(Circulation. 1995;91:2989-2994.)
© 1995 American Heart Association, Inc.
Articles |
Absence of Lethal Reperfusion Injury After 3 Hours of Reperfusion
A Study in a Single-Canine-Heart Model of Ischemia-Reperfusion
From the Division of Cardiology, Department of Medicine, and the Departments of Pathology (M.C.F.) and Cardiothoracic Surgery (A.C.), Cedars-Sinai Medical Center and the University of California School of Medicine, Los Angeles.
Correspondence to William Ganz, MD, Division of Cardiology, Room 5313, 8700 Beverly Blvd, Los Angeles, CA 90048.
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Abstract |
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Background Whether reperfusion can cause necrosis of previously viable myocytes (lethal reperfusion injury) remains controversial. Numerous studies examined the ability of various agents to prevent or limit reperfusion injury, but the results were contradictory. In a single-canine-heart model of ischemia-reperfusion, we previously demonstrated that 5 minutes of reperfusion does not increase the transmural extent of necrosis. Since the 5-minute period of reperfusion is considered by some to be too short for the full manifestation of reperfusion injury, we reexamined the issue of lethal reperfusion injury using a modification of the single-heart model of ischemia-reperfusion that allowed extending the reperfusion period to 3 hours.
Methods and Results In anesthetized, open-chest dogs, the distal half of the left anterior descending coronary artery (LAD) segment between the last diagonal branch and the apex was perfused via a shunt from the left carotid artery. The shunt was closed for periods of 90 to 180 minutes, depending on the ECG severity of ischemia, and reperfused for 3 hours. While the distal region was perfused from the carotid artery, the LAD was occluded proximal to the last diagonal branch for the same period of time as the distal region had been earlier. The time of occlusion was chosen such that the end of the occlusion period coincided with the end of the experiment. Thus, both regions of the LAD territory were subjected to identical periods of ischemia, but only the distal region was reperfused. At the end of the experiment, the boundary between the proximal (nonreperfused) and distal (reperfused) area was delineated by blue dye, and the heart was arrested, cut into slices 1 cm thick parallel to the LAD, and placed in triphenyltetrazolium chloride. The epicardial edges of necrosis in the reperfused and the nonreperfused regions were examined for any shift that might suggest a difference in the transmurality of necrosis. The areas of necrotic and viable myocardium were measured by planimetry within 1 cm on either side of the boundary. In all 14 dogs, the epicardial edges of necrosis ran as a single line across the boundary, and no shift was present. There was also no difference in the transmurality of necrosis between the reperfused and nonreperfused regions (64.9±20.7% versus 66.1±17.0% of left ventricular wall thickness, respectively; P=.32 by paired t test).
Conclusions In a single-canine-heart model of ischemia-reperfusion, there was no evidence of lethal reperfusion injury after 3 hours of reperfusion.
Key Words: myocardial infarction • ischemia • reperfusion
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Timely reperfusion of the acutely ischemic myocardium limits infarct size and reduces morbidity and mortality in patients with acute myocardial infarction. Some investigators believe, however, that reperfusion also has an adverse effect in that it inflicts irreversible damage on some of the previously viable myocytes, a phenomenon called "lethal reperfusion injury."1 2 3 The existence of lethal reperfusion injury is supported by numerous studies reporting marked reductions in infarct size by antioxidant and antileukocyte measures applied shortly before reperfusion.4 5 6 7 8 9 10 11 12 13 However, many other studies using similar approaches failed to demonstrate any effect on infarct size.3 14 15 16 17 18 19 In all these studies, groups of treated animals were compared with groups of untreated animals. In view of the contradictory results of therapeutic studies and to avoid the uncertainty resulting from the great natural variability of infarct size (due to variability of collateral blood flow and possibly other factors20 ) when groups of animals are compared, we previously performed a study in which the effect of reperfusion on infarct size could be assessed directly in one canine heart and in a single left anterior descending coronary artery (LAD) territory of ischemia, half of which was reperfused and half not.21 That study demonstrated the absence of lethal reperfusion injury after 5 minutes of reperfusion. The duration of reperfusion was limited to 5 minutes to avoid a significant difference in the duration of ischemia in the two regions. Five minutes of reperfusion was considered sufficient, since the burst of free radical release,22 23 contraction band formation, and explosive myocyte swelling24 25 26 all are known to occur within 2 minutes of reperfusion. However, some investigators consider 5 minutes of reperfusion too short for manifestation of the full impact of lethal reperfusion injury.27 28 Therefore, in the present study we reexamined the presence or absence of lethal reperfusion injury after 3 hours of reperfusion using a modification of our single-canine-heart model of ischemia-reperfusion.
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Methods |
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The study conformed to the guiding principles of the American Physiological Society and was approved by the Institutional Animal Use and Care Committee.
Surgical Preparation
Mongrel dogs of either sex, weighing 20
to 30 kg, were
anesthetized with 30 mg/kg IV sodium pentobarbital, intubated, and
ventilated with room air with a Harvard respirator. Saline-filled
catheters were placed in the femoral artery for measurement of blood
pressure and in the jugular vein for administration of drugs. The chest
was opened in the fifth left intercostal space, and the heart was
suspended in a pericardial cradle. The LAD was dissected free at two
points: (1) just proximal to the last diagonal branch and (2) halfway
between the last diagonal branch and the apex. Heparin was administered
as a 200-U/kg IV bolus initially, followed by hourly boluses of 100
U/kg. A shunt was formed from the left carotid artery to the LAD at the
point halfway between the last diagonal branch and the apex (Fig
1
). A needle inside an 18- or 22-gauge (1.3- or
1.1-mm-OD) polyethylene catheter was used to puncture the anterior wall
of the LAD. After penetration of the catheter into the artery, the
needle was removed, and a 4-mm-ID plastic tube was attached to the
polyethylene catheter without interrupting the blood flow in the LAD. A
suture was placed around the LAD just proximal to the tip of the
catheter to prevent retrograde blood flow beyond that point. Blood flow
in the shunt was continuously monitored by a Doppler flowmeter
(Transonic Systems, Inc). An ECG V lead was monitored from the chest
near the left ventricular apex. A heating pad was placed under the dog,
and the open chest was covered whenever possible to maintain a stable
body temperature.
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Assessment of Necrosis
Heart slices about 1 cm thick were
placed in
triphenyltetrazolium chloride (TTC) buffered in 0.2 mol/L Tris (pH 7.8)
at approximately 37°C for 15 minutes for demarcation of the area of
necrosis.29 They were subsequently photographed, and the
35-mm slides were projected at threefold magnification onto white
paper. The TTC-positive areas (dark red; viable myocardium) and the
TTC-negative areas (white or pale; necrotic myocardium) were outlined
and measured by planimetry. The transmural extent of necrosis was
expressed in percentage of left ventricular wall thickness:
TTC-negative areax100/(TTC-negative+TTC-positive
area).21
Protocol
After establishment of the carotid
artery–to–LAD shunt, there
was a 15-minute stabilization period. The adequacy of distal region
perfusion was indicated by blood flow in the shunt, by absence of
ischemic changes on the ECG, and by the normal color of the perfused
myocardium. The utility of the model depends on obtaining relatively
homogeneous yet nontransmural necrosis so that a distinct epicardial
boundary can be observed in the reperfused and nonreperfused
territories. The shunt was therefore closed for variable periods of
time ranging from 90 to 180 minutes, depending on the ECG severity of
ischemia. When the ST-segment elevation was mild, longer occlusion
periods were chosen to avoid small patchy necrosis; when the ST
elevation was severe and/or the QRS widened, shorter periods of
occlusion were chosen to avoid transmural or near-transmural necrosis.
The period of ischemia was followed by a 3-hour period of reperfusion.
The adequacy of reperfusion was indicated by the reactive hyperemic
response measured in the shunt and by return of normal color in the
reperfused myocardium. While the distal region was perfused, the
proximal LAD region was rendered ischemic by occlusion of the artery
proximal to the last diagonal branch. The time of occlusion was
selected such that the duration of proximal occlusion was identical
with the duration of the earlier distal occlusion and the end of the
proximal occlusion period coincided with the end of the 3-hour period
of distal reperfusion (Fig 2). Thus, the two regions
were subjected to identical periods of ischemia, but only the distal
region was reperfused.
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Before termination of the experiment, Monastral
blue dye (5
mL) was injected selectively into the distal region via the
perfusion catheter to delineate the boundary between the proximal and
the distal regions. This was immediately followed by an intravenous
injection of an overdose of potassium chloride to arrest the heart.
After arrest, the heart was expeditiously removed, cut parallel to the
LAD into slices 
1 cm thick, and placed in TTC.
In this model, the
transmural extent of necrosis in the distal
(reperfused) and the proximal (nonreperfused) regions of the
ischemic-reperfused LAD territory is assessed within 1 cm on either
side of the boundary between the two regions in two
ways21 : (1) The transmural progression of necrosis in the
two regions is considered similar when the epicardial edges of necrosis
in the two regions form a single line running parallel to the
epicardium. When the epicardial edges of necrosis in the two regions do
not form a single line, eg, one of them is closer to the epicardium,
the transmurality of necrosis is considered greater in that region.
When there was a difference between the two regions in our previous
study,21 the shift in the epicardial edge of necrosis was
most distinct at the boundary. Accordingly, lethal reperfusion injury,
if present, was expected to advance the epicardial edge of necrosis
in the distal, reperfused region toward the epicardium; the difference
in the transmurality of necrosis between the two regions would then
represent the extension of necrosis due to lethal reperfusion
injury (Fig 3). (2) The areas of necrotic and viable
myocardium were measured by planimetry within 1 cm on either side of
the boundary between the two regions, and the transmural extent of
necrosis was expressed in percent of left ventricular wall
thickness.
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Statistical Analysis
Data are presented as mean±SD.
Student's paired
t test was used to evaluate differences in the transmurality
of necrosis and hemodynamics. A value of P<.05 was
considered significant.
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Results |
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Sixteen dogs were excluded either because there was no necrosis or necrosis was minimal in both the reperfused and nonreperfused regions, despite a 3-hour duration of ischemia. In an additional 4 dogs, the infarct was transmural. Five dogs died of ventricular fibrillation during the experiment, and 4 dogs were lost due to various technical difficulties. In all 14 suitable dogs, the epicardial edges of necrosis in the reperfused and the nonreperfused regions ran as a single straight line across the boundary. No shift toward the epicardium was present in the reperfused region. A representative example is presented in Fig 4
. The mean transmurality of
necrosis in the reperfused and the nonreperfused regions was
64.9±20.7% versus 66.1±17.3% (mean±SD) of left
ventricular wall
thickness, respectively (P=.32). Detailed data on
transmurality of necrosis and duration of ischemia in the 14 dogs are
presented in Table 1.
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The resting flow in the shunt ranged from 8.5 to 11.7 mL/min. A brief
hyperemic response was observed immediately after reperfusion in all
cases. The blood pressure and heart rate during the periods of distal
and proximal myocardial ischemia were similar (Table 2).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study demonstrated that the transmurality of necrosis in the reperfused and the nonreperfused regions of a single LAD territory after 3 hours of reperfusion was similar. This finding is in accord with the observations of our previous study after only 5 minutes of reperfusion.21
Model
In both studies, a single-canine-heart model was used
in which the
reperfused and the nonreperfused (control) regions are juxtaposed and
readily compared in a single LAD territory. The previous
study21 also demonstrated that this single-heart method
can detect a difference in the transmurality of necrosis when a
difference does exist; eg, when the distal region is subjected to a
significantly longer period of ischemia than the proximal region. Under
those conditions, the epicardial edges of necrosis did not form a
single line but were clearly shifted away from each other at the
boundary between the two regions. When the two regions were subjected
to identical periods of ischemia (both with or without subsequent
reperfusion), no such shift was observed, and the measured
transmuralities of necrosis in the two regions were also similar.
Collateral Blood Flow
Collateral blood flow was not measured
in the present study.
Our previous study21 showed uniform collateral blood flow
when the territory distal to the last diagonal branch of the LAD was
made ischemic. When the proximal half of that territory was reperfused,
there was a small increase in collateral blood flow to the distal,
nonreperfused half. An increase in collateral blood flow from the
nonischemic half can also be assumed in the present study. It can
also be assumed that when the distal half is reperfused and the
proximal half is rendered ischemic, the flow in the collateral
connections between the two halves is reversed as a result of reversal
of the pressure gradient in the collateral connections. Such changes in
collateral blood flow could not have affected the basic findings of the
present study. If anything, collateral flow from the distal
reperfused half to the proximal ischemic half may have been greater
because of dilation of collaterals during the preceding period of
distal ischemia, thus working in favor of, not against, detection of
lethal reperfusion injury.
TTC Method
The accuracy of the TTC method in delineating
necrosis in the
early stages of myocardial infarction was validated
earlier29 and was confirmed again in our recent
study.21 Compared with the reperfused territory, the lack
of staining of necrotic myocardium is less distinct in the
nonreperfused territory. The lack of staining is due to absence of a
coenzyme NADH needed for TTC staining. The escape of NADH from
irreversibly injured nonreperfused myocytes is less complete than from
the reperfused myocytes. Reperfusion disrupts the cellular membranes by
causing explosive myocyte swelling and thereby markedly accelerates the
escape or washout of NADH. Our own correlative ultrastructural
studies21 29 and the studies by Lie et
al30 and Vivaldi et al31 demonstrated that
when any decrease in TTC staining is observed, electron microscopy
shows myocardial fibers to be uniformly necrotic. Any potential error
due to less distinct nonstaining of the nonreperfused myocardium would
lead to underestimation of the extent of necrosis in that region and
thus act in favor of, not against, finding lethal reperfusion
injury.
Other Studies
A number of investigators attempted to directly
prove or disprove
the existence of lethal reperfusion injury. Hoffman and
colleagues32 occluded two medium-sized coronary artery
branches, one from the LAD and one from the circumflex artery, in dogs.
After 3 hours of occlusion, only one of the two branches was reperfused
for 3 hours. Infarct sizes, expressed as a percentage of the area at
risk, were similar in the two regions. A potential weakness of the
study was that collateral blood flow was not measured to demonstrate
that ischemia was equally severe in the LAD and circumflex
territories.
Other investigators compared infarct sizes measured before and after reperfusion33 34 or at different times after reperfusion35 using antimyosin antibody fragments labeled with different isotopes. The infarct size measured after reperfusion was found to be larger than the one measured before reperfusion, and infarct size measured later after reperfusion was found to be larger than that measured earlier after reperfusion. Other investigators36 measured infarct size with the horseradish peroxidase method immediately after reperfusion and with the TTC method 3 hours after reperfusion. The infarct size determined 3 hours after reperfusion with the TTC method was larger. The authors of all these studies attributed the differences in infarct size to the effect of lethal reperfusion injury or to the continuing injurious effect of reperfusion. An alternative explanation for the above findings, however, may be provided by the observations of Khaw and colleagues.37 These investigators injected simultaneously, 15 minutes after reperfusion, two infarct size markers of widely differing molecular weights: 111In-labeled antimyosin antibody (molecular weight [MW], 88 200 D) and 99mTc-labeled pyrophosphate (MW, 630 D) and found that infarct size determined with the antimyosin antibody was considerably smaller. In a similar study, Takeda and colleagues38 assessed infarct size simultaneously with antimyosin antibody and 99mTc pyrophosphate and found that the antibody content in the infarct region was low unless the dog survived for 24 hours and that the two methods were comparable only when used >24 hours after the infarction. Antimyosin antibody, horseradish peroxidase, and technetium pyrophosphate delineate the extent of necrosis after penetration through the abnormally permeable membrane of irreversibly injured myocytes. However, membrane permeability of irreversibly injured myocytes is not constant: It increases progressively with continuing ischemia,39 rises abruptly during reperfusion because of explosive swelling and membrane disruption,25 and continues to rise for several hours thereafter because of continuing myocardial swelling40 and possibly other factors. Kent39 studied the uptake of plasma proteins by canine myocytes subjected to periods of ischemia ranging from 1 to 24 hours. In myocytes subjected to 1 to 3 hours of ischemia, albumin (MW, 69 000 D) was predominantly detected, gamma globulin (MW, 150 000 D) was present in much smaller quantities, and fibrinogen (MW, 340 000 D) was found only in hearts subjected to >6 hours of ischemia and then only in the subendocardium, in which necrosis was most advanced. Similar observations were made by Kent in human hearts.41
The progressive rise in myocardial membrane permeability during ischemia and after reperfusion also explains the differences in the rate of release of intracellular enzymes after myocardial infarction in humans: myoglobin (MW, 17 000 D), creatine kinase (MW, 82 600 D), and lactic dehydrogenase (MW, 134 000 D) appear in plasma at rates inversely related to their molecular weights.42
In addition to the temporal differences, there is also a transmural gradient in the degree of permeability as a result of the way necrosis progresses from the subendocardium toward the epicardium over several hours.43
In view of the above observations and considerations, we hypothesize that during the early hours of ischemia and early after reperfusion, antimyosin antibody or horseradish peroxidase is unable to penetrate the cell membranes of many irreversibly damaged myocytes, particularly those toward the epicardial edge of necrosis, but may do so hours later.38
The progressive nature of increased membrane permeability of irreversibly injured myocytes and the spatial differences in the uptake of extracellular molecules thus explain the differences in infarct size, either when a marker of large molecular weight and size is used sequentially or when a small-molecular-weight and a large-molecular-weight marker are applied simultaneously in the early hours of ischemia or early after reperfusion. Therefore, methods based on the intracellular uptake of large molecules underestimate, in our opinion, the extent of necrosis in the early hours of an infarction.
In conclusion, the present study, conducted in a single-canine-heart model of ischemia-reperfusion, failed to demonstrate a lethal reperfusion injury–induced extension of necrosis after 3 hours of reperfusion and validates our previous similar finding after only 5 minutes of reperfusion.
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Acknowledgments |
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This study was supported in part by grants from the Leslie and Susan Gonda Foundation and the Save A Heart Foundation.
Received November 9, 1994; revision received December 27, 1994; accepted December 27, 1994.
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E. A. Gill, Y. Kong, and L. D. Horwitz An Oligosaccharide Sialyl-Lewisx Analogue Does Not Reduce Myocardial Infarct Size After Ischemia and Reperfusion in Dogs Circulation, August 1, 1996; 94(3): 542 - 546. [Abstract] [Full Text]
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