Minireview:

Antioxidant Vitamin Supplementation

in Cardiovascular Diseases
Graziano Riccioni,
1
Tonino Bucciarelli,
2
Barbara Mancini,
2
Francesco Corradi,
1
Carmine Di Ilio,
2

Peter A. Mattei,
3
and Nicolantonio DOrazio
2
1
Cardiology Unit, San Camillo de Lellis Hospital, Manfredonia, Foggia, Italy;
2
Human Nutrition, and
3
Laboratory of Biostatistics, Biomedical Sciences Department; G. DAnnunzio University, Chieti, Italy.
Abstract. Cardiovascular disease is the most important adult health problem in wealthy countries, where
biological factors such as obesity, hypertension, dyslipidemia, diabetes, inappropriate diet, cigarette
smoking, and sedentary life-style have contributed to its dissemination. Research concerning nutritional
regimens has shown that persons who consume large amounts of fruit and vegetables have lower incidences
of cardiovascular diseases, stroke, and tumors, although the precise mechanisms for this protective eect
are elusive. Possible explanations include (a) increased consumption of dietary ber, (b) reduced consumption
of dietary cholesterol and other lipids, and (c) increased intake of the antioxidant vitamins (A, C, and E).
Numerous studies have raised the question whether vitamin supplements help to prevent cardiovascular
diseases. Results of randomized controlled trials of antioxidant vitamin supplements in large numbers of
participants has been ambiguous or contradictory. Tis minireview examines the relevant clinical reports
on dietary supplements of vitamins A, C, and E to determine whether they support the premise that
patients at risk of cardiovascular disease may be candidates for this therapeutic option.
Keywords: vitamins A, C, E, acute coronary syndrome, acute myocardial infarction, angina pectoris,
cardiac ischemia, antioxidant dietary supplements
Observational studies have demonstrated that acute
coronary syndromes (ACS), in particular unstable
angina (UA) and acute myocardial infarction
(AMI), share a common anatomical foundation.
Tese various clinical manifestations derive from a
basic pathophysiologic mechanism that consists of
the erosion or breach of an atherosclerotic plaque;
moreover, many thrombotic phenomena are
associated with this event [1-3]. ACS are the
consequence of acute or sub-acute primary oxygen
decit to the myocardium, which can result from
erosion of a atherosclerotic plaque, inammatory
phenomena, thrombosis, vasoconstriction, or
micro-embolization. Te Euro Heart Study,
conducted from September 2000 to May 2001 in
103 medical centers in 25 European countries,
reported 12% mortality within 6 mo for patients
with ACS who did not show an elevation of the ST
segment [4]. Tis study suggested that long-term
results might be improved in selected patients by a
clinical strategy that includes careful stratication
of the risks, administration of innovative drugs,
and revascularization procedures.
Te principal cardiovascular diseases (CVD)
include cardiac ischemic disease (CHD) with its
clinical manifestations (AMI, angina pectoris, and
sudden death), cerebrovascular diseases (stroke and
transitory ischemic attack), and peripheral vasculo-
pathies. Intensive eorts of researchers during the
past 50 years have been concentrated on CHD,
which represents 30-50% of the total prevalence of
CVD [5]. In the last 30 years, mortality from CHD
has been reduced by 50% [10,11], although CHD
Address correspondence to Graziano Riccioni, M.D., PhD.,
Via G. De Rogatis 12, CP 188, San Severo (FG) 71016, Italy;
tel 39 333 636 6661; fax 39 088 222 7022; e-mail griccioni@
hotmail.com.
0091-7370/07/0100-0089. $1.75. 2007 by the Association of Clinical Scientists, Inc.
Available online at www.annclinlabsci.org
Annals of Clinical & Laboratory Science, vol. 37, no. 1, 2007 89
remains the main cause of unexpected death in the
United States (approximately 500,000 deaths/yr)
and Europe (approximately 400,000 deaths/yr).
Mortality associated with CHD is attributed to
AMI (60%), chronic coronary insu ciency (22%),
and unexpected death (18%). A meta-analysis of
world-wide mortality showed that the main causes
were cerebrovascular disease, respiratory infections,
neonatal diarrhea, chronic obstructive pulmonary
disease, tuberculosis, varicella, accidents, and
respiratory tract tumors [6].
People at risk for primary and secondary CVD
appear less likely to use dietary supplements, despite
the possible benets shown in clinical trials [7].
Terefore, guidelines are needed for the general
public and health professionals regarding the
uncontrolled use of dietary supplements [7]. Te
current evidence does not support indiscriminate
use of vitamins A, C, E, or -carotene to prevent or
reduce CVD. In fact, some studies of oral
antioxidant supplementation have noted harmful
eect in some people [8-10]. Te aim of this paper
is to review published works with results that
support, conrm, or contradict the postulated
protective role of antioxidant vitamins in CVD.
Nutrition and atherosclerosis. Proper nutrition
could be considered as non-pharmacological
prevention and therapy of ischemic disease.
Nutrition is important in both primary and
secondary prevention, as many cardiovascular,
hepatic, and renal diseases are secondary to
qualitatively and quantitatively inappropriate diet
and life-style [11]. Dietary practices inuence the
pathogenesis of atherosclerotic plaques through
direct inuence on the determinants of athero-
sclerotic processes, such as plasma lipid accumulation
(triglycerides, HDL- and LDL-cholesterol, phos-
pholipids), structural integrity of circulating lipids
(oxidized-LDL), levels of plasma antioxidants,
production of free radicals, homocysteinemia,
hyperglycemia, blood pressure, platelet aggregation,
and lipid peroxidation [8,9].
Antioxidant vitamins. Numerous in-vivo and in-
vitro studies indicate that the atherosclerotic
processes (including endothelial damage and
proliferation, and the production of foam cells)
depend in part on the peroxidative state of LDL.
Antioxidant vitamins are one of the main defense
mechanisms of the bodys non-enzymatic anti-
oxidant systems. Ascorbic acid (vitamin C), alpha-
tocopherol (the principal constitutent of vitamin
E), and beta-carotene (pro-vitamin A) are the most
studied natural antioxidants. Large-scale clinical
trials have been conducted to determine whether
vitamin supplements with antioxidant action
decrease the risk of cardiovascular diseases. Some
experimental and epidemiological studies seem to
indicate benecial eects of antioxidant vitamin
supplementation on the development and progres-
sion of atherosclerotic plaques, resulting in
reduction of cardiovascular events. However, a
recently published study with well-dened primary
and secondary prevention endpoints does not
support this hypothesis [12].
Vitamin A. Vitamin A, the rst fat-soluble vitamin
to be identied, has 3 active forms: retinol, retinal,
and retinoic acid; collectively called retinoids. Te
most important of these is beta-carotene, which
has a high antioxidant eect [13,14]. Te carotenoids
have an important antioxidant role in quenching
free radical reactions, particularly those involving
singlet oxygen. Tis prevents damaging chain
reactions that cause lipid peroxidation and damage
to DNA, both of which are postulated precursors
of atherosclerotic processes [15,16]. Vitamin A and
carotenoids may have eects in various human
diseases such as diarrhea, acute respiratory
infections, ischemic heart disease, immunological
disorders, and bronchial asthma [17]. Many trials
have considered the eects of vitamin A dietary
supplements on cardiovascular events and have
yielded contradictory results. Te Nurses Health
Study (NHS), an epidemiological study conducted
in the USA on 34,486 women, evaluated through a
questionnaire the eect of the addition of vitamin
A to regular diets. No association was seen between
dietary supplements of vitamin A and the risk for
coronary disease [18].
Several randomized controlled studies reported
similar results. In the Physicians Health Study
(PHS), a randomized, prospective, double-blind,
placebo-controlled study of 22,071 physicians, the
oral supplementation of beta-carotene (50 mg on
Annals of Clinical & Laboratory Science, vol. 37, no. 1, 2007 90
alternating days; 12 yr follow-up), did not show a
signicant dierence between the treated and
control groups in respect to cardiovascular mortality
[19]. In another study, 5 major carotenoids (alpha-
and beta-carotene, beta-cryptoxanthin, lutein, and
lycopene) did not show protective eects against
AMI [20]. Te Beta Carotene and Retinol E cacy
Trial (CARET), a prospective, randomized,
placebo-controlled 4-yr study of 18,314 smokers,
was interrupted at 21 mo before its planned termin-
ation because patients treated with a combination
of beta-carotene and vitamin A showed increased
relative risk for lung cancer and cardiovascular
mortality [21]. Te Alpha Tocopherol Beta Carotene
Cancer Prevention (ATBC) study, which evaluated
beta-carotene (20 mg/day) supplementation in
1,862 male smokers with a previous MI, did not
show any signicant eect on cardiac-related
mortality [22].
Vitamin C. Vitamin C, an important water-soluble
substance, has 2 biologically active forms: ascorbic
acid and dehydroascorbic acid. Dietary vitamin C
is mostly supplied by fruits and vegetables. Its
biological role is related to its reducing capability;
ascorbate is readily oxidized to dehydroascorbate.
Vitamin C acts as a hydrogen donor to reverse
oxidation and hence is termed an antioxidant,
which can inactivate free radicals before they
damage proteins or lipids [16]. Te First National
Health and Nutrition Examination Survey
(NHANES) epidemiological follow-up study in
11,348 subjects, age 25 - 74 yr, reported that
individuals who received a high dose of vitamin C
(>50 mg/day) had lower overall total mortality rate
after 10 yr, and in particular lower mortality from
cardiovascular disease [23]. Te Health Profes-
sionals Follow-up Study reported that a relationship
between vitamin C intake and major coronary
events did not exist, although subjects whose
vitamin C intake exceeded 50 mg/day had a lower
rate of death from all cardiovascular diseases [24].
Vitamin Cs antioxidant action, which is more
eective than that of vitamin E or beta-carotene,
was considered as a possible mechanism of vascular
protection.
Joshipura et al [25] conducted a prospective
cohort study in a population of 54,251 women and
42,148 men who were followed for 8 yr and were
free of cardiovascular disease, cancer, and diabetes.
Te authors found that the consumption of fruits
and vegetables, particularly green leafy vegetables
and vitamin C-rich fruits and vegetables, appeared
to have a protective eect against coronary heart
disease (ie, nonfatal AMI or fatal coronary heart
disease). However, subsequent reviews and meta-
analyses of the relationship between antioxidants
and atherosclerotic cardiac disease did not conrm
these ndings. An analysis of 2 studies, the Nurses
Health Study (NHS) and Health Professionals
Follow-up Study, showed unclear reduction of
prevalence and mortality from cardiovascular
disease [26]. Increased production of free radicals
derived from exposures to tobacco smoke, radiation,
stress, insu cient physical activity, hypocaloric
diets, drugs, and toxic substances evidently
increases the need for vitamin C intake [27,28].
Two studies provide evidence contrary to the
protective eects of vitamin C. Kushi et al [18] in
the NHS epidemiogical study found no relationship
between vitamin C intake and major coronary
events. Kinlays et al [29] conducted a double-blind,
randomized, placebo-controlled trial of vitamin C
(1 g/day) supplement for 6 mo in 30 subjects with
coronary artery disease. Tey found that such long-
term oral vitamin C supplements did not improve
key mechanisms of atherosclerosis or endothelial
dysfunction, nor reduce LDL oxidation in vivo.
Vitamin E. Vitamin E is an important antioxidant
vitamin, playing an essential protective role against
free radical damage [30,31]. Vitamin E comprises a
group of substances belonging to 2 closely related
families: tocopherols and tocotrienols, each existing
in a number of isomeric forms: alpha, beta, gamma,
and delta. Te form that accounts for 90% of the
vitamin activity in tissues is alpha-tocopherol
[32,33]. Te chemical structure of tocopherols and
tocotrienols (which have an -OH group on the ring
structure) makes them eective hydrogen donors.
In donating hydrogen, vitamin E becomes oxidized,
preventing the oxidation of metabolically more
important substances, for example polyunsaturated
fatty acids (PUFA) in cell membranes. Tis is
important when free radicals are present, as these
highly reactive substances can attack double bonds,
Antioxidant vitamin supplementation in cardiovascular diseases 91
initiating chain reactions that generate more free
radicals. When fatty acids are damaged, lipid
peroxides are produced that can alter the function
of the cell membrane and cause irreversible damage
to metabolic pathways [34-37].
Te nutritional requirement for vitamin E (10
mg/day) varies with the dietary intake of PUFA.
Vitamin E is the most fat-soluble vitamin and is the
major vitamin component in cell membranes and
circulating lipoproteins. For this reason, vitamin E
is the main antagonist of lipid peroxidation. Its
protection of membranes is important for proper
functioning of the vascular endothelial barrier, for
reduction of proliferation stimuli for myocytes of
the tunica media, and for decrease in chemotactic
factors for monocytes [38]. Te protective role of
vitamin E for the endothelium is supported by a
stimulatory action on the synthesis of PGI
2
, a
vasodilator and platelet anti-aggregating agent [39].
Due to its fat solubility, vitamin E persists in
membrane lipoproteins for long periods and,
therefore, its dietary supplementation may not
require daily dosing [40].
Te Physicians Health Study (PHS) reported a
prospective nested case-control study of 531 male
physicians diagnosed with AMI, without prior
history of cardiovascular disease, paired with
control subjects and matched for age, smoking
habit, and plasma levels of alpha- and gamma-
tocopherol [20]. Te results indicated that the men
with higher plasma levels of gamma-tocopherol
tended to have increased risk of AMI. In the Nurses
Health Study (NHS), Kushi et al [18] found that
vitamin E supplements of 100-250 UI/day reduced
by 35 - 40% the incidence of major coronary events
(nonfatal myocardial infarction and death from
cardiac causes) among subjects in the highest
quintile of vitamin E intake, over a follow-up
period of 4 8 yr, compared to those in the lowest
quintile. Te benet was greatest in subjects taking
100 to 250 UI of supplemental vitamin E per day,
with little further benet at higher doses [18].
In the Cambridge Heart Antioxidant Study
(CHAOS), a randomized. controlled study of 2,002
patients with coronary artery disease (CAD),
vitamin E supplements (400-800 UI/day) reduced
the incidence of death from cardiovascular diseases
and AMI [38]. In the AlphaTocopherol Beta
Carotene Cancer Prevention (ATBC) trial, the
group of patients treated with alpha-tocopherol
supplement (50 mg/day) showed a lower number of
non-fatal AMI, but no reduction of the primary
study end-points (that is, cardiovascular death and
AMI) [22]. In the Secondary Prevention using
Antioxidants of Cardiovascular Disease in End-
stage renal disease (SPACE) trial, 196 patients with
pre-existing cardiovascular disease and under-
going chronic haemodialysis were enrolled in a
double-blind randomized controlled study (97
patients received vitamin E supplement (800 UI/
day) and 99 patients received a placebo) [41]. Tere
was signicant reduction of the primary end-points
(fatal and non-fatal AMI, ischemic stroke,
peripheral vascular disease, and unstable angina
(UA) in subjects receiving the high dose vitamin E
supplement [41].
Te Prevention Study of the Italian Group for
the Study of Survival in Myocardial Infarction
(GISSI) reported that vitamin E supplements (300
mg/day) were associated with a non-signicant
reduction of total mortality (relative risk 0.86; p =
0.081) [42]. Te Heart Outcomes Prevention
Evaluation Study (HOPE) did not demonstrate the
benets reported by SPACE in the use of vitamin E
at a dose of 400 UI/day [43].
Discussion
Te possible anti-atherogenic role of compounds
with antioxidant characteristics depends on the
various eects that free radicals can have on
pathological and physiological processes. LDL-
oxidation has a key role in the activation and
facilitation of atherogenesis. Antioxidants are
capable of preventing the oxidative catabolism of
nitric oxide (NO), a molecule with numerous
benecial eects.
A discrepancy exists between the results derived
from observational studies and randomized trials
with vitamin supplements. In observational studies
with coronary end-points, subjects with elevated
plasma levels of antioxidants were protected from
clinical complications of coronary disease (AMI
and angina), whereas subjects treated with
antioxidants in the interventional studies did not
show protection against coronary disease [44].
Annals of Clinical & Laboratory Science, vol. 37, no. 1, 2007 92
In studies with vitamin A supplements, there is
no evidence for a protective eect against AMI. In
a study of beta-carotene, a higher incidence of
coronary events was observed in the group that
received supplements compared to a control group.
Te mechanisms whereby fruits and vegetables
protect against CVD are likely to be multiple. Te
postulated benecial components of fruits and
vegetables include antioxidant vitamins, particularly
vitamin C, folate, ber, minerals, and potassium.
Tese dietary constituents can signicantly increase
the antioxidant capacity of serum and protect
against in vivo lipoperoxidation.
Several large-scale, double-blind, placebo-
controlled trials have clearly shown that vitamin E,
alone or in combination with other antioxidant
vitamins, reduces the risk of fatal or nonfatal AMI
in populations with CHD. Two end-point trials of
vitamin E, though with much smaller patient
populations, reported positive results (the SPACE
and CHAOS studies).
Descriptive, case-control, and prospective
cohort studies have shown inverse associations
between the frequency of CAD and dietary intake
of antioxidant vitamins. In contrast, randomized
therapeutic trials have thus far shown a lack of
benet with beta-carotene and a possible benet
with vitamin E.
As oxidative stress is involved in the pathogenesis
of atherosclerosis, during the past few years a variety
of substances with antioxidant actions have been
evaluated in clinical studies for primary and
secondary prevention of CVD. Te initial promising
reports on benecial eects with antioxidant
therapies against atherosclerosis, derived from
observational studies, were followed by generally
negative results reported from large randomized
controlled trials. For this reason, at the moment,
treatment with antioxidant vitamins (A, C, and E)
is not recommended for the prevention or treatment
of CAD. Tus, the United States Preventive Services
Task Force (USPSTF) concluded that the evidence
currently available is insu cient to recommend the
routine use of these supplements [45].
Although scientic rationale and observational
studies are convincing, randomised primary and
secondary intervention trials have failed to show
any consistent benet from the use of antioxidant
supplements on CVD, and some trials suggested
possible harmful eects in certain subgroups of
patients.
Trials that investigate the eect of a balanced
combination of antioxidants at levels achievable by
diet are clearly needed [46]. New strategies are
needed to clarify the exact role that antioxidants
may have on the prevention of atherosclerosis [47].
Tere is evidence that angiotensin converting
enzyme (ACE) inhibitors and angiotensin II type I
(AT1) receptor blockers may have benecial eects
on oxidative stress, in addition to their antihyper-
tensive properties. Statins, in addition to improving
lipid proles, may also lower oxidative stress [47,48].
Future antioxidant therapies need to be more
specic in targeting the site of action, be devoid of
deleterious eects on other signalling pathways,
and be targeted to a specic reactive oxygen species
(ROS) or cellular compartment [49-51].
Factors responsible for the disappointing and
discrepant results from observational and clinical
studies on the relationship between antioxidant
vitamins and CVD may include dierences in the
patients gender, age, body weight, duration of
treatment, vitamin supplement dosages. and dietary
habits. It may be important to re-evaluate the
selection of foods rich in antioxidant compounds
rather than the selection of supplements of these
substances [52-54].
Acknowledgements
Te authors thank Ray Pizzuto (English Medical
Unit, G. DAnnuzio University, Chieti, Italy) for
help in editing this article.
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