Oxidative Stress in Heart Failure: Current
Understanding and Prospective
OSxinidgaatli,v KehSatpreers,s PaanldacHe,eaanrtd FKauilmuraer
Pawan K. Singal, Neelam Khaper, Vince Palace,
and Dinender Kumar
Institute of Cardiovascular Sciences, St. Boniface General
Hospital Research Centre and Department of Physiology,
Faculty of Medicine, University of Manitoba, Winnipeg. Canada
Abstract. Our knowledge of the pathophysiology of heart
failure has advanced far beyond the classic concept of the
hemodynamic overload model and associated neurohumoral
changes. Current interest lies in understanding the fundamentals
of cellular defects to identify new molecular targets
for therapies. Some of the new target sites being explored
are in_ammatory cytokines, nitric oxide, oxidative
stress and apoptosis during the remodelling processes such
as cardiac hypertrophy and dilation. The present review
provides an overview of the chemistry/biochemistry of free
radicals as well as a discussion of some defense mechanisms
that have evolved and adapted to combat these toxic oxygen
species. The probable role of oxidative stress in the
pathogenesis of heart failure both from animal data and
heart failure patients is also presented.
Key Words. oxygen radicals, antioxidants, cardiac dysfunction
The Oxygen Story
Although we have witnessed a profound development
in the understanding of oxygen toxicity in heart disease
in the past three decades, the story of oxygen
toxicity started more than two centuries ago [1]. It was
Lavoisier, in 1785, who made the ~rst observation that
oxygen has two main effects, i.e. it supports life but it
also has toxic side effects [2]. More than a century later,
in 1899, Lorrain Smith demonstrated that increased
oxygen tension results in lung congestion in mice, rats
and pig [3]. At the beginning of the twentieth century,
Gomberg demonstrated the presence of triphenylmethyl
molecule as a radical species in organic chemistry
[4]. Subsequently, it was theorized that the damaging
effects of O2 were due to the formation of the
superoxide anion [5].
The pioneering work of McCord and Fridovich regarding
the discovery of superoxide dismutase [6], inspired
biologists and clinicians to study the role of free
radicals in biology and medicine. Thus, a large body
of evidence has accumulated showing that biological
systems are capable of producing a variety of reactive
oxidants which play an important role in various human
diseases [7,8]. Animal studies on catecholamineinduced
cardiomyopathy [9], adriamycin-induced
cardiomyopathy [10] and ischemia-reperfusion injury
[11] have now provided solid evidence for the role of
free radicals in the mediation of cardiac injury [1,12].
The present review provides some basic information
on free radicals and antioxidants and their signi~cance
in the pathogenesis of heart failure.
Oxygen Free Radicals
Free radicals are highly reactive atoms or molecules
with an unpaired electron in their outer orbits. The
production of free radicals occurs either by the addition
or by the removal of an electron in a reduction/
oxidation reaction. Since oxygen has two electrons
with parallel spin in its outermost shell, it is
characterized as a diradical which requires four electrons
to be completely reduced to water [13–15]. Oxygen
is also the terminal acceptor of electrons for oxidative
phosphorylation and this tetravalent reduction
is associated with the production of high energy phosphates
(Fig. 1). However, sequential univalent reduction
results in the formation of reactive oxygen intermediates
[7,8,13–15]. In the univalent reduction
pathway, the addition of a single electron to molecular
oxygen results in the production of superoxide anion
radical (O2
2?). The addition of another electron to the
O2
2? results in the formation of peroxide anion which
protonates to form hydrogen peroxide (H2O2). The latter
is not a radical by itself, but is capable of causing
cell damage by interacting with transition metals such
as iron. A single electron reduction of H2O2 results in
the formation of the hydroxyl radical (?OH) which is
highly reactive, has an extremely short half-life, and
therefore has a very limited diffusion capacity [13–15].
The addition of a fourth electron ~nally results in the
formation of water. The ~rst excited state of O2 is a
singlet oxygen (1O2) which can also initiate oxygen
Address for correspondence: Dr. Pawan K. Singal, Institute of
Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, 351 Tache Avenue, R3022,Winnipeg, MB R2H 2A6, Canada.
Email: psingal@sbrc.umanitoba.ca
111
Heart Failure Reviews 1999;4:111–120
© Kluwer Academic Publishers. Boston. Printed in U.S.A.
radical chain reactions [13,14]. This univalent electron
reduction reaction is illustrated in ~gure 1.
Reactive oxygen intermediates such as O2
2?, H2O2,
?OH and 1O2 are called activated oxygen species and are
collectively known as partially reduced forms of oxygen
(PRFO) [13]. Superoxide radical reacts with nitric
oxide during reperfusion to form peroxynitrite which
also has a harmful effect by opposing the vasodilatory
effect of nitric oxide [16]. These reactive species can
interact with macromolecules and initiate free radical
chain reactions resulting in membrane and cell damage
[13–15,17].
Free Radical Mediated Cell Injury
The targets of free radical attack are the cell membranes
and subcellular organelles. The lipid peroxidation
chain reaction is initiated by the removal of a
hydrogen atom from the unsaturated site in a fatty
acid resulting in the production of a lipid radical. This
radical can further react with other neighbouring
polyunsaturated fatty acids (PUFA) to propagate the
reaction [13,18]. The addition of an oxygen molecule
to these lipid radicals results in the formation of lipid
peroxides. Free radical-induced lipid peroxidation has
been suggested to alter membrane structure and function
[13–15]. Considerable evidence also suggests that
PRFO can modify protein structure and function ultimately
affecting cell metabolism. In this regard, proteins
rich in sulphydryl groups are highly susceptible
to free radical attack [13]. In the myocardium, oxygen
radicals have been shown to effect Na1/Ca11 exchange,
Na1-K1 ATPase and Ca11 ATPase activities
[19–22]. Free radicals can also attack the nucleic acids
by producing base damage, single strand breaks, adducts
and chromosomal aberrations. Such modi~cations
have been shown to cause cellular abnormalities
such as mutations and cell death [12–15].
Fig. 1. A diagramatic representation of the production of oxygen free radicals by univalent reduction pathway. Different antioxidants
(enzymatic and non-enzymatic) in the biological system may offer protection against free radical-induced injury.
112 Singal, Khaper, Palace, and Kumar
The Antioxidant Defense System in
the Heart
Under normal physiological conditions, the tissue concentration
of free radicals is maintained by a system of
enzymatic and non-enzymatic antioxidants that have
evolved and been conserved during the evolution of
aerobic life and constitute “antioxidant reserve” in the
heart [17].
Enzymatic Antioxidants
Superoxide dismutase (SOD)
This enzyme is the ~rst line of defense against free radical
attack. There are several different types ofSODthat
differ based on the metallic prosthetic group attached
within the protein structure. The most common forms
are CuZnSOD (molecular weight 32,000) which is present
in the cytoplasm and MnSOD (molecular weight
80,000) found in the mitochondria. Superoxide dismutase
activity has been reported to be signi~cantly less in
the heart than in the liver [23–25]. It was the discovery
of SOD which led to the realization that O2
2? is formed in
vivo in living organisms [6]. Two superoxide anions can
react together to produce a spontaneous dismutation,
however, this reaction is much faster in the presence of
SOD (23109M21 sec21) [13,23–25].
Glutathione peroxidase
This selenium-dependent enzyme (molecular weight
~84,000), which is present mainly in the cytoplasm, represents
the second line of defense against free radicalmediated
damage. It catalyzes the reduction of hydrogen
peroxides using glutathione (GSH) as a source of
reducing power and forming oxidized glutathione
(GSSG), water and/or alcohol. This enzyme is present in
relatively high concentrations in the human heart
[13,23,25] and is therefore considered an important antioxidant
enzyme in that organ. A non selenium-dependent
form of GSHPx, which is non-speci~c to H2O2, but
which dismutates organic peroxides is also present [26].
Catalase
This enzyme (molecular weight 240,000) is also very
important in the metabolism of hydrogen peroxide produced
by SOD. Present at relatively low concentrations
in the heart, it converts H2O2 to water and oxygen.
However, the difference between catalase and
glutathione peroxidase is that GSHPx is more effective
at low concentrations of H2O2, i.e., in lM range,
whereas catalase is more effective at the mM concentrations
of H2O2 [13,15,27].
Non-enzymatic antioxidants
Non-enzymatic antioxidants include vitamins such as
tocopherols, ascorbate and carotenes as well as other
biological molecules including glutathione, uric acid
and metal binding proteins.
Vitamin E
Vitamin E functions as one of the major antioxidant
defense systems in our body. Vitamin E is a generic
term that includes a group of eight structurally related
compounds. These are further sub-divided into two
groups: tocopherols and trienols. Of these, d-a-tocopherol
is the most common type of vitamin E absorbed
from the human diet [28]. It is a strong biological antioxidant.
Because of its lipophillicity, vitamin E offers
maximum protection against free radical attack in cellular
and subcellular membranes. it reacts with free
radicals, yielding lipid hydroperoxides which can be
removed by the GSHPx enzyme system. In this reaction,
vitamin E donates a hydrogen atom, resulting in
the generation of a hydroperoxide and vitamin E radical.
This effectively terminates lipid peroxide-mediated
chain reaction and is therefore called a “chain
breaking antioxidant” [1,13,28–30]. Vitamin E also
functions synergistically with ascorbic acid to terminate
free radical chain reactions. Recent studies have
reported a new role for vitamin E that is independent
of its antioxidant property. These include inhibition of
smooth muscle cell (SMC) proliferation and growth
during atherosclerosis, occurring mainly as a result of
its ability to activate the release of TGF-b [31].
Vitamin C
Vitamin C is a water-soluble molecule which quenches
reactive oxygen metabolites directly, with the resultant
formation of dehydroascorbate. Vitamin C is also
thought to play an important role in the regeneration
of a tocopherol. It is present in micromolar concentrations
in the cytoplasm as well as in serum [13,32].
b carotene
b carotene, a precursor of vitamin A, is known to
quench active oxygen species. These reactions operate
maximally at low-oxygen tension as compared to vitamin
E which reacts at high oxygen tension [33].
Epidemiological studies have shown that increased
levels of b carotene and other carotenoids are associated
with a decreased risk of cardiovascular diseases
[34,35].
Glutathione
Glutathione is a tripeptide which is present in high
concentrations in the majority of the eukaryotic cells.
One of its important functions is to protect cells
against peroxides generated during aerobic metabolism.
It undergoes redox cycling between the reduced
(GSH) and oxidized (GSSG) forms [13,36,37]. In the
heart, glutathione is predominantly (.95%) in the
GSH form. It also acts as a cosubstrate for GSHPx
and plays an important role in defending against free
radical-mediated lipid peroxidation. This results in the
Oxidative Stress and Heart Failure 113
increased formation of GSSG. Depletion of GSH to
20–30% of its normal concentration renders the cell
susceptible to free radical attack [38,39]. The redox
ratio, which is the ratio of reduced to oxidized glutathione
(GSH/GSSG) is used as a sensitive index of
oxidative stress. Speci~cally, an increase in the redox
ratio indicates reduced oxidative stress, and vice versa
[1,13–15].
Other Biological Molecules
Uric acid, a waste product of purine metabolism, has
been shown to directly interact with ?OH and prevent
oxidation [40], suggesting that there is antioxidant potential
for this molecule in biological systems [13]. Iron
chelators, such as desferrioxamine, inhibit lipid peroxidation
and reduces the injury associated with ischemia-
reperfusion [41,42]. Ubiquinone also acts as a
potent inhibitor of lipid peroxidation by directly
quenching free radicals [43]. Various metal binding
proteins such as ferritin, transferrin, metallothioneins
and ceruloplasmin are also known to inhibit lipid peroxidation
[13,44].
Methods of Measuring Free
Radical-Mediated Damage
Free radical-mediated damage includes oxidative
modi~cation of cellular proteins, lipids and nucleic acids.
Lipid peroxidation is a free radical-mediated process,
which involves the formation of lipid peroxides
within cell membranes and organelles [13,44,45]. Lipid
peroxidation is detected through the estimation of
malondialdehyde (MDA) either by UV light, HPLC or
the thiobarbituric acid (TBA) method [13,45,46]. Direct
detection of free radicals is done by ESR spectroscopy,
although with this technique it is not possible to detect
low concentrations of free radicals [13]. Other methods
of assessing oxidative stress include determination of
diene conjugates, measurement of gases such as ethane,
pentane and isoprotanes in exhaled air, measuring
the redox ratio and the content and activity of endogenous
antioxidants and quantifying lipid hydroperoxides.
Although the MDA assay has been shown to lack
speci~city, it may detect saturated and unsaturated
aldehydes as well as other non lipid-related substances
[46], when used in conjunction with studies of the redox
ratio as well as antioxidant activity, it provides meaningful
information [1,12].
Oxidative Stress and Antioxidants in
Heart Failure
The classic de~nition of oxidative stress includes “a disturbance
in the prooxidant and antioxidant balance, in
favour of the former” [47]. The most common pathological
conditions that are attributed to oxidative stress
mediated damage are atherosclerosis, diabetes, cancer,
arrhythmia, rheumatoid arthritis, in_ammatory bowel
disease, and several neurodegenerative diseases. In
fact, this list of pathological conditions related to oxidative
stress continues to grow. In recent years, substantial
evidence has accumulated from acute and chronic
studies to suggest the role of antioxidants and oxidative
stress in the pathogenesis of heart dysfunction and
failure both in animal studies and from clinical trials
[12,13,25]. Early studies on catecholamine-induced
cardiomyopathy [9,18], adriamycin-cardiomyopathy
[10] and ischemia-reperfusion injury [11] provided the
basis for further investigation on understanding free
radical involvement in cardiac injury [1,12,13].
Acute Studies
Ischemia-reperfusion (I/R) is one of the most extensively
studied models of acute heart failure. Increased
free radical production and depressed antioxidant reserve
has been documented to have serious functional
consequences after I/R. Many studies have reported
the production of free radicals in reperfused hearts in
animals [25,48,49] and humans [50,51]. Studies on isolated
perfused rat hearts showed increased production
of H2O2 during ischemia as well as early reperfusion
[52]. An inverse correlation between oxidative stress
and cardiac function has also been documented in patients
who were subjected to global ischemia and
reperfusion during coronary artery bypass graft surgery
[53]. In isolated perfused rabbit hearts, a decline
in developed force during ischemia was accompanied
by a progressive decline in tissue glutathione content
and in the redox ratio indicating increased oxidative
stress [23]. A decrease in non-enzymatic antioxidants
such as tocopherol, retinol and ascorbic acid and redox
ratio and an increase in lipid peroxides has also recently
been reported in rat hearts subjected to 45 min
of ischemia and 15 min of reperfusion [54]. A reduction
in infarct size by SOD and catalase administration was
also reported in dogs that underwent 90 min of ischemia
and 24 hrs of reperfusion [55]. Similarly, another
study using transgenic mice, which overexpressed
MnSOD, demonstrated improved cardiac
function and decreased release of lactate dehydrogenase
in mice hearts subjected to ischemia-reperfusion
[56]. Lack of protection with antioxidants has also
been reported in some studies. SOD was found ineffective
in modulating ischemia reperfusion-induced
changes in pig hearts [57].
There is now overwhelming evidence that oxidative
stress also plays a major role in myocardial stunning
[11]. It has recently been suggested that approximately
80–85% of stunning can be attributed to free
radicals and the rest (15–20%) is due to Ca11 overload
[58]. Antioxidant therapy suppressed the production of
free radicals and attenuated myocardial stunning, suggesting
a cause and effect relationship [11,59]. An ele-
114 Singal, Khaper, Palace, and Kumar
gant study by Li and colleagues, using adenovirus-mediated
gene transfer technique to introduce SOD in the
rabbits, demonstrated protection against myocardial
stunning [60].
Chronic Heart Failure
Catecholamine-induced cardiomyopathy
Increased plasma levels and decreased tissue levels of
catecholamines have been reported in acute MI and
heart failure conditions [61]. Excess catecholamines
have been shown to cause arrhythmias as well as
cardiomyopathy [9]. Production of free radicals upon
autooxidation of catecholamines play a critical role in
cardiomyopathy [9,18]. A recent study reported increased
lipid peroxidation in isoproterenol administered
rat hearts [62]. Pretreatment of rats with vitamin
E reduced catecholamine-induced arrhythmia and
other functional changes [63]. Conversely, animals fed
a vitamin E de~cient diet were found to be more susceptible
to adriamycin- [64] and catecholamine-induced
cardiomyopathic changes [18].
Adriamycin Cardiomyopathy
It is now well established that adriamycin
cardiomyopathy is associated with increased free radicals
and decreased antioxidant status in the heart
[65–68]. Direct evidence for free radical involvement
was provided by studies which showed that vitamin
E-treated mice were more resistant to adriamycin
cardiotoxicity [69]. Moreover, rats maintained on a vitamin
E de~cient diet were more susceptible to
adriamycin cardiotoxicity [10,64]. Treatment with
probucol, an antioxidant as well as a lipid-lowering
drug, modulated the pathogenesis of heart failure due
to adriamycin [66,67].
Diabetic Cardiomyopathy
Evidence is available to suggest the role of increased
oxidative stress and depressed antioxidant enzyme activities
in the pathogenesis of diabetic cardiomyopathy.
A decrease in myocardial SOD and catalase activity
and an increase in oxidative stress has been demonstrated
in STZ-induced diabetic rats [70]. Furthermore,
probucol treatment in these rats resulted in improved
cardiac function [70]. Similarly, some other
studies reported reduced oxidative stress upon vitamin
E supplementation in animals and patients [71–73].
Hypertrophy and Heart Failure
An increase in endogenous antioxidant enzyme activities
and a decrease in lipid peroxidation have been
reported in the hypertrophy stage induced by chronic
pressure overload in rats [74,75] and guinea pigs
[76,77]. Myocytes isolated from hypertrophied rat
hearts also showed increased antioxidants and reduced
lipid peroxidation [78]. The heart failure stage in
guinea pigs was characterized by depressed cardiac
function, dyspnea, as well as lung and liver congestion.
At this stage, a signi~cant decline in myocardial SOD
and GSHPx activities and a decrease in the redox ratio
were indicative of increased oxidative stress [76]. Antioxidant
treatment of the guinea pigs with vitamin E
decreased oxidative stress and delayed the occurrence
of heart failure [77]. In a chronic volume overload
model in dogs, decrease in contractility was associated
with an increase in MDA and a decrease in antioxidant
enzyme activity. Vitamin E treatment modulated some
of these changes [79].
Myocardial Infarction and
Congestive Heart Failure
Recent data from our laboratory have demonstrated
the role of oxidative stress in the pathogenesis of heart
failure following myocardial infarction (MI) [1,12].
Changes in myocardial antioxidants as well as oxidative
stress have been described in the surviving myocardium
of rats subjected to MI. These changes correlated
with cardiac function at different stages of failure
[80]. In this study, maintenance of hemodynamic function
in early stages (non-failure stage) was accompanied
by a signi~cant decrease in oxidative stress and
lipid peroxidation while the antioxidant reserve was
maintained. In late stages, where hemodynamic function
was depressed, the myocardial antioxidants
GSHPx, catalase, SOD and vitamin E were also
signi~cantly decreased while oxidative stress was increased
[80]. In addition to the myocardium, the levels
of vitamin E and A were also depleted in the storage
organs liver and kidney in rats with severe heart failure
[81]. Supplementation of these rats with vitamin E
before subjecting them to coronary artery ligation surgery
modulated these changes [81].
In a study of regional changes in the two ventricles
during the sequelae of heart failure, the antioxidant
de~cit and an increase in oxidative stress occurred ~rst
in the left ventricle [80]. In moderate to severe heart
failure stages, these changes also occurred in the right
ventricle [82]. Thus, oxidative stress and antioxidant
changes correlated with depressed cardiac function in
the respective ventricles. In another study, using the
same animal model, we reported that improved cardiac
function after treatment with the afterload reducing
drugs captopril or prazosin was related to the maintenance
of myocardial endogenous antioxidant status and
decrease in oxidative stress [83,84].
Antioxidant vitamins such as vitamin C, carotenoids
and vitamin E have been shown to decrease lipid peroxidation
and reduce atherogenesis and the risk of
coronary heart disease. Pretreatment with vitamin E
limited myocardial necrosis [85–87] while combined
Oxidative Stress and Heart Failure 115
pretreatment with vitamins E and C in ischemia-reperfusion
settings was found to protect the myocardium
and reduce the infarct size in pigs [88]. On the other
hand, pigs supplemented with oral vitamin E did not
show reduction in infarct size after ischemia-reperfusion
[89].
Clinical Studies
An increase in oxidative stress has recently also been
documented in heart failure patients. Malondialdehyde
levels were found to be signi~cantly higher in congestive
heart failure patients [90–92]. Increased breath
pentane (a byproduct of lipid peroxidation) levels were
reported in exhaled air of CHF patients and treatment
with captopril attenuated this rise and improved the
patient’s clinical condition [93,94]. Furthermore, it has
also been demonstrated that the increase in lipid peroxidation
correlates with the severity of heart failure
[92,95,96]. In addition to an increase in free radical
activity, a decrease in enzymatic and non-enzymatic
antioxidants has also been reported in patients with
congestive heart failure [90–92,96]. In another recent
study, Yucel and colleagues reported a signi~cant decrease
in blood glutathione and erythrocyte SOD activity
and an increase in lipid peroxidation in dilated
cardiomyopathic heart failure patients [97]. All of these
clinical studies provided strong support for the involvement
of oxidative stress in the pathogenesis of
heart failure.
Various clinical trials have examined the bene~cial effects
of antioxidant vitamins in MI and heart failure
conditions. The Health Professional Follow-up Study
[98] and the Nurses Health Study [99] found a decrease
in the incidence of coronary artery disease in men and
women supplemented with vitamin E. In another
study, a cocktail containing antioxidant vitamins A, C,
E and b-carotene resulted in a decrease in oxidative
stress as well as the infarct size in MI patients [100].
The Cambridge Heart Antioxidant Study (CHAOS)
reported a substantial decrease in the incidence of MI
in patients receiving vitamin E [101]. On the other
hand, some studies found no correlation between serum
alpha-tocopherol concentration and subsequent
episodes of MI on cardiovascular disease related death
[102,103].
Oxidative Stress, Apoptosis and
Heart Failure
Although the molecular mechanisms involved in initiating
oxidative stress are not known, some recent
studies have suggested the role of transcription factors
such as NFjB and cytokines in linking oxidative stress
to remodelling processes, such as apoptosis (Fig. 2).
Findings from several in vitro studies and animal models
suggest that apoptosis occurs in response to ischemia-
reperfusion, myocardial infarction, and chronic
pressure overload [104–107], all of which are conditions
that generate oxidative stress [12,13]. More recently,
the loss of myocytes through apoptosis or programmed
cell death, has been reported in the infarct regions of
myocardium from MI patients [108] as well as in patients
with end-stage heart failure [109,110]. The importance
of oxidative stress in apoptosis is also
con~rmed by the observation that knock-out mice lacking
MnSOD die early due to cardiomyopathy as compared
to normal mice [111]. Mechanistic investigations
of apoptosis suggest that tumor suppression protein
p53 triggers and Bcl2 inhibits the process in cardiomyocytes
[107,112]. The mechanism of action of Bcl2 for the
prevention of apoptosis has also been suggested to be
mediated by an antioxidant pathway whereby Bcl2
gene product interacts with MnSOD and inhibits apoptosis
[113]. Cytokines as potent inducers of apoptosis
have also recently been suggested in CHF conditions
[114]. Although the role of oxidative stress in apoptosis
and heart failure patients have been documented, the
exact contribution of apoptosis in heart failure still
remains to be established. Some studies suggest that
Fig. 2. Events linking oxidative stress and heart failure in
cardiac stress conditions.
116 Singal, Khaper, Palace, and Kumar
apoptosis contributes to only 0.2% of the total
cardiomyocyte death at any given time [110]. Furthermore,
the underlying molecular mechanisms that regulate
this remodelling event are still not fully understood.
However, more details are provided in other
papers in this focussed issue.
Cytokines and Oxidative Stress in
Heart Failure
Increasing evidence from both animal [115] and human
studies (116) have reported elevated levels of cytokines
such as tumor necrosis factor a (TNF-a), interleukin-
1a (IL-1a) and atrial naturietic factor in MI
and failure conditions (Fig. 2). Increased concentrations
of these cytokines were shown to have a direct
relation to the severity of failure [25,116,117]. Recent
studies suggest that the deleterious effect of TNF-a
is receptor-mediated and it also directly activates nitric
oxide, which is cytotoxic to myocardial cells by
virtue of its ability to produce free radicals and cause
apoptosis [118] (Fig. 2). The pathological potential of
TNF-a is demonstrated in a study where transgenic
mice overexpressing TNF-a in the heart developed
cardiomyopathy associated with apoptosis [119]. In a
recent study, it was demonstrated that TNF-a and
Ang II induce hypertrophy in cultured neonatal cardiac
myocytes by virtue of producing free radicals and
antioxidants such as BHA, vitamin E and catalase inhibited
this effect of TNF-a and Ang II by scavenging
the radicals [120]. Another new concept suggests that
TNF-a not only produces PRFO, but is also activated
by hydrogen peroxide, in the presence of a P38MAP
kinase [121]. Further studies are required to clarify
this point. A detailed discussion on these aspects is
presented in other articles in this focussed issue of
the journal.
Conclusions
Although there is convincing evidence from both animal
studies and patients that oxidative stress plays a
very important role in the pathogenesis of heart failure
there are not enough clinical trials which have assessed
the use of antioxidant therapy in the treatment of
heart failure. The laboratory ~ndings described here
suggest newer target sites for the prevention of heart
failure as well as better management of patients by
using appropriate antioxidant therapies.
Acknowledgments
Research reported here was done with grant support from the
Medical Research Council of Canada and the Heart and Stroke
Foundation of Manitoba. Dr. Singal is supported by a career
award from the Medical Research Council of Canada, Dr. Palace
by a fellowship from the Manitoba Health Research Council and
Ms. Khaper by the Heart and Stroke Foundation of Canada.
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