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(Circulation. 1995;92:1891-1901.)
© 1995 American Heart Association, Inc.
Articles |
Healing of Myocardial Infarcts in Dogs
Effects of Late Reperfusion
From the Department of Pathology, Duke University Medical Center, Durham, NC.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Early reperfusion salvages ischemic myocardium and limits myocardial infarct size. However, the effects of late reperfusion, after the possibility for limitation of infarct size has passed, have not been completely elucidated. The purpose of this study was to ascertain the effect of reperfusion after 6 hours of ischemia on the rate of infarct healing and on the size and geometry of the resulting scars, as determined by gross and microscopic quantification.
Methods and Results Myocardial infarcts were produced in anesthetized, open-chest dogs by occlusion of the circumflex coronary artery. They either were reperfused by removal of the occluding snare or were nonreperfused. The animals were allowed to recover for either 4 days, 2 weeks, or 6 weeks. At these times, infarct size, infarct dimensions (wall thickness and circumferential extent), and the proportion of infarct occupied by necrotic myocardium versus granulation tissue (evolving scar) were measured. At 4 days, infarcts were swollen in both nonreperfused and reperfused groups (increased thickness and circumferential extent of the area at risk). Conversely, at 6 weeks, the size, thickness, and circumferential extent of the scar all were decreased. Two common anatomic complications of human infarction, cardiac rupture and chronic infarct expansion (aneurysm), did not occur in this experimental model. Reperfusion at 6 hours did not affect initial infarct size (4 days) or scar size (6 weeks). At 2 weeks, reperfused infarcts were smaller and were composed of proportionately more granulation tissue and less nonresorbed necrosis than nonreperfused infarcts.
Conclusions Thus, reperfusion accelerated the rate of infarct repair, ie, the replacement of necrotic myocardium by scar. Acceleration of infarct repair may be a beneficial effect of late reperfusion even after the opportunity for limitation of infarct size has passed.
Key Words: ischemia • reperfusion • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Myocardial repair after infarction is a complex, dynamic process in which dead myocytes are removed and replaced by scar. Whereas progression of myocardial cell death may be completed within
6 hours, the process of infarct repair and scar
formation takes up to 6 weeks in dogs1 2 and may take
even
longer in humans.3 4 Although the mechanisms of
ischemic cell death have been widely studied, less is known
about factors that influence the process of infarct repair. With the development of acute thrombolytic therapy to restore blood flow to ischemic myocardium, much attention has been focused on the consequences of reperfusion on the early development of myocardial infarcts. It is now well established in canine hearts that early reperfusion (within 3 to 6 hours) is beneficial in that it halts the advancing "wave front" of ischemic cell death and thus salvages areas of tissue that are still reversibly injured.5 The consequences of myocardial reperfusion on infarct healing, however, are not well characterized.
Recent clinical studies have suggested that thrombolytic reperfusion or angioplasty performed beyond 6 hours from symptom onset could still improve ventricular function and overall survival,6 7 8 9 10 11 although it may increase the likelihood of cardiac rupture.8 The explanation for the beneficial clinical effect of late reperfusion is unclear. One possibility is that reperfusion might favorably influence myocardial infarct healing even when instituted too late to limit myocardial infarct size.9 12 13 In theory, late reperfusion could affect the rate of infarct repair (ie, the replacement of necrosis with scar), the likelihood of infarct complications (eg, cardiac rupture or aneurysm formation), or the final size of scar. For example, experimental studies using rats have shown that reperfusion after the time when myocardial salvage could be expected did limit infarct expansion during the healing phase.14 Thus, the present study was designed to evaluate, in canine hearts, the effects of late reperfusion (versus permanent coronary occlusion) on (1) the time course of infarct repair and (2) scar size (compared with predicted initial infarct size).
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The experiments reported here conformed to the American Physiological Society guidelines regarding the use of laboratory animals and to the standards in the "Guide for the Care and Use of Laboratory Animals," DHEW publication NIH 78-23. In general, animal selection, experimental procedures, and methods of assessing myocardial infarct size and predictors of infarct size were done according to the criteria developed in the multicenter AMPIM study.15
Animal Selection and Exclusion Criteria
Ninety mongrel dogs
of either sex (weight, 12 to 20 kg) were
entered into this study. Dogs were required to have a hematocrit of
32 to be included; beagles, pregnant dogs, and animals with evident
infection or circulating heartworm filariae were excluded.
Surgical Preparation
Dogs were fasted overnight before the
study and then were
anesthetized with 
40 mg/kg sodium pentobarbital (to effect).
Additional anesthetic was administered during the experiment as needed.
The dogs were intubated and ventilated at 200
mL · kg-1 · min-1 of room air
supplemented with low-flow oxygen. Aseptic surgical technique was
used, and 1 million U penicillin was given to prevent infection.
Catheters were placed in the right femoral artery and vein. The
arterial catheter was connected to a Statham transducer to
monitor blood pressure. Arterial blood gases were
maintained within physiological range by adjustment
of the ventilatory parameters when needed. A left
thoracotomy was performed at the fourth intercostal space, and the
heart was suspended in a pericardial cradle. The left circumflex artery
was isolated beneath the atrial appendage proximal to its first large
marginal branch. A piece of umbilical tape was passed around the artery
for later occlusion, which was done by snaring the artery into a small
plastic tube. Lead II of the standard ECG, arterial
pressure, left atrial pressure, and pericardial temperature were
recorded on a Gould four- or eight-channel recorder
throughout the experiment. Fluid loss was compensated for by continuous
infusion of saline into the right femoral vein.
Experimental Design
Dogs were subjected to either a permanent
coronary
occlusion or a 6-hour occlusion followed by reperfusion. In the
reperfused animals, reperfusion was achieved by sudden release of the
occluder immediately after an injection of streptokinase 20 000 U/kg
IV to mimic more closely the clinical situation of
thrombolytic reperfusion. The animals were assigned to
either 4-day, 2-week, or 6-week survival groups. For practical reasons,
this assignment was not done randomly. For each survival period,
however, animals were randomly assigned to the permanent occlusion
versus reperfusion groups. In all groups, regional myocardial blood
flow was measured by the microsphere technique as described
previously5 15 before ischemia, then 10 minutes
and 105 minutes into occlusion. The later time point was chosen to
compare with blood flows obtained at the same time in previous
studies.15 16 17 Four days, 2 weeks, or 6
weeks after these
initial procedures, dogs were reanesthetized, and their
hearts were excised for postmortem evaluations. Before they were
killed, the dogs from the 6-week survival groups were first used for an
electrophysiological study, the results of
which have been published previously.18
Postmortem Studies
The methods for measuring area at risk,
microscopic infarct
size, and collateral blood flow have been described previously in
detail.1 15 19
Area at Risk,
Wall Thinning, and Infarct Expansion
Measurements
Briefly, the anatomic boundaries of the occluded and
nonoccluded
vascular beds were defined by dual perfusion of dyes at
physiological perfusion pressure in the left main
and the circumflex coronary arteries. The perfusate to the
circumflex bed contained 1% triphenyl tetrazolium chloride, and that
to the nonischemic bed contained Monastral blue dye (0.5%,
Du Pont). The hearts then were fixed by immersion in 10% buffered
formalin for at least 4 days and cut into eight transverse sections,
which were weighed and photographed.
An enlarged projection of each slice was traced; the tracings were later digitized by use of a tablet connected to an IBM–compatible personal computer, and the size of the ischemic bed was calculated and expressed as a percentage of the left ventricle. In this regard, it should be noted that although the dual-perfusion technique usually yields sharp interfaces between the circumflex and the nonischemic beds in short-term studies, this was not always the case in hearts from the 2- and 6-week chronic survival groups. Because of development of extensive collateralization, there often was crossover of dyes into inappropriate vascular territories in these hearts. Thus, the borders of the ischemic bed were determined from not only the distribution of dyes but also the locations of epicardial branches of the coronary arteries and boundaries of the infarct, short-term studies having shown that infarcts have a lateral border zone that is very narrow and of constant width (1 to 2 mm).
To quantify wall thinning, a ventricular ring
through the
center of the infarct was used. Wall thickness in the ischemic
and nonischemic regions was measured at several sites (Fig 1
),
and the mean ratio of ischemic to
nonischemic wall thickness was calculated. An index of
infarct expansion (circumference index) was also estimated by
calculating on the same slice the ratio of ischemic to
nonischemic circumferential endocardial extent (Fig 1).
Thickness and circumference ratios in noninfarcted hearts were also
calculated in nine additional dogs from previous studies that had an
occlusion of the circumflex artery but did not develop any necrosis
because of high levels of collateral blood flow.
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The photographs of each heart slice also were used to evaluate subjectively the extent of hemorrhage into the infarct in the 4-day survival groups (hemorrhage was no longer evident in any dogs in the 2- or 6-week survival groups).
Infarct or Scar
Size and Infarct Composition
Myocardial blocks that encompassed the
entire ischemic
bed were obtained from five of the eight ventricular slices
and were used to prepare microscopic slides (two slides per block),
which were stained either with hematoxylin-eosin or Heidenhain's
variant of Mallory's connective tissue stain. Infarct size and the
fractions of necrotic myocardium versus granulation tissue
or scar were determined by tracing projections of the microscopic
slides and digitizing the tracings.
Regional Myocardial
Blood Flow
Regional myocardial blood flow was measured in the
nonischemic and central ischemic zones, the latter
consisting of the central 50% to 60% of the ischemic vascular
bed. Each region was subdivided into subendocardial, midmyocardial, and
subepicardial thirds. Myocardial blood flow was expressed in
milliliters per minute per gram.
Correction Factors
In 4-day-old infarcts, increased tissue weight (due to
edema, hemorrhage, and acute inflammation) causes an
overestimation of infarct size and an underestimation of collateral
blood flow. Later on, as necrotic tissue is replaced by scar, there is
a loss of infarct mass that leads to underestimation of original
infarct size and overestimation of collateral blood flow.1
Corrections for this changing anatomic reference base were done with
the measured preocclusion blood flow in samples of the region subjected
to ischemia, assuming that true preocclusion blood flow was
similar in the ischemic and nonischemic regions.
Under this assumption, ischemic blood flow values were
corrected for each sample with the following equation:
MBFic=(MBFiu)/{1-[(MBFpnu-MBFpiu)/MBFpnu]},
where FCic is the corrected ischemic zone blood
flow, MBFiu is the uncorrected (measured) ischemic
zone blood flow, MBFpiu is the measured preocclusion
ischemic blood flow, and MBFpnu is the measured
mean preocclusion flow in nonischemic samples from the same
layer.
Similarly, the size of the ischemic circumflex bed was corrected with the following equation1 : CBc=[CBux(MBFpiu/MBFpnu)]/{[CBux(MBFpiu/MBFpnu)]+(100-CBu)}, where CBc is the corrected circumflex bed, CBu is the uncorrected (measured) circumflex bed, and 100-CBu is the uncorrected nonischemic bed. The same correction was also made for infarct size. In addition, the regression line obtained between infarct size and collateral blood flow in the 4-day groups was used to calculate an estimated initial infarct size in the 2-week and 6-week animals, on the basis of their corrected collateral blood flow values.
Statistical Analysis
Data are expressed as group
mean±SEM. Statistical comparisons
were made by Student's paired or unpaired t test or, when
three or more groups were compared, by a one-way ANOVA followed by
Student's t test with the Bonferroni correction if ANOVA
was significant. To control for the variability of infarct size due to
collateral blood flow, infarct size was compared among groups by an
ANCOVA, with infarct size as a dependent variable and collateral
blood flow as a covariate. A value of P<.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Mortality and Animal Exclusion
Of 90 dogs initially entered into the study, 50 were used for the final analysis of data. One dog was excluded because of improper occlusion of the artery. Thirty-nine dogs died or were killed before completion of the study: 16 died during the open-chest procedure, ie, within the first 7 hours of ischemia (12 developed ventricular fibrillation during coronary occlusion, and 4 died of acute cardiac failure); 9 died during the first night after surgery, 4 during the second day, and 4 during the second week (presumably of dysrhythmias). In addition, 3 animals did not survive a second induction of anesthesia for wound repair; 2 had to be killed early because of severe lung infection and 1 because of distemper. Overall, there was no difference in mortality between the permanent and the temporary occlusion groups. Additionally, 3 dogs (1 from the 4-day reperfused group and 2 from the 2-week permanent group) were excluded from direct group comparison because they did not develop severe enough ischemia during the occlusion period (transmural collateral blood flow 10 minutes into ischemia of 0.47, 0.56, and 0.81 mL · min-1 · g-1, respectively). Those dogs were included, however, in the regression analyses of infarct measurements versus collateral flow.
Baseline Predictors of Infarct Size
Hemodynamic data from the
six groups, obtained at
the times when myocardial blood flow also was measured (ie, before
occlusion and 10 and 105 minutes into occlusion) are summarized in the
Table. There were no significant differences
between any of the parameters measured at any time
point.
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The estimated initial size of the area at risk (ie, corrected
for any
infarct swelling or shrinking; see "Methods") in the six groups
is presented in Fig 2. Area at risk did not
differ significantly among the six groups.
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Corrected transmural
collateral blood flow, measured 10 minutes or 105
minutes after occlusion, is included in the Table
. There were
no
significant differences in collateral blood flow between the six
groups. In addition, there were no significant differences in
collateral blood flow measured at 10 versus 105 minutes in any
group.
General Anatomic Features of Infarcts
The 4-day-old infarcts
had the general anatomic features
described previously.5 20 Those infarcts caused by
permanent coronary occlusion were characterized by a central
core of necrotic myocardium surrounded by a zone of
hemorrhage and acute inflammation (Fig 3A). There were also
patchy zones of
hemorrhage and inflammation within the central core of infarct,
located mainly around the large vessels. Much of the central core,
however, was devoid of either hemorrhage or inflammation,
presumably because of microvascular necrosis, with loss of
accessibility to blood-borne elements. In the 4-day infarcts that
had been reperfused, the pattern was similar except that
hemorrhage and the infiltration of inflammatory cells were
distributed more diffusely throughout the infarcts rather than being
confined to the peripheral rim.
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Six weeks after coronary artery
occlusion, in all but two
hearts, the necrotic muscle had been completely replaced by scar tissue
composed of fibroblasts in a dense collagen matrix (Fig 3B). A
small
area of necrosis persisted in two hearts (of nine) from the permanent
occlusion group, representing 10.8% and 1.8% of the total
infarct, respectively; nonresorbed necrotic myocytes were absent from
the infarcts of all eight hearts in the reperfused group.
Infarcts from
the 2-week groups were characterized by a central core of
persistent necrotic myocytes surrounded by an irregular rim of
inflammatory cells, macrophages, and young scar (granulation
tissue), composed of fibroblasts, new capillaries, and collagen (Fig
3B
through 3F). Qualitative comparison of reperfused versus nonreperfused
infarcts revealed proportionately more granulation tissue, with more
advanced collagen deposition, and proportionately less nonresorbed
necrosis in the reperfused infarcts.
Effect of Changing Infarct Composition on Thickness and
Circumferential Extent of Infarcts
Relative wall thickness in the
infarcted regions is shown in Fig 4. At 4 days, edema,
hemorrhage, and infiltrated
inflammatory cells caused a trend toward an increase in relative wall
thickness. In contrast, the progressive shrinkage of infarcts during
healing was associated with progressive reduction in relative wall
thickness. Reperfusion at 6 hours did not affect relative wall
thickness at any of the three times studied.
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The circumferential extent
of infarcts (Fig 5) was
increased at 4 days (early infarct expansion) but progressively
decreased during healing. Although Fig 5 illustrates means for
each
group, detailed evaluation of the data also revealed no infarct
expansion, even in the individual dogs with the lowest collateral blood
flows. Thus, although many of the infarcts in this study were large and
nearly transmural, late infarct expansion was not observed and
ventricular aneurysms did not occur. The
circumferential extent of the infarcts was not affected by reperfusion
at any of the times studied.
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Effect of Changing Infarct Composition on Preocclusion Regional
Myocardial Blood Flow and Myocardial Infarct Size
Fig 6
shows the effect of changing infarct
composition on preocclusion myocardial blood flow. Microspheres
were injected before coronary occlusion, but the tissue was, of
course, not counted until 4 days to 6 weeks later, by which time the
weight of the infarcted (circumflex) and noninfarcted (left anterior
descending, LAD) regions had changed, as a result of either early
swelling, later shrinkage associated with replacement of necrotic
muscle by scar in the infarcted region, or hypertrophy of
the noninfarcted region. These changes in tissue weight could lead to
either underestimation (in the case of edema or
hypertrophy) or overestimation (in the case of scar
shrinkage) of regional blood flows.
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Preocclusion blood flows in the
nonischemic (LAD) bed are
represented in Fig 6, left. There were no statistically
significant differences in nonischemic blood flow between
the six groups studied, although there was a trend toward lower flow in
the two groups studied at 6 weeks. Thus, although it is likely that
some hypertrophy of nonischemic
myocardium occurred especially by 6 weeks after infarction,
this hypertrophy-induced increase in tissue weight was
not sufficient to significantly alter the measured blood flows in the
LAD coronary region. The trend toward lower
nonischemic blood flow in the 6-week groups is
consistent with either modest myocardial
hypertrophy, gradual loss of a small fraction of
microspheres from the tissue, or both.
Preocclusion blood flows in the
infarcted (circumflex) bed are shown in
Fig 6, right. The changing tissue composition resulted first in
an
underestimation of myocardial blood flow in the circumflex region. This
underestimation has previously been shown to be caused by an increase
in tissue weight and is reflected by a preocclusion ratio of circumflex
to LAD flow of <1.0.1 After healing, conversion of
infarcts to scars of reduced mass resulted in an overestimation of flow
in the circumflex region, reflected by circumflex/LAD ratios
>1.0.1 These ratios of preocclusion blood flow
measurements were used to calculate corrected estimates of
postocclusion collateral blood flow reported below and of initial area
at risk and infarct size (see "Methods").
Fig
7 shows the ratios of measured to predicted infarct
sizes in the six groups. At 4 days, measured infarct size averaged 30%
to 40% of the left ventricle and was substantially larger than
predicted infarct size. At 6 weeks, infarcts were completely replaced
by scars, and measured scar size averaged 10% to 14% of the left
ventricle and was much smaller than predicted infarct size. At 2 weeks,
healing was partially complete, and measured infarct size was
intermediate between the 4-day and the 6-week values.
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The relation
between measured infarct (or scar) size and the corrected
collateral blood flow at each time period is shown in Fig 8. In
all groups, infarct size was inversely related to
collateral blood flow; ie, high flow was associated with small infarcts
and low flow with large infarcts. Over time, however, there was a
progressive downward shift of the regression curve, again indicating
shrinkage of infarcts as they were replaced by scar. At 4 days, the
permanent and reperfusion curves were superimposed, indicating no
effect of late reperfusion on infarct size. Similarly, the two curves
were equivalent at 6 weeks, indicating no effect of late reperfusion on
final scar size. At 2 weeks, however, the regression curve was shifted
downward by reperfusion. This visual observation was confirmed by an
ANCOVA using collateral blood flow as a covariate and infarct size as
the dependent variable. By this analysis, infarct size
(expressed as a percentage of left ventricle) was significantly smaller
in the 2-week reperfused group compared with the 2-week permanent group
(P<.01). Since the results at 4 days indicate no effect of
late reperfusion on infarct size, the difference at 2 weeks can
be explained best if the reperfused infarcts were healing more quickly
than the nonreperfused infarcts, ie, if reperfusion was accelerating
the downward shift of the regression curve toward the 6-week
position.
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indicates nonreperfused; 
,
reperfused.
To further assess this possibility, we quantified the degree
of
infarct healing by calculating the proportion of each infarct in the
2-week groups that was composed of nonresorbed necrotic muscle. The
relation between nonresorbed necrosis (expressed as a percentage of
total infarct) and collateral blood flow is shown in Fig 9.
Interestingly, there was an inverse relation between
the amount of nonresorbed necrosis and collateral blood flow; ie,
healing was most advanced in animals with high collateral blood flows
(and thus small infarcts). In such animals, necrotic myocytes were
nearly gone by 2 weeks, being entirely replaced by scar. In contrast,
with low collateral blood flow (and consequently larger infarcts),
there was much more nonresorbed necrosis at 2 weeks. Because infarcts
heal from their peripheral edges toward their centers, this
inverse relation most likely reflects the greater
surface-to-volume ratios of small versus large infarcts.
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In the reperfused group, there appeared to be less nonresorbed necrosis than in the permanent occlusion group for any amount of collateral blood flow. This downward shift in the regression suggests that reperfusion did accelerate the replacement of necrosis by granulation tissue. This difference, however, did not reach statistical significance (by ANCOVA, .05<P<.10).
Relation Between Initial Infarct Size and Late Scar
Size
To further characterize the determinants of ultimate scar size,
we
evaluated the relation between measured scar size at 6 weeks and
predicted 4-day infarct size (Fig 10). We calculated
the predicted 4-day infarct size in the 6-week dogs, using each dog's
corrected collateral blood flow measurement and extrapolating from the
regression line of infarct size versus collateral blood flow in the
4-day groups. For the purpose of establishing this regression line, the
reperfused and nonreperfused 4-day groups were pooled because
reperfusion had no effect on infarct size at 4 days. From this pooled
group, the regression equation was: infarct size (percentage of area at
risk)=86.1-118.3 x transmural mean collateral blood flow
(mL · min-1 · g-1)
(r=.91;
P<.01). As expected, there was a direct relation between
predicted 4-day infarct size and final scar size; ie, initial infarct
size was the main determinant of scar size. In addition, all data
points are below the diagonal line of unity, reflecting the fact that
scar size was always smaller than predicted infarct size at 4 days.
Interestingly, the regression line is not parallel with the line of
unity; there is a wider difference between the two lines for smaller
infarcts than there is for larger infarcts, suggesting that initially
small infarcts, whether reperfused or not, resulted in
disproportionately smaller scars when healing was complete.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In canine hearts subjected either to permanent occlusion of the left circumflex coronary artery or to 6 hours of occlusion followed by reperfusion, infarcts occur that undergo early myocardial swelling due to tissue edema, interstitial hemorrhage, and influx of leukocytes. In both nonreperfused and reperfused infarcts, this initial infarct swelling is followed by progressive shrinkage as necrotic myocytes are resorbed and replaced by granulation tissue, which gradually becomes converted to dense scar. In the present study, we observed that late reperfusion accelerated this process of healing, as evidenced by more complete replacement of necrotic myocardium by young scar at 2 weeks.
Temporal Changes in Myocardial Infarct Size and
Geometry
Our findings of early infarct expansion in both nonreperfused
and
reperfused groups are in concordance with results of other studies of
various species. Early infarct expansion has been shown to occur in
rats,21 22
dogs,2 23 24 and humans, in whom
it appears to correlate with an increased risk of cardiac
rupture.25 The absence of chronic infarct expansion (at 2
or 6 weeks after infarction) in the present study also is in
concordance with the previously reported absence of infarct expansion
in dogs at 7 days26 or 6 weeks.2 Other
studies, however, have produced chronic expansion in either
rats21 or dogs23 in the setting of transmural
infarction. Chronic infarct expansion also has been reported in dogs
when the animals were treated with the nonsteroidal
anti-inflammatory drug
indomethacin.27
The difference between our study and that of Eaton and Bulkley23 may be explained by the differences in method of inducing infarcts. In many of the dogs studied by Eaton and Bulkley, transmural infarcts were caused by embolization of a coronary artery with an inert polymer that solidified in small arteries and thereby precluded myocardial perfusion via collateral anastomoses. In contrast, snare occlusion of a coronary artery in dogs rarely produces completely transmural infarcts; collateral flow often preserves some subepicardial myocytes. In the present study, however, chronic infarct expansion (as would have been manifest by an increased circumference index) did not occur even in the largest, most transmural infarcts with the lowest collateral blood flow.
At 6 weeks,
scar size was always smaller than predicted infarct size at
4 days, and the regression line of the relation between scar size and
predicted infarct size (Fig 10) was not parallel with the line
of
unity. The explanation for this nonparallelism of slope is not
known, but a potentially important possibility is that initially small
infarcts, whether reperfused or not, not only healed faster but also
resulted in disproportionately smaller scars when healing was complete.
This conclusion would imply that slight salvage of
myocardium (either by reperfusion or by adjuvant therapy)
might be amplified over time into more significant limitation of scar
size.
This intriguing possibility must be tempered by caution, however, because the nonparallelism may be explained in part if differential errors occurred in the calculation of predicted infarct size. This could occur if hypertrophy of nonischemic myocardium was greater in hearts with initially large infarcts than in hearts with small infarcts, because hypertrophy of nonischemic myocardium would cause an underestimation of predicted initial infarct size. Thus, the nonparallel slope could be explained, in part, if hypertrophy of nonischemic myocardium was greater in hearts with initially large infarcts than in hearts with initially small ones. Unfortunately, we had no way to assess independently the extent of hypertrophy and the potential size of errors in the calculation of predicted infarct size in the hearts included in this study.
Effect of Late Reperfusion on Infarct Composition and
Remodeling
Our findings that infarcts reperfused at 6 hours were more
hemorrhagic than infarcts due to permanent coronary occlusion
is in concordance with similar observations by Roberts et
al,28 who compared nonreperfused versus reperfused
infarcts at 1 day. In addition, our results are consistent with
the findings of Geft et al,26 who showed no effect of
reperfusion on wall thickness of 7-day-old infarcts. The effect of
late reperfusion on infarct remodeling also has been studied in rats.
In a recent study, reperfusion 6 hours after coronary occlusion
in rats had no effect on the degree of infarct expansion observed at 1
week.29 On the contrary, in another study, reperfusion 2
hours after coronary occlusion inhibited infarct expansion and
reduced the frequency of aneurysms when assessed at 2
weeks14 (at which time infarct healing is complete in this
species). In the latter study, reperfusion had no effect on infarct
size; thus, the effect of reperfusion on infarct expansion was
apparently independent of any infarct limitation. No such beneficial
effect of reperfusion could have been detected in our study, since
chronic infarct expansion did not occur even in the permanently
occluded controls. Other experiments in rats have shown that late
reperfusion (after 90 minutes of ischemia) resulted in a
thicker scar assessed at 6 weeks.30 This also was not
observed in our present canine study.
Effect of Reperfusion on the Rate of Infarct Repair
The
present results show that reperfusion accelerates the
progressive reduction in infarct size during healing, an effect that
most likely is explained by faster resorption of necrotic
myocardium and its replacement by granulation tissue, which
progresses to scar. These results are consistent with previous
studies in rats.29 31 The mechanism through which
reperfusion accelerates healing is not entirely known. In part, the
explanation must include the fact that reperfusion quickly restores the
nutrient and oxygen supply to much of the ischemic region
(except for central areas with severe vascular damage and "no
reflow") and provides access to the region to the inflammatory cells
that begin the process of repair. In the absence of reperfusion, repair
may be slowed until collateral arterial vessels to the
ischemic region are able to restore adequate perfusion.
That
reperfusion accelerates the inflammatory response to an acute
myocardial infarct is supported by studies in which
111In-labeled neutrophils were used to assess the
effect of reperfusion on early polymorphonuclear leukocyte
(neutrophil) accumulation after myocardial ischemia. These
studies showed that reperfusion after 90 minutes of ischemia
resulted in a massive influx of neutrophils that began during the first
hour.32 The rate of accumulation was maximal during the
first 3 hours compared with any subsequent 3-hour
interval.33 In contrast, the maximal rate of influx of
polymorphonuclear leukocytes in nonreperfused ischemic
myocardium was only one third the rate observed in
reperfused myocardium, and this maximal rate was not
attained until 6 hours.34 Qualitative
histological observations of both canine and human
infarcts35 also have revealed an accelerated influx of
neutrophils in reperfused infarcts.
Similarities and Differences Between Canine and Human
Infarcts
The relevance of the present experimental results to the
understanding of the healing of human infarcts and the potential
effects of reperfusion depends on how well canine infarcts resemble
human infarcts. In the present experimental dog model, as in human
infarcts, coronary occlusion results in a variable
transmural extent of infarction. In both species, the subendocardial
zone is most susceptible to myocardial infarction, and the
subepicardial zone is variably spared.5 36 In dogs,
this
variation in transmural extent of infarction is inversely related to
the amount of collateral blood flow to the subepicardial
zone5 15 ; a similar relation probably occurs in
humans,
but collateral blood flow cannot be precisely mapped in patients. In
addition, the process of infarct healing is qualitatively similar in
the two species in that infarct healing involves an initial influx of
neutrophils, followed by an influx of macrophages and removal
of necrotic myocytes, which are replaced by granulation tissue and
collagen deposition ("organization" of the
infarct).3 The time course of healing also is similar,
albeit somewhat accelerated, in dogs versus
humans.1 2 3
There are, however, several important differences between canine and human infarcts.
1. A major complication of myocardial infarction in humans is cardiac rupture. Cardiac rupture usually occurs during the first week after a transmural infarct and has been reported as the cause of death in 5% to 25% of fatal infarcts among various series of patients.37 38 More recently, rupture was identified in 38% of autopsied patients who had been enrolled in clinical trials of thrombolytic agents, and it was proposed that, although reperfusion reduces overall mortality, late reperfusion may increase the risk of cardiac rupture in patients with transmural infarcts.8 In contrast, infarct rupture has never been observed in our canine experimental model despite the presence, in some cases, of large, nearly transmural infarcts. Moreover, spontaneous cardiac rupture has not been observed in other species, such as the rat and rabbit, even though these animals systematically develop large transmural infarcts.
Whether differences in the incidence of cardiac rupture between humans and experimental animals are due to differences in structural and mechanical properties of the scar tissue is not known. Studies using polarized light microscopy on healed canine infarcts, however, have revealed a high degree of collagen organization within the scar, thought to be indicative of mechanically resistant tissue.39
2. Another well-known complication of human infarcts is the development of chronic infarct expansion and ventricular aneurysm,40 which also was not reproduced in our present canine study. Since permanent coronary occlusion did cause transmural infarcts in some animals, the nonoccurrence of aneurysms in canine infarcts cannot be attributed to nontransmural infarction.
3. A third important difference between human and canine infarcts is that canine infarcts (whether permanent or reperfused) were never as hemorrhagic as the markedly hemorrhagic infarcts that have been observed in humans who have died of infarction after thrombolytic therapy.41 42 The reason for this difference is not clear. In the present experiments, we tried to mimic thrombolytic therapy by giving streptokinase at the time of reperfusion. We do not know, however, whether this achieved a thrombolytic state equivalent to that induced in humans. Previous canine studies suggested that streptokinase does not affect intramyocardial hemorrhage after coronary occlusion and reperfusion.43 Clinical studies have suggested that intramyocardial hemorrhage increases the risk of cardiac rupture,37 and one of us (K.A.R.) has observed cases of fatal myocardial infarction in which pericardial tamponade resulted from bleeding from a hemorrhagic infarct in the absence of a transmural rupture. Whether the severity of intramyocardial hemorrhage affects the healing process of myocardial infarcts such that scar size or the incidence of aneurysm formation could be affected is not known.
Because we administered streptokinase to all dogs undergoing reperfusion, we cannot completely rule out the possibility that streptokinase per se caused some or all of the observed differences between reperfused and nonreperfused infarcts. By eliminating microvascular fibrin thrombi, streptokinase might have either beneficial effects, eg, by improving microvascular reperfusion, or detrimental effects, eg, by causing intramyocardial hemorrhage. The presence or absence of an extravascular fibrin mesh, which provides a framework for ingrowth of capillary buds and fibroblasts in the necrotic tissue, also may substantially influence the early healing process. As stated above, we included streptokinase to mimic more closely the clinical situation in which reperfusion is achieved by thrombolysis. Whether similar results would have been observed with reperfusion alone, perhaps more akin to a clinical situation of reperfusion by coronary angioplasty without thrombolytic therapy, was not studied.
Conclusions and Possible Clinical Implications
The benefits
versus risks of late reperfusion in patients with
myocardial infarction have not been entirely resolved. A major finding
of this study was that late reperfusion accelerated infarct healing
even when infarct size was unaffected, an observation that could have
important clinical implications. The healing process of nonreperfused
myocardial infarcts eventually caught up with the healing process of
reperfused infarcts, in that all were converted to scars that were
indistinguishable in morphological character and size. Thus, any
benefit of late reperfusion that is attributable to faster infarct
healing would be expected to be a transient benefit. Nevertheless,
faster healing could shorten the period of vulnerability to several
common complications that occur during the healing phase of myocardial
infarction, eg, infarct expansion and aneurysms, as well as
cardiac rupture. Shortening the period of vulnerability to these
complications might be responsible, at least in part, for the increased
survival observed clinically even when reperfusion is performed too
late to induce any salvage of ischemic
tissue.9 12 13
The observation that small infarcts not only healed faster but also appeared to result in disproportionately smaller scars (irrespective of whether they had been reperfused) raises the intriguing possibility that slight salvage of myocardium (either by reperfusion or by adjuvant therapy) might be amplified over time into more significant limitation of scar size.
|
Acknowledgments |
|---|
The studies reported in this paper were supported by NIH grants HL-27416 and HL-23138. The authors are grateful to Spring E. Brooks for her excellent technical assistance and to Dr Richard S. Vander Heide for his editorial assistance in the preparation of the manuscript.
|
Footnotes |
|---|
Reprint requests to Keith A. Reimer, MD, PhD, Department of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710.
Received October 5, 1994; revision received April 11, 1995; accepted April 27, 1995.
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References |
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