(Circulation. 1997;96:659-666.)
© 1997 American Heart Association, Inc.
Articles |
Infarct Size, Myocardial Hemorrhage, and Recovery of Function After Mechanical Versus Pharmacological Reperfusion
Effects of Lytic State and Occlusion Time
From the Department of Cardiology, Gasthuisberg University Hospital, Leuven, Belgium.
Correspondence to Frans Van de Werf, MD, PhD, Department of Cardiology, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail frans.vandewerf{at}uz.kuleuven.ac.be
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Abstract |
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Background Whether myocardial reperfusion obtained with thrombolysis or primary angioplasty is associated with a similar recovery of function and with the same risk of hemorrhagic infarction is unknown. We evaluated the effects of mechanical and pharmacological reperfusion (with or without a plasma lytic state) on infarct size, myocardial hemorrhage, and left ventricular (LV) function in a canine model.
Methods and Results Six groups of six dogs were subjected to balloon occlusion of the left anterior descending coronary artery (LAD) followed by 2 hours of reperfusion. The study had a two-by-three factorial design with two occlusion periods (90 and 240 minutes) and three different reperfusion strategies (placebo, 0.4 mg/kg recombinant tissue plasminogen activator, and 40 µg/kg recombinant staphylokinase). In a seventh control group, LAD occlusion was maintained without reperfusion. All dogs received aspirin and heparin. A systemic lytic state was present in staphylokinase-treated dogs. Planimetry of LV slices showed larger infarcts (percent of area at risk) and more hemorrhage (percent of IA) after 240 minutes of occlusion than after 90 minutes of occlusion (54±17% versus 37±18% and 52±27% versus 29±27%, respectively; P<.01 for both comparisons), with no significant difference among treatments. Hemorrhage was not observed in the control group without reperfusion. LV angiography showed no differences in global and regional LV function between mechanical and pharmacological reperfusion.
Conclusions In this experimental model, hemorrhagic infarctions of similar extent were observed after both pharmacological and mechanical reperfusion. The extent of hemorrhage was increased by the delay in reperfusion but not by the presence of a lytic state.
Key Words: thrombolysis • angioplasty • myocardial infarction • reperfusion
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Thrombolysis has become standard treatment for acute transmural myocardial infarction.1 2 3 4 5 6 7 However, despite an overall clinical benefit, this reperfusion strategy is also associated with increased mortality during the first 24 hours.7 8 9 This excess of early deaths is surprising because restoration of blood flow was proven to reduce infarct size and increase electrical stability both in experimental10 11 12 and clinical13 studies. Data from clinical trials have shown that heart failure, arrhythmia, and ventricular rupture are the main cause of early mortality after thrombolysis.8 At autopsy, hemorrhagic infarctions have been observed after thrombolysis in many early deaths, in contrast to the "anemic" infarcts of nonreperfused patients and of those who underwent primary angioplasty.14 15 16 These findings suggest that myocardial hemorrhage after thrombolysis might be causally related to extension of necrosis and cardiac rupture and therefore to the observed excess of early deaths, especially when this therapy is given late.16 17 18 This hypothesis is supported by the recent findings of the US National Registry of Myocardial Infarction, indicating the possibility that thrombolysis increases the likelihood of cardiac rupture and that rupture could represent an early hemorrhagic complication of thrombolytic therapy.19
Previous experimental studies that have assessed the impact of thrombolysis on myocardial hemorrhage did not use the currently accepted doses of thrombolytic and/or adjunctive agents.20 21 22 23 24 Furthermore, the influence of CF and the effect of an overt lytic state received little attention. The aim of the present study was twofold: first, to compare the effect of mechanical reperfusion versus thrombolysis (with or without a lytic state) on infarct size, amount of hemorrhage, and recovery of left ventricular (LV) function; second, to evaluate the effect of different occlusion times with these reperfusion strategies in a canine model of acute myocardial infarction.
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Methods |
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Study Design
Seven groups of six mongrel dogs weighing 17 to 25 kg were subjected to balloon occlusion of the LAD. We have used a two-by-three factorial design with two occlusion periods (90 and 240 minutes) and three treatments (placebo, r-tPA, and r-Sak), giving a total of six reperfusion groups (90 minutes of occlusion with groups A [receiving placebo], B [r-tPA], and C [r-Sak] and 240 minutes of occlusion with groups D [placebo], E [r-tPA], and F [r-Sak]). Each occlusion period was followed by 2 hours of reperfusion. In a seventh control group, the LAD remained occluded for 240 minutes without subsequent reperfusion. r-Sak was chosen for this experiment because it is known to induce an overt lytic state in dogs, whereas it is highly fibrin specific in humans.25 We have used a balloon model because it allows perfect timing of occlusion and reperfusion periods. The group allocation was based on computer-generated randomization lists; data analysis was performed by individuals blinded to the allocated treatment. All experiments conformed to the Position of American Heart Association on Research Animal Use and were conducted with the approval of the Ethics Committee of the University of Leuven.
Experimental Protocol
Sedation was obtained with fluanisone (0.25 mg/kg IM, Hypnorm,
Janssen Pharmaceutica). After anesthesia with
Na-pentobarbital (30 mg/kg IV for induction and 0.1
mg·kg-1·min-1
for maintenance, Nembutal, Sanofi), each dog was intubated
(cuffed endotracheal tube, Portex Ltd) and mechanically ventilated with
a mixture of oxygen (20%) and air (Mark 7A respirator, Bird Corp).
Both carotid arteries, jugular veins, femoral arteries, and one femoral
vein were dissected free. All dogs received heparin (200 IU/kg as an
intra-arterial bolus followed by a continuous infusion of
20
IU·kg-1·h-1
IV, Heparine Rorer, Rhône-Poulenc Rorer) and aspirin (5 mg/kg IV
bolus, Aspegic, Synthelabo) after insertion of the arterial
sheaths (Cordis Corp). A balloon catheter of appropriate size (Quick,
Baxter Healthcare Corp) was advanced through a guiding catheter
(Marathon, Baxter Healthcare Corp) and positioned in the LAD distal to
the first diagonal branch. Balloon occlusion times were 90 and 240
minutes. The study treatments were begun 15 minutes before balloon
deflation and consisted of 30 minutes of intravenous
infusion of saline, r-tPA (0.1 mg/kg bolus and 0.01
mg·kg-1·min-1
infusion, Actylise, Boehringer Ingelheim GmbH), or r-Sak (10
µg/kg bolus and 1
µg·kg-1·min-1
infusion). Thus, dogs in the placebo groups were not given a
thrombolytic agent, and the reperfusion strategy was
purely mechanical. Complete occlusion and
recanalization of the LAD were documented by
angiography. LV angiograms were obtained at the end of the occlusion
and at the end of reperfusion in groups A through F and at 90 and 240
minutes in the control group (matching the angiograms at the end of the
occlusion period in the groups with reperfusion). Blood samples were
withdrawn for the dosage of fibrinogen and 
-2 antiplasmin at
baseline and after 45 and 120 minutes of reperfusion. The ventilation
was adjusted to maintain the pH and arterial blood gases
within physiological range. Body temperature was
kept constant with a heating pad. Ventricular
arrhythmias were treated with lidocaine (Xylocaine, Astra
Pharmaceuticals). At the end of the experiment, the dogs were
euthanatized with an intravenous injection of saturated
KCl. The hearts were examined for the presence of hemopericardium and
stained with Evans blue dye (nonischemic
myocardium) and
triphenyltetrazolium chloride (AR) as
previously described.26 27 On tetrazolium staining, normal
myocardium is known to appear bright red; infarcted
myocardium, pale yellow; and hemorrhage, dark
brown.20 24 28 29 The LV was cut perpendicular to the long
axis into 1-cm-thick slices. Calibrated photographs of the LV slices
were transferred onto photo-CD.
Infarct Size, Gross Myocardial Hemorrhage, and CF
Anatomic infarct size and gross myocardial hemorrhage
were measured by computer-assisted planimetry of the calibrated
pictures. The photo-CD images were transferred to a Power Macintosh
computer at very high resolution (1536x1024) and analyzed on a
large-screen monitor (Sony Trinitron Multiscan 20sfII) with the Adobe
Photoshop 3.0 software.30 In the first step, a small
manual selection was performed in the middle of the area to be measured
by the computer. The software determined the composition of fundamental
colors (red-green-blue) in the selected area at a resolution of 256
nuances per fundamental color. In the next step, all pixels with
similar color composition (that had all three fundamental colors within
±10 nuances of those in the initial area) were selected. In this way,
the cutoff between adjacent areas (eg, gross hemorrhage and IA)
was set according to the color composition at a predetermined tolerance
level of 20 nuances per fundamental color. Each automatic selection was
double-checked at 5- to 20-fold magnification, and manual corrections
were performed when needed (shade effects, inappropriate selection of
epicardial border and intramyocardial vessels as IAs, etc). The size
was expressed in pixels and converted to square centimeters according
to the calibration factor (1 cm2 corresponded to 12 500 to
43 000 square pixels, depending on the initial magnification of the
calibrated picture). To verify the reproducibility of the technique, a
second measurement was performed by another blinded investigator. The
correlation between the two measurements was excellent
(r=.99 for IA and r=.98 for HA). Because
corresponding areas were not equal on the two sides of the slice, we
calculated slice averages. Total IA, AR, LVA, and HA were calculated by
summation of the different slice averages.
The wide variations in infarct size in dog models are well known.27 31 32 33 Thus, corrections for CF and AR are a prerequisite for an accurate analysis of the effects of interventions on infarct size. The IA/AR ratio was used in several previous studies,11 12 21 but this ratio does not consider the influence of CF. We have controlled for this effect by including CF as a covariate for the IA/AR ratio in the statistical analysis.
Regional myocardial flow was evaluated with the colored microspheres dye-extraction technique. After 30 minutes of occlusion, blue microspheres (Dye-Trak Microsphere, Triton Technology Inc) were injected through a pigtail catheter in the LV cavity. A reference blood sample was withdrawn at a predetermined speed with a calibrated withdrawal pump (Harvard Apparatus). Tissue samples were obtained from the second and third LV slices (counting from the apex). The interface between ischemic and nonischemic areas was discarded. Samples from the subepicardial, midmyocardial, and subendocardial regions of the AR and nonischemic area were taken. After tissue digestion, the microsphere content was spectrophotometrically estimated as described elsewhere.34 Transmural flows in the AR and nonischemic area were calculated as the average of corresponding subepicardial, midmyocardial, and subendocardial flows.
LV Function
LV angiography was performed by injecting 1 mL/kg of a
low-osmolar ionic contrast medium (Hexabrix 320, Laboratoire Guerbet)
with an ECG-triggered power injector (Mark IV). All LV angiograms were
performed with dogs in the right decubitus position. In our experience,
angiograms obtained in this position allow the best evaluation of
anterior wall motion.26 Global LV EF,
end-diastolic volume, and regional wall motion were
analyzed. Regional wall motion abnormalities were assessed with
the centerline method.26 35 Hypokinesia was evaluated for
both extent (percentage of the contour) and amplitude (standardized
motion). Areas of hypokinesia were considered those with a chord
standardized motion of less than -1 SD unit.
Statistical Analysis
Statistical analysis was performed with the SAS
software.36 The main effects of occlusion time and
treatment and their interaction were tested with a two-way ANOVA, with
CF as a covariate. Repeated measures ANOVA was used when appropriate.
Multiple comparisons were performed with Tukey's studentized range
test. The influence of AR and CF on infarct size was evaluated with a
stepwise regression procedure (see the "Appendix" for more
details). The normal distribution was tested with Shapiro-Wilks
statistic. Results are given as mean±SD.
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Results |
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Seventy-seven dogs were included in the randomized part of the study. Of these, 22 developed ventricular fibrillation (17 during occlusion before randomization and 5 after reperfusion: 1 dog in the 90 minutes r-tPA group, 2 in the 90 minutes r-Sak group, 1 in the 240 minutes placebo group, and 1 in the 240 minutes r-Sak group) and were excluded. Another 10 dogs died of pump failure or electromechanical dissociation, all during the first 30 minutes of occlusion. Nine dogs were excluded because of technical problems (incomplete occlusion, unreliable CF measurements, or inadequate staining: 1 in the 90 minutes placebo group, 2 in the 90 minutes r-Sak group, 1 in the 240 minutes placebo group, 3 in the 240 minutes r-tPA group, and 2 in the 240 minutes r-Sak group). The randomization process continued until 36 dogs completed the study protocol, giving a total of 6 dogs per group. Ten additional dogs were included in the control group (persistent occlusion); 3 died of ventricular fibrillation, and 1 was excluded because of technical problems (inadequate staining).
Infarct Size and Myocardial Hemorrhage
Table 1
summarizes the results of planimetry and
regional myocardial blood flow. The effect of occlusion time on infarct
size (IA/AR ratio) was highly significant (P<.001), with
larger infarcts after 240 minutes of occlusion than after 90 minutes of
occlusion, but there was no significant treatment effect
(P=.43) or treatment-by-time interaction (P=.55).
The IA/AR ratio was smaller in groups D through F (240 minutes of
occlusion with reperfusion) than in the control group (240 minutes of
occlusion without reperfusion), but this difference was not
statistically significant. The mean IA/AR ratio was slightly lower in
the 240-minute r-Sak group compared with the 240-minute placebo and
r-tPA groups, but more CF was observed in these dogs. This influence
was taken into account in the statistical analysis; no
significant differences were observed among these three groups.
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A significant correlation was observed between CF and infarct size, as
Fig 1 shows.
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, 90 minutes placebo group; 
,
90 minutes r-tPA group; 
, 90 minutes r-Sak group; 
, 240
minutes placebo group; 
, 240 minutes r-tPA group; 
, 240
minutes r-Sak group; and x, control group).
The amount of myocardial hemorrhage was influenced by the
presence of reperfusion (myocardial hemorrhage was absent in
nonreperfused infarcts) and occlusion time, with larger
hemorrhages in the groups with 240 minutes of occlusion
compared with the 90-minute occlusion groups (P<.01). We
found an excellent correlation between the infarct size and the extent
of hemorrhage (r=.90, P<.0001; Fig 2). There were no treatment effects and no
treatment-by-time interaction. Hemorrhage was always confined
to the area of necrosis. There were no myocardial ruptures or
pericardial hemorrhages in the dogs that completed the study
protocol.
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LV Function
Global EF at the end of occlusion period was similar in the seven
study groups (Table 2). However, EF decreased during
reperfusion in the 240-minute occlusion groups and remained almost
unchanged in the 90-minute occlusion groups (significant interaction
between occlusion time and reperfusion, P=.02). There was no
treatment effect or treatment-by-time interaction. Poor but significant
correlations were observed between parameters of LV
function and infarct size (the best correlation was observed between
infarct size and EF at the end of reperfusion, r=.54,
P<.001). We could not find a significant correlation
between myocardial hemorrhage and parameters of LV
function. End-diastolic volume decreased during reperfusion
regardless of group and subgroup allocation (P<.0001).
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Wall motion analysis at the end of the occlusion period showed
similar results in the different groups (Table 2
). However, there was a
trend toward a reduction in the extent of hypokinesia during
reperfusion in the 90-minute occlusion groups (from 64±8% to
60±22%, P=.07) and toward an increase in the 240-minute
occlusion groups (from 67±12% to 69±16%, P=.08).
Paradoxical motion disappeared in 5 of 18 dogs with 90-minute occlusion
and in none of the dogs with 240-minute occlusion (P=.06).
No significant differences in mean standardized motion were observed
between treatments.
Hemostasis Parameters
The measurement of fibrinogen and -2 antiplasmin at different
time points showed the presence of an overt lytic state in the
staphylokinase-treated dogs. Fibrinogen was below detectable levels,
and -2 antiplasmin levels were <10% at 45 and 120 minutes of
reperfusion (P<.0001 for each time point, Fig 3).
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Discussion |
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Presence and Extent of Myocardial Hemorrhage
The recent meta-analysis on thrombolytic therapy by the Fibrinolytic Therapy Trialists' Collaborative Group and the findings of the US National Registry of Myocardial Infarction suggest the presence of an "early hazard" associated with this reperfusion strategy.7 19 The reasons for this excess of early deaths remain controversial. One suggested explanation is the occurrence of extensive myocardial hemorrhage after thrombolysis-induced reperfusion, leading to extension of necrosis and cardiac rupture. Whether the presence of a systemic lytic state induced by the thrombolytic regimen increases the likelihood of hemorrhage is unknown. Our observations indicate that the presence and extent of myocardial hemorrhage are not influenced by an overt lytic state but are determined primarily by the duration of coronary artery occlusion and the subsequent reperfusion process. Similar amounts of hemorrhage were found for the same duration of coronary artery occlusion despite large differences in fibrinogen and
-2
antiplasmin levels, whereas hemorrhage was absent in control
dogs with persistent occlusion. Furthermore, the extent of
hemorrhage increased from 30% of the IA after 90 minutes of
occlusion to 52% after 240 minutes of occlusion. These findings
support the hypothesis of an increased risk of myocardial
hemorrhage when reperfusion is obtained late. In our study,
mechanical reperfusion alone was associated with a similar amount of
hemorrhage. To the extent that these experimental conditions
also apply to patients undergoing primary angioplasty, our results
suggest that mechanical recanalization may also
cause myocardial hemorrhage.
Myocardial Hemorrhage and Cardiac Rupture
The question of whether myocardial hemorrhage leads to
rupture and is therefore responsible for the excess of early deaths
after thrombolysis cannot be answered from our study
because rupture did not occur in any of the dogs. The first arguments
for a possible association between thrombolysis,
myocardial hemorrhage, and early cardiac rupture came from
surgery and necropsy findings.16 18 The major drawback of
necropsy studies and case reports is their inherent lack of reliability
with regard to the true incidence of the phenomenon because
examinations are performed in only a limited number of cases. Because
rupture is a rare complication and because in our study
hemorrhage was observed in all reperfused myocardial
infarctions (and in no dogs with persistent coronary artery
occlusion), it seems unlikely that hemorrhage itself is the
direct cause of rupture. We found a significant correlation between
infarct size and extent of hemorrhage on one hand and a
significant increase in hemorrhage with time on the other hand.
We therefore concur with the hypothesis that myocardial
hemorrhage is a marker of reperfusion of severely damaged
myocardium. Because reperfusion accelerates necrosis of
irreversibly damaged myocardial cells,37 38 successful
thrombolysis may cause an earlier occurrence of cardiac
rupture (from 4 to 6 days in nonreperfused patients to 24 to 48 hours
as observed in clinical studies)19 39 and therefore may be
responsible for an excess of early deaths. This hypothesis is also
concordant with the increased risk of rupture in late-treated
patients.17 Our results suggest that a similar process may
occur after successful primary angioplasty. The incidence and timing of
cardiac rupture in patients who underwent primary angioplasty are not
known because only a small number of autopsy studies have been
reported.16 40 41 Although extrapolation of data from
animal experiments to patients should always be made very carefully,
our results support the idea that the presence and extent of myocardial
hemorrhage depend on the occurrence of reperfusion and the
preceding duration of coronary artery occlusion (and thus the
amount of necrosis), whereas the recanalization
strategy itself (pharmacological versus mechanical) and the presence of
a lytic state are of little importance.
Infarct Size
As could be expected, infarct size was clearly dependent on
the delay in reperfusion. However, there was no treatment effect, with
similar infarct sizes in dogs that received fibrinolytic agents and
those with pure mechanical reperfusion. Recently, Ohnishi et
al42 showed in a right coronary artery occlusion
model in dogs that the induction of a systemic lytic state and/or lysis
of intracoronary thrombi generates an injurious milieu with
serious adverse effects on the reperfused myocardium,
including motion abnormalities, delayed recovery of function,
contraction band necrosis, and increased polymorphonuclear
infiltration. Our observations that thrombolysis and an
overt systemic lytic state were not associated with larger infarcts
compared with mechanical reperfusion suggest that
fibrinolysis-related injury is of limited importance
for the total amount of necrosis. The excellent correlation between
hemorrhage and infarct size for all treatments and the absence
of hemorrhage in case of persistent occlusion groups further
support the concept that most of the myocardial damage is determined by
the occlusion time and the subsequent reperfusion process, and not by
the way reperfusion is obtained.
Recovery of LV Function
Global and regional LV functions were markedly depressed
after occlusion in all dogs. The immediate effect of reperfusion on
global EF was dependent on the occlusion time, with a slight increase
during reperfusion in the 90-minute occlusion groups and a further
decrease in the 240-minute occlusion groups. These results are similar
to previous experimental and clinical reports3 26 and are
compatible with the concept that early recovery of function is related
to timely reperfusion. The decrease in EF in the 240-minute occlusion
group is probably the result of a lack of improvement because of late
reperfusion and the occurrence of more reperfusion injury. The lack of
correlation between the extent of hemorrhage and recovery of LV
function further supports the hypothesis that myocardial
hemorrhage is a consequence of reperfusion and has only minor
effects on the LV performance. We could not observe any
difference between mechanical and pharmacological reperfusion in terms
of LV function. As in other studies,42 we observed a
decrease in end-diastolic volume after reperfusion,
possibly because of a decrease in LV compliance. This reduction was
also present after mechanical reperfusion.
Study Limitations
A first limitation of the study is that only gross myocardial
infarct size and hemorrhage were measured without microscopic
examinations or measurements of hemoglobin content. In designing the
study, we theorized that gross (and macroscopically visible) rather
than microscopic foci of hemorrhage may be causally related to
rupture, eg, by changing the mechanical properties of the LV wall or by
dissecting layers of myocardial tissue with incoagulable blood.
Furthermore, good correlations between macroscopic and microscopic
examinations have been reported.24 In addition, the
technique of computer-assisted planimetry with automatic color
recognition as used in this study is more sophisticated and probably
more accurate than other techniques used for measuring gross
anatomy in previous studies. Another limitation is that the
reperfusion model used clearly differs from the clinical setting. It is
possible that the sudden relief of occlusion by balloon deflation
instead of a more gradual reperfusion during lysis of an occlusive clot
may have influenced the ensuing amount of hemorrhage. The main
reason we used this model was that it allowed perfect timing of
occlusion and reperfusion and thus the comparison of the effects of
other factors. Finally, it must be stated that the potential importance
of hemorrhage for cardiac rupture could not be fully evaluated
in this study because no such events were observed in the dogs
studied.
Conclusions
In this canine model of acute myocardial infarction, reperfusion
therapy was associated with hemorrhagic infarction, which was not
observed after persistent coronary artery occlusion. We could
not find any difference between mechanical and pharmacological
reperfusion (whether or not associated with a lytic state) with regard
to infarct size, extent of myocardial hemorrhage, and recovery
of LV function. The amount of myocardial hemorrhage was
significantly related to infarct size and coronary artery
occlusion time. These experimental results support the concept that
reperfusion is the cause of myocardial hemorrhage and that
hemorrhage is a marker of both successful
reperfusion and the presence of severely damaged
myocardium. The results suggest that reperfusion obtained
by primary angioplasty may also induce myocardial
hemorrhage.
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Selected Abbreviations and Acronyms |
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Appendix 1 |
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We have evaluated the influence of the AR and CF on infarct size with a stepwise multiple regression analysis. Infarct size was taken as dependent variable, and AR and parameters describing CF (transmural, subepicardial, midmyocardial, and subendocardial flow in the central ischemic area; the ratios of the flow in AR over the flow in the nonischemic area in the previously mentioned myocardial layers; and the logarithms of the previous parameters) were taken as independent variables. The most powerful regressors were AR (r=.69) and the logarithm of the ratio of transmural flow in AR over transmural flow in the nonischemic area [log(CF), r=.78 after inclusion into the model]. Therefore, to control for both AR and CF, log(CF) was included as a covariate for the IA/AR ratio in the statistical analysis.
Received October 16, 1996; revision received January 7, 1997; accepted January 21, 1997.
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