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Departments of 1 Pathology and 3 Pharmacology, Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, The Netherlands; and Departments of 2 Cardiothoracic Surgery and 4 Cardiology, Medical University of South Carolina, Charleston, South Carolina 29425
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Recent studies have been directed at
modulating the heart failure process through inhibition of activated
matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP
inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency
alters the course of postinfarction chamber remodeling and induced
chronic myocardial infarction (MI) in wild-type (WT) and
TIMP-1
/ mice. Left ventricular (LV) pressure-volume
loops obtained from WT and TIMP-1/ mice demonstrated
that LV end-diastolic volume [52 ± 4 (WT) vs. 71 ± 6 (TIMP-1/) µl] and LV end-diastolic pressure
[9.0 ± 1.2 (WT) vs. 12.7 ± 1.4 (TIMP-1/)
mmHg] were significantly increased in the TIMP-1/ mice
2 wk after MI. LV contractility was reduced to a similar degree in the
WT and TIMP-1/ groups after MI, as indicated by a
significant fall in the LV end-systolic pressure-volume relationship.
Ventricular weight and cross-sectional areas of LV myocytes were
significantly increased in TIMP-1/ mice, indicating
that the hypertrophic response was more pronounced. The observed
significant loss of fibrillar collagen in the TIMP-1/
controls may have been an important contributory factor for the observed LV alterations in the TIMP-1/ mice after MI.
These findings demonstrate that TIMP-1 deficiency amplifies adverse LV
remodeling after MI in mice and emphasizes the importance of local
endogenous control of cardiac MMP activity by TIMP-1.
myocardial remodeling; pressure-volume loops
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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MATRIX METALLOPROTEINASES (MMPs) are a fundamental proteolytic system responsible for extracellular matrix protein degradation within the myocardium. Under ambient conditions, the myocardial MMPs largely reside in their latent form, whereas after a pathological stimulus the pool of latent MMPs becomes activated, as has been demonstrated for human, rat, and porcine myocardium (3, 6, 33, 34). Prevention of the breakdown of the myocardial extracellular matrix with pharmacological broad-spectrum MMP inhibitors in animal models of cardiomyopathy and myocardial infarction (MI) has demonstrated effects on the left ventricular (LV) architectural remodeling process (4, 20, 27, 32). An important endogenous regulator of overall MMP activity are the tissue inhibitors of MMPs (TIMPs) (18, 19). Normally, the TIMPs are in delicate balance with the MMPs and matrix is digested in a highly regulated fashion. A loss of TIMP-mediated inhibitory control has also been reported to occur in several cardiac pathologies (1, 25). For example, in end-stage cardiomyopathic disease in humans, increased MMP activity is paralleled by decreased TIMP-1, -3, and -4 expression (18). In a preliminary report, it was demonstrated that in TIMP-1-null mice, LV chamber enlargement occurred as a function of age, suggesting that constitutive expression of TIMP-1 is necessary for the maintenance of LV myocardial geometry (29). This study tested the hypothesis that TIMP-1 deficiency would modify the LV chamber and myocardial matrix remodeling after MI compared with age-matched wild-type (WT) mice, despite identical MI size.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental animals.
The mice used in these studies were adult inbred 129 Sv mice from which
a stable line of TIMP-1-deficient (TIMP-1/) mice was
created through the use of a replacement vector carrying a stop
codon-containing oligonucleotide and the neo resistance cassette with
the 5' end of the TIMP-1 coding frame (23, 29). The
original breeding pairs used to develop the mice for this study were a
kind gift from Dr. Paul J. Soloway (Roswell Park Cancer Institute,
Buffalo, NY). Tail clips and a PCR protocol were used to
confirm the genotype. All studies were done on age-matched mice (2 mo
of age), and the groups were balanced with respect to gender. MI was
induced surgically by chronic ligation of the coronary artery in
TIMP-1/ mice (n = 29) and age-matched
littermates (n = 33) according to recently described
methods (21). Nonoperated TIMP-1/ mice
(n = 15) and littermates (n = 12)
served as controls. Terminal studies, including echocardiography, LV
conductance volumetry, morphometry, and histology were performed 14 days after MI, as described below. All animals were treated and cared
for in accordance with the National Institutes of Health
Guidelines for the Care and Use of Laboratory Animals
(National Research Council, Washington, DC, 1996).
Echocardiographic measurements. Echocardiography was performed before MI and 2 wk after MI. Mice were sedated (40 mg/kg ketamine and 2 mg/kg xylazine) and placed in a recumbent position on a warming blanket to maintain ambient body temperature. Heart rate was determined from a surface ECG. From a transthoracic approach described previously (9, 29, 31), two-dimensional targeted echocardiographic recordings were obtained with an optimized 15-mHz transducer (15-6L UltraBand; Agilent Technologies, Abbyville, SC) integrated with a digital imaging system (Sonos 5500 Ultraharmonic Imaging System; Agilent Technologies). The two-dimensional parasternal long-axis view of the LV was recorded to precisely define the LV long axis and papillary muscles. The LV endocardial border was manually defined and LV areas at end diastole were computed by planimetry.
LV conductance volumetry.
A 1.1-mm steel endotracheal tube was placed, and the anesthesized mice
were mechanically ventilated (MiniVent 845; Hugo Sachs/Harvard Apparatus, March-Hugstetten, Germany). The mice were positioned on a
feedback temperature-controlled operating table (Vestavia Scientific,
Birmingham, AL). Under microscopic guidance (Zeiss OPMI), the right
carotid artery was exposed. A precalibrated four-electrode pressure
sensor catheter (1.4-Fr, SPR-839; Millar Instruments, Houston, TX) was
positioned in the LV. The catheter was interfaced to a
pressure-conductance unit (ARIA, MPCU-200; Millar Instruments), in
which electrical excitation was performed under digital control (DAQ,
PV Analysis Software; Millar Instruments). The continuous digital
pressure and conductance signals were integrated with an ECG signal
(PowerLab; AD Instruments) and displayed in real time with a
dual-display heads-up flat screen (Sony Electronics). This allowed for
optimal placement of the LV catheter with respect to the LV conductance
signal. The LV conductance signal was converted to a LV volume with an
algorithm described previously (8, 10, 11, 15, 36). One of
the important factors in this algorithm is the determination of a
parallel conductance volume coefficient (Vp)
(8). In the present study, Vp was computed by
using an isotonic saline injection in age-matched WT mice
(n = 3). Briefly, a 5-µl bolus of 15% hypertonic
saline was injected into the external jugular vein and the LV
pressure-conductance signals were continuously acquired. The saline
bolus caused a significant LV volume shift without a marked change in
LV systolic pressure (Fig.
1A). The isochronal LV
systolic and diastolic volumes were plotted along with the line of
identity (Fig. 1B). From the intersection of these two
lines, a mean value of 26 µl was computed for Vp. This factor was used in the software algorithms (PVAN; Millar Instruments) to compute absolute LV volumes. This saline calibration was
repeated on a weekly basis in both WT and TIMP-1/ mice
to ensure that the computed Vp remained within 10% of
predicted values.
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Immunohistochemistry and morphometry.
At completion of the hemodynamic studies, 0.5 ml of 0.1 mM cadmium
chloride were injected into the LV to arrest the hearts in diastole.
After perfusion with PBS, hearts were excised, weighed, routinely
processed, and imbedded in paraffin. Infarct size, LV diameter,
thickness of the infarcted wall, and collagen deposition were studied 2 wk after surgery in the TIMP-1/ and WT groups with a
computerized morphometry system (Quantimet 570; Leica, Cambridge, UK)
on AZAN- or Sirius red-stained sections (21). Myocyte
cross-sectional area was determined on hematoxylin and eosin-stained
slides with computer-assisted methods described previously
(33). Immunohistochemistry was performed to quantify macrophages (moma-2 monoclonal antibody on cryostat sections; Ref.
17), endothelial cells (anti-thrombomodulin polyclonal antibody; kindly provided by Dr. Peter Carmeliet, Center for Transgene Technology and Gene Therapy, Leuven, Belgium), T cells (anti CD-3; DAKO), smooth muscle cells, and myofibroblasts (mouse anti-human 
-smooth muscle actin; DAKO). Cell numbers were counted per
0.1-mm2 infarcted area by light microscopy at ×40
magnification with a grid.
Statistics.
Data are expressed as means ± SE. Indexes of function and
geometry were compared in controls and at 2 wk after MI in
TIMP-1/ and WT groups with ANOVA, with post hoc mean
separation performed by Bonferroni bounds. Means between groups were
compared with the use of the Mann-Whitney U-test. A value of
P < 0.05 was considered statistically significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Overall survival after MI surgery was comparable between WT and
TIMP-1/ mice; however, it may be notable that those
TIMP-1/ mice that did die died earlier after MI surgery
than the WT mice. Of the 33 WT and 29 TIMP-1/ mice that
underwent MI surgery, 3 WT (10%) and 8 TIMP-1/ (27%)
mice did not recover from their anesthesia after surgery. In the WT
group, eight additional animals died between days 2 and
10 because of LV rupture (n = 3) or acute
heart failure (n = 5), as judged by postmortem findings
(large infarct, cardiac dilatation, pleural effusion, and severe lung
congestion). In the TIMP-1/ group, no animals were lost
after the first day after surgery. The MI sizes determined by
quantitative morphometric planimetry were identical between the WT and
TIMP-1/ mice. [MI size: 42 ± 3% (WT) vs.
42 ± 3% (TIMP-1/) of the LV circumference].
LV geometry and function.
Long-axis LV echocardiography indicated that LV dilatation was
significantly increased in the TIMP-1/ group in
response to MI, and representative echocardiograms are shown in Fig.
2A. The absolute values for LV
end-diastolic area (LVEDA) were obtained from echocardiograms from WT
and TIMP-1/ mice before and 2 wk after MI. In WT mice,
LVEDA was 140 ± 6 × 103 cm2 and
increased to 176 ± 8 × 103 cm2 in
response to MI (P < 0.05). In the
TIMP-1/ mice, LVEDA was 163 ± 4 × 103 cm2 and significantly increased to
201 ± 5 × 103 cm2 after MI. Both
LVEDA values were significantly elevated in TIMP-1/
groups compared with the corresponding WT groups (both
P < 0.05; n = 11-15 per group).
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/ mice. At 2 wk after MI, definable changes in
the P-V loops were observed in both WT and TIMP-1/ mice
(Fig. 2B). As can be seen from Fig. 2, a parallel rightward shift of the P-V loop occurred after MI in both WT and
TIMP-1/ mice; however, in the TIMP-1/
mice, this rightward shift was greater. LV end-diastolic volume increased after MI in both groups of mice but was higher in the TIMP-1/ mice compared with the WT mice (Fig.
2C). In addition, LV end-diastolic pressure increased
significantly in the TIMP-1/ mice at 2 wk after MI
compared with age-matched controls or with WT post-MI values (Fig. 2,
B and D). Other hemodynamic parameters are
summarized in Table 1. Under control
conditions, ambient mean arterial pressure and LV peak pressure were
slightly but significantly higher in the TIMP-1/ mice
compared with the WT mice. Although LV architectural remodeling occurred in both WT and TIMP-1/ mice after MI, LV
ejection fraction was unchanged from respective control values. LV
dP/dtmax appeared higher in the control
TIMP-1/ group but decreased after MI. The time constant
of isovolumic relaxation (
) was significantly prolonged in the
TIMP-1/ mice after MI and was not significantly
affected in the WT group.
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/ mice. LV radial systolic
stress at the septum was similar to posterior free wall values in
control WT and TIMP-1
/ mice (207 ± 48 and 234 ± 28 g/cm2). After MI, LV radial systolic stress at the
posterior free wall increased by over sixfold in both WT and
TIMP-1/ mice and remained unchanged at the septum from
control values in both WT and TIMP-1/ groups (Fig.
3). Thus the increased LV dilatation in
the TIMP-1/ mice after MI was not translated into
increased radial wall stress because of the parallel increase in wall
thickness (i.e., mass).
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/
control mice (0.032 ± 0.009 and 0.030 ± 0.007 dyn · cm · mg · mmHg1,
respectively; P = 0.83). After MI, the ESPVR
significantly fell to a similar degree in both WT and
TIMP-1/ mice compared with reference controls
(0.016 ± 0.004 and 0.014 ± 0.005 dyn · cm · mg · mmHg1,
respectively; P < 0.05). Thus, despite a preservation
of steady-state LV ejection fraction, LV contractility was
significantly reduced in both WT and TIMP-1/ groups
after MI.
LV myocardial morphometry.
Ventricular mass was significantly larger in the
TIMP-1/ mice compared with the WT mice in both control
and MI animals. The absolute increase in ventricular mass in response
to MI was higher in the TIMP-1/ group, indicating that
the hypertrophic response was more pronounced in
TIMP-1/ than in WT mice (Fig.
4A). Cross-sectional areas of
LV myocytes were measured in a circumferential orientation in both WT
and TIMP-1/ mice and also revealed an increased
hypertrophic response after MI in the TIMP-1/ group
(Fig. 4B).
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/ mice. With Sirius red staining, the
percentage of the myocardial section occupied by fibrillar collagen was
computed. Extensive collagen deposition was found in the center of the
infarcts, with no differences observed between TIMP-1/
and WT mice. However, in the septum of TIMP-1/ control
animals, we found significantly lower collagen percentages than in WT
controls, indicating that there was a difference in structural
composition of the hearts at the starting point of the experiment.
These reduced collagen levels, together with the observed increase in
infarct length in the TIMP-1/ infarcts (Table 2),
indicate that the remodeling of the infarct region is altered in the
TIMP-1/ mice.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although alterations in MMP and TIMPs have been identified in
end-stage human heart failure, it has remained unclear whether interruption in the balance between MMPs and TIMPs within the myocardium can directly influence the LV architectural remodeling process after specific pathological stimuli such as MI. The present study demonstrated that a loss of function of TIMP-1 in mice caused significant alterations in LV geometry and function with respect to the
post-MI remodeling process. Specifically, the present study demonstrated that in TIMP-1/ mice, a greater degree of
LV dilation occurred, which was accompanied by a greater hypertrophic
response, increased LV filling pressures, and abnormalities in active
myocardial relaxation.
The majority of past studies that have examined the LV architectural
remodeling process in mice after MI have used transthoracic echocardiography (13, 30). The present study employed this technique and demonstrated that significant LV dilation occurred in
mice after induction of an MI, and the degree of LV dilation that
occurred in the WT mice is consistent with past reports (21, 27). In age-matched TIMP-1/ mice, LV
echocardiographic dimensions were larger than in WT mice, which was
expected from past observations from this laboratory (29).
However, it is difficult to assess absolute LV volumes from
echocardiographic measurements, particularly after MI. Accordingly, the
present study used conductance volumetry to more carefully assess
indexes of LV geometry and function in mice after MI. As expected, LV
volumes were significantly greater in mice after MI in both WT and
TIMP-1/ groups but were disproportionately higher in
TIMP-1/ mice after MI. Despite the significant LV
chamber remodeling that occurred in both WT and TIMP-1/
mice, LV ejection fraction was preserved compared with referenced control values. The present studies were performed at 14 days after MI,
and therefore it remains to be established whether a longer time
interval after MI would have resulted in the development of decreased
LV ejection fraction. However, results from the present study did
demonstrate abnormalities in underlying LV contractile function, which
would suggest that the development to overt LV failure would be likely
with longer followup periods. Specifically, a significant fall in LV
ESPVR occurred in both WT and TIMP-1/ mice after MI.
Whether the significant LV chamber remodeling that occurred in the
TIMP-1/ mice after MI coupled with the diminished
contractile function would accelerate the progression to LV pump
failure remains to be established and warrants further study.
In the present study, a loss of myocardial matrix integrity may have directly affected myocardial contractile performance. Specifically, the maintenance of myocardial fiber alignment and geometry within the LV free wall is determined, at least in part, by the myocyte-integrin-matrix interface (28). The architecture of the myocardial collagen matrix with respect to cardiac muscle alignment was described in early electron microscopy studies (2, 26). In addition, realignment of cardiac muscle fibers was reported previously to occur in rodent models of MI (24). Thus defects in the myocyte-matrix relationship within the post-MI myocardium could significantly influence the transduction of myocyte shortening into muscle fiber shortening.
There are several possible mechanisms for the relatively preserved LV
ejection fractions in the current mouse model. First, in this 129 Sv
mouse strain, the development of overt LV pump failure may take longer
to develop than those reported previously. Second, LV ejection fraction
is highly dependent on loading conditions. The present study
demonstrated that an index of LV systolic function was significantly
reduced in both WT and TIMP-1/ MI mice. Thus a defect
in LV function was demonstrated in the present study. Third, the
present study cannot discount whether the MI or catheterization
procedure superimposed on the MI caused mitral regurgitation. This low
impedance outlet would cause a pseudonormalization of LV ejection
fraction. This possibility is supported by the fact that the LV ESPVR
was reduced in the MI mice. Thus future studies that directly determine
whether this murine model of MI causes significant papillary muscle
injury leading to mitral regurgitation is warranted. This is
particularly important because MR in and of itself can cause
significant LV chamber remodeling and influence local MMP/TIMP
myocardial levels (22).
Myocardial hypertrophy occurred in the TIMP-1/ mice
after MI, as evidenced by greater ventricular mass and myocyte
cross-sectional area. Because a greater degree of LV dilation occurred
in the TIMP-1/ mice, this hypertrophic response was
likely due to increased stress placed on the viable myocardium.
However, recent results have demonstrated that TIMPs may have multiple
biological effects with respect to cell growth and viability
(12). Thus the greater degree of myocardial hypertrophy in
the TIMP-1/ mice was likely multifactorial. The
increased LV volumes and hypertrophy that occurred in the
TIMP-1/ mice after MI likely gave rise to specific
changes in LV diastolic function. Specifically, LV end-diastolic
pressure was increased and myocardial active relaxation () was
prolonged in TIMP-1/ mice after MI. The mechanism for
the prolongation of isovolumic relaxation time in
TIMP-1/ mice is likely to be multifactorial. Isovolumic
relaxation can be influenced by LV loading conditions, different
degrees of hypertrophy, and abnormalities in calcium handling/reuptake.
It is likely that all of these were present in the post-MI mice.
Moreover, the degree of LV hypertrophy was greater in the
TIMP-1/ mice after MI, which would likely be manifested
as a prolongation in myocardial active relaxation. However, whether and
to what degree other processes, such as calcium handling, are affected to a more severe degree in TIMP-1/ mice remain to be examined.
The fibrillar collagen matrix forms the structural backbone of the myocardium (2). This network provides strength and stiffness to the myocardium and also contributes to the maintenance of myocyte alignment and geometry (35). Disruption of the structural collagens has been implicated in the pathophysiology of dilated cardiomyopathy. Recently, Kim and colleagues (16) demonstrated that direct disruption of the extracellular matrix in the heart by chronic myocardial overexpression of MMP-1 resulted in marked deterioration of systolic and diastolic function at 12 mo of age. TIMP-1 deficiency, which theoretically also results in increased MMP activity, has comparable cardiac effects. In the present study, LV sections were prepared for morphological assessment of the MI wound healing response as well as characterization of cellular and extracellular remodeling. Thus LV myocardial samples were not available for careful biochemical assessment of MMP levels and activational states. Four TIMP subtypes have been identified to date, which may be differentially regulated in the progression of the heart failure process (18). TIMPs may play several biological roles in tissue remodeling, including growth regulation (12). In light of the results of the present study, future research regarding the specific effects of TIMP-1 deletion on relative myocardial MMP levels and the expression of alternative TIMP proteins after the induction of MI is warranted.
In a previous study (29) we demonstrated that
TIMP-1/ mice, in the absence of an underlying
myocardial disease, had reduced content of myocardial fibrillar
collagen at 4 mo of age. In the present study, we confirmed these
results and additionally showed that these TIMP-1/
hearts, with an inadequate fibrillar collagen matrix, exhibited more
extensive LV dilatation in response to MI. Thus loss of fibrillar collagen at the starting point of our experiments (i.e., at the moment
of MI induction) may have been an important contributory factor for the
alterations in LV geometry in the TIMP-1/ mice after MI.
The egress of inflammatory cells from the vasculature, as well as the
migration of inflammatory cells through the infarcted tissue, is
dependent on a number of orchestrated steps, including the activation
of proteases. These protease systems are highly redundant, but
reduction in the activity of MMP-9 or the serine proteinase plasmin has
been shown to modify the inflammatory response after MI in mice
(5, 7, 14). The present study demonstrates that TIMP-1
deficiency does not have an apparent effect on the inflammatory
response of the heart. This may be due to the fact that at 2 wk after
MI the initial inflammatory response is largely completed or because
other TIMP molecules may have compensated for the lack of TIMP-1.
However, on the basis of the observations that fibrillar collagen was
reduced and that the length of the MI was larger in the
TIMP-1/ mice, we conclude that structural remodeling of
the MI region was altered in the absence of TIMP-1.
In the control state, ambient mean arterial pressure was higher in the
TIMP-1/ mice. The TIMP-1/ murine
construct was a global gene deletion and therefore potentially may have
influenced vascular structure and function. Specifically, alterations
in extracellular structure may have influenced vascular resistive
properties. In the present study, LV stroke volume was also slightly
higher in the control TIMP-1/ mice. Although remaining
speculative, these factors likely contributed to the differences in
arterial pressure observed in the control TIMP-1/ mice.
Future studies that directly examine vasomotor tone and vascular
structure in these TIMP-1/ mice will be necessary to
more carefully address this issue.
In conclusion, this study emphasizes the importance of local endogenous control of MMPs by TIMP-1 for the remodeling process of the heart after MI, not only with respect to extracellular matrix structure but also with respect to myocyte growth and myocardial function. Furthermore, the results from the present study emphasize the therapeutic potential for modifying post-MI architectural remodeling through local regulation of myocardial MMP activity.
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ACKNOWLEDGEMENTS |
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This work was funded by Netherlands Heart Foundation Grant 99.054 and by National Heart, Lung, and Blood Institute Grants HL-45024, HL-97012, and PO1-HL-48788.
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. G. Spinale, Cardiothoracic Surgery, Rm. 625, Strom Thurmond Research Bldg., 770 MUSC Complex, Medical Univ. of South Carolina, 114 Doughty St., Charleston, SC 29425.
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.
First published September 26, 2002;10.1152/ajpheart.00511.2002
Received 27 June 2002; accepted in final form 18 September 2002.
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METHODS
RESULTS
DISCUSSION
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P < 0.05 vs. WT-MI mice.
