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Am J Physiol Heart Circ Physiol 287: H2697–H2704, 2004.
First published August 19, 2004; doi:10.1152/ajpheart.00160.2004.
Remodeling in myocardium adjacent to an infarction in the pig left ventricle
Scott D. Zimmerman, John Criscione, and James W. Covell
School of Medicine, University of California, San Diego, La Jolla, California 92093
Submitted 23 February 2004; accepted in final form 16 August 2004
the present study, we have defined the condition of the initial
end diastolic configuration of the tissue with a transmural array
of gold beads before coronary occlusion and calculated the
deformation of the tissue occurring at 4 wk (deformed configuration). The resulting deformation represents a remodeling
strain. With this approach it is possible to estimate not only
tissue loss but also rearrangement of the components of the
myocardium (e.g., myofiber orientation or arrangement into
radial laminae). Although data exist regarding regional
changes in uniaxial dimensions after MI (29), it is not possible
to relate these measurements to components of the wall (e.g.,
myofiber direction). Therefore, the purpose of the present study
was to examine the hypotheses that changes in the adjacent
tissue are related not only to known myocyte elongation but
also to myofiber rearrangement and changes in the extracellular
matrix in the adjacent tissue. We tested these hypotheses by
determining the structure of the remodeled wall and threedimensional remodeling deformation during the 3 wk after
acute coronary occlusion in the pig.
METHODS
AFTER MYOCARDIAL INFARCTION (MI), cardiac remodeling is characterized by wall thinning, chamber dilation, and increased
ventricular sphericity. Early chamber dilation after coronary
occlusion results both from changes in the infarcted myocardium (9, 29) as well as changes in the normally perfused
myocardium.
Remodeling of the noninfarcted ventricular wall post-MI
occurs, in part, because of structural changes in myocytes (14)
and in part due to rearrangement of myofibrils and changes in
the cardiac interstitium. Myocyte responses to MI may include
cellular hypertrophy and reexpression of a fetal phenotype
(34). Myocytes in noninfarcted myocardium elongate, which is
perhaps structurally more important. Myocyte length increases
after MI and is greater in tissue adjacent to the infarct than
more remote myocardium (14). Changes in the structure of the
“normal” ventricular wall adjacent to the infarcted area involve
all three components of the myocardium (myocytes, fibroblasts
and the extracellular matrix, and the coronary vasculature) and
their three-dimensional structural relationship. Because it is not
possible to assess the structure of the tissue before the infarct,
assessing changes in these components of the tissue requires
tracking material markers in the remodeling tissue over long
periods of time with a three-dimensional approach as well as a
detailed histological evaluation of the remodeled structure. In
Surgical preparation. All experiments were conducted in accordance with American Association for Accreditation of Laboratory
Animal Care guidelines for the use of animals in research and were
approved by the University of California San Diego Institutional
Animal Care and Use Committee.
The surgical protocol and bead implantation technique have been
described in detail previously (35). Eleven Hampshire farm-raised
pigs weighing 23.3 ⫾ 3.2 kg were sedated with 24 mg/kg ketamine
and pretreated with 0.03 mg/kg atropine. Anesthesia was induced with
4 –5% isofluorane with the use of a mask. All animals were then
intubated, ventilated, and maintained with a mixture of isofluorane
(1%), nitrous oxide, and oxygen. The heart was exposed via a fifth
interspace thoracotomy. During the procedure, arterial pressure was
monitored via a catheter inserted into the right femoral artery via a
cutdown. Cardiac support (0.33 ␮g 䡠 kg⫺1 䡠 min⫺1 dobutamine-HCl)
and antiarrhythmics (0.04 ml/kg, single bolus lidocaine-HCl, 2%)
were administered as necessary during the procedure to maintain
femoral artery pressure at ⬎65 mmHg (dobutamine) and to prevent
prolonged episodes of ventricular tachycardia (lidocaine). Inotropic
support and lidocaine were discontinued as soon as the chest was
closed, and no animals received postoperative support.
A 40-cm-long fluid-filled catheter (model S-54-HL, Tygon) was
inserted through the apex into the left ventricular (LV) chamber and
tunneled to the back of the neck, allowing for chronic measurement of
LV pressure. The larger of the first or the second marginal branch of
the left circumflex coronary artery (Fig. 1) was dissected free and
temporarily constricted (⬃5–10 s) to visualize the ischemic border. In
the pig with little collateral circulation, the ischemic area appears
blanched with a bluish tinge. Three columns of three radio-opaque
gold beads (0.8 – 0.9 mm diameter) were implanted transmurally
within the LV wall. The nearest column was placed ⬃1 cm from the
Address for reprint requests and other correspondence: S. Zimmerman, Dept. of
Biomedical Sciences, Southwest Missouri State Univ., 901 S. National Ave.,
Springfield, MO 65804-0027 (E-mail: [email protected]).
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.
myofiber rearrangement; finite deformation; remodeling strains
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Zimmerman, Scott D., John Criscione, and James W. Covell.
Remodeling in myocardium adjacent to an infarction in the pig left
ventricle. Am J Physiol Heart Circ Physiol 287: H2697–H2704, 2004.
First published August 19, 2004; doi:10.1152/ajpheart.00160.2004.—
Changes in the structure of the “normal” ventricular wall adjacent to
an infarcted area involve all components of the myocardium (myocytes, fibroblasts and the extracellular matrix, and the coronary vasculature) and their three-dimensional structural relationship. Assessing changes in these components requires tracking material markers in
the remodeling tissue over long periods of time with a three-dimensional approach as well as a detailed histological evaluation of the
remodeled structure. The purpose of the present study was to examine
the hypotheses that changes in the tissue adjacent to an infarct are
related to myocyte elongation, myofiber rearrangement, and changes
in the laminar architecture of the adjacent tissue. Three weeks after
myocardial infarction, noninfarcted tissue adjacent to the infarct
remodeled by expansion along the direction of the fibers and in the
cross fiber direction. These changes are consistent with myocyte
elongation and myofiber rearrangement (slippage), as well as a change
in cell shape to a more elliptical cross section with the major axis in
the epicardial tangent plane, and indicate that reorientation of fibers
either via “cell slippage” or changes in orientation of the laminar
structure of the ventricular wall are quantitatively important aspects of
the remodeling of the normally perfused myocardium.
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Fig. 1. Schematic representation of surgical preparation, bead
placement, and coronary artery ligation site. LCx, left circumflex coronary artery; LAD, left anterior descending coronary
artery. x1–x3, cicumferential, longitudinal, and radial axes,
respectively.
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Strain calculations. After each biplane X-ray experiment, a calibration phantom with beads embedded in known locations was imaged and used for perspective calibration (30). In particular, digitizing
the two views of the phantom allowed calculation of a calibration
transformation matrix from the known phantom bead positions and
the pixel-based coordinates of the images of the calibration phantom.
The resolution of this technique has been calculated at 0.2 mm (30).
A least-squares finite-element method was used to calculate nonhomogeneous distributions of three-dimensional finite strain, as described elsewhere (17). Briefly, LV pressure tracings and ECG synchronized with a frame grabber (model DT2651, Data Translation)
were used to define end-diastolic frames. At least two frames were
averaged to obtain each end-diastolic view and the three-dimensional
coordinates of each bead were computed from the calibration transformation matrix. The coordinates were then converted to cardiac
coordinates defined by the apex and base beads. Three normal strains
(E11, E22, and E33) quantified stretch or shortening along local
circumferential (X1), longitudinal (X2), or radial (X3) axes. Three shear
strains (E12, E13, and E23) quantified changes in angle between pairs
of initially orthogonal axes. Remodeling strains were calculated as the
bead set deformed between the control diastolic and the 3 wk postinfarct diastolic configurations (22, 28, 31).
The myofiber and sheet orientations were measured in the remodeled configuration, and to estimate their orientations back to the initial
configuration we followed the method outlined in the appendix of
Takayama et al. (28). Briefly, it is assumed that circumferential
segments in the initial configuration remain circumferential and that
planes parallel to the epicardium in the initial configuration remain
parallel to the epicardium. These two conditions allow the strain alone
to specify the mapping of material segments from the initial configuration to the final configuration. Moreover, this mapping is one-toone for all of the remodeling strain fields that were measured in this
study. Hence, the solution was obtained once we correctly guessed (in
an iterative computational manner) an initial myofiber orientation ␣0
that (when strained as measured) gave rise to the measured orientation
␣1. The same approach was used for finding the initial sheet orientation ␤0 from the measured strain field and measured orientation ␤1.
Changes in LV chamber size were estimated from a calculation of
the distance from the apex-base axis (linear distance from the apex
bead to the base bead) to the epicardial centroid of the bead set.
Tissue processing. At the time of death, animals were again sedated
with ketamine (24 mg/kg) and pretreated with atropine (0.03 mg/kg).
Anesthesia was induced with isofluorane (4 –5%) with the use of a
mask. All animals were then intubated, ventilated, and maintained
with a mixture of isofluorane (1%), nitrous oxide, and oxygen. The
heart was exposed via a medial sternotomy. Once the heart was
exposed and any noncardiac tissue dissected away, an overdose of
pentobarbital was administered. Hearts were arrested via infusion of a
hyperkalemic-cardiopelegic solution, dissected free, trimmed of the
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ischemic border and in red contracting myocardium. Bead columns
were implanted perpendicular to the epicardium by temporarily suturing a platform onto the epicardium above the desired location. A
trocar was used to insert each bead to a predetermined depth. This was
repeated until three to four beads were in the myocardium in each
column and three columns of beads were completed. After the
platform was removed, a larger gold bead (1 mm diameter) was
sutured on the epicardium to mark each transmural column. Beads
were also sutured to the LV apex and the bifurcation of the left
coronary artery to define an apex-base cardiac coordinate system for
the transmural bead set (Fig. 1). Data are reported on 6 of the 11
animals. Two animals did not survive the initial surgery. Both had
arrhythmias after coronary ligation and did not survive the first 24 h.
The remaining three animals were excluded because the marker set
was not adequate (not transmural or had overlapping markers precluding visualization with the biplane system). No animals developed
clinical evidence of heart failure.
The deepest bead in three columns in each of the six animals
averaged 75% of the distance from epicardium to endocardium (32%96%). Data for strains referenced to the sheet-fiber axis system are
presented in five animals. The average depth of the deepest bead for
the five animals was 83% (53%-96%) of the distance from epicardium
to endocardium. For presentation of strain data results are averaged
for the inner (n ⫽ 5) and outer (n ⫽ 6) halves of the wall for each
animal. Transmural data is presented at six binned depths [0%-2.5%
(6); 5%-12% (6); 24%-28% (6); 36%-37% (5); 66%-78% (5); and
84%-94% (4), where the number in parenthesis indicates the number
of animals contributing to each bin].
Control studies. Saline infusion was occasionally used to elevate
left ventricular end diastolic pressure ⬎10 mmHg so that data could
be captured at the same end-diastolic pressure at control and 3 wk
after coronary occlusion. With respiration suspended during expiration, three-dimensional control locations of each bead were assessed
by biplane cineradiography for three to four cardiac cycles (⬃3.3 s).
The dissected artery was then ligated. Ischemia was verified visually
by tissue blanching and akinesis. The infarct region was covered with
a patch of pericardium, which was not reapproximated, and the chest
was closed. Air was evacuated from the chest, anesthesia was discontinued, and animals were allowed to recover. All pigs received 400 mg
Sulfamethoxazole/80 mg Trimethoprim in oral suspension for 5 days
after surgery. The catheter in the left ventricle was flushed and filled
with heparin every other day.
Conscious animal studies. Before surgery, all animals were habituated to a canvas sling and the laboratory over the course of 1–2 wk.
Three weeks after coronary ligation animals, they were placed in the
sling and biplane X-ray images of the cardiac beads were taken. The
animals were given 0 –1.0 mg/kg iv diazepam as necessary for mild
sedation. LV pressure and heart rate were monitored throughout the
procedure.
REMODELING POSTMYOCARDIAL INFARCTION
great vessels and atria, and weighed. The right and left coronary
arteries were cannulated via their respective ostia and hearts were
fixed by perfusion at 120 mmHg with 10% buffered formalin (Fisher
Scientific) while suspended in saline (zero distending pressure). The
entire isolation and fixation process lasted ⬍40 min. The right
ventricular wall was removed, and a plastic rod was inserted through
the apex, which extended beyond the base along the apex-base axis.
The LV chamber was filled with silicone, which was allowed to set for
48 h. Hearts were placed in a cutting apparatus, supported by the rod.
The apparatus allowed cuts to be made in the LV wall perpendicular
to the apex-base axis. Tissue blocks containing bead sets were
removed, dehydrated, embedded in paraffin, and sectioned to 10 ␮m
in the epicardial tangent plane. Sections were mounted and stained for
collagen with picrosirius red. Each tissue section was oriented with
the cardiac circumferential axis horizontal on the image and acquired
at ⫻20 total magnification with the use of a color video camera (Sony
CCD/RGB) mounted on a microscope and connected to a Macintosh
computer (Quadra 900 with NIH Image version 1.61 software).
Images were analyzed for collagen area fraction and muscle fiber
orientation relative to the circumferential axis of the heart. Mean angle
for each tissue depth was determined by averaging 10 measurements
within 2 nonadjacent fields in the tissue section. In this way, we could
generate a progression of muscle fiber angles transmurally through the
noninfarcted wall.
Methods for identifying sheet orientation. It was possible to determine sheet angle in a block of tissue adjacent to the block of tissue,
which contained the bead set in five of the six animals. Because this
initial block was used to histologically determine the myocyte angles,
an adjacent region of tissue was used. A through-wall block of fixed
tissue was excised with dimensions (in mm) 3 ⫻ 3 ⫻ n, where n is the
ventricular wall thickness (rounded down to the mm). Two cuts (3 mm
apart) were in the circumferential plane whereas the other two cuts (3
mm apart) were in the apex-base plane. After the apex side was
marked, a custom made sledge-type slicer was used to cut the block
in cross-section at 1-mm intervals parallel to the epicardial surface to
yield n blocks with dimensions (in mm) 3 ⫻ 3 ⫻ 1. The order of the
1-mm slices from epicardium to endocardium was preserved by
gluing them with cyanoacrylic adhesive, to a piece of paper with the
epicardial side facing up and with the marked apex side toward the
bottom of the paper. The slices were infiltrated for 1 wk and embedded with JB-4 plastic embedding media (Polysciences) according to
the product instructions for infiltration and embedding.
The embedded tissue is translucent and the myofiber direction can
be seen on transillumination with a dissecting microscope. After the
plastic was allowed to soften by exposing the sample to air for 2 h, 2
parallel, cross-fiber cuts (1 mm apart) were made with a utility knife.
This cut sample was mounted so it could be sectioned with the
microtome blade in a plane transverse to the myofiber. Figure 2
displays such a section. ␤, the sheet orientation angle, is the angle
subtended by the sheet gap and the radial direction, and ␤ is positive
if the sheet gap points toward the positive cross-fiber direction (see
Fig. 3 for explanation of fiber and sheet coordinates). For the sample
in Fig. 2, ␤ ⫽ ⫺44° on average.
Statistics. Cardiac strain, muscle fiber angle, and fiber strain data
were each analyzed for an effect of ventricular wall depth by one-way
ANOVA with repeated measures (SPSS; Chicago, IL). Each strain
data point was assessed for a significant difference from zero by
one-sample t-test with a Bonferroni correction for repeated tests. For
graphical and statistical comparisons, the absolute value of the change
in sheet and fiber angle was averaged at all sites in each animal and
was assessed for a significant difference from zero by one-sample
t-test with a Bonferroni correction for repeated tests.
RESULTS
End-diastolic remodeling strains. Remodeling strains were
calculated by comparing the end-diastolic configuration of the
transmural gold bead set in control (preinfarction) and 3-wk
post-MI configuration. There was no significant difference in
end diastolic pressure (control, mean ⫽ 11.3, range 3.0 –7.0
mmHg; 3 wk, mean ⫽ 13.2, range 2.0 –20.3 mmHg) at the two
points in time.
End-diastolic remodeling strains referred to cardiac coordinates. Remodeling strains averaged for the inner and outer
halves of the wall are shown in Fig. 4. Circumferential strain
was positive at all depths and significantly different from zero
with the greatest strain magnitude occurring from the midwall
to the endocardium. Radial remodeling strains were not significantly different from zero in the outer third of the wall
becoming negative and significantly different from zero at
Fig. 3. Nomenclature of the fiber (A) and sheet (B) coordinate
systems. Once the fiber and sheet angles were identified, the
cardiac coordinate system from Fig. 1 was rotated into the
respective angles. The in-fiber axis (F) was defined by the long
axis of the myocytes. The in-sheet axis (F) was the same as the
in-fiber axis. The sheet thickness axis (N) was defined by the
orientation of the sheet. Strains were then recalculated to reflect
this new coordinate system and reveal the resulting changes in
the tissues due to changes in sheet orientation. ECC, cross fiber
remodeling strain; EFF, fiber remodeling strain; ENN, strain
normal to the sheet; ERR, radial strain; ESS, sheet strain remodeling.
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Fig. 2. Thick section (15 ␮m) of myocardial block that was mounted in the
microtome so that the blade cuts perpendicular to the myofiber. The sample is
1 mm in minor dimension, and the paper that is seen below the tissue was glued
to the endocardial side before being embedded. The radial direction points up,
the cross-fiber direction points to the left, and the myofiber direction is directly
into the page. The myofibers are arranged in sheets that are about four cells
thick, and the gaps between the sheets are the lines evident in the image.
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DISCUSSION
Fig. 4. Normal remodeling strains in cardiac coordinates averaged for the
inner (N ⫽ 5) and outer (N ⫽ 6) half of the spared myocardium ventricular
wall. Bars indicate one SD. A: E11, E22, and E33, normal stretch or shortening
strains. B: E12, E13, and E23, in-plane shear, circumferential-transverse shear,
and longitudinal-transverse shear, respectively.
depths below the midwall. Shear in the plane of the ventricular
wall (in-plane shear, E12) and circumferential-transverse shear
(E13) were not different from zero at any depth. Longitudinaltransverse shear strains (E23) were positive and significantly
different from zero at the endocardium.
Changes in tissue volume and chamber radius. Changes in
tissue volume were calculated from the product of the three
principal remodeling stretch ratios. The average 3-wk volume
ratio was 1.10 ⫾ 0.11 (means ⫾ SE) suggesting that during the
3 wk after coronary occlusion, noninfarcted myocardium encompassing the gold beads increased 10% in volume on average. The increase in volume was most prominent in the
epicardial and endocardial regions with a less prominent volume change at the midwall. Changes in LV radius were
estimated from a calculation of the distance from the apex-base
axis (linear distance from the apex bead to the base bead) to the
epicardial centroid of the bead set. Chamber radius increased
2.12 ⫾ 0.83 mm (means ⫾ SD).
Changes in fiber and sheet angle. Myocyte fiber angle was
⫺65.4 ⫾ 7.5° at the epicardium and linearly progressed to
50.3 ⫾ 7.2° at the endocardium. Subepicardial, midwall and
subendocardial collagen area fractions were similar (9.7 ⫾
3.6%, 8.8 ⫾ 2.3%, and 8.2 ⫾ 3.4%, respectively).
Because myofiber and sheet orientation were determined
only in the remodeled configuration, it was necessary to estimate the original fiber and sheet orientation to use as a
reference for calculating strain components. This was done as
described earlier from the measured strains. Figure 5 shows the
AJP-Heart Circ Physiol • VOL
Three weeks after MI, noninfarcted tissue adjacent to the
infarct remodeled by expansion along the direction of the fibers
and in the cross-fiber direction. The laminar structure of the
wall is remodeled as well. Myocardial sheets thicken substantially and shorten modestly. These changes are consistent with
myocyte elongation and myofiber rearrangement (slippage)
and/or a change in myocyte cross sectional shape. Although
this is the first study to clearly demonstrate cross-fiber remodeling, these data are qualitatively consistent with a wealth of
previous data showing increased ventricular dimensions (18,
25), changes in myocyte shape (13, 14), and myocyte rearrangement (33) after infarction. Moreover, these data indicate
that reorientation of fibers either via cell slippage (33) or
rearrangement within laminae (5, 16) are the major changes in
early tissue remodeling after infarction in the pig.
Fig. 5. Absolute value of the change in fiber and sheet angle from control to
3 wk after coronary occlusion. Bars indicate one SD. The change in both fiber
and sheet angle is significantly different from zero (P ⬎ 0.05).
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estimated changes in muscle fiber and sheet orientation at all
sites across the wall in five animals. There was a small change
in muscle fiber angle in the spared myocardium adjacent to an
infarction [average 4.1 ⫾ 2.4°: absolute value of (control ⫺ 3
wk)], whereas the average change in sheet angle was approximately twofold greater (9.4 ⫾ 8.2°).
Remodeling strains in fiber coordinates. Figure 6 summarizes the remodeling deformation expressed in fiber sheet
coordinates. Transmural average fiber remodeling strain was
positive and significantly different from zero. The changes
were maximal near the endocardium (0.23 ⫾ 0.19). Cross-fiber
remodeling strain was also positive and at the inner half of the
wall significantly different from zero. Radial remodeling strain
was different from zero only at the endocardium (negative
values indicate modest endocardial wall thinning). Shearing
deformation tended to be small and with only positive values of
cross-fiber radial strain achieving significance at the endocardium.
Remodeling strains in fiber sheet coordinate system. Strains
in the fiber sheet coordinate system reflected again the positive
fiber strain across the wall, which was accompanied by a
significant and large sheet thickening deformation (Fig. 7). On
average, there were no significant shearing deformations when
strains were expressed in the fiber sheet reference system and
there was minor sheet shortening at the endocardium.
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After infarction, global remodeling of the infarcted ventricle
occurs rapidly. Initial enlargement of the infarcted ventricle
may occur as a direct result of lost contractile tissue and a
subsequent decrease in stroke volume that causes increased end
diastolic volume (24). Remodeling of the post-MI ventricle is
characterized by chamber dilation in mouse (23), rat (4, 19, 32)
and large animal models (10). Fifty days post-MI, the transverse LV dimension increased 22% in the rat and 35% in the
dog (10). Interestingly, there seems to be some interspecies
variability in chamber remodeling. Whereas the two species
had similar infarct sizes, the relative increase in ventricular
globularity postinfarction was greater in the rat than the dog
(10). LV dilation after infarction also occurs in humans. Two
weeks after a patient’s first MI, end-diastolic volume increased
27.6%, as measured by MRI (18). The hearts in the present
study also increased in size, as reflected by an increase in
chamber dimension of ⬎2 mm at the same end diastolic
pressure 3 wk after infarction.
In the present study, changes in chamber dimensions were
also accompanied by changes in the structure of the ventricular
wall. Three weeks postinfarction, there was a 10% increase in
tissue volume in spared myocardium adjacent to the infarct.
This increase in tissue volume was uniform across the wall,
and qualitatively agrees with the volume change observed in
myocytes isolated from rat hearts 3 to 4 wk postinfarction.
Within 72 h of surgically induced infarction, rat myocytes
exhibit a 14% increase in length and a 28% increase in volume
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(1). Eight-weeks post-MI, ovine myocytes in noninfarcted
tissue adjacent to the MI exhibited an 18% increase in length
and a 36% increase in volume (14). Changes in myocyte
diameter are less consistent. In rats, the increased volume and
length were accompanied by a 6% increase in diameter (1).
However, ovine myocytes showed no change in cell crosssectional area or myocyte width (14). Our data suggest a
13.3–23.8% strain in the direction of the myocytes (see Fig. 5),
which is in close agreement with the increase in length from
isolated myocytes (14% to 22%). Thus myocyte length
changes may contribute significantly to ventricular remodeling
postMI. Although we did not measure myocyte cross-sectional
area, the small increase in tissue volume in this study (⬃10%)
is substantially less than the 28 –36% increase seen in individual myocytes (1, 14) implying either fewer cells across the wall
or a change in myocyte density. The latter seems unlikely
based on the data of Weisman et al. (33). Apoptosis may be a
contributing factor in the decrease in myocytes across the
remodeling ventricular wall (21).
Our remodeling data directly show for the fist time substantial cross-fiber remodeling in the “normal” tissue adjacent to an
infarct. In our data, both cross-fiber remodeling deformation
and radial cross-fiber shear were positive and significantly
different from zero in the inner half of the ventricular wall.
These data provide strong support for the concept of cell
slippage, which has been inferred from measurements of myocyte density (unchanged) and the number of myocytes across
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Fig. 6. Average transmural remodeling strains in
the fiber coordinate reference system 3 wk after
coronary artery ligation in the pig. EFC, fiber crossfiber strain; EFR, radial strain; ECR, cross-fiber radial
strain. Values are means ⫾ SD.
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the wall (decreased) in several experimental studies after MI
(20, 32). However, these and previous results cannot exclude
several other potential mechanisms that may explain crossfiber remodeling. Kramer et al. (14) and Gerdes et al. (7) have
mentioned changes in cell shape in the failing myocardium as
a possibility and have presented preliminary data supporting
this contention. These data provide evidence that the type of
hypertrophy is reflected in differential myocyte shape change.
In the present study, myocytes with larger in-plane dimension
would explain the large positive cross-fiber strains and very
large positive sheet normal strains. However, there is no direct
evidence for this shape change in our post-infarct spared
myocardium. Changes in the interstial space would also explain these changes. However, no changes in myocyte density
have been reported. Collagen content in the present study, as
reflected by picrosirus red staining, averaged 8.9 ⫾ 3.05% and
was not different from values determined with the same technique (12) in pigs. Thus changes in the interstitial volume seem
unlikely. However, significant changes in the structure of the
wall of the ventricle as observed in this study imply that the
organization of the matrix is also altered. Indeed, other recent
studies (26), which indicate that collagenase activity is essential for ventricular remodeling, imply that these changes may
allow the remodeling to occur. Myocyte dropout due to apoptosis has been shown to be present postinfarction but would not
explain the positive cross-fiber strains.
The significant positive cross-fiber radial remodeling strains
in the present study could be explained by the following: a
rotation of myocytes as proposed by Weisman and others (20,
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32); by changes in cell shape; or by alterations in the orientation laminar architecture (␤) (5, 16). However, because there
were no significant changes in sheet normal shear, the latter
possibility seems unlikely. In the present study, the inner half
of the ventricular wall adjacent to a MI thinned substantially.
In rats, noninfarcted myocardium may thin (32), remain un-
Fig. 8. Schematic representation of potential mechanisms of cross-fiber remodeling.
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Fig. 7. Average transmural remodeling strains in
the fiber-sheet reference system 3 wk after coronary
artery ligation in the pig. EFS, fiber sheet strain; EFN,
fiber normal strain. Values are means ⫾ SD.
REMODELING POSTMYOCARDIAL INFARCTION
AJP-Heart Circ Physiol • VOL
diastolic pressure where bead configuration was measured (11
mmHg).
In summary, 3 wk after MI, noninfarcted tissue adjacent to
the infarct remodeled by expansion along the direction of the
fibers and in the cross-fiber direction. These changes are
consistent with myocyte elongation and myofiber rearrangement (slippage) as well as a change in cell shape to a more
elliptical cross section with the major axis in the epicardial
tangent plane. Although this is the first study to clearly demonstrate cross-fiber remodeling, these data are qualitatively
consistent with a wealth of previous data showing increased
ventricular dimensions (18, 25), changes in myocyte shape (13,
15), and myocyte rearrangement (33) after MI. Moreover,
these data indicate that reorientation of fibers either via cell
slippage (32) or changes in orientation of the laminar structure
(5, 16) of the ventricular wall are quantitatively important
aspects of the remodeling of the adjacent normally perfused
myocardium.
GRANTS
This research was supported by National Heart, Lung, and Blood Institute
Grant HL-43617 and by Training Grant HL-7444 (to S. Zimmerman).
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distending pressure. Thus the sheet angle changes here may
well include a component due to the difference between zero
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