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Dietary Supplements and Cardiovascular Disease: What is the Evidence and What Should We Recommend?

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It is important to realize the different kinds of evidence in support of health benefits of natural products. One type of evidence is epidemiologic evidence. Epidemiologic information may offer the first suggestion that certain natural products in the diet may influence the risk and course of chronic diseases like cardiovascular disease, diabetes, and cancer. Cross-cultural studies might indicate that populations that have high or low intake of certain compounds have different incidence of cardiovascular disease. This does not prove that supplementation with these compounds would necessarily change the course of cardiovascular disease. Genetic and environmental factors may all contribute to the effects observed in the epidemiologic studies. Cohort studies, which follow groups of people and their intake of certain compounds, also provide suggestive evidence for their effects. A third type of evidence comes from randomized controlled clinical trials. In these trials, compounds are administered to a large population, which is then followed for clearly defined disease events. Randomized clinical trials offer the strongest scientific evidence for or against health benefits. These studies often use pure compounds or standardized preparations. Often, compounds for which epidemiologic studies suggest benefit, and mechanistic studies show effects, fail to do so in large randomized clinical trials. There have also been surprising results of increased disease risk from certain natural products, suggesting the need for caution and for ongoing studies to obtain evidence of the best possible quality. It is important to approach results of studies with a critical eye, and to always consider the quality of the information and how strongly it supports an effect.
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Dietary Supplements and Cardiovascular
Disease: What is the Evidence
and What Should We Recommend?
Satoshi Kashiwagi and Paul L. Huang
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital
and Harvard Medical School, Charlestown, MA,
USA
1. Introduction
1.1 Importance of cardiovascular disease and scope of this chapter
Cardiovascular disease, diabetes, and obesity are important causes of morbidity and
mortality. Cardiovascular disease affects 80 million Americans and is the leading cause of
death (Lloyd-Jones et al., 2009). Diabetes and obesity are also increasing at alarming rates,
and together, the three conditions have a significant impact on public health (Ogden et al.,
2006). Cardiovascular disease, diabetes and obesity can be influenced by lifestyle changes,
including diet and physical activity (McCullough et al., 2000). The American Heart
Association recommends a diet rich in vegetables and fruits, whole grains, high-fiber foods,
with lean meats and poultry, moderate consumption of fish, an emphasis on fat-free or low
fat dairy products, and limiting the amount of saturated fat, trans fat and cholesterol
(Lichtenstein et al., 2006).
Among natural products found in food, fish oils, vitamin E, and soy isoflavones have been
studied for their effects on cardiovascular disease. Many of these compounds are available
as food supplements. There is a great interest among the public and in the lay press about
the use of these compounds to treat or prevent disease. The scope of this chapter is to review
the evidence for the effects of these compounds on cardiovascular disease, so that physicians
and patients may better understand their health effects, in an effort to reduce the risk for
cardiovascular disease, diabetes and obesity.
1.2 Types of evidence: Epidemiologic, mechanistic, and randomized clinical trials
It is important to realize the different kinds of evidence in support of health benefits of
natural products. One type of evidence is epidemiologic evidence. Epidemiologic information
may offer the first suggestion that certain natural products in the diet may influence the risk
and course of chronic diseases like cardiovascular disease, diabetes, and cancer. Cross-
cultural studies might indicate that populations that have high or low intake of certain
compounds have different incidence of cardiovascular disease. This does not prove that
supplementation with these compounds would necessarily change the course of
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450
cardiovascular disease. Genetic and environmental factors may all contribute to the effects
observed in the epidemiologic studies. Cohort studies, which follow groups of people and
their intake of certain compounds, also provide suggestive evidence for their effects.
A second type of evidence comes from mechanistic studies in the laboratory or in animal
models. Here, the natural products or compounds in question are added to cells or enzyme
reactions, to see what their effects are. Studies may be done in animal models of human
disease, for example apoE knockout mice that develop diet-induced atherosclerosis. They may
be carried out on blood vessels from animals to see whether the compounds affect vascular
function. Mechanistic studies help determine the possible molecular and cellular mechanisms
and pathways involved in biological function. However, just because a compound has an
effect in these experiments or animals models does not mean that taking them will necessarily
reduce disease in people. Many of these experiments are done in vitro, not in vivo.
A third type of evidence comes from randomized controlled clinical trials. In these trials,
compounds are administered to a large population, which is then followed for clearly
defined disease events. Randomized clinical trials offer the strongest scientific evidence for
or against health benefits. These studies often use pure compounds or standardized
preparations. Often, compounds for which epidemiologic studies suggest benefit, and
mechanistic studies show effects, fail to do so in large randomized clinical trials. There have
also been surprising results of increased disease risk from certain natural products,
suggesting the need for caution and for ongoing studies to obtain evidence of the best
possible quality. It is important to approach results of studies with a critical eye, and to
always consider the quality of the information and how strongly it supports an effect.
In this article, three specific classes of compounds—omega-3 fatty acids, vitamin E, and soy
isoflavones—are reviewed. Evidence for their biological effects are presented, categorized
separately according to type of evidence: epidemiological studies, mechanistic studies, and
where available, randomized controlled trials. It is hoped that this review will provide the
basis for evidence-based recommendations to patients regarding these compounds and food
supplements.
2. Fish oils: Omega-3 fatty acids
2.1 Structure and food sources
While many fatty acids serve as energy stores that are broken down by the body to generate
energy, omega-3 and omega-6 fatty acids are two types of polyunsaturated fatty acids that
serve as precursors to biologically active molecules, including prostaglandins, leukotrienes,
and thromboxanes. This role gives them particular importance in the diet.
Polyunsaturated fatty acids are a family of long-chain (typically 18-24 carbon atoms) fatty
acids containing two or more double bonds. Omega-3 and omega-6 refer to the position of
the last double bond. The convention in chemical nomenclature is to label the COOH carbon
as the first carbon, and the one furthest from this as the last, or omega, carbon. Thus, omega-3
fatty acids contain a double bond three carbons from the end of the molecule furthest from
the COOH group. Given that the length of the hydrocarbon chain is variable, the length is
sometimes referred to as “n,” so omega-3 fatty acids are also known as n-3 fatty acids, and
omega-6 fatty acids as n-6 fatty acids.
Dietary Supplements and Cardiovascular Disease:
What is the Evidence and What Should We Recommend? 451
Fig. 1. Structures of omega-6 and omega-3 fatty acids
Omega-3 fatty acids differ from omega-6 fatty acids by the location of their first double bond
from the methyl (CH3) end of the fatty acid. Omega-3 fatty acids include -linolenic acid
(ALA), eicosapentanoic acid (EPA), and docosahexanoic acid (DHA). Omega-6 fatty acids
include linoleic acid (LA), arachidonic acid (AA), and docosapentanoic acid (DPA). In the
chemical names, the number of carbon atoms is given first, separated by a colon from the
number of double bonds, followed by the position of the first double bond.
The structures of omega-3 and omega-6 fatty acids are shown in Figure 1. Representative
omega-3 fatty acids are -linolenic acid (ALA), eicosapentanoic acid (EPA), and
docosahexanoic acid (DHA). Of these, the parent omega-3 fatty acid is ALA, an 18 carbon
fatty acid with three double bonds, the last of which is located between carbons 15 and 16
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452
(the n-3 position). Therefore, in shorthand, ALA is C18:3 n-3. ALA serves as the precursor to
the omega-3 fatty acids EPA (C20:5 n-3) and DHA (C22:6 n-3) by the addition of carbons to
the chain (elongation) and by the replacement of single bonds by double bonds
(desaturation). Likewise, representative omega-6 fatty acids are linoleic acid (LA),
arachidonic acid (AA), and docosapentanoic acid. LA is an 18 carbon fatty acid with two
double bonds, with the last one located at the n-6 position (C18:2 n-6). LA serves as a
precursor to AA (C20:4 n-6) and docosapentanoic acid (C22:5 n-6), which are formed by
elongation and desaturation.
The parent fatty acids of the omega-3 family (ALA) and omega-6 family (LA) cannot be
made by the human body, so they are essential fatty acids. They must be supplied in the diet.
LA is found in vegetable oils like soybean and canola, and also in nuts, seeds, vegetables,
legumes, grains, and fruit. ALA is found in vegetable sources like flaxseed, but only 5% of
ALA is converted to DHA and EPA. The richest sources of DHA and EPA are fish and fish
oils.
2.2 Biological roles of omega-3 and omega-6 fatty acids
Omega-3 and -6 fatty acids are important biologically because they influence production of
prostaglandins, leukotrienes, and thromboxanes. These mediators affect many diverse
processes, and are involved in inflammation, pain, and thrombosis (Calder, 2006).
Moreover, omega-3 and omega-6 fatty acids are separate families that cannot be
interconverted by the human body. Because they compete for the same enzymes, the ratio of
omega-3 to omega-6 fatty acids in the diet influences the relative amounts of prostaglandins
and leukotrienes that are synthesized from arachidonic acid.
2.3 Epidemiologic data on fish oils and cardiovascular disease
Epidemiologic data from fish-eating populations like the Greenland Inuits established a link
between fish oil consumption and lower incidence of cardiovascular disease (Dyerberg et
al., 1975). Fish oil consumption was also linked with low levels of triglycerides, plasma
cholesterol and very low-density lipoproteins (VLDL) and high levels of high-density
lipoproteins (HDL), all of which would protect against cardiovascular disease.
2.4 Mechanistic studies
Omega-3 fatty acids may influence cardiovascular disease through effects on lipid profiles,
eicosanoid pathways, and susceptibility to arrythmias.
2.4.1 Lipid profiles
Omega-3 fatty acids decrease plasma cholesterol concentrations in animal models
(Fernandez & West, 2005). They increase hepatic LDL receptor number and LDL turnover in
vivo (Fernandez & McNamar, 1989, Fernandez et al., 1992), and bind to peroxisome
proliferator activated receptors (PPARs), liver X receptors (LXRs), hepatic nuclear factor-4
(HNF-4), and sterol regulatory element binding proteins (SREBPs) (Jump, 2002). Omega-3
fatty acids suppress SREBP-1 expression, leading to decreased lipogenesis and VLDL
secretion (Field et al., 2003), increased LPL activity (Illingworth & Schmidt, 1993), and
Dietary Supplements and Cardiovascular Disease:
What is the Evidence and What Should We Recommend? 453
decreased apoC3 levels (Shachter, 2001). They also decrease lipogenesis and VLDL secretion
while increasing reverse cholesterol transport (Vasandani et al., 2002).
2.4.2 Eicosanoid metabolism
Omega-3 and omega-6 fatty acids are precursors to a broad array of structurally diverse and
potent bioactive lipids, including eicosanoids, prostaglandins, and thromboxanes.
Eicosanoids are produced from arachidonic acid, EPA, and dihomolinolenic acid when these
fatty acids are released from membranes by phospholipase A2 (Zhou & Nilsson, 2001). The
availability of these eicosanoid precursors depends on dietary levels of these molecules, as
well as the parent fatty acids of each family: ALA for omega-3 fatty acids, and LA for
omega-6 fatty acids. Because omega-6 and omega-3 fatty acids cannot be interconverted,
their relative ratios are important.
Arachidonic acid, an omega-6 fatty acid, is a precursor of prostaglandins, leukotrienes and
related compounds that mediate inflammation. Because omega-3 fatty acids compete with
omega-6 fatty acid metabolism, increased consumption of omega-3 fatty acids (particularly
DHA and EPA) results in the partial replacement of arachidonic acid in cell membranes by
EPA and DHA, and a decrease in the production of biological mediators derived from AA.
Intake of 6 g DHA/d decreased production of prostaglandin E2 by 60% and leukotriene B4
by 75% in endotoxin-stimulated mononuclear cells (Kelley et al., 1999). Other studies have
shown a shift in the relative amounts of prostaglandin I2 and thromboxane A2, resulting in
vasodilation and reduced thrombosis (von Schacky et al., 1985, Goodnight et al., 1989).
Omega-3 fatty acids, particularly DHA and EPA in fish oil, may themselves reduce
expression of ICAM-1 on the surface of stimulated blood monocytes (Hughes et al., 1996),
and decrease hydrogen peroxide production (Fisher et al., 1990).
2.4.3 Antiarrhythmic effects
DHA and EPA may be preferentially incorporated into membrane phospholipids,
accounting for an antiarrhythmic effect after dietary intake (Nair et al., 1999). These fatty
acids directly influence conduction of several membrane ion channels (Leaf et al., 2003),
inhibit voltage-gated sodium currents and L-type calcium currents (Kang et al., 1995), and
shift the steady-state inactivation potential to more negative values in cardiomyocytes.
These results provide an electrophysiological basis for antiarrhythmic effects.
2.5 Clinical studies
Dietary intake of omega-3 fatty acids, particularly DHA and EPA found in fatty fish or fish-
oil supplements, reduces risk of CVD (Kris-Etherton et al., 2002, Wang et al., 2006). The
strongest evidence comes from the Italian GISSI trial (1999), a secondary prevention study in
over 11,000 patients with recent myocardial infarction. Supplementation with 0.85 g EPA
and DHA per day reduced all-cause mortality by 21%, cardiac death by 35%, and sudden
death by 45%. No effect was found on stroke. In contrast, a Norwegian study of 300 patients
following MI, randomized to a higher intake of omega-3 fatty acids (3.4 g EPA and DPA per
day), failed to show a difference in CVD events, but there was a high background of fish oil
intake in both groups. Several other small studies suggested beneficial trends in CVD and
PVD, but these were not statistically significant (Sacks et al., 1995, Nilsen et al., 2001).
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454
In these studies, patients with implantable cardiac defibrillators (ICD) were excluded.
Several randomized controlled trials, ranging in size from 200 to over 500 patients, studied
fish oil consumption in patients with ICDs (Raitt et al., 2005,Brouwer et al., 2006). These
studies showed no change in mortality from fish oil consumption. It is possible that the
beneficial effects of fish oils may not be observed in the ICD population, because these
patients all have defibrillators and therefore cardiac arrhythmic sudden death would be
removed from both groups.
Primary prevention trials, which study patients in the general population who do not have
known heart disease, have not shown as strong an effect as the GISSI trial. Most primary
prevention data on fish oils comes from large cohort studies from China, Japan, and the
United States (Dolecek, 1992, Nagata et al., 2002) and others. In aggregate, these studies
included over 343,000 subjects, and showed reductions in all-cause mortality, cardiac
mortality, and sudden death. Interestingly, in one of these studies (Mozaffarian et al., 2003),
the protection was found with tuna and other nonfried fish, while consumption of fried fish
or fried fish sandwiches was associated with increased cardiovascular events.
3. Vitamin E
3.1 Structure and food sources
Vitamin E is a fat-soluble vitamin that exists in at least eight naturally occurring forms, as
shown in Figure 2. Tocotrienols differ from tocopherols by the presence of three double
bonds in their isoprenoid side chains. The -, -, -, and - forms are defined by the identity
of the R groups on the chromanol rings. Vitamin E found naturally in food is primarily -
tocopherol, but -tocopherol is the predominant form found in supplements, and is also the
most biologically active form.
Vitamin E is an essential vitamin because it cannot be synthesized by the body. Sources of
vitamin E include nuts and seeds, such as almonds, peanuts, sunflower seeds, and filberts.
Tocopherols are similar in structure to tocotrienols, except that tocotrienols have three
double bonds in the phytyl side chains. There are three positions on the chromanol ring,
denoted R1, R2, and R3. The particular identity of the tocopherol or tocotrienol is determined
by the identities of these side chains. Vitamin E found naturally in food is primarily -
tocopherol. -tocopherol, which is the most biologically active, is the predominant form
found in supplements.
Vitamin E is also found in vegetable oils (soy, corn or sunflower), and their derivatives
(margarine), cereals and grains. Vitamin E is found in potato chips and tomato products
because of the vegetable oils that they contain.
3.2 Biological roles of vitamin E
Vitamin E is an antioxidant, because it breaks chain reactions that are propagated by free
radicals. Vitamin E is present in biological membranes, and serves as an important lipid
soluble antioxidant. It reacts with oxidant molecules and protects cell membranes from lipid
peroxidation by trapping peroxyl radicals. One molecule of -tocopherol per 1,000
phospholipids can protect cellular membranes. -tocopherol can also be regenerated from
its tocopheroxyl radical by an electron donor like vitamin C.
Dietary Supplements and Cardiovascular Disease:
What is the Evidence and What Should We Recommend? 455
Fig. 2. Structures of tocopherols and tocotrienols
3.3 Epidemiologic data on vitamin E and cardiovascular disease
High intake of vitamin E is epidemiologically associated with lower cardiovascular disease
risk. The World Health Organization/Monica project performed cross-cultural analysis on
vitamin intake in populations with different incidence of coronary heart disease mortality.
Differences in cardiovascular mortality were primarily attributable to plasma levels of
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456
vitamin E in middle-aged men representing 16 European study populations (Gey et al.,
1991).
Several cohort studies showed similar results. The US Nurse’s Health Study followed a
cohort of 87,245 female nurses between the ages of 34 and 59 years, over an eight year
period. Supplementation with -tocopherol for at least two years was associated with
reduced risk of cardiovascular disease (Stampfer et al., 1993). Incidence of heart disease was
30-40% lower in those with the highest intakes of vitamin E. Another cohort study followed
39,910 male health professionals between the ages of 40 and 75. Consumption of more than
60 IU/d of vitamin E was associated with a 40% relative risk reduction of cardiovascular
disease (Rimm et al., 1993). Vitamin E intake from food was inversely associated with CVD
risk in 34,486 postmenopausal women (Kushi et al., 1996).
3.4 Mechanistic studies
In ex vivo human studies, monocytes isolated from healthy human subjects supplemented
with -tocopherol showed decreased LDL oxidation (Devaraj et al., 1996). In other studies,
vitamin E supplementation failed to affect lipid oxidation, including isoprostanes and 4-
hydroxynonenal (breakdown products of fatty acid autooxidation) (Meagher et al., 2001).
One animal study showed that vitamin E intake inversely correlates with atherosclerotic
lesions and liver peroxidation in apoE knockout mice (Ferre et al., 2001). In another study,
vitamin E and coenzyme Q (CoQ) supplementation significantly reduced tissue lipid
hydroperoxide formation and limited the development of atherosclerosis in apoE knockout
mice (Thomas et al., 2001). However, still other studies found that vitamin E did not reduce
atherosclerosis in apoE knockout mice (Paul et al., 2001), or fatty streak formation in
C57/Bl6 mice (Munday et al., 1998). The degree of lipid oxidation in vascular tissue also
failed to correlate with the extent of the lesions in apoE knockout mice (Wu et al., 2006).
Thus, animal studies do not show uniform benefit of vitamin E supplementation in
preventing LDL oxidation or reducing atherosclerosis.
3.5 Clinical trials on vitamin E
3.5.1 Vitamin E and cardiovascular disease
Some clinical trials suggest a benefit of vitamin E in reducing cardiovascular disease. The
Cambridge Heart Antioxidant Study (CHAOS) randomized 2,002 patients with coronary
disease to -tocopherol (400 to 800 IU) or placebo. The vitamin E treated groups showed 1.9
fold reductions in cardiovascular death and nonfatal myocardial infarction (Stephens et al.,
1996). The Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage
Renal Disease (SPACE) trial randomized 192 renal failure patients undergoing hemodialysis
to 800 IU vitamin E or placebo. The vitamin E treated group showed a significant decrease
in both fatal and nonfatal cardiovascular endpoints (Boaz et al., 2000).
Other clinical trials failed to show benefit. In the GISSI study, 11,324 patients were given
omega-3 fatty acids, vitamin E at 300 mg per day, both, or neither, and followed over a 3½
year period. Two-way analysis did not show any reduction in fatal or nonfatal
cardiovascular events from vitamin E supplementation (Marchioli et al., 2002), (1999). The
Heart Outcomes Prevention Evaluation (HOPE) trial was a multinational study of over 9,500
Dietary Supplements and Cardiovascular Disease:
What is the Evidence and What Should We Recommend? 457
patients with known cardiovascular disease, randomized to the angiotensin converting
enzyme inhibitor ramipril, natural source vitamin E at 400 IU per day, both, or neither. Over
a 4½ year follow-up, there was no reduction in fatal or nonfatal cardiovascular events in the
vitamin E treated groups (Yusuf et al., 2000). In an extension study (HOPE –TOO), almost
4000 subjects continued to take vitamin E or placebo for an additional 2½ years (Lonn et al.,
2005). Despite this 7 year total follow-up period, there was no significant protection against
cardiovascular disease, stroke, or death.
Of concern, the HOPE-TOO study showed a higher incidence of heart failure in the
treated group. In the Women’s Angiographic Vitamin and Estrogen Study, 423 post-
menopausal women with coronary disease took supplements with 400 IU vitamin E or
placebo (Waters et al., 2002). Not only did women taking vitamin E not show
cardiovascular benefit, but there was an increase in all-cause mortality. In the Physicians
Health Study II, 15,000 health physicians age 50 or over were randomized to -tocopherol
(400 IU), 500 mg vitamin C, both, or placebo (Sesso et al., 2008). Over a follow-up period
of 8 years, neither vitamin E nor vitamin C resulted in a decrease in cardiovascular events,
stroke, or cardiovascular mortality. In contrast, -tocopherol was associated with an
increase in hemorrhagic stroke. Taking the results of all of these results together,
including a meta-analysis (Miller et al., 2005), vitamin E is not recommended for the
purpose of reducing cardiovascular risk.
3.5.2 Vitamin E and diabetes
Oxidative stress and inflammation have been implicated in the pathogenesis of diabetes(Ho
& Bray, 1999). Vitamin E treatment (600 mg per day) improved insulin-mediated glucose
disposal in 36 healthy, nondiabetic volunteers (Facchini et al., 2000). A prospective cohort
study showed that plasma concentration of -tocopherol was inversely related to fasting
plasma glucose concentration and oxidative stress markers in 101 women at high risk of
type 2 diabetes in Finland (Ylonen et al., 2003). In secondary prevention trials, 600 mg/day
of vitamin E supplementation significantly decreased markers of oxidative stress and
improved brachial artery reactivity in 40 patients with diabetes (Paolisso et al., 2000).
However, the Insulin Resistance and Atherosclerosis Study (IRAS) cohort study showed no
protective effect for either reported intake of vitamin E or plasma concentration of -
tocopherol in 895 nondiabetic adults (Mayer-Davis et al., 2002). In another study, high levels
of -tocopherol and -carotene were associated with decreased risk of non-insulin
dependent diabetes mellitus, but the association disappeared after adjustment for
cardiovascular risk factors (Reunanen et al., 1998). Whether vitamin E influences the
development of diabetes is not clear and warrants further investigation.
4. Phytoestrogens
4.1 Structure and food sources of phytoestrogens
Phytoestrogens are flavonoids that have similar chemical structure to estrogen. They include
isoflavones, coumestans, and lignans (Kurzer & Xu, 1997). Figure 3 shows a comparison of
the chemical structures of estradiol (a naturally occurring human estrogen), genistein (an
isoflavone), and coumestrol (a coumestan). A number of these compounds have been
identified in fruits, vegetables, and whole grains commonly consumed as food. Soybeans,
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458
clover and alfalfa sprouts, and oilseeds (such as flaxseed) are the most significant dietary
sources.
Fig. 3. Structures of isoflavones and coumestans compared with estrogen
The structure of estradiol, a natural estrogen, is shown along with the structures of
genistein, a prototypic isoflavone found in soy, and coumestrol, a prototypic coumestan.
4.2 Epidemiology data on phytoestrogens and cardiovascular disease
While typical isoflavone intake is less than 1 mg per day in Western countries, intakes of 20-
50 mg per day are common in Asian countries such as China and Japan, where soy is a
traditional staple food (Adlercreutz & Mazur, 1997). These countries also have shown
reduced incidence of cardiovascular disease compared with Western countries, an effect that
is diminishing as Western eating habits and diets are adopted.
4.3 Biological activities of phytoestrogens
Dietary phytoestrogens may play an important role in prevention of menopausal symptoms,
osteoporosis, cancer, and cardiovascular disease. The major mechanisms of biological action
for the phytoestrogens are those mediated by estrogen receptors (estrogenic and
antiestrogenic effects), effects on tyrosine kinase and DNA topoisomerase activities,
suppression of angiogenesis, and antioxidant effects.
Although not as active as 17-estradiol, phytoestrogens compete with estradiol for binding
to estrogen receptors (ER), particularly ER (Kuiper et al., 1998). ER, present in high
Dietary Supplements and Cardiovascular Disease:
What is the Evidence and What Should We Recommend? 459
concentrations in ovary and testis, binds phytoestrogens with higher affinity, and may
mediate some of their biological effects (Kuiper et al., 1998). Alternatively, soy isoflavones
may be natural selective estrogen receptor modulators (SERMs) with both agonist and
antagonist activities (Setchell, 2001).
Soy isoflavones decrease total cholesterol, LDL, and triglycerides, and increase HDL levels
(Clarkson et al., 2001). They also lower blood pressure and improve endothelial reactivity
(Teede et al., 2001, Steinberg et al., 2003). Supplementation of isoflavones derived from red
clover containing genistein, daidzein, biochanin, and formononetin significantly improved
arterial compliance in elderly men and women (Nestel et al., 1999).
Several studies reveal the potential of phytoestrogens to induce hormone-dependent cancers
(e.g. breast and endometrium) (McMichael-Phillips et al., 1998), leading to safety concerns.
Because of this, a maximum daily intake level for phytoestrogens has been suggested in
several countries (Sirtori et al., 2005).
Summary of key points
Omega-3 fatty acids
Important omega-3 fatty acids include EPA and DHA
Mechanisms for omega-3 fatty acids include
-reduced inflammation due to decreased prostaglandin and
leukotriene synthesis
-reduced thrombosis and platelet aggregation
-direct antiarrythmic effects in cell membranes
Large studies confirm that omega-3 fatty acid intake reduces
cardiovascular disease and sudden death
The American Heart Association recommends eating fish twice
a week, and daily intake of 1 g EPA and DHA to reduce
cardiovascular disease
Vitamin E
Vitamin E is an essential fat soluble vitamin that is an
antioxidant
Animal studies do not uniformly show beneficial effects
Vitamin E reduced cardiovascular risk in two studies (CHAOS
and SPACE), but not in others (GISSI, HOPE-TOO)
Vitamin E supplementation has been associated with higher
incidence of heart failure, so routine supplementation with
vitamin E is not recommended
Phytoestrogens
Phytoestrogens, including soy isoflavones, are plant
compounds with chemical structures that resemble estrogens
Mechanisms include improved lipid profiles and improved
endothelial reactivity
Phytoestrogens may induce hormone dependent cancers
(breast and endometrial), leading to recommendations on
maximum dail
y
intake
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460
5. Conclusions and evidence-based recommendations
Omega-3 fatty acids have been clearly shown in epidemiological studies and clinical trials to
reduce the incidence of cardiovascular disease. Thus, the American Heart Association
recommends eating fish (particularly fatty fish) at least twice a week. They also recommend
foods rich in ALA (flaxseed, canola, and soybean oils; flaxseed and walnuts). For patients
with documented coronary heart disease, the recommended level of consumption is 1 g of
EPA+DHA per day, either from fish (preferably), or supplementation. For subjects with
elevated triglyceride levels, 2-4 grams of EPA+DHA is recommended as supplementation
(Kris-Etherton et al., 2002).
At this time, the evidence does not justify the use of vitamin E supplements for CVD risk
reduction, both because of lack of evidence for benefit and possible adverse effect reflected
in the increases in all-cause mortality and hemorrhagic stroke. However, a balanced diet
with emphasis on antioxidant-rich fruits, vegetables, and whole grains is recommended
(Kris-Etherton et al., 2004). Whether antioxidant vitamin supplements including vitamin E
influence the development of diabetes, in which oxidative stress plays an important role, is
not clear and warrants further investigation.
Supplementing the diet with soy protein has failed to confirm phytoestrogens as the
responsible agent for beneficial cardiovascular effects. Furthermore, soy phytoestrogens
may increase carcinogenesis. Thus, isoflavone supplements are not currently recommended
(Sacks et al., 2006). Soy foods may still be beneficial to cardiovascular and overall health
because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low
content of saturated fat (Krauss et al., 2000).
Epidemiologic evidence has suggested an array of potentially beneficial compounds in
foods. While there have been many mechanistic studies in the laboratory or in animal
models, large scale randomized controlled clinical trials are necessary to prove or disprove
their effects on health and safety, particularly in light of possible toxicities. Until the results
of such studies are available, a diet consistent with American Heart Association
recommendations (Kris-Etherton et al., 2004), with emphasis on antioxidant-rich fruits,
vegetables, and whole grains, appears to be the most sensible approach.
6. Acknowledgements
PLH acknowledges grant support from Public Health Service grant R01-NS33335 from the
National Institute of Neurologic Diseases and Stroke, and grant R01-HL048426 from the
National Heart Lung and Blood Institute.
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... Obesity, diabetes, and cardiovascular ailment are all key causes of death rate. Cardiac disorders are the primary reason of death in the US, affecting 80 million people (Kashiwagi& L., 2012). Coronary artery disease is another name for coronary heart disease. ...
... The American Heart Association suggests that nutrition abundant in fruits, vegetables, whole grains, and meals with high amounts of fiber, as well as lean meats and fowl, moderate seafood intake, milk goods which are free from fat or having low fat content, and restricting saturated fat, trans fat, and cholesterol (Kashiwagi, 2012). ...
Chapter
Cardiovascular disease (CVD) has overcome as the top cause of mortality worldwide, and it is an increasing public health concern. Dietary variables are crucial in the etiology of CVD and may influence CVD risk to a great extent, although they have received much less attention. The preventive benefits of dietary supplements in the prevention of Coronary Heart Disease have sparked a surge of interest. There has been a paradigm shift in nutritional epidemiology in the last decade, with researchers looking at connections between dietary habits and health. Specific dietary methods to address cardiovascular risk factors, such as the Dietary Approaches to Stop Hypertension diet and Therapeutic Lifestyle Changes, are based on food-based principles and have been demonstrated to be beneficial in treating hypertension and hypercholesterolemia, respectively. As a result, these diets considerably lower the risk of coronary heart disease. On the impact of foods and dietary supplements on the risk of coronary heart disease, a number of
... (DHA), whereas ω − 6 contain linoleic acid (LA), arachidonic acid (AA), and docosapentanoic acid (DPA) [2,4]. A balance between ω − 6 and ω − 3 ratio, exerting pro-inflammatory and anti-inflammatory properties, respectively, is a crucial factor for maintaining health resilience and has been shown to be associated with incidence of chronic inflammatory diseases such as inflammatory bowel diseases (IBD), cardiovascular disease, and cancer [3,5]. ...
... Ω − 3 PUFAs are associated with anti-inflammatory and immunoregulatory functions, mediated by a variety of downstream lipid metabolites [51]. These fatty acids are biologically significant since they affect the production of prostaglandins (PG), leukotrienes (LT), and thromboxanes (TB), which impact many diverse processes related to inflammation, pain, and thrombosis [4]. ω − 3 can also decrease oxidative stress, resulting from imbalances between free radicals and antioxidants [52]. ...
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Conference Paper
Phytoestrogens have become one of the more topical areas of interest in clinical nutrition. These non-nutrient bioactive compounds are ubiquitous to the plant kingdom and possess a wide range of biological properties that contribute to the many different health-related benefits reported for soy foods and flaxseeds-two of the most abundant dietary sources of phytoestrogens. Reviewed is the recent knowledge related to their pharmacokinetics and clinical effects. focusing mainly on isoflavones that are found in high concentrations in soy foods. Arguments are made for considering soy isoflavones as natural selective estrogen receptor modulators (SERMs) based upon recent data of their conformational binding to estrogen receptors. Rebuttal is made to several key and important issues related to the recent concerns about the safety of soy and its constituent isoflavones. This article is not intended to be a comprehensive review of the literature but merely highlight recent research with key historical perspectives.