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(Circulation. 1997;96:2414-2420.)
© 1997 American Heart Association, Inc.
Articles |
Right and Left Myocardial Antioxidant Responses During Heart Failure Subsequent to Myocardial Infarction
From the Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Correspondence to Dr Pawan K. Singal, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, 351 Tache Ave, Room R3022, Winnipeg, Manitoba R2H 2A6, Canada. E-mail psingal{at}sbrc.umanitoba.ca
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Abstract |
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Background Heart failure subsequent to myocardial infarction (MI) is accompanied by depressed antioxidants and increased oxidative stress in the myocardium. Antioxidant enzyme activities and oxidative stress were examined in the viable left (LV) and right (RV) ventricles in relation to their hemodynamic function.
Methods and Results The left coronary artery in
rats was ligated. At 1 week after MI, LV systolic pressure
(LVSP), LV end-diastolic pressure (LVEDP), and RV
end-diastolic pressure (RVEDP) remained near control
values, whereas RV systolic pressure (RVSP) was significantly
elevated. In the 4, 8, and 16 week post-MI animals, LVSP was
significantly reduced, with values of 112.0±1.57, 99.9±0.52, and
89.2±1.4 mm Hg, whereas LVEDP was significantly elevated, with
values of 8.2±0.52, 17.4±1.7, and 31.4±1.5 mm Hg,
respectively. RVEDP was higher at 8 and 16 weeks, and RVSP was
significantly reduced at 16 weeks. At 1 week after MI, myocardial
catalase activity in the LV was maintained near control levels, whereas
in the RV, it was 134% compared with its control value. At 4, 8, and
16 weeks, catalase activity in the LV was 71%, 48%, and 28% of
respective controls. Catalase activity in the RV was significantly
reduced only at 16 weeks. A similar trend was seen with respect to
glutathione peroxidase activity. Reduced/oxidized glutathione ratio was
significantly depressed in the LV at 1, 4, 8, and 16 weeks, whereas in
the RV, this ratio was significantly reduced only at 8 and 16 weeks.
Myocardial lipid peroxidation in the LV at 4, 8, and 16 weeks was
elevated by 
40%, 51%, and 100%, respectively, whereas in the RV,
an increase of 50% was seen only at 16 weeks.
Conclusions These data show that heart failure subsequent to MI is associated with an antioxidant deficit as well as increased oxidative stress, first in the LV, followed by the RV. Furthermore, these changes correlated with the hemodynamic function in each of the ventricles, suggesting their role in the pathogenesis of ventricular dysfunction.
Key Words: heart failure • antioxidants • myocardial infarction • free radicals
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Introduction |
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Surviving patients with MI are at an increased risk for the occurrence of CHF, reinfarction, arrhythmias, and sudden cardiac death.1 2 3 However, CHF continues to be the prominent clinical problem after MI, with a poor long-term prognosis, as indicated by the 5-year mortality rate of
50% from the time of
diagnosis.4 The clinical syndrome of heart failure is
dominated by hemodynamic abnormalities, impaired
exercise capacity, and fluid retention.5 Although a number of mechanisms have been postulated to explain the pathogenesis of heart failure and its associated clinical manifestations, the precise details of the cellular and subcellular alterations remain to be elucidated. Because no single mechanism that could fully explain the development of the depressed cardiac function has been identified, it is likely that the cause is multifactorial. In this regard, there has been a recent surge in experimental studies suggesting that a decrease in antioxidant status and an increase in oxidative stress may be intimately involved in the pathogenesis of cardiac dysfunction and CHF, for a variety of reasons.6 7 8 9 10 A limited number of clinical studies have also provided evidence for an increase in oxidative stress in patients suffering from coronary artery disease and MI,11 12 13 and antioxidant therapy has been shown to reduce oxidative stress and improve prognosis in MI patients.11 14
In a coronary artery ligation model of MI in rats, we reported that the pathogenesis of heart failure was accompanied by an antioxidant deficit and increased oxidative stress in the myocardium.15 Furthermore, in the same experimental model, improved hemodynamic function after treatments with the afterload-reducing drugs captopril and prazosin was also shown to be accompanied by an improved antioxidant status.16 However, measurement of antioxidant and oxidative stress changes in these studies was done in the viable left and right ventricles pooled together, and this approach may have masked any differential changes in the two ventricles during the sequelae of CHF. Thus, in the present study, we examined myocardial antioxidant and oxidative stress changes in the viable left and right ventricles separately during heart failure subsequent to left ventricular MI. For an analysis of these changes in relation to function, right and left ventricular pressures were also recorded.
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Methods |
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Experimental Model
MI was produced in male Sprague-Dawley rats weighing 150±10 g via occlusion of the left coronary artery.15 In this procedure, the animals were anesthetized with 5% isoflurane in an induction chamber, and a left intercostal thoracotomy was performed under aseptic conditions. The skin was incised along the left sternal border, and the third and fourth ribs were cut proximal to the sternum. The pericardial sac was perforated, and the heart was exteriorized through the intercostal space. The left coronary artery was ligated
1 to 2 mm
from its origin with a 6-0 silk thread. After the left coronary
artery occlusion, the heart was repositioned in the chest. The thoracic
cavity was closed by reapproximation of the ribs along with a
purse-string suture of the incised muscles. Before the skin was
sutured, air in the chest was removed with a syringe. Throughout this
surgical procedure, a maintenance dose of
anesthesia (1.5% to 3% isoflurane) was delivered with a
positive-pressure ventilation system consisting of 95% O2.
The mortality among the coronary artery–ligated animals was
35% within the first 24 hours. It should be pointed out that with the surgical procedure used in this study, most of the experimental animals develop an infarct size ranging between 30% and 50% of the left ventricular mass. Rats with infarcts comprising <20% of the left ventricular mass were not included for further investigations. Control animals were treated in a similar fashion, with the exception that the suture around the left coronary artery was not tied. No mortality was observed in the sham-operated control animals within 24 hours of the operation. After the operation, animals were placed in a chamber in which an oxygen atmosphere was maintained and were allowed to recover. Analgesia (buprenorphine, 0.01 to 0.05 mg/kg body wt) was given subcutaneously every 12 hours for up to 48 hours after surgery. Animals had access to food and water ad libitum and were used at 1, 4, 8, and 16 weeks for different studies.
Hemodynamic Studies
Animals were anesthetized with sodium pentobarbital (50
mg/kg IP). A miniature pressure transducer (Millar Micro-Tip)
was inserted into the right carotid artery and then advanced into the
left ventricle. LVEDP and LVSP were recorded on a computer with an
Axotape Data Acquisition Program. For recording of right
ventricular pressures, the miniature pressure transducer
was inserted into the right jugular vein and then advanced into the
right ventricle. After hemodynamic recordings,
the animals were killed and the hearts and other organs were removed
for further studies.
Tissue Weights
Pieces of tissues from the lungs and liver were removed and
weighed. For the determination of dry weight, these were placed in an
oven at 65°C until a constant weight was reached. Ratios of wet to
dry weight were calculated for lungs and liver.
Biochemical Assays
Connective tissue, atria, and the scar tissue were carefully
removed from all hearts. The viable portion of the left ventricle with
the septum was separated from the right ventricle. Scar tissue was
distinct from viable myocardium because of its white color
and thin texture as opposed to the reddish-brown color and thick
texture of the surviving myocardium. These right and left
ventricles were separately analyzed for antioxidant and
oxidative stress changes. Before homogenization,
hearts were placed in a 0.2 mol/L Tris–0.16 mol/L KCl
buffer, pH 7.4. The hearts were allowed to beat for a short period of
time in the buffer, which allowed perfusion of the
myocardium so as to minimize the extent of contamination by
blood-derived elements on antioxidant enzyme measurements.
Antioxidant Changes
Glutathione Peroxidase
GSHPx activity was determined by a method described
elsewhere.17 Tissue was homogenized 1:10 in
75 mmol/L phosphate buffer, pH 7.0. Homogenate
was centrifuged at 20 000g for 25 minutes, and the
supernatant was aspirated and assayed for total cytosolic GSHPx
activity. GSHPx activity was assayed in a 3-mL cuvette containing 2.0
mL of 75 mmol/L phosphate buffer, pH 7.0. The following
solutions were then added: 50 µL of 60 mmol/L
glutathione, 100 µL glutathione reductase solution (30 U/mL), 50 µL
of 0.12 mol/L NaN3, 100 µL of 15
mmol/L Na2EDTA, 100 µL of 3.0 mmol/L
NADPH, and 100 µL of cytosolic fraction. The reaction was started by
the addition of 100 µL of 7.5 mmol/L hydrogen peroxide,
and the conversion of NADPH to NADP was monitored by a continuous
recording of the change of absorbance at 340 nm at 1-minute
intervals for 5 minutes. GSHPx activity was expressed as nanomoles
of reduced NADPH oxidized to NADP per minute per milligram protein,
with a molar extinction coefficient for NADPH at 340 nm of
6.22x106.
Catalase
Catalase activity was determined by a method described
elsewhere.18 Tissue was homogenized in (1:10)
50 mmol/L potassium phosphate buffer, pH 7.4, and the
homogenate was centrifuged at 40 000g
for 30 minutes. Supernatant (50 µL) was added to a 3-mL cuvette that
contained 2.95 mL of 19 mmol/L hydrogen peroxide in 50
mmol/L potassium phosphate buffer, pH 7.4. Changes in absorbance
at 240 nm were continuously followed for 5 minutes. Catalase activity
was expressed as units per milligram protein.
Oxidative Stress Changes
Thiobarbituric Acid Reactive Substances
Lipid peroxide content in myocardium was
determined by quantifying the TBARS as described
previously.19 Tissue was homogenized in (10%
wt/vol) 0.2 mol/L Tris–0.16 mol/L KCl buffer, pH 7.4,
and incubated for 1 hour at 37°C in a water bath. A 2-mL aliquot was
withdrawn from the incubation mixture and pipetted into a 12-mL Corning
culture tube. This was followed by the addition of 2.0 mL of 40%
trichloroacetic acid and 1.0 mL of 0.2% thiobarbituric acid. To
minimize peroxidation during the assay procedure, 100 µL of 2%
butylated hydroxytoluene was added to the thiobarbituric acid reagent
mixture. Tubes were then boiled for 15 minutes and cooled on ice for 15
minutes. Two milliliters of 70% trichloroacetic acid was added, and
tubes were allowed to stand for 20 minutes, at which time the tubes
were subsequently centrifuged at 800g for 20
minutes. The developed color was read at 532 nm on a spectrophotometer.
Commercially available malondialdehyde was used as a standard.
Glutathione
Concentrations of total glutathione (GSSG+GSH) were measured in
the myocardium by the glutathione reductase/DTNB recycling
assay.20 The rate of TNB formation is followed at 412 nm
and is proportional to the sum of GSH+GSSG present. Myocardial
tissue was homogenized in 5% sulfosalicylic acid. The
tissue homogenate was centrifuged for 10 minutes at
10 000g. Supernatant was stored at 4°C until assayed.
GSSG alone was measured by treatment of the sulfosalicylic acid
supernatant with 2-vinylpyridine and triethanolamine. The solution was
vigorously mixed, and the final pH of the solution was adjusted to
between 6 and 7. After 60 minutes, the derivatized samples were assayed
as described above in the DTNB–GSSG reductase recycling assay. GSH
values were calculated as the difference between total (GSSG+GSH) and
GSSG concentrations. Values are reported in GSH equivalents and
expressed as micromoles per gram tissue weight.
Proteins and Statistical Analysis
Proteins were determined by a method described
elsewhere.21 Data were expressed as mean±SEM. For a
statistical analysis of the data, group means were compared by
one-way ANOVA, and ANOVA followed by Bonferroni's test was used to
identify differences between groups. Values of P<.05 were
considered significant.
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Results |
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General Observations
After coronary artery ligation, rats were observed on a regular basis for their general behavior and any signs of heart failure. In the sham-operated as well as in the coronary artery–ligated animals, nothing unusual was noted until about 12 weeks after the surgery. At this point, labored breathing, cyanosis of the limbs, and abdominal enlargement were noted in the coronary artery–ligated animals. In addition, these animals displayed marked lethargy. At autopsy, congested lungs as well as hepatomegaly associated with a black-cherry color of the liver were noted in the 16-week post-MI animals.
Hemodynamic Studies
Animals were assessed for left and right ventricular
functions (peak systolic and end-diastolic
pressures) at 1, 4, 8, and 16 weeks after MI; these data are shown in
Table 1
. There was no change in either
the LVEDP or LVSP in the coronary artery–ligated animals at 1
week after MI. However, there was a significant increase in the LVEDP
and a significant decrease in the LVSP in the infarcted animals
relative to their controls at 4, 8, and 16 weeks after MI. These
changes were progressive and became more pronounced as the period of
after MI increased from 4 to 16 weeks. With respect to right
ventricular function, no change in the RVEDP was observed
at 1 and 4 weeks in the infarcted animals compared with their
respective controls. RVEDP was elevated in the post-MI animals at 8 and
16 weeks. In the infarcted animals, a significant elevation in the RVSP
was observed at 1 week after MI. This pressure was near control levels
in the 4- and 8-week groups, and a significant depression in the RVSP
was seen at 16 weeks.
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Tissue Weights
The ratios of wet to dry weight in lung and liver of infarcted
animals were no different from their respective controls at 1 and 4
weeks after MI. However, this ratio for lungs was significantly higher
at 8 and 16 weeks, whereas in the liver, the ratio was significantly
increased only at 16 weeks after MI (Table 2).
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Myocardial Antioxidant Enzymes
Myocardial catalase and GSHPx activities were examined in the
viable left and right ventricles separately at 1, 4, 8, and 16 weeks
after MI and compared with their respective control levels. At 1 week,
catalase activity in the left ventricle was maintained near that of its
respective control levels, whereas in the right ventricle it was 134%
compared with the controls, and this increase was statistically
significant (Fig 1). At 4, 8, and 16
weeks, catalase activity in the left ventricle was 71%, 48%, and 28%
of the respective control values. In contrast, catalase activity in the
right ventricle was no different from the respective controls at 4 and
8 weeks after MI, whereas a significant decrease was observed at 16
weeks. Catalase activity in the right ventricle remained significantly
higher than in the corresponding left ventricle at all time points. A
similar pattern of changes in the two ventricles was seen for GSHPx
activities (Fig 2).
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Significantly different
(P<.05) from corresponding experimental LV tissue.
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Oxidative Stress Studies
The amount of lipid peroxidation was determined by evaluation of
myocardial TBARS; these data are shown in Fig 3. At 1 week, no change was observed in
the amount of TBARS in either the left or right ventricle relative to
respective control levels. At 4, 8, and 16 weeks, however, myocardial
TBARS in the left ventricle were elevated by 40%, 51%, and 100%,
respectively, compared with their controls. In contrast, levels of
myocardial TBARS were not changed in the right ventricle until 8 weeks,
but at 16 weeks, a significant increase was observed relative to
respective controls.
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Myocardial reduced (GSH) and oxidized (GSSG) glutathione levels were
also examined in the surviving left and right ventricular
tissue of MI animals and compared with their respective controls (Table 3). At 1 week, GSH levels in the left
ventricle were unchanged from controls, whereas GSH levels in the right
ventricle were significantly increased above control levels. At 4, 8,
and 16 weeks, GSH levels in the left ventricle were 70%, 60%, and
44% of control values. GSH levels in the right ventricle showed no
statistically significant changes until 8 and 16 weeks, when 19% and
35% decreases were observed, respectively. However, GSH levels in the
right ventricle remained significantly higher than those of the left
ventricle. GSSG contents in both the left and right ventricles were
unchanged from their respective controls at 1 week. However, GSSG
content was significantly elevated at 4, 8, and 16 weeks in the left
ventricle compared with the values in left ventricular
controls and those of the right ventricle in MI animals. The GSSG
levels in the right ventricle were increased significantly only at 16
weeks after MI.
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The GSH/GSSG ratio was also analyzed; these data are shown in
Fig 4. Baseline values for this ratio in
control right and left ventricles were not different from each other.
This ratio was marginally increased in the right ventricle of infarcted
animals, but these differences were not statistically different
relative to controls at 1 week. A significant depression in the
GSH/GSSG ratio in the left ventricle was seen at 1, 4, 8, and 16 weeks
relative to controls, whereas a significant decrease in this ratio in
the right ventricle was observed only at 8 and 16 weeks. In the MI
animals, the ratio in the right ventricle was higher than in the left
ventricle at all time points.
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Discussion |
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MI and Heart Failure: Right Follows Left
Maintenance of LVSP and LVEDP in the 1-week experimental MI group indicated sustained left ventricular functioning in these animals. Maintenance of RVEDP and a significant increase in RVSP indicated enhanced functioning of the right ventricle. No clinical signs of heart failure were evident, and ratios of wet to dry weight of lungs and liver also did not suggest any heart failure. Thus, these animals were considered to be in a "nonfailure" stage. In the 4-week experimental MI group, LVEDP was elevated and LVSP was depressed. RVEDP and RVSP were both maintained. Absence of lung or liver congestion indicated that these animals had some functional abnormalities without any influence on the tissues upstream. This stage was designated "mild heart failure." At 8 weeks, a further reduction in LVSP and an increase in LVEDP were seen; RVEDP was elevated and RVSP sustained. Pulmonary edema without liver congestion was apparent; thus, these animals were considered to be in a stage of "moderate heart failure." At 16 weeks, the greatest elevation in LVEDP and depression in LVSP were also accompanied by a significant increase in the RVEDP and decrease in the RVSP. Pulmonary edema and liver congestion were both present. In addition, animals from the 16 week post-MI group displayed overt clinical signs of heart failure consisting of dyspnea, abdominal enlargement and ascites, cyanosis of peripheral extremities, and markedly lethargic behavior. Thus, the 16 week post-MI group was considered to be in a stage of "severe heart failure." The proposed segregation of experimental MI animals into nonfailure and mild, moderate, and severe stages of heart failure at 1, 4, 8, and 16 weeks, respectively, is being adopted here for a more objective comparison of the hemodynamic function with the biochemical changes in antioxidants and oxidative stress in each of the ventricles. It is emphasized that this classification is strictly arbitrary. Although deterioration of contractile function occurred in both ventricles over a 16-week period, changes in the right ventricle did not appear until 4 to 8 weeks after the changes in the left ventricle.
Oxidative Stress and Cardiac Function: Experimental
Studies
Although heart failure subsequent to MI has been reported to be
associated with an antioxidant deficit as well as increased oxidative
stress,15 the present study demonstrates for the first
time that these changes are regionally specific and occur in a
characteristic fashion, first in the left ventricle and then in the
right ventricle. Furthermore, these regionally specific changes
correlated with the severity of dysfunction and failure in each of the
ventricles. In a variety of experimental studies, the presence of an
antioxidant deficit has been reported to be one of the mechanisms
mediating the development of heart failure.8 22 23 It is
important to emphasize, however, that the present study does not
establish whether these antioxidant changes are a cause or an effect of
CHF. Pathological tissue damage can result secondarily in decreases in
the activity of antioxidant enzymes and elevations in lipid peroxides.
Further experiments are necessary to test this hypothesis. However, the
present study does provide strong evidence of a tight correlation
between the myocardial antioxidant status and cardiac
function/dysfunction in each of the respective ventricles subsequent to
left ventricular MI. One week after MI, sustained cardiac
function in the left ventricle was accompanied by the
maintenance of antioxidants, whereas the hyperfunctioning right
ventricle showed a significant increase in the antioxidant status. An
increase in the myocardial antioxidant status in the right ventricle at
this stage was more clearly evidenced by a significantly higher redox
ratio compared with the left ventricle, indicating reduced oxidative
stress in the right ventricle.6 24 25 An increase in the
myocardial redox state has been reported in various conditions
affecting the heart, and the change is associated with maintained or
improved hemodynamic
function.8 22 24 26
Previous studies have shown that left ventricular failure after chronic MI is associated with improved or sustained right ventricular function.27 28 The precise mechanism by which left ventricular MI leads to sustained functioning of the right ventricle is currently unknown. Postulates that have been put forth to explain this phenomenon include (1) pulmonary hypertension arising from medial hypertrophy of the muscular branches of the pulmonary artery after infarction,29 (2) altered pressure gradient across the pulmonary vascular bed during left ventricular failure,28 and (3) sustained systemic arterial pressure in the face of reduced cardiac output as a consequence of left ventricular failure.29 However, the present study demonstrates for the first time that maintenance of the myocardial endogenous antioxidant status in the right ventricle after left ventricular MI may serve to sustain right ventricular function, whereas a deficit in the antioxidant defense system may predispose the right ventricle to oxidative damage and subsequent myocardial dysfunction.
Mild failure at 4 weeks after MI was accompanied by significant depressions in enzymatic antioxidants in the left ventricle but not in the viable right ventricle. An increase in oxidative stress in the left ventricle at this stage was evidenced by a significant decrease in GSH/GSSG ratio and a significant increase in TBARS. Increases in TBARS have been reported in heart failure secondary to adriamycin cardiotoxicity7 and chronic pressure overload of the heart.30 In the present study, moderate failure was associated with a further reduction in antioxidants as well as a further increase in TBARS in the left ventricle but not in the right ventricle. Not only was the severe failure stage accompanied by the greatest deficit in antioxidant status and the most pronounced increase in oxidative stress in the left ventricle, but involvement of the right ventricle with respect to antioxidant deficit and elevated oxidative stress was also found to occur. These findings suggest that a relative deficit in myocardial endogenous antioxidants and higher oxidative stress may play a pathophysiological role in heart failure subsequent to left ventricular MI. Furthermore, these findings also provide evidence that although the left ventricle begins to fail at 4 weeks after MI, progressing to severe failure at 16 weeks, right ventricular function is maintained for a longer period, showing failure only at 16 weeks. In addition, in each of the ventricles, the increase in oxidative stress precedes the depressed function.
In the present study, enzymatic antioxidant measurements consisted of GSHPx and catalase activities. SOD activity was not measured. Although SOD is the first line of defense against oxygen free radical–mediated damage, it acts to increase the levels of hydrogen peroxide by virtue of catalyzing the dismutation of superoxide anion to hydrogen peroxide.6 As a result, catalase and GSHPx become the most crucial antioxidant enzymes, because they both act to detoxify the elevated levels of peroxides generated by the enzymatic action of SOD. Thus, we deliberately chose to measure GSHPx and catalase activities only.
Oxidative Stress and Cardiac Function: Clinical Studies
Recently, clinical studies of heart failure patients have
corroborated the findings obtained from the various animal models of
heart failure. In patients with CHF, pentane, a product of lipid
peroxidation, was found to be significantly elevated compared with
healthy age-matched subjects.12 31 32 33 Furthermore, it has
also been demonstrated that in CHF patients, lipid peroxidation
increases in proportion to the severity of heart failure as assessed in
the exhaled air or in the plasma.13 33 In patients, plasma
levels of vitamin E, a "chain-breaking antioxidant," were found
to be progressively decreased by 26% during the first 48 hours after
the onset of acute MI,34 and these reductions in vitamin E
coincided with a period of increased risk for subsequent
reinfarction.35 Thus, the concept that a relative deficit
in the antioxidant reserve may mediate the pathogenesis of heart
failure23 is supported by these studies. Significant
increases in blood free radical levels and significant depressions in
blood vitamin E levels have been documented in coronary artery
disease patients during coronary artery bypass graft
surgery.36 Preoperative oral administration of vitamin E
and vitamin A to coronary artery disease patients for 5 days
before coronary artery bypass graft surgery prevented the rise
in blood free radicals and reductions in blood vitamin E levels
associated with revascularization.37
Clinical trials examining the effect of combined treatment for 28 days
with antioxidant vitamins A, C, and E and ß-carotene in patients with
acute MI have demonstrated a protective effect against further cardiac
necrosis and oxidative stress.11 Furthermore, vitamin E
treatment in patients with overt clinical and angiographic
coronary atherosclerosis reduced the rate of
nonfatal MI.14 In most of these studies, the sample size
was small and follow-up time was relatively short.
Oxidative Stress Changes: Molecular Mechanisms
Molecular mechanisms for the depressed activities of these
antioxidants are not known. Antioxidant enzymes have been shown to be
substrate-stimulated as well as inactivated under oxidative
stress.38 39 40 41 Sympathectomy42
and a subchronic ß-blockade43 have also been shown to
modify myocardial antioxidant enzyme activities. Alterations in
antioxidant enzymes under a wide range of
physiological and pathological conditions such as
age,44 exercise,45 46
ß-thalassemia,47
hypertrophy,22 30 48 heart
failure,30 and hypoxia49 have been
reported. Irrespective of the mechanism, these studies clearly document
a dynamic nature of the endogenous antioxidant status that
adjusts to the physiological and
pathophysiological conditions imposed.
Conclusions
This study reveals that heart failure subsequent to left
ventricular MI is associated with an antioxidant deficit
first in the left ventricle and, in the more chronic stages, then in
the right ventricle. Compensatory antioxidant adjustments observed
early in the right ventricle may serve to protect the surviving
myocardium against oxidative stress injury and thereby
sustain cardiac function. In contrast, depressed cardiac function and
heart failure may occur as a consequence of an increase in oxidative
stress and a relative antioxidant deficiency. The study suggests the
potential therapeutic value of chronic antioxidant therapy in
modulating/preventing the development of heart failure as well
as providing a basis for the formulation of more mechanistically
oriented investigations.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a group grant from the Medical Research Council of Canada, Group in Experimental Cardiology (Dr Singal). Dr Singal is a career investigator of the Medical Research Council of Canada.
Received March 14, 1997; revision received May 23, 1997; accepted May 28, 1997.
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