Antioxidants

STEINBERG ET AL. WERE AMONG THE FIRST TO
indicate that modified low-density lipoprotein (LDL)
cholesterol could be responsible for the accumulation
of lipid within macrophages, a crucial step in the early
formation of atheromatous plaques.

Only some antioxidants prevent the oxidation of
LDL cholesterol, which plays an important role in the
pathogenesis of the atherosclerotic process and its progression
to blockage of arteries (see the chapter Atherosclerosis/
Atherothrombosis). The harmful effect of LDL
cholesterol is augmented by oxidized LDL cholesterol
particles. Prevention of the oxidation of LDL cholesterol
particles by chemical agents and natural products is an area
of intensive research. Natural substances and chemical
compounds, which may protect lipids from attack by
oxygen free radicals increase resistance to lipid peroxidation,
reverse endothelial dysfunction, and increase nitric
oxide (NO) mediated vasodilation will remain an interesting
area of research and development, despite the
negative results observed in many clinical trials.

It is important to emphasize that it is not certain exactly
where and how LDL cholesterol gets oxidized within the
human body.More important, vitamin C is a water-soluble
vitamin and is thus confined to the extracellular fluids but
vitamin E gains entry into lipoproteins. It is known that
large doses of beta-carotene do not prevent LDL oxidation.
Thus, antioxidants have subtle and important differences
that impact on their probable therapeutic benefits.
After the past few years of conflicting results, the critical
question remains: Do antioxidants actually work? The role
of antioxidants in protecting people against heart disease
remains controversial. There appears to be little doubt,
however, that antioxidants present in the Mediterranean
diet possess cardioprotective effects; recent experimental
work indicates that French red wines are cardioprotective
beyond the effect on increasing HDL cholesterol.

I. STATINS
Statins are well-known, cholesterol-lowering agents. They
are competitive inhibitors of 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase, which is the key
enzyme catabolizing the early rate-limiting step in the biosynthesis
of cholesterol within the hepatocyte. They lower
LDL cholesterol in blood and thus prevent heart attacks
and death from myocardial infarction as well as strokes.
More important, statins have been shown to prevent lipoprotein
oxidation, and it is believed that some of their
salutary effects may be related to this action. They appear
to improve survival in patients with ischemic and nonischemic
heart failure. Nitric oxide synthesis is diminished
in heart failure; statins enhance endothelial NO synthase
(eNOS) activity and improve endothelial function.

II. VITAMIN E
Antioxidant nutrients, particularly vitamin E, are still
widely used with the hope of preventing cancer, heart
disease, and dementia. Although, clinical trials have not
shown protection from cancer, the correct ‘‘protective’’
dose may not have been used in some trials. Also, the
partially favorable effect of vitamin E on amyloid deposition
in the brain and its effect on dementia remains to
be clarified.
Vitamin E is a fat-soluble vitamin found in vegetables
and seed oils, particularly soybean and safflower, and
sunflower seeds, corn, nuts, whole grains, and wheat germ.
Increased dietary intake has not been shown to decrease the
incidence of heart disease or cancer. With aging, however,
the vitamin E content of blood platelets decreases; this
action may predispose individuals to clumping of platelets
and cause a risk of clotting. The elderly may thus benefit
from some vitamin supplements.

III. VITAMIN C
Although vitamin C, ascorbic acid, is one of the most
important antioxidants in extracellular fluids, it traps
peroxyl radicals and inhibits lipid peroxidation. Several
studies indicate that there is no apparent benefit in the
prevention of cardiovascular disease with use of vitamin C.
1. The Nurse’s Prospective Observational Study of 87,000
female nurses followed for a mean of 8 years and
health professionals study in which 39,000 male health
professionals were followed for 4 years showed no
reduced risk for coronary revascularization, myocardial
infarction, or death from coronary heart disease among
persons using vitamin C.
2. A randomized controlled trial carried out in China
found no reduction in total mortality or mortality from
cardiovascular diseases in 29,584 healthy adults given
vitamin C over 5 years.
Vitamin C is known to have antioxidant properties, but
its effects appear to be modest and may only be observed in
patients at very high risk; this includes patients with heart
failure in whom vitamin C has not been adequately tested,
particularly in combination with vitamin E. Ascorbic
acid has been shown to normalize endothelial function
by restoring NO-mediated vasodilatation of endothelium
in patients with hypertension, but it does not cause a
lowering of blood pressure.

IV. BETA-CAROTENE
Results of several clinical trials indicated that beta-carotene
supplementation is not beneficial in the prevention of
cardiovascular disease or its complications.
1. The Carotene and Retinol Efficacy Trial (CARET) trial
included 8314 men and women with a history of
cigarette smoking or occupational exposure to asbestos
receiving beta-carotene (30 mg per day), and retinol
(25,000 IU per day). This trial was stopped early
because the incidence of mortality from lung cancer
was excessive. However, the population studied in these
trials was already at high risk for lung cancer.
2. The physician’s health study randomized 22071 male
physicians taking beta-carotene (50 mg per day),
aspirin 325 mg, both, or neither for 12 years. There
were no cardiovascular benefits from beta-carotene
administration.
3. In the Alpha Tocopherol Beta-Carotene Cancer Prevention
Trial (ATBC) the effects of daily doses of 50 IU
of vitamin E, 20 mg of beta-carotene, both, or placebo
for 5 to 8 years in 29133 smokers with a previous
myocardial infarct were monitored. The study found
no reduction in risk for major coronary events with any
of the antioxidants.

V. MEDITERRANEAN DIET
The Mediterranean diet contains a substantial amount
of antioxidants and has been shown to be substantially
cardioprotective. However, there are many other cardioprotective
facets in this diet, including an abundance of
beneficial alpha-linolenic acid

VI. DIETARY PLANT-DERIVED
FLAVONOIDS
These naturally derived products from several sources
including red grape juice, red wine, soy products, and
nuts (particularly almonds, walnuts, and hazel nuts), are
receiving attention for their antioxidant and cardioprotective
properties.

VII. FRENCH RED WINE
French red wine appears to be more cardioprotective
than wine from other countries. Although the data for
differences in red and white wine remain controversial, and
it appears that all alcoholic beverages carry some
cardioprotective properties, it seems that French red wine
possesses further cardioprotective properties.
In a German study by Wallerath et al., three German
and six French red wines were assessed. The study tested
the effect of red wine on endothelial-type NO synthase
expression, eNOS expression, and eNOS activity in
human endothelial cells. Incubation of endothelial cells
with red wines from France upregulated eNOS, mRNA
and protein expression. In contrast, red wines from
Germany showed little or no effect on eNOS expression.
Endothelial cells treated with French red wine produced
up to three times more bioactive NO than control cells.
French red wines increased the activity of other eNOS
promoters, with a transstimulated sequence located in the
proximal 326 bp of the promoter sequence. The eNOS
mRNA stability was also increased by red wine. No
significant difference in the Enos mRNA expression
could be detected between the ‘‘en barrique’’ (matured
in oak barrels) and ‘‘non-barrique’’ (matured in steel tanks)
produced French wines.
Long-term, French red wine consumption in low
doses could involve an upregulation of eNOS expression.
This would lead to moderate, but sustained elevations of
vascular NO.
The numerous phenolic acids, polyphenols, and flavonoids
contained in French red wines are likely constituents
probably mediating the expressional upregulation of
Enos. French red wines contain high polyphenol levels
compared with wines from other regions leading to an
enhanced production or bioactive NO. Apart from the
other known beneficial effects of red wine on dyslipidemia,
the enhanced NO activity could contribute to further
cardiovascular protection beyond that observed with
other alcoholic beverages. In addition, the following
observation may be relevant: red wine may have specific
anti-inflammatory and antiproliferative effects. The acute
administration of red wine reduces the increase in nuclear
factor kb (NF–kB) responsible for promoting the expression
of several inflammatory genes resulting from a
high-fat meal, a finding that has not been observed for
vodka. This finding and the study by Cuveas et al.
suggested that red wine may be particularly cardioprotective
in individuals consuming high-fat diets. These two
important findings may explain the French paradox.

VIII. PROBUCOL
Two small studies have demonstrated that probucol, a drug
used in the 1970s for lowering serum cholesterol, which
was abandoned because of adverse effects, has important
additional antioxidant properties. Probucol significantly
reduces restenosis when administered one month before
and continued for six months after percutaneous transluminal
coronary angioplasty (PTCA). The small group,
317 patients, used in these studies limits the conclusions
regarding the benefits of this drug.
Because several clinical trials during the past 20 years
have not altered the restenosis rate after PTCA, which still
remains at more than 33%, any agent or natural product
that reduces restenosis rates would be a welcome addition
to the cardiologic armamentarium.