(Circulation. 1996;94:94-101.)
© 1996 American Heart Association, Inc.
Articles |
Rate of Collagen Deposition During Healing and Ventricular Remodeling After Myocardial Infarction in Rat and Dog Models
From the Cardiology Division of the Department of Medicine, University of Alberta, and the University of Alberta Hospital, Edmonton, Alberta, Canada.
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Abstract |
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Background We hypothesized that the rate and amount of infarct collagen deposition during healing after myocardial infarction might influence ventricular remodeling in rat and dog models. The purpose of this study was to compare rates of infarct collagen deposition and ventricular remodeling in the two models.
Methods and Results Infarcted rat and dog hearts were removed at fixed time intervals between 1 and 50 days for measuring remodeling parameters and infarct and noninfarct collagen content (mg/g hydroxyproline). Collagen was less in sham rat (n=29) than dog (n=30) ventricles (3.32 versus 4.57 mg/g, P<.001) and markedly lower in the rat (n=48) than dog (n=59) infarcts throughout healing and by 50 days (9.98 versus 56.74 mg/g, P<.0001). Infarct collagen leveled off earlier and healing (histology) was completed sooner in the rat. Infarct scars were also thinner in the rat, with more (P<.0001) thinning and bulging (mm/g), and greater increase in ventricular volume. Although the mass to volume ratio decreased (P<.001) in both models, global remodeling was different, with greater transverse axis widening and globularity in the dog. Although infarct size, transmurality, heart rate, filling pressure, and blood pressure were greater in the rat, infarcts 10% to 30% in size in both models showed similar differences in infarct collagen and remodeling.
Conclusions Compared with dog infarcts, rat infarcts exhibited faster healing and infarct collagen deposition and markedly lower infarct collagen. In addition to larger, more transmural, and thinner infarcts, and greater hemodynamic load, the lower infarct collagen in that model might be an important factor in the greater regional remodeling.
Key Words: myocardial infarction • remodeling • ventricles • collagen
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Introduction |
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Healing and ventricular remodeling after myocardial infarction are dynamic processes that progress in parallel.1 2 During healing, collagen deposition in the infarct zone (IZ) increases resistance to distention.3 4 The rate and amount of collagen deposition in the IZ during healing might influence ventricular remodeling. Dog5 6 7 8 and rat9 10 11 12 13 models of myocardial infarction are used to assess the efficacy of agents that limit postinfarct ventricular remodeling.14 15 16 17 Healing of the IZ to yield a scar takes 3 weeks in the rat9 10 11 12 13 and 6 weeks in the dog.5 Infarct collagen content increases rapidly over the first few weeks, plateaus thereafter, and influences remodeling in the dog.5 Collagen deposition in the already expanded IZ fixes and remodels the regional shape abnormality and contributes to aneurysm formation.5 Systematic comparison of the rate of infarct collagen deposition and ventricular remodeling in the rat and dog models has not been made.
The aim of this study was to compare the rates of IZ collagen deposition and left ventricular remodeling during healing after coronary artery ligation in rat and dog models of myocardial infarction.
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Methods |
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Protocols and procedures were approved by an institutional animal welfare committee and conformed to the guiding principles of the American Physiological Society.
Myocardial Infarction in the Rat
Left ventricular infarction was made using a
modification of the procedure of Selye et al,18 as
described by Pfeffer et al.10 Briefly,
Sprague-Dawley rats of either sex weighing 250 to 350 g were
anesthetized with ether, intubated, and ventilated by a
positive-pressure rodent respirator. Sterile left lateral
thoracotomy and pericardiotomy were made, the heart was extruded, and
the left coronary artery ligated near its origin. The
pericardium was closed, the heart returned to the chest cavity, the
lungs inflated, and the chest closed. In sham-operated rats, the
coronary artery was not ligated. Mortality was 40% in the
first 48 hours. All rats were housed under 12-hour light/dark cycles
and had standard rat chow and free access to water.
Myocardial Infarction in the Dog
Anterior left ventricular infarction was made as
described previously.16 17 19 Briefly, mongrel dogs
(weight, 18 to 22 kg) of either sex were anesthetized (sodium
pentobarbital, 30 mg/kg IV), intubated, and ventilated. The heart was
exposed through a left lateral thoracotomy and pericardiotomy. The left
anterior descending coronary artery was ligated in the mid
region. Mortality was 10% in the first 48 hours.16 17 The
pericardium was closed, the lungs inflated, and the chest closed.
Sham-operated dogs did not have coronary ligation. All dogs
had standard food and free access to water.
Experimental Design
The animals were reanesthetized at predetermined
intervals: rats at 1, 2, 3, 4, 7, 14, 21, 42, and 50 days and dogs at
1, 2, 3, 4, 7, 14, 21, 28, 35, 42, and 50 days. In selected animals,
the right carotid artery, right jugular vein, and left atrial appendage
were cannulated. Left atrial and arterial pressures
(Statham P23Db) and heart rates (ECGs) were measured. All chests were
opened and hearts arrested in diastole with
intravenous potassium chloride. The hearts were then
removed, rinsed in cold saline, and fixed in distention (15-cm pressure
head) for 48 hours using 10% phosphate-buffered formalin to
preserve diastolic proportions.16 17 The left
ventricles were dissected from other chambers, structures, and tissues,
including epicardial fat, valves, chordae, and adherent pericardium. A
dissecting microscope was used for rat hearts. The ventricles were then
sliced into five equally spaced transverse sections (1 to 2 mm thick in
rats; 1 to 2 cm thick in dogs) parallel to the
atrioventricular groove. Hearts of animals that died in
cages were not included. Hearts without histological
evidence of infarction in coronary ligation groups (49% rats;
12% dogs) were excluded.
Measurement of Remodeling Parameters
The maximum longitudinal dimension before left
ventricular sectioning and the maximum short-axis
dimension after sectioning were measured. The ratio was used as a
global shape index of globularity.20 21 The left
ventricular sections were weighed, and outlines of the
rings and infarct scars were made on plastic overlays. Infarct size and
topographic parameters, including the "thinning"
ratio (ratio of average thickness of infarcted wall to average
thickness of the normal wall) were measured by computerized planimetry
(Hewlett Packard 9835A computer and 9874A digitizer interfaced with a
VAX 750 computer), as described previously.5 16 17 The
maximum depth of infarct scar bulge in millimeters was measured on the
contoured sections as an index of regional dilation.17
Ventricular volumes were computed from the short-axis
areas and the long-axis length by the modified Simpson's rule, as
used for echocardiographic studies during
remodeling.16 17 Infarct transmurality was calculated as
the ratio of the maximum thickness of the infarct scar and the
thickness of the left ventricular
wall.22 23
Histopathology
Histopathological and morphometric analyses for
infarction and collagen were performed on triplicate 5-µm sections
(from the ring in the middle of the IZ) stained with hematoxylin and
eosin, Mallory's stain, or Masson's trichrome, respectively, as
described previously.5 24 25 Features of necrosis and
healing were graded (0, absent; 1, mild; 2, moderate; and 3,
severe).
Measurement of Collagen Content
Myocardial hydroxyproline, a marker for collagen, was measured
in transmural samples (25 to 100 mg) taken from center regions of the
IZ and the noninfarct zone (NIZ) in the remaining four left
ventricular rings, as described previously.5
Unlike that study,5 in which the whole sample was assayed,
the IZ was grossly dissected from normal tissue for this study. Samples
were freeze-dried to constant weight for 12 hours, reweighed, and
hydrolyzed in 6N HCl at 125°C for 3 hours at 200 psi pressure in an
autoclave. Instead of neutralization and decoloration, 1-mL aliquots of
the acid hydrolysate were evaporated, washed with 1 mL water, and
redried in tubes, as described by Bergman and Loxley.26
Hydroxyproline content was measured on a spectrophotometer (Unican
SP-1800) by the method of Neuman and Logan27 as modified
by Martin and Axelrod28 and expressed in milligrams per
gram of dry tissue weight.
Statistics
Data were analyzed in blinded fashion. ANOVA was used
for the significance of differences within and between groups. Results
are presented as mean±SEM. Statistical significance was set at
P<.05.
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Results |
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There were 59 sham (29 rats; 30 dogs) and 107 infarcted (48 rats; 59 dogs) hearts. In 40 infarcted rats and 50 infarcted dogs, the final heart rate (385 versus 112 bpm, P<.001), mean arterial pressure (112 versus 101 mm Hg, P<.05), and mean left atrial pressure (16 versus 13 mm Hg, P<.05) were higher in the rat.
Regional Collagen Content in Sham Rat and Dog Hearts
Collagen content (mg/g hydroxyproline) was less in sham rat than
dog hearts at all levels from base to apex (Table 1
).
Excluding the annular ring, collagen content was less in the pooled 87
samples from 19 rats than the 62 samples from 10 dogs (3.32±0.07
versus 4.57±0.13, P<.0001). The content in the section
containing the annulus was 7.36±0.28 in rats and 11.55±1.10 in dogs,
both higher (P<.0001) than the average for the lower five
sections. Minor differences in content were found in the other sections
from base to apex. Comparisons of collagen content in rat and dog
ventricles were therefore made at corresponding levels (rings 3 and 4).
Formalin fixation did not influence collagen content. Thus, the content
in 3 formalin-fixed rat hearts (12 samples) and 1 unfixed heart (4
samples) were 3.21±0.22 versus 3.14±0.20, P=NS. In
addition, collagen did not change in sham hearts between day 1 and 4 to
6 weeks (Table 2), and the content in septal and free
wall regions did not differ over these intervals. Anatomic
parameters in the sham hearts (Table 3) are
consistent with the quantitatively larger ventricle in dogs.
However, the ratios of ventricular weight to body weight,
ventricular volume to body weight, or
ventricular mass to volume were also larger for dogs.
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Regional Collagen Content in Infarcted Rat and Dog
Ventricles
Throughout healing, less collagen was deposited in the IZ of rats
than dogs (Fig 1). Over the first 3 weeks after
infarction in the rat, collagen content increased slightly in the
normal left ventricular free wall (2.65±0.11 versus
3.44±0.91, P=NS) and the septal region (2.65±0.53 versus
4.07±1.16, P=NS). In contrast, a more marked increase was
found in the IZ of the free wall over the same interval (3.03±0.11
versus 9.98±0.40, P<.003). Collagen in the IZ had
increased threefold by the first week and reached a plateau between 7
and 14 days. Further increase was seen between 21 and 50 days in the
normal free wall (3.44 versus 4.57, P=NS) and septum (4.07
versus 5.54, P=.3). At day 50, collagen was higher than
baseline for the normal free wall (5.61 versus 2.67, P=.06)
and septum (5.54 versus 2.65, P=.06). However, collagen in
the IZ did not change during that time (9.98 versus 9.98,
P=NS). In contrast, collagen in the IZ of the dog ventricle
increased much more, from 4.56 mg/g on day 1 to 56.74 mg/g by day 50
(P<.0001). The increase in the dog was consistently
greater throughout healing. Thus, IZ collagen in dogs increased
1.5-fold by 1 week, 4-fold by 2 weeks, and 7-fold by 3 weeks and
leveled off to between 8-fold and 11-fold increases between 28 and 50
days. At 50 days, IZ collagen content was nearly 5-fold lower in the
rat than dog ventricle (9.98 versus 56.74 mg/g, P<.001).
Collagen content of the NIZ did not change over the 50 days in
dogs.
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Histological Parameters of Healing in
Rat and Dog Infarcts
The rat and dog infarcts differed in location, size, and
transmurality. As reported previously for the rat9 and
dog,16 17 19 the infarcts involved the left
ventricular free wall and apex and spared the septum in
rats and involved the anteroapical and anteroseptal regions in dogs.
Infarct size was larger (P<.0001) in rats (29±1%; range,
15% to 46%) than dogs (14±1%; range, 3% to 40%). As noted before
for the rat28 and dog,7 infarcts in both
animals showed a rim of subepicardial sparing and contraction bands at
the infarct margins, consistent with collateral inflow.
However, sparing was quantitatively more in dog ventricles.
Maximum infarct transmurality was more (P<.001) in rats
(0.92±0.01; range, 0.8 to 1.0) than in dogs (0.84±0.02; range, 0.3 to
1.0). Importantly, histological changes evolved more
rapidly in rats (Table 4).
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Infarct Size and Infarct Remodeling in Rat and Dog
Ventricles
Infarct size (as % left ventricular mass) was larger
throughout the 50 days in rats and decreased over that time in both
rats and dogs (Fig 2A). Thus, infarct sizes were 44%
versus 17% (P<.03) on day 1 and 17% versus 10%
(P<.05) on day 50. The decrease in size over 50 days was
greater in the rat than dog ventricle (61% versus 41%). There was
more infarct wall thinning and thinner scars in rats. Between day 1 and
day 50, the infarct to noninfarct wall thickness ratio decreased from
0.85 to 0.15 (P<.001) in rats and 0.89 to 0.40
(P<.001) in dogs (Fig 2B). This greater thinning in the rat
infarct (82% versus 55%) was associated with thinner walls (Fig 2C).
Between days 1 and 50, infarct wall thickness decreased from 1.75 to
0.33 mm in rats (P<.001) and 13.5 to 5.5 mm in dogs
(P<.001). During that time, noninfarct wall thickness
increased slightly in the rat (but not in the dog) and mainly from day
14 to day 50 (2.00±0.02 versus 2.25±0.03 mm, P<.001).
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P for groups at
corresponding time intervals.
There was more IZ remodeling, with more regional bulging in the rat
left ventricle, in mm (Fig 3A) and in mm/g (Fig 3B).
Between days 1 and 50, bulging of the IZ increased in rats (0.75 to
2.67 mm, P<.01) and dogs (2.50 to 8.00 mm,
P<.001), and percent increases (256 versus 220) were
similar (Fig 3A). Bulging normalized to body weight also increased in
rats (3.69 to 9.09 mm/g, P<.001) and dogs
(1.1x10-4 to
4.1x10-4 mm/g, P<.001) but
was much more (P<.0001) in rats (Fig 3B).
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Mass and Volume in Rat and Dog Ventricles
Ventricular mass (normalized to body weight) remained
greater in dogs over the 50 days (Fig 4A). Compared with
sham, ventricular mass increased slightly during the
inflammatory stage both in rats (2.20 versus 2.10 mg/g,
P=NS) and dogs (4.76x103 versus
4.17x103 mg/g, P=NS). Ventricular
mass then decreased during scar thinning by day 14 in rats
(1.94±0.05 versus 2.20±0.02 mg/g, P<.0001) and day
20 in dogs (3.34±0.17x103 versus
4.76±0.44x103 mg/g, P<.02). Subsequently,
ventricular mass increased by day 50 both in rats
(2.24±0.03 versus 1.94±0.05 mg/g, P<.006) and dogs
(3.48x103 versus 3.34x103 mg/g,
P=NS). By day 50, ventricular mass exceeded the
value in sham rat but not dog ventricles. Ventricular
volume, normalized to body weight (Fig 4B), increased more over 50 days
in rats than dogs (101% versus 87%). Compared with sham, the increase
in volume by day 50 was also more in rats (118% versus 86%). Over the
50 days, the volume to mass ratio (Fig 4C) decreased in rats
(0.81±0.03 versus 1.53±0.03, P<.001) and dogs (0.84±0.13
versus 2.02±0.14, P<.001). The percent decrease in volume
to mass ratio was similar in dogs and rats (58% versus 47%).
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Global Shape in Rat and Dog Ventricles
Over the 50 days, the transverse left ventricular
dimension (Fig 5A) increased both in the rat (8.9 versus
7.3 mm, P<.01) and the dog (25.8 versus 19.1 mm,
P<.01), but the increase was slightly more in the dog (35%
versus 22%). In contrast, the longitudinal dimension increased
steadily (by 63%) in the rat ventricle (16.3 versus 10 mm,
P<.001) but did not show significant increase by 50 days in
the dog ventricle (52 versus 56 mm, P=NS). The transverse to
longitudinal dimension ratio therefore decreased in the rat but not in
the dog ventricle (Fig 5B).
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Infarct Size, Collagen, and Remodeling
For equivalent infarct size (range, 10% to 30%; mean, 21%
versus 17%; P<.05), infarct collagen was less in the rat
than the dog (8.9 versus 21.6 mg/g, P<.005). More
important, IZ bulging (7.3 versus
2.9x10-4 mm/g, P<.0001),
thinning (0.29 versus 0.64, P<.0001), global dilation (1.9
versus 3.4 µL/g, P<.0001), and globularity (0.50 versus
0.40, P<.0002) were greater in the rat ventricle. Final
heart rate (370 versus 108 bpm, P<.001), mean blood
pressure (111 versus 102 mm Hg, P<.1), and mean filling
pressure (15 versus 13 mm Hg, P<.1) were also higher in the
rat.
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Discussion |
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There are four new findings in this study. First, less infarct collagen is deposited in the rat than the dog. This occurs throughout healing and despite the relatively larger infarcts in the rat. Second, infarct healing is completed sooner and infarct collagen is deposited earlier in the rat. The comparative data indicate that infarct collagen plateaus earlier in the rat, between 1 and 2 weeks, compared with 4 and 6 weeks in the dog. Third, the lower infarct collagen in the rat is associated with more severe remodeling, more bulging of the IZ, more ventricular dilation, and more globularity. Fourth, hypertrophy of the NIZ occurs sooner and is more marked in the rat than the dog. This hypertrophy in the rat is associated with a mild but significant increase in NIZ collagen.
Remodeling in Rat and Dog Infarction
Major factors that might have contributed to the qualitative,
quantitative, and temporal differences in healing and remodeling
between the two models, besides the difference in species, include the
larger infarct size, greater hemodynamic load, and
lower infarct collagen in the rat. The effects of infarct size,
hemodynamic loading, and infarct healing have been
reviewed.1 2 5 Different infarct locations due to
differences in coronary anatomy,7 29 with
nearly 100% sparing of the ventricular septum in the rat,
might have played a role. The dog has two left coronary artery
branches supplying the left ventricle, whereas the rat has one left
coronary artery that gives off several branches at the high
anterior base. Bulging involved mainly the free wall in the rat and the
apex in the dog in this study. The fact that only the coronary
artery is ligated in the dog while both artery and vein are ligated in
the rat also might have contributed to differences in infarct
transmurality, healing, and remodeling.
Collagen and Postinfarct Remodeling
Evidence from several laboratories suggests that collagen
deposition after infarction is important for preserving
ventricular structure and function.23 30 31 32 33 34 35
The role of the supporting collagen framework in maintaining
ventricular shape and size has been
reviewed.36 Experimental data in rabbit3 and
dog4 37 infarction models suggest that preinfarction
collagen contributes to mechanical strength and resistance to
distention. In this study, collagen in the NIZ and in sham hearts was
slightly less for rats than dogs (3.3 versus 4.6 mg/g). By day 50,
collagen in the IZ increased about 12-fold in dogs, as reported
before,4 5 37 and 2.5-fold in rats. Infarct collagen
increased 5-fold, from 2.8 to 14.8 mg/g by 8 days in the rabbit
model,3 and 10-fold, from 5 to 52 mg/g in infarcted human
hearts,38 suggesting more IZ collagen with increasing
heart size. In 1-day-old dog infarct tissue, tensile strength is
preserved,39 probably because collagen is mostly of the
normal, preinfarction type.
If preinfarction collagen content correlates with strength,3 40 why do spontaneous ruptures occur early in infarcted human ventricles,41 albeit before new scar formation and when infarct collagen is low? Why is postmortem rupture threshold (balloon technique) lower during infarct healing in dogs,4 37 when IZ collagen has increased severalfold? Why should the IZ bulge when collagen in the IZ is so much higher than in the NIZ?2 4 5
There are two potential explanations for these paradoxes. First, the normal supporting collagen matrix is disrupted early during myocardial ischemia42 and infarction.22 23 31 32 33 34 35 Rupture of the intermyocyte collagen struts and myocyte slippage appears to be the primary cellular mechanism for early dilation and increased diastolic distensibility of the IZ.31 32 33 34 35 Activation of matrix metalloproteinases probably mediates these changes.43 Indeed, polarized microscopy shows disorganization of collagen fibrils and decreased collagen quantity during infarct expansion.32 35 Collagen fibroskeleton (silver staining) is absent at the site of rupture in human hearts.44 A mild decrease in IZ collagen occurs in early dog infarction.45 Spontaneous rupture has been observed within infarct tissue in early anteroapical infarction in the dog.4 That left ventricular rupture threshold should decrease after infarction4 is therefore consistent with the concept of early collagen matrix disruption (and possibly decreased collagen content) and regional weakening.
Second, new collagen deposited in the IZ may be biochemically or
structurally weaker. Indeed, new IZ collagen deposited during early
healing in the dog is mostly immature, and mature collagen is not
produced until after 7 to 14 days.45 Normal myocardial
collagen is mature and predominantly type I, which has tensile strength
similar to steel.40 In contrast, immature collagen is
weaker.32 40 Type III collagen, which is deposited during
healing, has little tensile strength. Whether collagen maturity or the
type I/type III collagen ratio in the IZ is restored during healing is
controversial. The recent finding that both types I and III procollagen
mRNA are increased by 21 days but only type I mRNA remains elevated at
90 days in the rat46 suggests that the type I/III collagen
ratio might increase between 21 and 90 days. Moreover, 15-week-old
infarct scars from the rabbit still sustain irreversible
strain.47 Nevertheless, mechanically produced ruptures
after older infarcts in the dog occur in border regions, in adjacent
myocardium where collagen content is lower and presumably
normal.4 Late spontaneous ruptures41 in
ventricles with developing infarct scars also occur at scar borders and
not within the scar itself. As collagen content in the IZ increases,
the mechanical resistance to distention increases in infarcted dog
ventricles.4 This supports the idea that collagen
deposition in the IZ strengthens the area and resists
distention.4 The recent finding that mature collagen
crosslinking in the IZ of 13-week rat infarcts exceeds that of the
NIZ48 suggests that the tensile strength of scar collagen
may eventually exceed that of normal myocardium.
Further resistance to distention might be provided by conversion of
fibroblasts to myofibroblasts containing 
-actin protein
filaments.49 The latter was seen in human infarcts between
4 days and 17 years old,49 suggesting continuing scar
remodeling.
It is thus reasonable to expect that a lower collagen content in the IZ promotes remodeling with more IZ bulging. In addition, lower NIZ collagen might promote global ventricular distention. In this study, collagen content in the NIZ increased slightly over the 50 days in the rat but not in the dog. Continued remodeling of the NIZ beyond scar formation, with collagen deposition and fibrosis, has been shown in rats46 and humans.49 50 51 In hearts from patients undergoing cardiac transplantation months to years after infarction, increased NIZ collagen is mainly type I,50 and interstitial fibrosis, eccentric hypertrophy, and a decreased mass to volume ratio are present.51 The pattern of types I and III procollagen mRNA expression is quite different for the IZ and NIZ of the rat, suggesting that collagen synthesis might be regulated differently in the two zones.46 Differential regulation of collagen synthesis in the two zones might occur in dog and human hearts as well.
Implications
The overall results of this study support the idea that less IZ
collagen offers less resistance to distention and promotes remodeling.
Conversely, more IZ collagen resists regional distention and is
associated with less remodeling. More NIZ collagen and
hypertrophy in the rat suggest that there might be more
fibrosis associated with postinfarction hypertrophy in that
model. It is possible that the larger infarct size in rats triggers a
greater healing response involving the whole heart. Although a constant
relation exists between workload and the ratio of wall thickness to
chamber radius, this relation is true provided shape does not change as
the ventricle enlarges.52 In this study, mismatches in the
mass to volume ratio were seen as shape changed in both models during
postinfarct healing. From the Laplace law, the greater
ventricular radius and wall tension explains the greater
wall thickness in the dog than rat heart. The slightly higher NIZ
collagen in the sham dog than sham rat ventricle also can be explained
by the same mechanism. Thus, more IZ collagen in the dog may be part of
that general adaptive growth response rather than an attempt to resist
distention. Since relatively more regional bulging in the rat ventricle
was not associated with more IZ collagen on a milligram per gram basis
(compared with the dog), this could represent a maladaptive
response. Although ACE inhibition has been shown to decrease NIZ
collagen in the rat,53 IZ collagen and remodeling were not
studied. However, a decrease in IZ collagen with ACE inhibition in dogs
(to levels still higher than in the rat) was associated with flatter
scars despite the small infarcts.54
Several factors might explain the greater decrease in infarct size and infarct thinning over time in the rat. First, less collateral inflow (during infarct healing) might have contributed to greater tissue injury, less inflammatory cell infiltrate, and less fibroblast response, although we did not detect differences in histological parameters. Second, the thinner ventricular wall might promote more rapid resolution of edema and more infarct thinning. Third, although we did not quantify myofibroblasts, the larger infarcts might have resulted in more myofibroblasts and more granulation tissue contraction.
There were several limitations in this study. Infarct size and ventricular loading were not controlled. Our measure of infarct size provided an index of necrosis and did not address programmed myocyte cell death. Collagen types and serial hemodynamics were not measured. We did not reduce infarct collagen in the dog to the level in the rat and demonstrate more remodeling. Conversely, we did not increase infarct collagen in the rat to the level in the dog and confirm less remodeling.
The rat and dog models of postinfarct remodeling have their merits and limitations.8 9 The differences in rate of healing, IZ collagen deposition, NIZ hypertrophy, and other remodeling parameters in the IZ and NIZ between the two models are pertinent to the interpretation of effects of interventions that limit postinfarct ventricular remodeling in these models. Furthermore, without clinical pathophysiological studies, caution should be exercised in extrapolating findings in rats or dogs directly to humans.
Conclusions
A comparison of rat and dog models of postinfarction remodeling
revealed that in addition to more rapid healing and a higher rate of
collagen deposition, the rat model was associated with less IZ collagen
deposition despite larger infarct size. The rat ventricle with less IZ
collagen, larger and more transmural infarction, thinner walls, and
greater hemodynamic load was associated with
severalfold more regional bulging and a different pattern of global
remodeling. The lower IZ collagen in the rat might be an important
factor in the greater regional remodeling found in that model.
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Acknowledgments |
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This study was supported in part by a grant from the Medical Research Council of Canada, Ottawa, Ontario. We are grateful for the assistance of Vijayan Menon, BSc, with computing and Catherine Graham with typing.
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Footnotes |
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Reprint requests to Dr B.I. Jugdutt, 2C2.43 Walter MacKenzie Health Sciences Centre, Division of Cardiology, Department of Medicine, Edmonton, Alberta, Canada T6G 2R7.
Received October 19, 1995; revision received December 19, 1995; accepted December 22, 1995.
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