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Cardiovascular Section, Boston University Medical Center, and Myocardial Biology Unit and Cardiac Muscle Research Laboratory, Boston University School of Medicine, Boston, Massachusetts 02118
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Endothelin (ET) A (ETA) receptors activate matrix metalloproteinases (MMP). Since endothelin-1 (ET) is increased in myocardium late postmyocardial infarction (MI), we hypothesized that stimulation of ETA receptors contributes to activation of myocardial MMPs late post-MI. Three days post-MI, rats were randomized to treatment with the ETA-selective receptor antagonist sitaxsentan (n = 12) or a control group (n = 12). Six weeks later, there were rightward shifts of the left ventricular (LV) end-diastolic and end-systolic pressure-volume relationships, as measured ex vivo by the isovolumic Langendorff technique. Both shifts were markedly attenuated by sitaxsentan. In LV myocardium remote from the infarct, the activities of MMP-1, MMP-2, and MMP-9 were increased in the post-MI group, and the increases were prevented by sitaxsentan treatment. Expression of tissue inhibitor of MMP-1 was decreased post-MI, and the decrease was prevented by sitaxsentan treatment. Chronic post-MI remodeling is associated with activation of MMPs in myocardium remote from the infarct. Inhibition of ETA receptors prevents MMP activation and LV dilation, suggesting that ET, acting via the ETA receptor, contributes to chronic post-MI remodeling by its effects on MMP activity.
endothelin; left ventricle; remodeling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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AFTER MYOCARDIAL INFARCTION (MI), the left ventricle (LV) undergoes "remodeling," a chronic process marked by chamber dilation, myocardial hypertrophy, and alterations in the extracellular matrix (5, 8, 22). Plasma levels of endothelin (ET)-1 are elevated in patients with chronic heart failure (4). Furthermore, the expression of ET and its receptors is increased in the myocardium late post-MI in the rat (30, 34). These observations have raised the possibility that ET plays a role in chronic myocardial remodeling post-MI (7). This thesis is supported by the demonstration that chronic treatment with ET-receptor antagonists decreases chamber dilation, improves LV function, and increases survival post-MI in the rat (12, 25, 26, 33).
ET binds to two receptor subtypes, ETA and ETB (36). In the vasculature, ETA receptors predominate on vascular smooth muscle cells, where they mediate constriction. ETB receptors primarily mediate relaxation via an endothelium-dependent relaxing factor-dependent mechanism. In the myocardium, ETA receptors predominate on myocytes (24), where they stimulate hypertrophic growth (37). ETA and ETB receptors are present on cardiac fibroblasts (18). In cardiac fibroblasts in vitro, ET receptors appear to mediate both collagen synthesis and degradation (14).
MMP activity is increased in the myocardium of patients with heart failure (41) and in animal models of heart failure (6). Increased MMP activity can lead to degradation of fibrillar collagen that is important for the structural integrity of the ventricle. These observations have led to the suggestion that increased MMP activity contributes to pathological LV remodeling by promoting chamber dilation (23). We tested the hypothesis that ETA receptors regulate MMP activity in the myocardium late post-MI. Accordingly, beginning on day 3 post-MI, rats were treated with sitaxsentan, an ET-receptor antagonist that is ~6,000-fold selective for the ETA subtype (43). Six weeks post-MI, LV chamber volume and contractile function were measured using the isovolumic (balloon-in-LV) Langendorff technique. The activity of myocardial MMPs was measured by in-gel zymography, and protein levels of tissue inhibitors of metalloproteinases (TIMPs) were measured by immunoblotting in myocardium remote from the area of infarction.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MI protocol.
MI was caused in adult male Wistar rats (250-300 g; Charles River)
by ligation of the left coronary artery by the technique of Pfeffer et
al. (29), as previously described (13).
Briefly, rats were anesthetized with pentobarbital sodium (25 mg/kg
ip), intubated with a fine polyethylene tube, and ventilated
mechanically with room air (70 min
1) using a rodent
ventilator (Harvard Apparatus, Boston, MA). After local anesthesia with
lidocaine, a lateral thoracotomy was performed, the heart was
exteriorized, and a ligature was placed around the proximal portion of
the left coronary artery. The heart was returned to its normal
position, and the chest was closed. Sham-operated hearts were treated
similarly, except no suture was placed around the coronary artery. All
rats were kept in single animal cages and had free access to standard
rat chow and water. Perioperative mortality in the first 48 h was
~40%.
Treatment protocol.
A fresh solution of sitaxsentan was prepared each day by adding the
soluble salt to distilled water. The treatment group received this
solution as drinking water for 6 wk, starting on day 3 post-MI. The amount of drinking water was progressively increased from 50 to 100 ml/day over the course of the study. However, the total daily
dose of sitaxsentan was held constant at 90 mg/kg body wt. Control rats
received equivalent amounts of water without drug. At 6 wk, arterial
blood (1 ml) was withdrawn from the right carotid artery and
centrifuged, and the plasma was frozen at 
70°C for measurement of
sitaxsentan. The mean plasma concentration of sitaxsentan was 55 ± 9 µg/ml in the treatment group.
In vivo hemodynamic measurements. Six weeks post-MI, resting hemodynamics were measured under light anesthesia with pentobarbital sodium (10 mg/kg ip), which allowed spontaneous respiration. A 2-F Millar microtip catheter was advanced via the right carotid artery into the LV. After measurement of LV pressures, the catheter was withdrawn to the aorta.
In vitro myocardial function. After in vivo measurements were completed, rats were heparinized (200 IU iv), the chest was opened, and the beating heart was rapidly excised and placed on the Langendorff apparatus within 10 s, as described previously (10), using an isolated, erythrocyte-perfused, isovolumically beating preparation. The perfusate consisted of a Krebs-Henseleit buffer with bovine red blood cells at a hematocrit of 40%. The buffer contained (mmol/l) 118 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3, 5.5 glucose, 1.0 lactate, and 0.4 palmitic acid and 4 g/100 ml BSA (Sigma Chemical, St. Louis, MO). A collapsed thin-walled polyvinylchloride film balloon attached to a cannula was placed in the LV via the left atrium and secured in place by sutures. The balloon was connected to a pressure transducer (Statham P23 dB, Spectramed) for constant measurement of LV pressure. All data were recorded by a chart recorder (Gould, Oxnard, CA). Post-MI and sham-operated hearts were perfused at constant pressure of 90 and 80 mmHg, respectively, to normalize coronary flow to heart weight. Coronary perfusate flow was measured by timed collection of the coronary venous effluent.
The LV balloon was filled with saline to an end-diastolic pressure of 10 mmHg, and the heart was paced at 5 Hz by an electric stimulator (model 59, Grass Instruments) and allowed to stabilize for 15 min. Systolic and diastolic pressure-volume relationships were then determined by filling the LV balloon in 0.1-ml increments up to the volume that produced an end-diastolic pressure of 45 mmHg. This procedure was performed twice, and the data from the second run were analyzed. The diastolic pressures generated for given volumes were used to describe a diastolic pressure-volume relationship by an exponential curve and equation (p = b * ekV, where p is pressure, b is y-intercept, k is slope, and V is volume) as described by Fletcher et al. (11). Only pressure-volume relationships with R2 > 0.95 were included in the analysis. The formula was solved for given pressures, and a final exponential pressure-volume relationship for each heart was determined. The systolic pressure-volume relationship was determined by averaging the generated pressures at each given volume for the hearts in a treatment group. Because the systolic pressure-volume curve fits a linear relationship over most of the observed pressure range, the slope and y-intercept were calculated.Infarct size and tissue collection. After the pressure-volume relationship was recorded, hearts were removed from the perfusion system and immediately placed in iced saline. Total heart weight was determined, the atria were removed from the ventricles, the right ventricle (RV) and LV were separated, the infarcted region of the LV was dissected from the noninfarcted region, and each was weighed and frozen immediately in liquid nitrogen. Infarct size was expressed as the ratio of the infarct to total LV mass. Lung and liver weights were measured before and after the samples were dried for 5 days.
Assessment of mRNA. RNA was extracted and subjected to Northern hybridization, as previously described (39) using full-length cDNAs for rat prepro-atrial natriuretic peptide (ANP) and sarcoplasmic/endoplasmic reticulum calcium-ATPase (SERCA2). Blots were quantified by PhosphorImager (Bio-Rad), and mRNA levels were normalized by reprobing with an oligonucleotide complementary to 18S rRNA (17).
Assessment of hydroxyproline content, MMP, tissue and urokinse
plasminogen activator activities, and TIMP protein levels.
Aliquots of frozen remote LV (~100 mg) were homogenized with the use
of a Teflon dounce homogenizer and sonicated in 50 mM Tris · HCl (pH 7.6), 0.2 M NaCl, 5 mM CaCl2, 0.02%
(wt/vol) Brij 35, and 0.02% (wt/vol) NaN3 at 4°C. An
aliquot of crude homogenate was frozen for spectrophotometric
quantitation of hydroxyproline content by the method of Bergman and
Loxley (1). The remaining homogenate was centrifuged at
10,000 g for 20 min. Protein content of the supernatant was
quantified by the Bradford method. Extracts were stored at 80°C.
-casein (15 mg/ml; Sigma Chemical) as the substrate, as
described previously (14). Clear, digested regions representing MMP activity were quantified using an imaging densitometer (model GS700, Bio-Rad), and molecular weights were estimated using prestained molecular weight markers.
Tissue plasminogen activator (tPA) and urokinase plasminogen activator
(uPA) activity (per 100 µg of protein) were measured by in-gel
zymography with human plasminogen (20 µg/ml; Sigma Chemical) and
-casein (0.4 mg/ml) polymerized in the gel. Gels were washed in
2.5% Triton X-100 for 30 min, in water with 1 mmol/l
1,10-phenanthroline (metal chelator to inhibit MMPs) for 30 min, and
then overnight at 37°C in 50 mmol/l Tris · HCl, pH 8, 5 mmol/l CaCl2, 0.02% NaN3, and 1 mmol/l
1,10-phenanthroline. Gels were stained, destained, and quantified as
for MMP gels.
TIMP protein levels (per 100 µg of protein) were measured by SDS-PAGE
and Western blotting with polyclonal rabbit antibodies recognizing
TIMP-1 and TIMP-2 and a polyclonal sheep antibody recognizing TIMP-4
(Chemicon). Reduced samples were separated in 12% SDS-polyacrylamide
gels. After separation, proteins were transferred electrophoretically
to nitrocellulose membrane. Membranes were blocked with 5% nonfat dry
milk in Tris-buffered saline (50 mmol/l Tris, pH 7.4, 150 mmol/l NaCl)
with 0.05% Tween 20 (TBST) for 1 h at room temperature. The
primary antibodies were diluted 1:5,000 in 4% nonfat dry milk in TBST
and incubated overnight at 4°C. The membranes were washed in TBST for
1 h with six changes of buffer. The secondary antibody
(horseradish peroxidase-conjugated goat anti-rabbit IgG or donkey
anti-sheep IgG; Santa Cruz) was diluted 1:100,000 in 4% nonfat dry
milk in TBST for 1 h at room temperature. The membranes were again
washed in TBST for 1 h with six changes of buffer. Signals were
detected using enhanced chemiluminescence with a luminol substrate
(Super Signal, Pierce) and exposed to film. Signals were quantified
using a densitometer (model GS-700, Bio-Rad), and molecular weights
were estimated using prestained molecular weight markers and human
TIMP-1 and TIMP-2 standards (Chemicon).
Statistical methods. Values are means ± SE. Comparison of single parameters was performed by ANOVA. Comparison of pressure-volume relationships between experimental groups was performed by two-way ANOVA. If ANOVA indicated a significant difference or interaction, values at specific points were tested by the method of least significant differences. P < 0.05 was considered to be significant. All statistical procedures were performed using the StatView statistical software package (version 5.0, SAS Institute, Cary, NC).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Survival post-MI. Twenty-nine infarcted rats survived the initial 48-h post-MI period and were randomized to control or sitaxsentan treatment beginning on day 3. One MI control rat died on day 4. Of the remaining 28 infarcted rats, 12 control and 12 sitaxsentan-treated animals survived to the 6-wk terminal study, as did 4 of 4 sham-operated animals.
In vivo hemodynamics.
Six weeks post-MI, heart rate was similar in the control and
sitaxsentan-treated groups (Table 1). LV
end-diastolic pressure (LVEDP) was increased to a similar degree in the
control and sitaxsentan-treated groups (vs. sham-operated). LV systolic
pressure was similar in all three groups. LV developed pressure tended
to be lower in the control MI group, which was not different from the
sitaxsentan-treated group. Maximal and minimal rate of pressure
development (dP/dt) were decreased to a similar degree in
the control and sitaxsentan-treated groups.
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Morphometrics.
Infarct size was similar in the control MI and sitaxsentan-treated
groups (Table 2). Body weight and tibial
length were similar in the three groups. In the infarcted animals, the
LV weight-to-body weight ratio was decreased in the sitaxsentan-treated
versus the control MI group, as was the RV weight-to-body weight ratio.
In the infarcted animals, ascites was noted in two control rats but in
no sitaxsentan-treated animals. Pleural effusions were noted in two
sitaxsentan-treated animals and one control animal.
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ANP and SERCA2 mRNA levels. The level of mRNA for ANP was increased 192 ± 25% (P = 0.006) in remote LV myocardium from the MI control animals (vs. sham-operated animals) and was increased to a similar degree in sitaxsentan-treated animals [184 ± 36%, P = nonsignificant (NS) vs. MI control animals]. SERCA2 mRNA levels were similar in all three groups (data not shown).
Effects of sitaxsentan on LV volume and contractile function in
vitro.
At 6 wk post-MI, the LVEDP-to-volume ratio was shifted rightward
(P < 0.01, control vs. sham-operated; Fig.
1). This rightward shift was prevented in
the sitaxsentan-treated group, which did not differ from the
sham-operated group.
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Hydroxyproline content. Collagen content, as reflected by hydroxyproline, increased in remote myocardium post-MI (3.1 ± 0.3 vs. 5.2 ± 0.5 µg hydroxyproline/2.5 mg protein, P = 0.001 vs. sham-operated). Sitaxsentan treatment tended to increase hydroxyproline content post-MI (7.5 ± 1.1 µg/2.5 mg protein, P = 0.07 vs. untreated MI).
MMP activity.
Total gelatinase activity was increased by 65 ± 16% in the
control MI group (P = 0.044 vs. sham-operated), and
this increase was prevented in the sitaxsentan-treated animals (20 ± 12%, P = 0.037 vs. control MI and P = NS vs. sham-operated; Fig. 3). Likewise, total caseinase activity was increased by 76 ± 17% in the control MI group (P = 0.029 vs. sham-operated), and
this increase was prevented in the sitaxsentan-treated animals (18 ± 20%, P = 0.038 vs. control MI and P = NS
vs. sham-operated; Fig. 3). The specific activities of MMP-1 (57/48
kDa), MMP-2 (72/66 kDa), MMP-9 (95/88 kDa), and 92-kDa caseinase were
increased in the control MI group, and all the increases were prevented
in the sitaxsentan-treated group (Fig.
4). The activities of tPA and uPA were
similar in all three groups (Fig. 5).
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TIMP protein levels.
The level of TIMP-1 protein as determined by Western blotting was
decreased in the control MI group (vs. sham-operated), and the decrease
was prevented in the sitaxsentan-treated group (Fig. 6). The levels of TIMP-2 and TIMP-4 did
not differ in the control MI and sham-operated groups and were not
affected by sitaxsentan treatment.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of sitaxsentan on post-MI remodeling. Post-MI remodeling was associated with a rightward shift in the LV diastolic pressure-volume relationship, indicating dilation of the LV chamber. This rightward shift was markedly attenuated by sitaxsentan treatment. A similar antiremodeling effect has been reported for other ET-receptor antagonists, including bosentan (12, 26), BQ-123 (33), and LU-135252 (25). In contrast, when an ET-receptor antagonist was initiated early, within the first 24 h post-MI, there was adverse remodeling with more LV dilation (15, 27), suggesting that the timing of anti-ET treatment post-MI may be critical. Sitaxsentan treatment had no apparent effect on MI size, suggesting that by day 3, when treatment was started, MMP activity may not have been critical to scar formation. It is interesting that this temporal pattern appears to differ from that observed with angiotensin-converting enzyme inhibitors or angiotensin-receptor antagonists, which reduce scar size and collagen content even when given in the first 24 h post-MI (9, 40, 44).
Post-MI remodeling was also associated with myocardial hypertrophy, as indicated by increases in LV and RV mass and the expression of ANP mRNA. Sitaxsentan treatment prevented RV and LV hypertrophy but did not inhibit the expression of ANP mRNA. Although ANP expression is commonly associated with myocardial hypertrophy (2), it is recognized that the signaling pathways for myocyte hypertrophy and ANP induction may diverge with regard to the effects of ET (19). This result differs from that of Sakai et al. (35), who found that the increase in ANP mRNA 3 mo post-MI was prevented by treatment with the ET-receptor blocker BQ-123, but is similar to that of Oie et al. (28), who found no effect of bosentan on ANP mRNA at 2 wk post-MI. In our animals, ANP mRNA was only modestly increased at 6 wk, and therefore it is possible that the increase in ANP would be prevented at a later time.Effects on LV contractile function. Sitaxsentan did not exert measurable effects on resting LV hemodynamics measured in vivo. In particular, the post-MI changes in LVEDP, developed pressure, and maximum and minimum dP/dt were not affected by sitaxsentan. A decrease in LVEDP has been observed in some (33), but not all (12), studies of ET-receptor blockers post-MI.
The LV systolic pressure-volume relationship was shifted rightward post-MI, indicating that these hearts were able to generate a comparable systolic pressure, albeit at a higher end-diastolic volume. Sitaxsentan treatment attenuated the rightward shift in this relationship. Similar beneficial effects on LV contractile function late post-MI have been observed with bosentan (12, 25) and BQ-123 (33). An advantage of the isovolumic Langendorff approach is that it allows contractile function to be assessed over a wide range of controlled loading conditions and, thus, may detect changes in contractile function that are not apparent under basal in vivo conditions.Metalloproteinase activation post-MI. A new finding of this study is that late post-MI there was increased MMP lytic activity by in vitro zymography in LV myocardium remote from the infarct. Although increased MMP lytic activity has been demonstrated early post-MI in the infarct region (32), there is little information available regarding MMP activation in remote myocardium late post-MI. Our data demonstrate increases in total MMP activity, as well as activation of several specific MMPs, including MMP-1, MMP-2, and MMP-9. This activation was associated with a decrease in TIMP-1 protein expression. MMPs may be activated by tPA and uPA, but neither was elevated in our post-MI animals.
An increase in lytic activity has been shown in the myocardium of patients with end-stage heart failure (21, 41) and in animal models of myocardial failure, including the rapid-paced pig (6). These observations have been interpreted to indicate an increase in MMP activity. Since TIMPs are not active during in vitro zymography, the observation of increased MMP lytic activity per se need not be associated with increased MMP activity in vivo. However, since we also observed decreased expression of TIMP-1 post-MI, the finding of increased lytic activity suggests that MMP activity is increased in vivo and, furthermore, raises the possibility that a decrease in TIMP-1 contributes to increased MMP activity in vivo. A decrease in TIMP-1 activity has been demonstrated in failing human myocardium (21).Effect of sitaxsentan on MMP activation post-MI. A second new finding of this study is that chronic treatment with sitaxsentan abolished MMP activation and prevented the decrease in TIMP-1 activity. It is possible that sitaxsentan decreased MMP activity by a direct action on cardiac fibroblasts, which are a major source of interstitial MMPs. However, because it has been shown that ETA receptor stimulation decreases MMP activity in cardiac fibroblasts in vitro (14), the anticipated effect of ETA receptor blockade would be an increase in MMP activity. An alternative explanation is that sitaxsentan caused a decrease in MMP activity indirectly through its vasodilator effects, leading to a decrease in myocardial wall stresses and/or the activity of other pathways that are involved in the regulation of collagen balance.
There is increased expression of ET mRNA and protein in remote myocardium late post-MI (20). Therefore, it is possible that MMPs play a role in the antiremodeling effect of sitaxsentan. In this regard, it is noteworthy that Spinale et al. (38) showed that a specific MMP inhibitor can reduce the extent of LV dilation in the paced-pig model of heart failure. Likewise, Rohde et al. (31) showed that another MMP inhibitor can decrease the extent of early LV dilation in the first 3 days post-MI in the mouse. Thus our data are consistent with the thesis that increased ET pathway signaling in the remote myocardium late post-MI leads to MMP activation. A corollary of this thesis is that the beneficial effect of sitaxsentan on LV dilation is mediated, at least in part, by a decrease in ET-stimulated MMP activity. ET can stimulate myocyte hypertrophy (16, 37) and exert profound effects on gene expression (37) that might also contribute to the antiremodeling effects of sitaxsentan.Collagen content post-MI. Hydroxyproline content was increased in remote myocardium post-MI, suggesting increased collagen content. This finding is similar to that of Cleutjens et al. (3). We further observed that treatment with sitaxsentan tended to increase hydroxyproline content and is, therefore, consistent with the observed inhibition of MMP activity by sitaxsentan. However, this finding should be interpreted with caution, since collagen content per se does not reflect other important properties, such as the type and quality of the collagen. For example, increased MMP activity may increase net collagen content while decreasing the abundance of fine collagen struts (42). Further elucidation of the effects of ET and ET blockade on collagen architecture is needed to address this issue.
In conclusion, these findings demonstrate that ET, acting via the ETA receptor, plays an important role in chronic post-MI remodeling. The data further show that chronic post-MI remodeling is associated with activation of MMPs, which can be prevented by treatment with an ETA-receptor antagonist. This later finding suggests that ET is involved in MMP activation and is consistent with the thesis that MMP activation plays a pathophysiological role in chronic post-MI remodeling. Finally, the data suggest that sitaxsentan may prevent chronic post-MI remodeling, at least in part, by preventing the activation of MMPs.| |
ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-42539 (W. S. Colucci) and HL-61639 (W. S. Colucci); a grant from the Max Kade Foundation, New York, NY (B. K. Podesser); a Beginning Grant-in-Aid from the American Heart Association, Massachusetts Affiliate (D. A. Siwik); and a grant from the Texas Biotechnology Corporation.
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FOOTNOTES |
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* B. K. Podesser and D. A. Siwik contributed equally to the study.
Present address of B. K. Podesser: Dept. of Cardiothoracic Surgery, AKH Wien, University of Vienna School of Medicine, Vienna, Austria.
Address for reprint requests and other correspondence: W. S. Colucci, Cardiovascular Section, Boston University Medical Center, 88 East Newton St., Boston, MA 02118 (E-mail: wilson.colucci{at}bmc.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 11 April 2000; accepted in final form 12 October 2000.
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TOP
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METHODS
RESULTS
DISCUSSION
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P < 0.01 vs. Sham. 
P < 0.01 vs. MI + Sitax; §P < 0.05 vs. MI + Sitax.
