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Division of Cardiology and The Molecular Cardiology Research Institute, Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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We investigated
the suitability of studying ventricular remodeling in a mouse model of
myocardial infarction (MI). We performed left coronary ligation
(n = 22) or a sham procedure
(n = 21) on normal C57BL/6J mice. Six
weeks later, animals underwent echocardiography and hemodynamic
evaluation. Left ventricular (LV) volume at a common distending
pressure was calculated from passive pressure-volume curves. The MI
group exhibited lower systolic blood pressure
(P < 0.05), higher LV end-diastolic
pressure (P < 0.05), and lower peak
first derivative of LV pressure
(dP/dt,
P < 0.05) than the sham group. Mice
with moderate (<40%, n = 11) and
large (
40%, n = 11) MIs displayed
increased LV mass-to-body weight ratio
(P < 0.02 and
P < 0.01, respectively, vs. sham
group), whereas only the large-MI group exhibited increased right
ventricular mass-to-body weight ratio
(P < 0.01). LV volumes were
increased in the moderate-MI group (P = 0.059 vs. sham group) and to a much greater extent in the large-MI
group (P < 0.0001 vs. sham group).
The moderate- and large-MI groups also exhibited increases in LV
end-diastolic diameter (P < 0.03 and
P < 0.0001, respectively, vs. sham
group) and LV end-systolic diameter (P < 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening
(P < 0.01 for both). These data
demonstrate ventricular remodeling in a mouse model of MI and confirm
the feasibility of quantifying indexes of remodeling in vivo and
postmortem. This model will be of particular usefulness when applied to
transgenic strains.
myocardial hypertrophy; ventricular dilatation; echocardiography; hemodynamics
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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THE RAT MODEL OF MYOCARDIAL infarction (MI) has been
used extensively in the study of ventricular remodeling (3, 9, 13, 17,
18, 20, 23). The mouse, however, has emerged as a powerful experimental
species because of the increasing availability of transgenic strains
(15), which are now becoming important in the study of cardiovascular
disease (10). Therefore, characterizing an applicable model of MI in
the mouse is important to examine post-MI ventricular remodeling by
utilizing transgenic mice, wherein the manipulation of specific genes
may allow further mechanistic insight. For example, mice expressing
disrupted, nonfunctional angiotensin II type 1 (7) and angiotensin II
type 2 receptors (4, 6), as well as mice that overexpress the genes
encoding the 
2-adrenergic
receptor (14) and -adrenergic receptor kinase (8), may provide new
insights into the pathophysiology of post-MI ventricular remodeling if
a mouse model of MI were available.
The objective of this study was to examine the degree to which left ventricular (LV) remodeling occurs after MI in wild-type mice and to assess the feasibility of quantifying hemodynamics and parameters of ventricular remodeling. In this study we chose a 6-wk time point utilized by some investigators in the rat MI model (20). Additionally, only a modest degree of LV dilatation was present in our preliminary studies at 2 wk.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals. Fifty-five male C57BL/6J (Charles River) mice, 8-10 wk old and 20-25 g body wt, were housed at no more than five per cage in our American Association for Accreditation of Laboratory Animal Care-approved animal facility with 12:12-h light-dark cycles and given free access to standard rodent chow (PROLAB, Syracuse, NY) and water. This protocol was approved by our Institutional Animal Research Committee.
Left coronary ligation. Mice were anesthetized using a mixture of ketamine (40 mg/kg) and pentobarbital sodium (33 mg/kg) via intraperitoneal injection. They were weighed, and the chest wall was shaved and prepared. In the supine position, endotracheal intubation was performed under direct laryngoscopy (1), and mice were ventilated with a small animal respirator (Harvard Apparatus; tidal volume = 1.0 ml, rate = 120 breaths/min). Proper intubation was confirmed by observation of chest expansion and retraction during ventilated breaths.
All surgical procedures were carried out with an operating microscope (Zeiss) at ×5 to ×24 magnification. A left thoracotomy was performed. The pectoralis muscle groups were cut transversely, exposing the thoracic cage. Occasionally, the internal mammary artery was severed, but bleeding usually stopped spontaneously or with application of pressure (with a sterile cotton swab) for
20 s. The fourth
intercostal space was entered using scissors and blunt dissection. Two
6-0 silk sutures (Ethicon) were placed around the upper and lower ribs
for retraction. The thymus was retracted upward, and the left lung was
collapsed using a sterile cotton swab. A brief period of extreme
bradycardia was often observed during manipulation of thoracic
contents. Pressure was then applied to the right thorax to displace the
heart leftward. A 7-0 silk suture (Ethicon) was occasionally placed
into the anteroseptal portion of the LV for upward retraction to
provide better exposure. Next, a 7-0 silk suture was placed through the
myocardium into the anterolateral LV wall. This area corresponds to the
course of the left anterior descending artery in the mouse (12). The suture was positioned approximately midway between the apex and base.
Before ligation, left coronary artery entrapment was confirmed by
upward traction. The apex of the LV was observed for evidence of
myocardial blanching indicating interruption in coronary flow. The
suture was then tied. If the myocardium did not blanch after the first
ligature, then a second ligature was placed usually more laterally
until proper blanching, confirming epicardial ischemia, was
noted. For animals undergoing a sham operation, the ligature was placed
in an identical location but not tied tightly. The lungs were
reexpanded using positive pressure at end expiration. The chest cavity
was closed in layers with 6-0 silk, and the animal was gradually weaned
from the respirator. Once spontaneous respiration resumed, the
endotracheal tube was removed, and the animal was placed under a
heating lamp. The animals remained in a supervised setting until fully
conscious, when they were returned to their cages and given standard
chow and water ad libitum.
Echocardiography. On the same day as the terminal hemodynamic study, 6 wk after surgery, 12 sham and 11 MI mice underwent transthoracic echocardiographic evaluation. A commercially available echocardiography system (HDI 3000, ATL, Bothell, WA) was utilized with a dynamically focused 10-MHz linear array transducer using a depth setting of 1.5 cm. Animals were anesthetized with a combination of ketamine and xylazine (10 mg/kg) administered by intraperitoneal injection. Mice were then placed supine in the left lateral decubitus position, and two-dimensional images and M-mode tracings (sweep speed = 50-100 mm/s) were recorded from the short-axis view at the high papillary muscle level. Care was taken not to apply too much pressure to the chest wall. This method of obtaining echocardiographic data in mice has been described previously (22).
The M-mode tracings were printed on glossy paper by using a digital color printer (model UP-1800MD, Sony). These images were coded so that measurements were performed in a blinded fashion. LV end-diastolic diameter (EDD), end-systolic diameter (ESD), and systolic and diastolic posterior wall thickness were measured to the nearest 0.1 mm, averaging three cardiac cycles. Fractional shortening (FS) was calculated using the following equation
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Hemodynamic evaluation. Six weeks after surgery, animals underwent hemodynamic study. The mouse was anesthetized as described above using a mixture of ketamine and xylazine by intraperitoneal injection. The anterior cervical area was then shaved, and the animals were weighed. After a right cervical incision, the right external jugular vein was localized by blunt dissection and cannulated with silicone rubber tubing (0.025 in. OD) connected to a pressure transducer (Transpac II, Abbott, Chicago, IL). The tubing was advanced proximally into the right atrium (~10 mm). A 0.3-ml bolus of saline was administered to ensure adequate intravascular volume.
The right carotid artery was localized and ligated distally, with care taken not to entrap the vagus nerve. A small clamp was placed proximally to obstruct antegrade flow, and a transverse incision was made. A segment of flame-stretched Teflon tubing (originally 0.040 in. OD stretched to ~0.015 in. OD) was inserted and secured in place. After at least 2 min had passed to allow stabilization, systemic arterial pressure was recorded using a multichannel chart recorder (model EVR, Electronics for Medicine, PPG Biomedical Systems Division, Pleasantville, NY) interfaced with a Macintosh Powerbook (Apple) computer (model 5300CS) using the MacLab 4s computerized recording and analysis system (AD Instruments, Milford, MA). All hemodynamic tracings were recorded and analyzed on the computer.LV pressure. The cervical incision was then extended medially, and the animal was intubated using a 22-gauge Teflon Angiocath inserted directly into the trachea via tracheotomy. The animal was ventilated using a small animal respirator, as described above. Next, a left thoracotomy was performed as described above through the intercostal space below that on which the original procedure was performed. The apex of the heart was usually visible via this approach. The LV apex was immediately punctured using a 25-gauge fluid-filled needle attached to a pressure transducer (Transpac II). Optimal tracings were obtained using a 25-gauge needle and a filter setting of 2,500 Hz. Only recordings obtained using this combination were analyzed. Carotid arterial and LV pressures were monitored simultaneously to ensure that the LV pressure was not damped. LV pressure and its first derivative (dP/dt) were recorded using the monitor and computer apparatus, as described above. With the animal still under anesthesia, euthanasia was achieved with injection of 0.3 ml of 1 N KCl via the jugular venous catheter, arresting the heart in diastole.
Wall stress calculation. LV meridian systolic and diastolic wall stress were calculated using the following formula (2)
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Passive pressure-volume relations.
A midline sternotomy was performed, and the heart and great vessels
were isolated. A double-lumen catheter with a small balloon constructed
from polyethylene plastic film ligated at its tip was inserted through
the mitral valve into the LV. The balloon was constructed to
accommodate at least 200 µl of saline before generating any pressure
itself from distension. The LV was then emptied of its contents, and
the right ventricle (RV) was incised to prevent compressive effects.
The balloon was inflated to 50 µl and quickly deflated to allow
unfolding of the material within the ventricle. Passive pressure-volume
curves were generated by sequential injections of 2.0-4.0 µl
with use of a syringe with a repeating dispenser (model PB600-1,
Hamilton) attached, which delivers exactly 1.0 µl of saline with each
increment. LV pressure was recorded after each injection. The volume
infusion was complete when the LV pressure reached 40 mmHg. The heart
was then excised, and the atria and great vessels were trimmed away.
Next, the RV free wall was trimmed carefully away from the LV (with
septum intact). The LV and the RV free wall were weighed to the nearest 0.1 mg and indexed by body weight (BW, in kg). The ventricles were then
immersed in 10% buffered Formalin. After 24-48 h of fixation, the
LV was sectioned transversely into three equal segments from apex to
base and embedded in paraffin.
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Morphometric evaluation. Serial 5-µm sections were prepared using a standard microtome. Sections were mounted and stained with hematoxylin and eosin for determination of infarct size. Quantitative histological analyses were performed on a Power Macintosh 7100 AV computer (Apple) using the public domain, NIH Image program,1 as described elsewhere (21, 23). The image analysis system consists of a Hitachi VK-C370 color videocamera, CCTV Fujinon lens, and Olympus BX40 microscope. Infarct size was determined by the method described by Pfeffer et al. (18). Infarct length was measured along the endo- and epicardial surfaces from each of the three LV sections, and values from all three sections were summed. Total LV circumference was calculated as the sum of endo- and epicardial segment lengths from all three LV sections. Infarct size (in percent) was calculated as total infarct circumference divided by total LV circumference times 100 (18).
Statistical analysis.
Values are means ± SD unless otherwise indicated. Student's two
tailed t-test was used to compare data
from the MI group as a whole and sham animals.
P < 0.05 was considered
significant. The MI group was divided by median infarct size into
moderate (<40%, n = 11) and large
MIs (40, n = 11). When these groups were compared with the sham group and each other, ANOVA was performed using the Bonferroni/Dunn correction for multiple-group comparisons.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Procedure and survival. Thirty-four mice underwent thoracotomy with left coronary ligation, of which 23 (68%) survived during the follow-up period. Of these 23 animals, 1 did not exhibit an infarction by histological examination and was therefore excluded from the analysis. The mean infarct size of the animals that survived to the time of the follow-up study was 38.6 ± 15.2% (range 14-65%). Of the 11 animals that died, 4 died immediately after the procedure (within 2 h). Four of the remaining seven deaths occurred within 6 days and were confirmed secondary to cardiac rupture by autopsy; three animals died late in the post-MI course (20, 28, and 32 days). Of these seven chronic deaths, four hearts were available for histological analysis and exhibited a mean infarct size of 54 ± 7% (range 48-64%). All 21 of the sham-operated controls survived. The mean follow-up time for the surviving sham and MI groups was 41 ± 2 days.
Figure 1 shows a thoracotomy in which epicardial ischemia has been induced. The ligature has been placed in the anterolateral LV wall; the myocardium beyond this suture is blanched and akinetic.
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Hemodynamics. Hemodynamic data were obtained for all animals, but LV dP/dt measurements were possible in only 19 sham and 12 MI mice. Our methodology has evolved during the course of this initial study; many of the early dP/dt tracings were suboptimal until the most suitable needle (25-gauge) and filter (set at 2,500 Hz) combination was determined. Only recordings using this combination of needle size and filtering were analyzed and included in these data. Figure 3 demonstrates examples of LV pressure and LV dP/dt obtained from a sham-operated and an MI mouse. The MI mouse displays a lower LV dP/dt and a higher LV end-diastolic pressure (LVEDP) than the sham-operated mouse.
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40%)]. The MI mice as a whole exhibited
lower systolic (P < 0.05) and diastolic blood pressures (P < 0.05)
than the sham group. LVEDP was higher in the all-infarct
group (P < 0.01), which also
demonstrated lower LV peak positive and negative
dP/dt
(P < 0.05 for both). Coinciding with
the increased LVEDP was an increase in lung weight-to-BW ratio in the
whole MI group vs. the sham group (6.51 ± 1.42 vs. 5.27 ± 0.83 g/kg BW, respectively, P < 0.02).
However, liver weight-to-BW ratios were similar in the sham and MI
groups (47.4 ± 3.1 and 47.7 ± 6.6 g/kg, respectively,
P = NS), implying the absence of RV
failure in the MI animals.
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Ventricular mass and volumes. Table 2 displays values for LV (including the septum) and RV mass (free wall) corrected for BW in the sham-operated and MI animals. Data for the MI group as a whole are listed in the all-infarcts column and then divided by median infarct size into moderate and large MIs. The MI mice as a whole exhibited a greater LV-to-BW ratio (P < 0.01) and RV-to-BW ratio (P < 0.02) than the sham group. Figure 4 displays graphically mean LV and RV masses indexed by BW for the sham and moderate- and large-MI groups. The moderate- and large-MI groups exhibited significantly greater LV-to-BW ratios than the sham group (P < 0.02 and P < 0.01, respectively). However, only the large-MI group exhibited a significant increase in RV-to-BW ratio (P < 0.01 vs. sham and moderate-MI groups).
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Echocardiography.
Two-dimensional and M-mode echocardiography were performed on a subset
of sham and MI animals. Examples of short-axis images and M-mode
tracings obtained from a sham-operated and a large-MI mouse are shown
in Fig. 6. These examples demonstrate
marked LV dilatation in the MI mouse. The echocardiographic
measurements are presented in Table 3. Data
for the whole MI group (n = 11) are
again divided by median infarct size into moderate (<40%, n = 6) and large (40%,
n = 5) groups. The MI group as a whole demonstrated significantly greater LVEDD and LVESD along with depressed
FS (all P < 0.01) than the sham
group (n = 12). The moderate-MI group
exhibited a modest increase in LVEDD compared with the sham group that
approached statistical significance (P = 0.0289). However, the large-MI group displayed a markedly increased LVEDD compared with the sham and moderate-MI groups
(P < 0.0001). The moderate-MI group
had a greater LVESD than the sham group (P < 0.01). The large-MI group
exhibited an increased LVESD compared with the sham and moderate-MI
groups (P < 0.0001). Accordingly, FS
was significantly lower in the moderate- and large-MI groups than in
the sham group (P < 0.01 and
P < 0.0001, respectively). The
large-MI group exhibited the greatest degree of LV dysfunction by this
parameter.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study documents a significant degree of ventricular remodeling 6 wk after MI in the mouse. In addition, we present an approach whereby ventricular remodeling can be quantified using noninvasive and invasive methodology in vivo, in addition to postmortem examination of ventricular mass and volumes. Normal C57BL/6J mice were studied, since this strain is frequently used to develop transgenic animals. Because of the small size of the mouse heart, induction of MIs and measurement of hemodynamics are technically challenging. Many researchers have utilized ex vivo preparations to overcome some of the technical difficulties (11). Inducing MIs in mice was initially described nearly 20 years ago (24). More recently, Michael et al. (12) comprehensively described mouse coronary anatomy and methods of coronary ligation. Their study was primarily acute, investigating ischemia and reperfusion. Some of their animals were allowed to survive chronically, but no data on long-term survival, hemodynamics, or indexes of ventricular remodeling were included in their report. Hutter et al. (5) reported an in vivo study of ischemia and reperfusion. This experiment, performed in mice overexpressing heat shock protein 72, was acute, and no chronic data were reported. To our knowledge, our paper is the first to describe a chronic MI model in the mouse and demonstrates the quantitative evaluation of hemodynamics and parameters of ventricular remodeling.
In the present study the MI group as a whole manifested increased LVEDP and depressed positive and negative LV dP/dt. When these data were analyzed with respect to infarct size, only the large-MI group demonstrated a significant, although modest, rise in LVEDP. Both groups exhibited trends for lower peak positive LV dP/dt than the sham group. Paradoxically, positive and negative dP/dt values were even lower in the moderate- than in the large-MI group. The reason for these findings is unclear. However, in comparing the MI groups, these values were statistically similar as a result of the small number of animals and wide confidence intervals. It is possible that greater hemodynamic derangement would have been evident if the animals were studied later in the post-MI period, allowing for the development of LV decompensation and overt heart failure in a greater number of mice.
The infarctions observed in mice were notable for extensive apical
involvement observed grossly and histologically. In humans, early and
late ventricular remodeling is most prevalent after a transmural
anteroapical infarction (17). In our series, 6 wk after MI, animals
with moderate (<40%) and large (40%) infarcts displayed
significant increases in LV mass indexed by BW compared with sham
animals. This implies substantial hypertrophy of the surviving LV
myocardium. Increased RV mass was observed only in those mice with
large infarcts, supporting some degree of LV failure in this group. The
moderate-MI group exhibited an ~50% greater mean LV volume as
determined through passive pressure-volume curves constructed
immediately postmortem. The large-MI group, however, developed marked
LV dilatation given the nearly threefold increase in LV volume compared
with the sham animals. Collectively, these findings confirm a
substantial degree of ventricular remodeling after MI in this mouse
model. We chose the 6-wk time point for two reasons. First, this period
of time has been used by investigators studying ventricular remodeling
in rats (20). Second, our preliminary studies showed only a modest
degree of LV dilatation at 2 wk. On the basis of our data, a 6-wk
follow-up period should be adequate to study the effect of
pharmacological and/or genetic interventions on LV dilatation
in mice after MI.
We applied echocardiographic techniques to many of these mice to assess the feasibility of noninvasively assessing LV size and function. Indeed, the increase in LVEDD observed in the moderate- and large-MI groups correlated well with LV volume (at a common distending pressure of 10 mmHg) determined via passive pressure-volume relations. LVEDD was modestly elevated in the moderate-MI group. The large-MI group demonstrated a markedly elevated EDD that was significant compared with the sham and moderate-MI groups. Both MI groups exhibited depressed FS; however, the large-MI group demonstrated the most severe LV dysfunction by this parameter. By combining the hemodynamic and echocardiographic data, we derived LV meridian wall stress in systole and diastole. We observed trends for a greater LV meridian diastolic wall stress in the MI groups. Only the large-MI group demonstrated a significantly elevated systolic wall stress. These noninvasive, in vivo measurements will allow the serial evaluation of remodeling after MI in this model.
Among all the variables studied in this report, we found that LVEDD and LV volume correlated significantly with infarct size. However, neither the hemodynamic parameters nor ventricular mass measurements correlated with infarct size in mice.
The findings in the mouse MI model are similar in some respects to
those observed in the rat. First, there is an increase in LV mass and
volume, particularly in animals with large (40%) infarcts.
Additionally, the large-MI group displayed increased RV mass,
presumably the result of RV overload related to LV failure, consistent
with the increased LVEDP observed in this group. In accordance with
this finding, Pfeffer et al. (18) observed increases in LVEDP only in
the rats with the largest (>47%) infarcts in their series. One
important difference observed in the mouse MI model is the significant
incidence of LV rupture in mice with large infarcts. The reason for
this observation may be related to the extensive apical involvement of
these infarcts, with a resultant higher wall stress due to an increase
in chamber sphericity and radius. Accordingly, we observed a
significantly greater LV systolic wall stress in only the large-MI
group, which may explain, in part, the propensity for rupture. This
interesting finding warrants further investigation.
This model is most useful in its application to transgenic strains of mice harboring genetic alterations that may be of particular interest in the study of ventricular remodeling. For this reason, it is important to develop this model and to fully characterize in normal mice the effects of MI on indexes of remodeling. Having accomplished this, our laboratory is now examining post-MI remodeling in mice with an angiotensin II, type 1A-receptor "knockout" (7) to examine the role of this receptor specifically in ventricular remodeling.
Limitations. The method we employed to measure LV pressure and its LV dP/dt has drawbacks, in that LV apical puncture is necessary, with recording through a fluid-filled needle. Koch and colleagues (8) used a left thoracotomy and entered the LV from the left atrium, crossing the mitral valve. This approach is not feasible in our model for two reasons: 1) infarcted mice develop adhesions that make manipulation of the heart difficult, and 2) mice with large infarcts are often hemodynamically tenuous and cannot tolerate an extensive thoracotomy. The mean dP/dt values we obtained in the sham group are similar to the control values reported by Koch and colleagues. Recording LVEDP by an open-chest approach with positive-pressure ventilation may have lowered the LVEDP in the infarcted animals. Conversely, frequent flushing of the arterial and LV catheters may have increased the LVEDP in some animals. We have had limited success crossing the aortic valve from the carotid artery using a fluid-filled catheter. However, significant aortic insufficiency may result, and this approach is not successful in a large percentage of cases. Given the small size of the animals, a 2-Fr (Millar) catheter is too large to cannulate the carotid artery. Newer 1.4-Fr (Millar) catheters may make closed-chest measurement of LV hemodynamics possible in most mice.
The heart rates we observed in these mice were relatively slow (mean overall rate of 260 beats/min) compared with conscious mice (generally 400-600 beats/min). This is likely related to the use of ketamine-xylazine anesthesia, an observation reported by other investigators (22). Lower heart rates may result in a decreased LV dP/dt based on the force-frequency relationship. However, the same anesthesia was applied to all animals, making comparison of the MI and sham groups valid. In subsequent studies with this model (unpublished data) and in other murine models within our laboratory (1), using a combination of ketamine and pentobarbital, we observed heart rates in the range of 400-650 beats/min. The wall stress calculations utilized hemodynamic measurements that were obtained on the same day as the echocardiographic studies, but at a different time. In addition, the formula assumes uniform wall thickness, which is not the case in MI animals. LV pressures measured in a closed-chest fashion may allow simultaneous imaging, improving the accuracy of these calculations.Summary. This study documents evidence of ventricular remodeling 6 wk after MI in the mouse. We have demonstrated the feasibility of measuring hemodynamics and quantifying indexes of ventricular remodeling invasively and noninvasively in this mouse MI model. Application of this model to transgenic mice, particularly those with disruptions in angiotensin II signaling (4, 6, 7), is in progress and will allow us a novel approach to investigate the pathogenesis of post-MI ventricular remodeling.
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ACKNOWLEDGEMENTS |
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This work was supported by a Merck Medical School Grant and a New England Medical Center Research Grant.
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FOOTNOTES |
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1 National Institutes of Health Image Analysis Program is available from the internet by anonymous ftp from Zippy.nimh.nih.gov or on floppy disk (Part No. PB93-504868, 1995) from NTIS, 5285 Port Royal Rd., Springfield, VA 22161.
Address for reprint requests: M. A. Konstam, Div. of Cardiology, Dept. of Medicine, New England Medical Center, Box 108, 750 Washington St., Boston, MA 02111.
Received 2 October 1997; accepted in final form 26 January 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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P < 0.01 vs. sham
group; § P < 0.01 vs.
moderate-MI group.
, Sham-operated animals
(n = 12); 
, infarcted
animals (n = 11).
B: regression plot showing a
significant correlation between LVEDD and infarct size in MI group
(n = 11).