent reduction in risk for coronary events and
coronary deaths, for each 10 g/day increment in
dietary fiber (Pereira et al. 2004). The effect was
independent of the type of soluble fiber. A doseresponse relationship was noted, with an absolute
lowering of LDL-C by 1.12 mg/dl/g (Anderson et al.
2000). Reduction in Low Density LipoproteinCholesterol is is similar to that of doubling the dose
of statins (approximately 6%) (Moreyra et al. 2005).
Fenugreek is used as treatment of diabetes with
additional lipid-modifying and antiinflammatory,
antipyretic effects. The dietary fibers glucomannan
and sterol saponins lead to reduced VLDL production
(Boban et al. 2006). The lack of substantial human
studies and animal studies refutes the effectiveness
of Fenugreek for dyslipidemia. Flax seeds contain
fiber and lignans and reduce the levels of 7 alpha
hydrolyase and acyl CoA cholesterol transferase
(ACAT) (Houston et al. 2009). Flax seeds and ALA
are antiinflammatory, increase endothelial nitric oxide
synthase, improve endothelial dysfunction, contain
phytoestrogens and decrease vascular smooth muscle
M Choudhary and V Tomer
992
hypertrophy, reduce oxidative stress, and retard
development of atherosclerosis. These reduce TC and
LDL by 5-15 percent, lipoprotein (a) by 14 percent,
and TG by 36 percent (Houston et al. 2009). These
effects do not apply to flax seed oil. In the seven
countries study, CHD was reduced with ALA
consumption. The Lyon Diet Trial demonstrated that
intake of flax reduced CHD and total deaths by 5070 percent (Houston et al. 2009). The dose required
for these effects ranges from 14 to 40 g of flax seeds
per day.
4.9 Plant Sterols and Stanols
Among the sterols of plant origin B-sitosterol is most
abundant. Others include campesterol, stigmasterol,
and stenol (Nijjar et al. 2010). Sitosterol differs from
cholesterol by an additional ethyl group at C-24
leading to its poor absorption (Fernandez and VegaLopez 2005). Vegetable oils are the main sources of
phytosterols (Patch et al. 2006). Phytosterols in the
gut lower the micellar solubility of dietary and biliary
cholesterol, lowering the amount available for
absorption and increasing bile acid secretion (Patch
et al. 2006). They also interact with enterocyte ATPbinding cassette transport proteins (ABCG 8 and 5)
to direct cholesterol back into the intestinal lumen
(Berger et al. 2004). They have anti-inflammatory
action leading to decrease in hs-CRP, interleukin (IL)
6, IL-1 , TNF , phospholipase 2, and fibrinogen
(Sabeva et al. 2011). Around 2-3 g phytosterol/
stanols/day lower LDL-C by 6-15 percent (Goldberg
et al. 2006). TC decreases by 8 percent, LDL
decreases by 10 percent (range 6-15%) with no
change in TGs or HDL on doses of 2-3 g/day in
divided doses with meals (Berger et al 2004).
4.10 Polyphenols
Polyphenols are simple phenolic molecules to highly
polymerized compounds with molecular weights of
greater than 30,000 Da (German and Walzem 2000).
Stilbenes, anthocyanins, condensed tannins
(proanthocyanidins), in grape and wine, tetrahydro-carbolines, dietary indoleamines, melatonin, and
serotonin, in different plant foods are hypothesized
to impart health benefits, associated with
Mediterranean dietary style. Polyphenols alter
cellular metabolism and signaling, which is consistent
with reducing arterial disease (German and Walzem
2000, Omenn et al. 1996, Hamblin et al. 2007).
4.11 Probiotics
Probiotic bacteria ferment carbohydrates to produce
short-chain FAs, which decrease serum lipids by
inhibiting hepatic cholesterol synthesis and
redistributing cholesterol from plasma to the liver
(Agerholm-Larsen et al. 2000). Probiotics reduce
lipids by coprecipitation with bile salts, deconjugation
to bile salts, incorporation of cholesterol into the
cellular membrane, and microbial assimilation of
cholesterol. Probiotics increase antioxidant potential,
lowering blood pressure, leptin, fibrinogen, F-(2)
isoprostanes, and interleukin 6 and decreased
monocytes adhesion to endothelial cells. Probiotic
for 4-6 weeks reduces TC by 4-12 percent, LDL by
5-8 percent, and TGs by 10 percent (Houston et al
2009). Humans are recommended to consume a high
quality mixed probiotic on a daily basis.
4.12 Soy Proteins
Substitution of animal protein with vegetable protein
appears to be associated with a lower risk of CHD
(Sacks et al. 2006, Carroll 1991). Soy decreases the
micellar content and absorption of lipids by fiber,
isoflavones, and phytoestrogens (Nijjar et al. 2010).
Soy proteins increase LDL receptor expression in
human beings (Baum et al. 1998). Soy nuts (25 g soy
protein) lead to 9.9 and 6.8 percent reduction in
systolic and diastolic BP in hypertensive
postmenopausal women (Welty et al. 2007), possibly
peptides obtained by hydrolysis of soy protein have
angiotensin converting enzyme (ACE) inhibition
property (Welty et al. 2006). Protein hydrolysates
from sesame and rice appeared to be also effective
with ACE inhibition (Nakano et al. 2006, Li et al.
2007). With 30-50 g soy per day, total cholesterol
(TC), LDL-C, and TG decreased by 2-9.3, 4-12.9,
and 10.5 percent, respectively, with 2.4 percent
increase in HDL-C (Harland and Haffner 2008,
Reynolds et al. 2006).
Cardioprotective Effect of Nutraceuticals — The Emerging Evidences
5. Conclusion
Nutraceuticals are medicinal foods that play a role in
maintaining well being, enhancing health, modulating
immunity and thereby preventing as well as treating
specific diseases. The role of nutraceuticals in CVD
has been found to be active and quite effective in a
large number of studies. Evidences indicate that the
mechanistic actions of natural compounds involve a
wide array of biological processes, including
activation of antioxidant defenses, signal transduction
pathways, cell survival-associated gene expression,
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