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Circulation. 1995;92:1891-1901

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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

Vincent Richard, PhD; Charles E. Murry, MD, PhD; Keith A. Reimer, MD, PhD

From the Department of Pathology, Duke University Medical Center, Durham, NC.


*    Abstract
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 *Abstract
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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


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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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).


*    Methods
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 *Methods
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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 {approx}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 1Down), 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 1Down). 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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  		Figure 1. Diagram showing measurement of thickness and circumference indexes. Wall thickness was measured in four regions of the ischemic region and in four regions in the corresponding nonischemic region. These measurements were minimum thicknesses obtained between papillary muscles or muscular trabeculae. The thickness index was defined as the ratio of the mean ischemic to nonischemic thicknesses, (1+2+3+4)/(5+6+7+8). The endocardial circumferential extent of each region was measured (using a smooth line, as depicted, ignoring the endocardial irregularity caused by papillary muscles or muscular trabeculae). The circumference index was defined as the ratio of ischemic to nonischemic endocardial circumferential extent (A/B).

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.


*    Results
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 up arrowMethods
*Results
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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 TableDownDown. There were no significant differences between any of the parameters measured at any time point.


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  		Table 1. Hemodynamic Data for All Groups of Dogs


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  		Table 1B. Hemodynamic Data for All Groups of Dogs—Continued

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 2Down. Area at risk did not differ significantly among the six groups.



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  		Figure 2. Bar graph showing estimated initial size of the area at risk (AAR) in the six groups studied. The measured size of the AAR was corrected for infarct swelling or condensation (see "Methods"). There were no significant differences in the corrected size of the AAR between any of the six groups. Open bars indicate permanent occlusion infarcts; filled bars, reperfused infarcts; and LV, left ventricle.

Corrected transmural collateral blood flow, measured 10 minutes or 105 minutes after occlusion, is included in the TableUp. 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 3ADown). 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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  		Figure 3. Facing page. Representative histological sections from infarcts in the four groups. A through D, Transmural sections from the central region of the infarcted circumflex vascular territory (posterior wall of the left ventricle). In each case, the section is oriented with the endocardium at the top and epicardium at the bottom. The posterior papillary muscle projects above the adjacent endocardial surface in each of the four sections. Each section was selected because it was considered representative of its group; all four had comparable collateral blood flows. All microscopic sections were stained with Heidenhain's aniline blue (Heidenhain's variant of Mallory's connective tissue stain), which stains muscle dark red and collagen blue. A through D are printed at the same magnification. Thus, decreasing wall thickness with increasing age of infarct is readily evident. A, Four days; permanent occlusion: most of the section is composed of a core of myocyte necrosis with little hemorrhage or inflammation. There is some myocardium in the subepicardial zone, primarily in the lower left and right corners of the section, which survived the infarct (V). The core (C) of the infarct and the viable subepicardial areas are separated by a peripheral rim of necrosis in which there is hemorrhage and an intense inflammatory response (arrows). The central zone is nearly devoid of inflammation because of microvascular necrosis and obstruction. The relative sizes of the central and peripheral zones varied among dogs in both the permanent and reperfused groups. Although reperfusion at 6 hours did not affect overall infarct size, it did result, on average, in a smaller central necrotic core and a correspondingly larger peripheral zone of inflammation and hemorrhage. Overall, hemorrhage was more severe in the reperfused infarcts. B, Six weeks; permanent coronary occlusion: no necrotic myocardium remains; the infarct has been completely replaced by scar (blue areas in subendocardial and middle zones). Viable myocardium (red) is present in the subepicardial third of the section. The myocardial wall can be seen to be markedly thinned compared with A. C, Two weeks; permanent occlusion: there is a central core of necrotic myocardium (deep red areas in subendocardial and middle zones) surrounded by a rim of granulation tissue (young developing scar; pale blue–stained areas). Myocardium that survived the initial infarct (red) is seen in the subepicardium, primarily in the lower left corner of the illustration. The area in the box is illustrated at higher magnification in E. D, Two weeks; reperfused infarct: the features are qualitatively similar to those seen in B, but there is proportionately more granulation tissue (young scar) and less nonresorbed necrotic myocardium, and the scar has a higher collagen content evidenced by the deeper blue staining. The area in the box is illustrated at higher magnification in F.

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 3BUp). 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 3BUp 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 4Down. 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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  		Figure 4. Bar graph showing wall thickness indexes. Ratios of infarcted to noninfarcted wall thicknesses are shown from the six infarct groups. An additional comparison group is shown. This group was selected from our previous database of dogs that had a coronary occlusion but no necrosis (because of high levels of collateral blood flow). Compared with hearts with no infarct, there was a trend toward increased wall thickness in the 4-day groups and a significant decrease in the 6-week groups. Reperfusion did not significantly affect wall thickness at any time point. **P<.01 vs corresponding 6-week groups; {dagger}{dagger}P<.01 vs noninfarcted. Open bars indicate permanent infarcts; solid bars, reperfused infarcts.

The circumferential extent of infarcts (Fig 5Down) was increased at 4 days (early infarct expansion) but progressively decreased during healing. Although Fig 5Down 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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  		Figure 5. Bar graph showing infarct circumference indexes. Ratios of infarcted to noninfarcted partial circumferences are shown for the six groups studied and the retrospective group without infarcts (see legend of Fig 4Up). Compared with the area at risk in hearts without infarcts, the infarct region was significantly expanded at 4 days. At 2 weeks, the circumferential extent had returned to normal, and at 6 weeks, the circumference index was significantly smaller than in noninfarcted hearts. Reperfusion did not affect infarct expansion significantly at any time point. *P<.05 vs corresponding 4-day groups; {dagger}P<.05 and {dagger}{dagger}P<.01 vs noninfarcted. Open bars indicate permanent infarcts; solid bars, reperfused infarcts.

Effect of Changing Infarct Composition on Preocclusion Regional Myocardial Blood Flow and Myocardial Infarct Size
Fig 6Down 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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  		Figure 6. Bar graph showing measured (uncorrected) preocclusion regional blood flow in the noninfarcted left anterior descending (LAD) bed and the infarcted left circumflex (LCX) bed. LAD blood flow was similar in all groups, although there was a trend toward reduced flow in the 6-week groups. This trend most likely reflects compensatory hypertrophy of noninfarcted myocardium. Neither factor, however, that might have decreased measured LAD region flow over time, namely compensatory hypertrophy and true microsphere loss, altered flow to a statistically detectable extent. LCX blood flow at 4 days was significantly lower than LAD blood flow, as a consequence of infarct swelling. At 2 weeks and 6 weeks, uncorrected LCX blood flow had increased, secondary to healing-induced tissue shrinking. *P<.05 and **P<.01 vs corresponding 4-day groups. {dagger}P<.05 and {dagger}{dagger}P<.01 vs noninfarcted LAD region. Open bars indicate permanent infarcts; solid bars, reperfused infarcts.

Preocclusion blood flows in the nonischemic (LAD) bed are represented in Fig 6Up, 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 6Up, 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 7Down 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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  		Figure 7. Bar graph showing 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 was an average of 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. Reperfusion at 6 hours had no effect on either infarct size or later scar size when evaluated by this group comparison. *P<.05 and **P<.01 vs corresponding 4-day groups. {dagger}{dagger}P<.01 vs initial (predicted) infarct size. Open bars indicate permanent infarcts; solid bars, reperfused infarcts.

The relation between measured infarct (or scar) size and the corrected collateral blood flow at each time period is shown in Fig 8Down. 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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  		Figure 8. Scatterplots showing relation between measured infarct size (expressed as percent of left ventricle [LV]) and corrected collateral blood flow in the six groups. In each group, there was an inverse correlation between infarct size and collateral blood flow. For any level of collateral blood flow, infarcts from the 6-week groups were smaller compared with 4 days. In both the 4-day and the 6-week groups, reperfusion did not affect the relation between infarct size and collateral blood flow compared with the groups with permanent ischemia. At the 2-week time point, however, reperfused infarcts were smaller than their nonreperfused counterparts at any level of collateral blood flow. This visual observation was confirmed by ANCOVA, taking infarct size as the independent variable and collateral blood flow as the covariate (P<.01). Thus, reperfusion accelerated the loss of tissue mass that accompanies infarct healing. {triangleup} indicates nonreperfused; {bullet}, 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 9Down. 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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  		Figure 9. Scatterplot showing relation between nonresorbed necrosis and collateral blood flow in the 2-week group. In the permanent ischemia group, there was an inverse relation between nonresorbed necrosis and collateral blood flow, ie, small infarcts healed faster than large infarcts. This relation was slightly shifted downward by reperfusion (.05<P<.10 by ANCOVA), suggesting that reperfusion accelerates the process of infarct repair, ie, the replacement of necrotic myocardium by scar. {triangleup} indicates nonreperfused; {bullet}, reperfused.

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 10Down). 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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  		Figure 10. Scatterplot showing relation between measured scar size and predicted initial infarct size in the 6-week groups. Initial infarct size was estimated on the basis of the corrected collateral blood flow values (see "Methods"). The line of unity (ie, scar size=initial infarct size) also is represented. There was a direct relation between scar size and predicted infarct size, suggesting that initial infarct size is the major determinant of later scar size. This regression line, however, is not parallel with the line of unity. There is a wider difference between the two lines for smaller infarcts than for larger infarcts. One possible explanation for this relation is that initially smaller infarcts result in disproportionately even smaller scars when healing is complete. AAR indicates area at risk.


*    Discussion
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*Discussion
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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 10Up) 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 {approx}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.


*    References
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*References
 

  1. Reimer KA, Jennings RB. The changing anatomic reference base of evolving myocardial infarction: underestimation of myocardial collateral blood flow and overestimation of experimental anatomic infarct size due to tissue edema, hemorrhage and acute inflammation. Circulation. 1979;60:866-876. [Free Full Text]
  2. Jugdutt BI, Amy RWM. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol. 1986;7:91-102. [Abstract]
  3. Mallory GK, White PD, Salcedo-Salagar J. The speed of healing of myocardial infarction: a study of the pathologic anatomy in seventy-two cases. Am Heart J. 1939;18:647-671.
  4. Jennings RB, Steenbergen C Jr, Hackel DB. The heart. In: Rubin E, Farber JL, eds. Pathology. Philadelphia, Pa: JB Lippincott Co; 1994:502-555.
  5. Reimer KA, Jennings RB. The `wavefront phenomenon' of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40:633-644. [Medline] [Order article via Infotrieve]
  6. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-360. [Medline] [Order article via Infotrieve]
  7. Ellis SG, O'Neill WW, Bates E, Walton JA, Nabel EG, Topol EJ. Coronary angioplasty as primary therapy for acute myocardial infarction 6 to 48 hours after symptom onset: report of an initial experience. J Am Coll Cardiol. 1989;13:1122-1126. [Abstract]
  8. Honan MB, Harrell FE Jr, Reimer KA, Califf RM, Mark DB, Pryor DB, Hlatky MA. Cardiac rupture, mortality and the timing of thrombolytic therapy: a meta-analysis. J Am Coll Cardiol. 1990;16:359-367. [Abstract]
  9. Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium: the open artery hypothesis. Circulation. 1993;88:2426-2436. Review. [Free Full Text]
  10. Yusuf S, Collins R, Petro R, Furberg C, Stampfer MJ, Goldhaber SZ, Hennekens CH. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side effects for 33 randomized controlled trials. Eur Heart J. 1985;6:566-585.
  11. LATE Study Group. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet. 1993;342:759-766. [Medline] [Order article via Infotrieve]
  12. Califf RM. Myocardial reperfusion: is it ever too late? J Am Coll Cardiol. 1989;13:1130-1132. [Medline] [Order article via Infotrieve]
  13. Pfeffer MA, Braunwald EB. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1163-1172.
  14. Hochman JS, Choo H. Limitation of myocardial expansion by reperfusion independent of myocardial salvage. Circulation. 1987;75:299-306. [Abstract/Free Full Text]
  15. Reimer KA, Jennings RB, Cobb FR, Murdock RH Jr, Greenfield JC Jr, Becker LC, Bulkley BH, Hutchins GM, Schwartz RP Jr, Bailey KR, Passamani ER. Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study: comparison of the unconscious and conscious dog models. Circ Res. 1985;56:651-665. [Abstract/Free Full Text]
  16. Reimer KA, Jennings RB. Verapamil in two reperfusion models of myocardial infarction: temporary protection of severely ischemic myocardium without limitation of ultimate infarct size. Lab Invest. 1984;51:655-666. [Medline] [Order article via Infotrieve]
  17. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136. [Abstract/Free Full Text]
  18. Wharton JM, Richard VJ, Murry CE, Dixon EG, Reimer KA, Meador J, Smith WM, Ideker RE. Electrophysiological effects of monophasic and biphasic stimuli in normal and infarcted dogs. PACE Pacing Clin Electrophysiol. 1990;13:1158-1172. [Medline] [Order article via Infotrieve]
  19. Richard VJ, Murry CE, Jennings RB, Reimer KA. Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs. Circulation. 1988;78:473-480. [Abstract/Free Full Text]
  20. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death, I: myocardial infarct size vs. duration of coronary occlusion in dogs. Circulation. 1977;56:786-794. [Abstract/Free Full Text]
  21. Hochman JS, Bulkley BH. Expansion of acute myocardial infarction: an experimental study. Circulation. 1982;65:1446-1450. [Abstract/Free Full Text]
  22. Weisman HF, Bush DE, Mannisi JA, Weisfeldt ML, Healy B. Cellular mechanisms of infarct expansion. Circulation. 1988;78:186-201. [Abstract/Free Full Text]
  23. Eaton LW, Bulkley BH. Expansion of acute myocardial infarction: its relationship to infarct morphology in a canine model. Circ Res. 1981;49:80-88. [Free Full Text]
  24. Kass DA, Maughan WL, Ciuffo AA, Graves W, Healy B, Weisfeldt ML. Disproportionate epicardial dilation after transmural infarction of canine left ventricle: acute and chronic differences. J Am Coll Cardiol. 1988;11:177-185. [Abstract]
  25. Schuster EH, Bulkley BH. Expansion of transmural myocardial infarction: a pathophysiologic factor in cardiac rupture. Circulation. 1979;60:1532-1538. [Free Full Text]
  26. Geft IL, Fishbein MC, Hashida J, Ninomiya K, Nishizawa S, Haendchen R, Venkatesh N, Y-Rit J, Yano J, Ganz WS. Effects of late reperfusion after myocardial necrosis is complete. Am Heart J. 1984;107:623-629. [Medline] [Order article via Infotrieve]
  27. Hammerman H, Schoen FJ, Braunwald E, Kloner RA. Drug-induced expansion of infarct: morphologic and functional correlations. Circulation. 1984;69:611-617. [Abstract/Free Full Text]
  28. Roberts CS, Schoen FJ, Kloner RA. Effect of coronary reperfusion on myocardial hemorrhage and infarct healing. Am J Cardiol. 1983;52:610-614. [Medline] [Order article via Infotrieve]
  29. Morita M, Kawashima S, Ueno M, Kubota A, Iwasaki T. Effects of late reperfusion on infarct expansion and infarct healing in conscious rats. Am J Pathol. 1993;143:419-430. [Abstract]
  30. Hale SL, Kloner RA. Left ventricular topographic alterations in the completely healed rat infarct caused by early and late coronary artery reperfusion. Am Heart J. 1988;116:1508-1513. [Medline] [Order article via Infotrieve]
  31. Boyle MP, Weisman HF. Limitation of infarct expansion and ventricular remodeling by late reperfusion: study of time course and mechanism in a rat model. Circulation. 1993;88:2872-2883. [Abstract/Free Full Text]
  32. Go LO, Murry CE, Richard VJ, Weischedel GR, Jennings RB, Reimer KA. Myocardial neutrophil accumulation during reperfusion after reversible and irreversible ischemic injury. Am J Physiol. 1988;255:H1188-H1198. [Abstract/Free Full Text]
  33. Tanaka M, Brooks SE, Yue CC, DiBernardo LR, Jennings RB, Reimer KA. Time course of PMN influx in reperfused myocardium after 90 minutes of ischemia in dogs. Circulation. 1990;82(suppl III):III-275. Abstract.
  34. Yue CC, Tanaka M, DiBernardo LR, Brooks SE, Matsuda M, Jennings RB, Reimer KA. Time course of PMN influx in ischemic myocardium during 24 hours of coronary occlusion in dogs. Circulation. 1990;82(suppl III):III-276. Abstract.
  35. Reimer KA, Jennings RB. Myocardial ischemia, hypoxia, and infarction. In: Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE, eds. The Heart and Cardiovascular System, Vol 2. New York, NY: Raven Press; 1991:1875-1974.
  36. Lee JT, Ideker RE, Reimer KA. Myocardial infarct size and location in relation to the coronary vascular bed at risk in man. Circulation. 1981;64:526-534. [Abstract/Free Full Text]
  37. Lewis AJ, Burchell HB, Titus JL. Clinical and pathologic features of postinfarction cardiac rupture. Am J Cardiol. 1969;23:43-53. [Medline] [Order article via Infotrieve]
  38. Naeim F, Maza LM, Robbins SL. Cardiac rupture during myocardial infarction. Circulation. 1972;45:1231-1239. [Abstract/Free Full Text]
  39. Whittaker P, Boughner DR, Kloner RA. Analysis of healing after myocardial infarction using polarized light microscopy. Am J Pathol. 1989;134:879-893. [Abstract]
  40. Hutchins GM, Bulkley BH. Infarct expansion versus extension: two different complications of acute myocardial infarction. Am J Cardiol. 1978;41:1127-1132. [Medline] [Order article via Infotrieve]
  41. Kao KJ, Hackel DB, Kong Y-H. Hemorrhagic myocardial infarction after streptokinase treatment for acute coronary thrombosis. Arch Pathol Lab Med. 1984;108:121-124. [Medline] [Order article via Infotrieve]
  42. Mathey DG, Schofer J, Kuck KH, Beil U, Kloppel G. Transmural, haemorrhagic myocardial infarction after intracoronary streptokinase: clinical, angiographic and necropsy findings. Br Heart J. 1982;48:546-551. [Free Full Text]
  43. Kloner RA, Alker KJ. The effect of streptokinase on intramyocardial hemorrhage, infarct size, and the no-reflow phenomenon during coronary reperfusion. Circulation. 1984;70:513-521.[Abstract/Free Full Text]



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