(Circulation. 1999;99:121-126.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Mobilization of Antioxidant Vitamin Pools and Hemodynamic Function After 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 3022, Winnipeg, Manitoba R2H 2A6, Canada. E-mail psingal{at}sbrc.umanitoba.ca
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Abstract |
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Background—Although most previous studies have attempted to correlate plasma concentrations of vitamins with specific cardiovascular end points, metabolic considerations suggest that changes in myocardial tissue and storage organs may be better indicators of myocardial oxidative stress.
Methods and Results—Rats fed commercial chow or a diet enriched with vitamin E for 2 weeks were subjected to either a surgical myocardial infarction (MI) or a sham procedure. Rats were hemodynamically assessed 16 weeks after surgery, and their heart, liver, kidney, and plasma were analyzed for antioxidant vitamins E (tocopherol) and A (retinol and total retinyl esters). At 16 weeks, MI rats on a control diet showed depressed peak systolic and elevated diastolic pressures in both right and left ventricles compared with their sham controls. Plasma concentrations of vitamins E and A in MI rats were not different from sham controls fed the same diet. However, concentrations of vitamin E in left ventricle and liver and of vitamin A in liver (retinol) and kidney (retinyl esters) were decreased in rats with MI compared with the sham controls. Vitamin E supplementation improved hemodynamic function in rats with MI and increased plasma, myocardial, liver, and kidney concentrations of vitamin E. The vitamin E diet also prevented the loss of total retinyl esters from the kidney but not of retinol from the liver in MI rats.
Conclusions—Dietary supplements of vitamin E can sustain better cardiac function subsequent to MI. Antioxidant vitamin levels in the myocardium or in storage organs and not in plasma may be better indicators of myocardial oxidative stress.
Key Words: heart failure • free radicals • myocardial infarction • antioxidants
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Introduction |
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Current interest in the antioxidant vitamins E and A as they relate to heart disease has evolved from the growing realization that free radical–mediated tissue damage is involved in the pathogenesis and progression of several forms of cardiac dysfunction.1 2 3 Several large-scale epidemiological studies have recently shown an inverse relationship between vitamin E and A consumption and the risk of cardiovascular disease.4 5 Furthermore, experimental evidence has shown depletion of these antioxidant vitamins in different cardiac abnormalities.6 7 8 9 However, there is also experimental evidence suggesting that plasma and/or myocardial concentrations of vitamins E and A are not related to oxidative stress or depressed cardiac function.10 11 Clearly, more work is required to clarify the role of antioxidant vitamins in heart failure.
In the majority of past studies, plasma was the target site for analysis of vitamin concentrations. A few studies have also considered vitamin concentrations specifically in heart tissue.9 The myocardium and resident blood plasma are certainly expected to be the tissues initially affected by free radical production during cardiac disturbances. However, the heart contains only a small proportion of the body's total antioxidant vitamin pool. Larger stores, present in the liver and kidney, are thought to function as reservoirs.12 13 Therefore, potential increases in the utilization of antioxidant vitamins in the heart and plasma after a disruptive cardiac event may be buffered by mobilization of vitamins from other larger storage pools in the body. In fact, in animals exposed to chemicals that alter vitamin A metabolism, liver and kidney have been reported to be more sensitive indicators of vitamin A status than serum concentrations.14
In the present study, antioxidant vitamin E and A concentrations in the plasma, myocardium, liver, and kidney were measured in hemodynamically assessed rats with or without myocardial infarction (MI). The effects of dietary vitamin E supplementation for 16 weeks on vitamin E and A status, as well as hemodynamic function in these groups, were also examined.
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Methods |
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Animals and Surgical Treatment
Male Sprague-Dawley rats (125±7 g; n=60), housed in pairs, were randomly assigned to either a basal diet (rat chow, PMI feeds) or a vitamin E–enriched diet (1545 mg of tocopherol acetate per kilogram of feed). After 2 weeks on these diets, each group was further subdivided into an MI and a sham group (n=15 each). Rats in the MI groups were anesthetized and underwent surgery to ligate the left coronary artery, as described previously.9 Using this surgical procedure, we have previously shown that an infarct is produced that reaches
50%
of the left ventricle. To reduce variability due to differences in
infarct size, rats with infarcts of <20% of the left
ventricular mass were not included in the present
study.15 Rats in the control groups underwent the
same procedure, except that the suture was not tied around the
coronary artery. After recovering from the procedures, rats
were kept on diets identical to their presurgical grouping for an
additional 16 weeks. At the end of 16 weeks, animals were anesthetized with sodium pentobarbital (50 mg/kg IP), and their left and right ventricular functions were assessed by a miniature pressure transducer.9 After these assessments, animals were killed, and the heart, liver, and kidney were removed and immediately frozen in liquid nitrogen. Plasma was isolated from whole blood by centrifugation and similarly frozen.
All of the animals used in the present study were maintained and treated in accordance with the policies and procedures of the Canadian Council on Animal Care.
Vitamin Measurement
Vitamin E (tocopherol) and vitamin A (retinol and
retinyl esters) were measured in the myocardium, liver,
kidney, and plasma, as well as in the feed, by use of an extraction
procedure and reverse-phase high-performance liquid
chromatography (HPLC) detection
method.16
Synthesis and Structural Confirmation of Vitamin A
Esters
Because only the palmitate ester of Vitamin A is commercially
available, HPLC standards for other vitamin A esters were synthesized
by use of a modification of a cholesterol ester synthesis
method. All preparatory steps were performed under subdued light
conditions and in amber vials. Briefly, 2020 nmol of vitamin A
(retinol) suspended in toluene was placed by means of a pipette
into a vial that contained 6060 nmol of the appropriate lipid
anhydride, also suspended in toluene. Contents of the vial were
thoroughly mixed. Each sample was completely dried under vacuum in a
rotary evaporator at room temperature, purged with nitrogen, tightly
capped, and incubated in the dark at 68°C in a water bath for 8 to 12
hours. Samples were then resuspended in HPLC mobile phase and
analyzed by the HPLC method.16 Retention
times for each unknown ester were established, and post-HPLC eluant
fractions corresponding to these intervals were collected and dried
under vacuum. After suspension in the HPLC mobile phase, the samples
were eluted by the same HPLC separation procedure. Each eluant
corresponding to a vitamin A ester peak retention time was
analyzed by mass spectrometry to confirm the vitamin A ester in
that peak.
Data Analysis
All data are presented as mean±SEM. Group means were
analyzed by ANOVA followed by Bonferroni pairwise t
tests to identify differences between specific means. Statistical
significance was set at P<0.05.
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Results |
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Hemodynamics
Results from the hemodynamic assessments of right and left ventricles from the 4 groups are summarized in the Table
. Animals fed the basal diet
in the 16-week post-MI group showed an elevation in
left-ventricular end-diastolic pressure and a
depression of left-ventricular peak systolic
pressure compared with control rats fed the same diet. A similar
pattern of pressure changes was present in the right ventricle.
Control animals fed the diet supplemented with vitamin E showed no
change in any of their hemodynamic
parameters compared with animals on the basal diet. Vitamin
E feeding significantly attenuated the rise in
left-ventricular end-diastolic pressure as well
as the drop in left-ventricular peak systolic
pressure in the MI group, but both of the values were significantly
different from control levels. Values for the right ventricle
(end-diastolic and peak systolic pressures) in the
vitamin E–supplemented MI group were maintained near control
levels.
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Vitamin E Consumption and Tissue Concentrations
Vitamin E content was 40.6±1.4 mg/kg in the basal diet and
1545±101 mg/kg in the enriched diet. Analysis of each diet at
the beginning and end of the experiment determined that loss of vitamin
E was <4% and was not significantly different between any batch of
the diet preparations. There were no significant differences in the
intake of vitamin E per day between the 2 basal diet groups
(sham=1.15±0.02 mg/d per animal; MI=1.11±0.04 mg/d per animal) or the
enriched-diet groups (sham=32.53±1.03 mg/d per animal; MI=32.03±0.9
mg/d per animal).
Vitamin E concentrations in plasma, left ventricle, right ventricle,
liver, and kidney are shown in Figure 1.
Vitamin E concentration was highest in the liver and left and right
ventricles, followed by kidney and plasma. MI depleted
tocopherol in the left ventricles by >32% and in the
liver by 37% in rats fed the basal diet compared with their sham
controls. MI in rats fed the basal diet had no effect on vitamin E
levels in the plasma, right ventricle, or kidney.
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. Note
that the scale for concentration (vertical axis) given on the left is
different for each tissue.
The vitamin E–enriched diet significantly (P<0.05)
elevated concentrations of the vitamin in all of the tissues from sham
animals (Figure 1
). The maximum percent increase was in the liver
(340%), followed by plasma (250%), both ventricles (60%), and kidney
(26%). A significant gain in vitamin E concentrations was also seen in
all of the tissues in the supplemented MI animals. However, in the MI
animals, left ventricular vitamin E concentration was
significantly less (-25%) than the sham controls supplemented with
vitamin E. There was a trend toward lower vitamin E concentrations in
the liver of MI rats fed the enriched diet compared with their diet
controls, but the difference was not statistically significant.
Tissue Concentrations of Vitamin A (Retinol and Total Retinyl
Esters)
Using synthesized and authenticated vitamin A ester standards, we
performed analyses of different vitamin A esters in the
heart, liver, kidney, and plasma tissues from rats fed the
basal and enriched diets. Retinol was present in all tissues
(liver>kidney
LV, RV, and plasma). At least 5 retinyl esters were
routinely detected in the liver (palmitatestearate>oleate
>linoleate>octanoate), 3 in the kidney
(palmitatestearate>octanoate), and only 1 (palmitate) in the plasma
and the heart. Although retinyl palmitate was detectable in plasma and
in both the right and left ventricles, its concentration was highly
variable and was generally <0.002 nmol/g.
Retinol concentrations in the plasma, left ventricle, right ventricle,
liver, and kidney are shown for all 4 experimental groups in Figure 2. Plasma retinol concentrations were
unaffected by MI. Sham and MI rats fed the vitamin E–enriched diet had
significantly higher concentrations of retinol in plasma than their
respective basal diet controls. Neither dietary vitamin E supplements
nor MI had any effect on left or right ventricular retinol
concentrations. MI depleted liver retinol by 34% in rats fed the basal
diet compared with their sham controls, and this depletion was not
significantly attenuated by vitamin E supplementation. Kidney retinol
concentrations were unaffected by MI or vitamin E supplementation.
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Total retinyl esters are shown only for liver and kidney (Figure 3). Retinyl ester concentrations in
plasma and myocardial tissue are not given because of their low values
and high variability. Liver retinyl ester concentrations were not
significantly different in the control and MI groups maintained on the
basal diet. The vitamin E–enriched diet significantly increased
retinyl esters in both control and MI groups. Retinyl ester
concentrations significantly declined after MI in the kidneys of rats
fed the basal diet compared with their sham controls, but these
differences were not evident between the vitamin E–enriched, control,
and MI groups.
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Discussion |
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Antioxidants and Heart Failure: Cause and Effect
Previously, we9 reported that heart failure subsequent to MI in rats correlated with a decrease in antioxidant enzymes, catalase, and glutathione peroxidase, as well as an increase in oxidative stress. In the present study, depressed left ventricular function in the MI rats was also associated with a decrease in the nonenzymatic antioxidant vitamin E. There are now many experimental9 17 18 19 and clinical20 21 22 studies documenting a close relationship between antioxidant deficit and cardiac dysfunction. In the present study, a diet supplemented with vitamin E improved endogenous levels of this vitamin and modulated the decline in cardiac function in the MI group. These data clearly demonstrate that an increase in myocardial antioxidant concentrations helps sustain cardiac function subsequent to MI, thus suggesting that a decrease in antioxidant reserve may be a causative factor.
Antioxidant Dynamics: Tissue and Plasma Concentrations
The heart contains a relatively small fraction of the total
antioxidant vitamin complement in the body. Any depletion of vitamins
(E and A) in the heart tissue or plasma may be buffered by mobilization
of these vitamins from the other large storage
pools.23 How vitamins E and A are absorbed in the
gut and reach the heart, liver, and kidney through the plasma is shown
in Figure 4. Unlike vitamin A, vitamin E
concentrations in the plasma are not tightly regulated by a specific
transport protein, and they may fluctuate
significantly.24 However, the liver still plays
an important role in the distribution of vitamin E to extrahepatic
tissues, including the heart. The present study highlights the
importance of monitoring tissue rather than plasma content of vitamins
to detect the relationship with cardiac events. It is obvious that
obtaining tissue samples to assess antioxidant vitamin content is not
practical in a clinical setting. In this regard, at least 2 studies
have recently shown that short-term peaks of vitamin A in the plasma,
after an administered dose, can be used to calculate liver stores of
the vitamin.25 26
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) for export to plasma. Exchange of vitamin E occurs
between target organ cells and various types of lipoprotein
particles.
Vitamin E Changes
Although concentrations of vitamin E were not different in the
plasma of rats subjected to MI, significant depletions of this vitamin
did occur in the myocardium and liver. It has been reported
that myocardial vitamin E concentrations decline in response to
disruptive cardiac events,27 including
MI.9 This decline probably reflects increased
demand for the vitamin due to elevated oxidative
stress.9 28 Although the percent decline in
vitamin E in the left ventricle (32%) and liver (37%) of rats with MI
in the present study was comparable, the liver, because of its
larger size, suffered a much higher net loss of vitamin E. Taking
tissue weight into account, the total loss of vitamin E in liver was
550 µg compared with a 15-µg loss from the heart. Possibly, the
depletion of vitamin E from the liver occurs as the vitamin is
mobilized from this large storage pool to replenish the depleted
vitamin level in the oxidatively stressed left ventricle.
Others29 have also noted the importance of the
liver in redistributing vitamin E to tissues with transitory higher
requirements.
In addition, our results show that by supplementing the diet with vitamin E, myocardial and hepatic concentrations of vitamin E can be elevated relative to baseline levels, even in animals with surgical MI. It is likely that MI does not influence vitamin E absorption at the gut level. Results from the kidney suggest that this organ is not as important as the liver for storing or supplying vitamin E to the heart after MI.
Vitamin A Changes
How the heart derives its retinol from the plasma and how both the
liver and kidney can release retinol from the esterified forms when
retinol binding protein (RBP) in the plasma is unoccupied by the
retinol ligand are shown in Figure 4. In the current study, retinol
concentrations in both the plasma and left ventricular
tissue were unaffected by MI. However, liver retinol concentrations
declined by 34% in rats with surgical MI compared with sham control
rats, representing a mean total loss of 
60 µg of
retinol after MI. This depletion occurred despite an ample supply of
vitamin A from the commercial diet used in the present study (ie,
1160 IU/kg body weight per day). It has been
reported20 that 50 000 IU/d of dietary vitamin
A, which for a 75-kg person translates to 667 IU/d per kilogram,
given as a part of an antioxidant therapy regimen, was effective in
reducing oxidative stress and infarct size in patients with suspected
MI. The relatively high supply in the basal diet in the present
study may have contributed to the fact that storage forms of vitamin A,
ie, total retinyl esters, were not significantly depleted in the liver
of MI rats.
In contrast to the liver, total retinyl esters (ie, retinyl octanoate plus retinyl palmitate plus retinyl stearate) in the kidney declined significantly. The kidneys contribute a significant amount of retinol to the plasma by recapturing retinol and RBP that are not bound to transthyretin (TTR) and are therefore small enough to be filtered through the glomerulus.30 The recaptured retinol is either esterified or bound to RBP for reentry to the plasma pool. Actually, newly acquired retinol is preferentially esterified over resident intracellular retinol.31 Delivery of retinol by the complete plasma transport complex (retinol-RBP-TTR) appears to be important for this process, at least in liver stellate cells.32 The kidney is also known to contain stellate cells.33 Because kidneys maintain retinol concentrations by scavenging retinol through the glomerulus in a form that can be preferentially esterified by the kidney stellate cells, this process may be compromised after MI.
Supplementation with dietary vitamin E elevated plasma concentrations of vitamin A and allowed kidney vitamin A esters to return to baseline, even after MI. These effects are almost certainly related to the fact that vitamins E and A are complimentary antioxidants, such that supplementation with vitamin E spares vitamin A.34 Retinol has been shown to be an effective peroxyl radical scavenger. In fact, it may be even more effective than tocopherol, by virtue of its shorter polyene chain that affords it increased mobility and better access to peroxyl radicals in the membrane.35 However, the ability of retinol to scavenge aqueous initiator species is far below that of tocopherol owing to the fact that it lacks a hydroxyl group at the membrane surface.35 Rats supplemented with vitamin E still had lower vitamin A in the liver after MI, which suggests that this organ may experience different stresses on its vitamin A pool and its handling capabilities after MI.36
Conclusions
Results from this study suggest that analysis of plasma as
the sole indicator of vitamin status may not yield accurate information
because this vector is affected much later in the evolution of heart
failure, when storage-organ concentrations are depleted.
Analyses of antioxidants in storage organs, therefore, offers a
more reliable indication of antioxidant consumption after disruptive
cardiac events. Furthermore, dietary supplements of vitamin E increase
storage-organ concentrations of vitamins E and A and maintain cardiac
function, even after MI. Although it is clear that storage-organ
concentrations are an important part of antioxidant vitamin
homeostasis, additional studies are required to elucidate their exact
kinetic relationships.
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Acknowledgments |
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This work was supported by a grant from the Medical Research Council of Canada to the Group in Experimental Cardiology (Dr Singal). Dr Singal is a career investigator of the Medical Research Council of Canada. Dr Palace and Mr Hill were supported by fellowships from the Manitoba Health Research Council.
Received May 12, 1998; revision received August 21, 1998; accepted September 3, 1998.
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N. Khaper and P. K. Singal Modulation of oxidative stress by a selective inhibition of angiotensin II type 1 receptors in MI rats J. Am. Coll. Cardiol., April 1, 2001; 37(5): 1461 - 1466. [Abstract] [Full Text] [PDF]
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