(Circulation. 1995;92:500-510.)
© 1995 American Heart Association, Inc.
Articles |
Deleterious Effects of a Systemic Lytic State on Reperfused Myocardium
Minimization of Reperfusion Injury and Enhanced Recovery of Myocardial Function by Direct Angioplasty
Presented in part in abstract form at the American Heart Association Scientific Sessions, Dallas, Tex, 1994, and at the American College of Cardiology Scientific Session, New Orleans, La, 1995.
From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Mo.
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Abstract |
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Background The beneficial effects of flow restoration and the deleterious impact of reperfusion injury on ischemic myocardium are well known. However, most experimental studies have induced reperfusion by mechanical release of nonthrombotic occlusions, only occasionally in the presence of a systemic lytic state. Conditions differ markedly in patients undergoing pharmacological or mechanical recanalization of thrombotically occluded coronary arteries. Accordingly, this study was designed to determine whether the method of coronary occlusion and mode of recanalization influence the response of the heart to reperfusion.
Methods and Results The acute effects of reperfusion on right ventricular (RV) function and histology were studied in open-chest dogs subjected to right coronary artery (RCA) balloon occlusion and deflation alone (group 1), pharmacological lysis of thrombotic occlusions (group 2), balloon occlusion with reperfusion induced by balloon deflation in the presence of a systemic lytic state (group 3), and recanalization of thrombotically occluded vessels by direct angioplasty (group 4). In all groups, 1 hour of RCA occlusion led to RV free wall (FW) dyskinesis. In group 1, reperfusion promptly improved RVFW function, with normal RVFW thickness and only minimal edema by microscopy. In contrast, in group 2, clot lysis led to acute RVFW swelling and impaired recovery of RVFW contraction associated with striking interstitial edema, contraction band necrosis, and hemorrhage by microscopy. In group 3, balloon deflation in the presence of a lytic state led to a similar but less severe pattern of abrupt RVFW swelling and impaired recovery of RVFW function but lesser histological alterations than in group 2. However, mechanical recanalization of thrombotically occluded vessels (group 4) led to prompt recovery of RVFW function without significant RVFW swelling or histological abnormalities.
Conclusions Our observations indicate that the responses of ischemic myocardium to reperfusion are influenced by factors beyond those effects attributable to ischemia and reperfusion per se. Pharmacological lysis of coronary thrombi results in alterations characteristic of reperfusion injury and associated with impaired functional recovery. Such changes are also evident, although to a lesser extent, when reperfusion of nonthrombotic occlusions is induced by mechanical recanalization in the presence of a systemic lytic state but not in its absence. However, such effects were not seen with direct mechanical recanalization of thrombotically occluded vessels. In aggregate, these findings indicate that induction of a systemic lytic state, together with products released by lysis of intracoronary thrombi, generates an injurious milieu that exerts adverse effects on reperfused myocardium.
Key Words: reperfusion • thrombolysis • angioplasty • myocardium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Beneficial effects of reperfusion on ischemic myocardium have been extensively documented in animals1 2 3 4 5 and humans.6 7 8 9 However, reperfusion may be a "double-edged sword," resulting in striking biochemical and structural derangements in reperfused myocardium that are absent after ischemic insults alone.10 11 12 13 14 15 In patients with acute myocardial infarction, in whom recanalization of thrombotically occluded coronary arteries is induced pharmacologically6 7 8 9 16 17 18 19 20 or by catheter-based interventions,21 22 23 24 25 timely reperfusion salvages jeopardized myocardium and improves survival. However, early improvement of regional and global ventricular performance may be modest.6 7 8 9 10 16 17 18 19 20 21 22 23 24 25 26 The delay in maximal recovery of contractile function is consistent with "stunned myocardium," the term for impaired contraction persisting beyond the interval of ischemia in viable heart muscle.10 14 15 16 17 18 19 20 26 Reperfusion injury has been implicated as one factor that may contribute to stunning. However, most experimental studies of reperfusion have used mechanical means to induce reperfusion by release of nonthrombotic occlusion.1 2 3 4 5 11 12 13 Only rarely has this been done in association with a systemic lytic state.27 28 29 Furthermore, similarities and differences in the responses of ischemic myocardium to recanalization of thrombotically occluded vessels by thrombolysis versus primary angioplasty have received little attention.30 31
We have characterized effects on right ventricular (RV) structure and function of ischemia and reperfusion induced by balloon occlusion of the right coronary artery (RCA).32 One hour of occlusion results in severe RV free wall (FW) dysfunction. Reperfusion induced by balloon deflation results in prompt improvement of RVFW contraction without evidence of reperfusion injury, documented by the lack of acute RVFW swelling by ultrasound and the absence of edema or contraction band necrosis by microscopy. In contrast, reperfusion after left coronary artery occlusion of similar duration induces acute wall swelling, persistent contraction abnormalities, and histological alterations indicative of reperfusion injury associated with ischemic necro- sis.1 2 3 4 5 11 12 13 14 15 This unique response of the right ventricle thus provides an attractive model to determine whether the method of occlusion (thrombotic versus nonthrombotic) and conditions of reperfusion (induction of systemic lytic state versus mechanical recanalization) exert effects on ischemic myocardium above and beyond those attributable to ischemia and reperfusion per se. Accordingly, we studied open-chest dogs to define acute effects on RV function and histology of RCA balloon occlusion and reperfusion alone, reperfusion induced by pharmacological lysis of thrombotic occlusions, balloon occlusion with reperfusion induced by balloon deflation in the presence of a systemic lytic state, and thrombotic occlusion with recanalization induced by direct angioplasty alone.
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Methods |
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Experimental Preparation
Studies were performed in four groups of open-chest conditioned dogs (25 to 35 kg) subjected to occlusion of the proximal RCA for 1 hour and reperfusion for 1 hour. Group 1 animals (n=8) were subjected to balloon occlusion with reperfusion induced by balloon deflation alone; in group 2 (n=17), thrombotic occlusion was induced by intracoronary insertion of a copper-coated coil, and reperfusion was induced by pharmacological clot lysis; group 3 animals (n=6) underwent balloon occlusion with a systemic lytic state induced before reperfusion, which was induced by balloon deflation; in group 4 animals (n=9), thrombotic occlusion was elicited by intracoronary insertion of a copper-coated stent, and reperfusion was induced by direct angioplasty. All animals were anesthetized (morphine sulfate 1 mg/kg sc and nembutal 30 mg/kg IV) and mechanically ventilated with a mixture of room air supplemented with oxygen. Femoral arteries and veins, a carotid artery, and a jugular vein were surgically isolated and cannulated with vascular sheaths (Cordis Corp). A thoracotomy was performed in the fifth left intercostal interspace to provide access for an ultrasonic probe. Micromanometer-tipped catheters (Millar Instruments) were inserted for measurement of RV and left ventricular (LV) pressures. Ventilation was adjusted to maintain arterial blood gases and pH within the physiological range. Core body temperature was maintained as close to baseline as possible with the aid of a heating blanket.
Data Acquisition
Transepicardial two-dimensional short-axis
echocardiograms
(Hewlett-Packard Instruments) were obtained with a 5-MHz transducer
placed directly on the LV free wall with animals in the right lateral
recumbent position as previously described.32 33
Images
were recorded on videotape for quantitative off-line analysis with
a calibrated microcomputer system (Hewlett-Packard). Atrial and
ventricular pressures and the ECG were recorded with a strip-chart
recorder (Gould Medical Instruments). Coronary angiograms were recorded
on cineangiographic film at 30 frames per second.
Experimental Protocol
After completion of instrumentation,
baseline hemodynamic and
echocardiographic measurements were recorded. To prevent malignant
ventricular arrhythmias during ischemia, lidocaine (40 mg IV)
was administered. Group 1 and 3 animals were given heparin (bolus of
5000 U followed by an infusion of 500 U/h) before instrumentation of
the RCA. Group 2 and 4 animals were not given heparin.
Acute RCA
Occlusion
In all animals, the RCA was engaged with an 8F large lumen
guiding catheter (JL4 or hockey-stick configurations, 0.084-in. ID,
Cordis Corp), and coronary angiography was performed with nonionic
contrast medium. In groups 1 and 3, balloon occlusion of the RCA
proximal to the major RV branches was induced by standard angioplasty
techniques as previously described.32 In group 2 animals,
thrombotic RCA occlusion was induced by placement of an intracoronary
copper coil as previously described.33 Because the ID of
the copper coils precludes passage of a dilatation apparatus for direct
angioplasty, thrombotic occlusion was induced in group 4 animals by
insertion of intracoronary stents (Johnson & Johnson unpolished stents
that were copper coated in our laboratory) as previously
described.34 The stent was placed over a 2.5- to 3.0-mm
balloon catheter that was advanced over a 0.018-in. guide wire
previously positioned in the distal RCA. The balloon was positioned in
the proximal RCA, inflated to 6 atm, and deflated. The wire, balloon,
and guide wire were then removed, and an angiogram was performed to
confirm the position of the stent. In group 2 and 4 animals, the onset
of thrombotic occlusion was detected by echocardiographic monitoring
and changes in RVFW motion assessed at 5-minute intervals. Complete RCA
occlusion was confirmed by intermittent ostial flush injections
performed every 10 minutes or immediately on documentation of
alterations in RVFW contraction by ultrasound. In all groups,
hemodynamic and echocardiographic studies were repeated immediately and
60 minutes after occlusion.
Acute Reperfusion
In
group 1 animals, after 60 minutes of occlusion the balloon
catheter was deflated and removed and the angiography repeated. In
group 2 animals, after 50 minutes of occlusion heparin was administered
(5000 U bolus, 500 U/h infusion), and a systemic lytic state was
induced by administration of either streptokinase 8000 U/kg IV over 20
minutes, (n=7) or tissue-type plasminogen activator (t-PA, Activase,
Genentech) 1 mg/kg IV over 1 minute (n=10). The dose of t-PA was
selected to be one that induced substantial (>30%) conversion of
plasminogen in blood to plasmin (systemic lytic state). Two different
agents (streptokinase and t-PA) were used in the present study to
avoid the likelihood that results would be specific to a particular
drug rather than related to the systemic lytic state per se. In all
group 2 animals, after documentation of reperfusion by ultrasound and
coronary arteriography, angiographic injections were repeated every 15
minutes to document coronary arterial patency and flow (Thrombolysis in
Myocardial Infarction7 grades 0 through 3). In group 3
animals, a systemic lytic state was induced (streptokinase 8000 U/kg IV
over 20 minutes) 20 minutes before balloon deflation. In group 4
animals, after 60 minutes of occlusion, heparin was administered and
direct angioplasty performed. An 8F guiding catheter was engaged in the
RCA, and an angiogram was performed. A 0.018-in.-high torque guide wire
(Cordis) was then maneuvered through the thrombosed stent and
positioned in the distal RCA. A balloon catheter (2.5 to 3.0 mm) was
then advanced over the wire into the stent and inflated two or three
times at 4 to 6 atm pressure for 30 to 60 seconds. The balloon was
withdrawn into the guide and coronary angiography repeated. If proximal
residual thrombus was evident, as indicated by angiographic filling
defects, the balloon was advanced into the coronary segments affected
and reinflated at 2 to 4 atm for 30 seconds. Distal thrombi, when
present, were disrupted mechanically with the guide wire. After
successful recanalization, coronary angiograms were
repeated every 15 minutes to document coronary patency and flow.
In all groups, hemodynamic and echocardiographic measurements were recorded 5, 15, 30, and 60 minutes after reperfusion; then the animals were killed. The hearts were quickly excised, immersed in 10% formalin, and prepared for histology. All experiments conformed to the position of the American Heart Association on research animal use and were conducted with the approval of the Washington University Committee on Humane Care of Laboratory Animals.
Data Analysis
Hemodynamic indexes of ventricular function
analyzed included
peak systolic pressure, maximal (+) and (-) dP/dt, and
end-diastolic pressure. Echocardiographic criteria of
ventricular performance were analyzed according to methods previously
described.32 33 34 35
Quantitative histopathologic analysis
of the RVFW slice at the midpapillary muscle level was performed as
previously described.32 33 Histological features
evaluated
by light microscopy included analysis of (1) myocellular size; (2)
contraction band necrosis; (3) presence of interstitial edema, defined
as widening of the spaces between myocytes; (4) intramyocardial
hemorrhage and neutrophil infiltration, defined as the presence of
erythrocytes or neutrophils in the interstitial spaces; and (5)
vascular plugging, defined as accumulation of erythrocytes or
neutrophils in arterioles, capillaries, and/or venules. Because the
spatial distribution and regional severity of the histological changes
noted are often heterogeneous, morphometry based on point
counting in microscopic grids may be limited. Therefore, we used a
modified point counting approach by applying a qualitative scoring
method to describe the extent and severity of each histopathologic
abnormality within individual grid zones.32 Thus,
specimens were analyzed by light microscopy at a magnification of x100
with the use of a transparent grid consisting of 1-mm squares
superimposed on the microscopic field. Within each square, the presence
and severity of histological abnormalities (interstitial edema,
hemorrhage, and neutrophil infiltration) were individually scored as
none (0), mild (1+), moderate (2+), or severe (3+). In each
case, the
total for all squares analyzed within the RVFW middle segment was
determined, and the percentage of the segment involved and mean
severity score for each abnormality were calculated. Delineation and
analysis of the extent of contraction band necrosis required higher
magnification (x400). Accordingly, each square was divided visually
into four quadrants, and the presence and extent of contraction bands
within the entire square were determined as none (zero quadrants), mild
(1+, one quadrant), moderate (2+, two quadrants), or severe
(3+, three
quadrants). The total extent and severity of contraction bands in the
middle RVFW segment were then calculated.
To assess myocardial cell swelling, the diameters of myocytes in the middle RVFW segment were measured with the use of computer-assisted analysis of digitized microscopic images.33 Twelve samples from each specimen were imaged at a magnification of x400 with a video microscope (Optiphoto-2 microscope, Nikon, Inc) equipped with color imaging camera (Javelin Electrics) and video monitor (Sony). Images were digitized by use of a Navista+ videographics card (Truevision Inc) installed on a Macintosh IIci computer (Apple Inc) and were stored on a 200-megabyte hard disk (Apple Inc). Analysis was performed with IMAGE 1.47 software. Measurements were calibrated by digitizing images of a standardized micrometer. A transparent sheet with five randomly marked dots (points) was superimposed on the computer display. The maximum width of the cell located at each point was measured with a computer-directed cursor. In each segment, 60 cells were measured, and the average cell width was calculated for each animal. Histological findings in each animal were reviewed by an expert (J.E.S.) blinded to the treatment group.
Data are given as mean±SEM. Comparisons were made by ANOVA for repeated measures with respect to changes in values within each animal. Comparisons between groups were made by two-way ANOVA. A difference was considered to be significant with respect to the 95% confidence limits.
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Effects of Acute RCA Occlusion
At baseline, all hemodynamic and echocardiographic measurements were normal in all animals (Figs 1 through 6
).
In group 1, 2 of 8 animals developed ventricular fibrillation while the
balloon was inflated and were excluded from analysis. In group 2, 7
of 17 animals were excluded, including 3 in which technical limitations
precluded delivery of the coil to the desired target site, 3 in which
refractory ventricular arrhythmias occurred after thrombotic occlusion
and reperfusion, and 1 in which pharmacological thrombolysis was
unsuccessful. In group 3, 1 animal was excluded in which refractory
ventricular fibrillation developed during reperfusion. In group 4, 2
animals were excluded in which ventricular fibrillation occurred during
reperfusion: 1 in which initial direct percutaneous transluminal
coronary angioplasty (PTCA) failed, and 1 in which recurrent thrombotic
occlusion occurred.
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, group 1;
, group 2; 
, group 3; and 
, group 4. BASE indicates
baseline; OCCLX, peak occlusion; REP, 1 hour after reperfusion.
Pressures are in millimeters of mercury; dP/dt is in millimeters of
mercury per second. *P<.05 with respect to significant
changes over time within each group.
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In the 26 other animals constituting those
analyzed, RCA occlusion
resulted in equivalent alterations in echocardiographic parameters and
hemodynamics in all four groups (Figs 1 through
6
).
In keeping with
previous findings,32 33 35 RCA occlusion
resulted in loss
of RVFW systolic thickening and shortening, RVFW dyskinesis, and
depressed global RV performance indicated by diminished RV fractional
area change (FAC) (Figs 1 through
6).
RV diastolic function also was
impaired, reflected by gross RV dilatation, depressed RV maximal (-)
dP/dt, and elevated RV filling pressures. Interventricular septal
curvature was reversed, and there was equalization of right atrial, RV,
and LV diastolic filling pressures. As noted previously, RV systolic
performance was generated predominantly by the interventricular septum,
which thickened and bulged paradoxically into the right ventricle (Figs 1
through 4).
Depressed RV systolic function led to diminished LV
preload, but LV filling pressure was unchanged, indicating LV diastolic
dysfunction. These changes were evident in all animals within 5 minutes
of RCA occlusion and persisted without further significant change
throughout the entire ischemic interval. During occlusion,
there were no significant differences between the groups with respect
to the direction or magnitude of changes in echocardiographic or
hemodynamic variables.
Effects of Reperfusion of Nonthrombotic Occlusions in the Absence
of a Lytic State (Group 1)
After balloon occlusion (mean duration,
64.7±1.5 minutes; range,
60 to 69 minutes), reperfusion induced by balloon deflation alone
resulted in a widely patent RCA in all animals. In keeping with
observations from previous studies of 1-hour balloon
occlusions,32 reperfusion resulted in prompt and striking
improvement in RVFW systolic thickening and motion and consequently
global RV performance (Figs 1, 5, and
6). RV systolic function improved
despite a reduction in the magnitude of compensatory paradoxical septal
motion. RV diastolic function also recovered, reflected by enhanced RV
maximal (-) dP/dt, reduced RV diastolic area, and decreased RV filling
pressure. Improvement in RV performance was evident within 5 minutes of
reperfusion, with further recovery that plateaued by 30 minutes in all
animals. After 60 minutes of reperfusion, postmortem analysis
showed no gross abnormalities. In all animals, histopathologic
analysis demonstrated normal myocardium or minimal interstitial
edema only (Figs 7 and 8). In 1 animal,
minimal contraction band necrosis was evident with some interstitial
hemorrhage and neutrophil accumulation.
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Effects of Reperfusion Induced by Pharmacological Lysis of
Thrombotic Occlusions (Group 2)
Thrombolysis successfully recanalized
the RCA in 10 animals (5
with t-PA; 5 with streptokinase). The mean interval to reperfusion was
14.5±2.3 minutes. Thus, the mean duration of occlusion was
69.7±2.8
minutes (range, 51 to 80 minutes), a value not significantly different
from that for the other groups. In contrast to the prompt and striking
recovery of RVFW function after balloon deflation, reperfusion induced
by clot lysis resulted in minimal recovery of RVFW contraction for the
group overall (Figs 2 and 6). Individual animals
manifested variable
immediate responses to reperfusion induced by thrombolysis. Two
patterns were evident, differentiated by the extent of initial
improvement in RVFW contraction and the presence or absence of RVFW
swelling within the first 5 minutes. RVFW thickening and shortening
improved promptly after reperfusion in 3 animals; in 7 others, RVFW
contraction failed to recover at all. The lack of early recovery of
RVFW function was associated with abrupt reperfusion-induced increments
in RVFW diastolic thickness (Fig 2) not seen initially in
animals
manifesting early return of contraction or evident at any time in group
1 animals. These striking increases in diastolic thickness progressed
over the 60-minute observation interval (Fig 2). Although they
were
most prominent in the middle segments of the RVFW at all intervals,
they also often extended into the anterior and posterior segments.
Animals in which thrombolytic reperfusion led to immediate improvement
in RVFW function did not manifest striking initial increases in RVFW
diastolic thickness. However, in all such animals, increments in wall
thickness developed slowly and progressively over time. By 60 minutes,
the magnitude was similar to that in animals manifesting abrupt wall
thickening. Furthermore, in animals with initial recovery of RVFW
contraction, the subsequent progressive increments in wall thickness
were associated with a deterioration in RVFW function. In fact, at 60
minutes, no differences were detectable in the two subsets with respect
to RVFW end-diastolic wall thickness or RVFW function.
Thus, compared with animals subjected to balloon occlusion-reperfusion,
animals in which clot lysis was induced exhibited markedly depressed
RVFW function (Fig 6).
Although RVFW swelling was
associated with depressed RVFW function, in
keeping with our previous observations,32 33
increments in
diastolic wall thickness were paralleled by reductions in the extent of
RVFW dyskinesis. Thus, despite the lack of recovery of RVFW
contraction, global RV performance improved as the mechanically
disadvantageous dyskinetic RVFW became less distensible in association
with the increased wall thickness. The RVFW appeared thick and
edematous but without evidence of grossly visible hemorrhage.
Interstitial edema, myocardial cell swelling, contraction band
necrosis, and intramyocardial hemorrhage were evident microscopically
(Figs 7 and 8). In the group overall, moderate
or severe interstitial
edema involved >40% of the middle RVFW segment. Myocyte swelling was
evident and was markedly greater than that seen in the other three
groups (Figs 7 and 8). In all animals,
thrombolytic reperfusion
resulted in striking and diffuse contraction band necrosis, with
moderate or severe involvement of 35% of the middle RVFW segment, a
phenomenon only rarely seen in the other groups (Figs 7 and
8).
Contraction band necrosis was seen exclusively in regions with
interstitial edema and usually was severe. Although differences in
intramyocardial hemorrhage between the groups were not statistically
significant, 4 of 10 animals in group 2 exhibited striking hemorrhage,
an incidence not seen in any other group. Neutrophil infiltration was
striking also in 3 of 10 group 2 animals. Hemorrhage and neutrophil
accumulation, when present, occurred exclusively in regions with
intense edema and contraction band necrosis.
Recanalization Without Thrombotic Occlusions but With Systemic
Lytic State (Group 3)
Reperfusion by balloon deflation resulted in
prompt restoration of
RCA flow with a mean duration of occlusion of 61±0.5 minutes (range,
60 to 62 minutes), similar to that in other groups. However, in
contrast to group 1, minimal recovery of RVFW function was evident
(Figs 3, 5, and 6). The response
was most similar to that in group 2
animals. Reperfusion led to significant increments in RVFW diastolic
thickness associated with depressed RVFW contraction (Figs 3
and 6). As
in group 2, the immediate responses of individual animals varied. RVFW
swelling occurred abruptly in 4 animals; in 3, RVFW function failed to
recover (Fig 3), and in 1, RVFW function improved in 60 minutes
in
association with a gradual decrease of wall thickness beginning 30
minutes after reperfusion. In 1 animal, reperfusion resulted in prompt
improvement of RVFW function that later deteriorated in parallel with
progressively increasing RVFW diastolic thickness. As in group 2
animals, the increases in wall thickness were associated with reduced
RVFW dyskinesis. Consequently, global RV performance improved despite
profound depression of RVFW contraction (Figs 3 and
6).
Increased RVFW thickness and improved RVFAC were
associated with
decreases in end-systolic and end-diastolic areas. Although
RV diastolic size decreased after reperfusion, RV filling pressure
increased, probably reflecting altered compliance associated with RVFW
swelling. Mild interstitial edema and increased myocyte diameter were
evident microscopically, both more striking though not statistically
different from changes in group 1 (Figs 7 and
8). There was no evidence
of contraction bands or neutrophil accumulation. Although the overall
extent of intramyocardial hemorrhage was not different from that seen
in group 1, diffuse vascular congestion characterized by plugging with
clumped erythrocytes was evident (Fig 8), a pattern not seen in
other
groups.
Effects of Reperfusion of Thrombotic Occlusions by Direct
Angioplasty (Group 4)
Reperfusion by direct angioplasty resulted in
prompt restoration
of flow in all animals. In 1, nonocclusive residual thrombus was
successfully resolved with repeated balloon inflation. The mean
duration of occlusion was 69±4 minutes (range, 60 to 82 minutes),
which was not significantly different from that in other groups. In all
animals, reperfusion by direct angioplasty resulted in prompt recovery
of RVFW contraction and consequently enhanced global RV performance
(Figs 4 through 6). As in group 1
and in contrast to animals reperfused
in the presence of a systemic lytic state, improvement in RVFW
performance was not associated with RVFW swelling. Compared with
thrombolysis of thrombotic occlusions,
recanalization of thrombi by PTCA resulted in
minimal histological abnormalities (Figs 7 and
8), with only mild
interstitial edema, slight myocyte swelling, rare contraction bands,
and no intramyocardial hemorrhage or neutrophil accumulation.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our observations indicate that the responses of ischemic myocardium to reperfusion are influenced by factors beyond those effects attributable to ischemia and reperfusion per se. Pharmacological lysis of coronary thrombi associated with the induction of a systemic lytic state results in immediate echocardiographic and early histological alterations in ischemic myocardium characteristic of reperfusion injury and associated with impaired functional recovery. Such changes also are evident, although to a lesser extent, when reperfusion of nonthrombotic occlusions is induced by mechanical recanalization (balloon deflation) with a concomitant systemic lytic state but not in the absence of a lytic state. Thus, the presence of a systemic lytic state exerts independent adverse effects on reperfused myocardium. However, such effects were not seen with direct recanalization of thrombotic occlusions by mechanical interventions. In aggregate, these findings indicate that the induction of a systemic lytic state, together with products released by lysis of intracoronary thrombi, generates a unique and injurious milieu that exerts adverse effects on reperfused myocardium.
Common Effects of Occlusion and Disparate Effects of
Reperfusion
Our findings are consistent with those of previous studies
documenting deleterious effects of acute RCA occlusion on RV
function.32 33 35 Thus, ischemia results
in RVFW
dyskinesis and depressed global RV performance, regardless of the
method of induction of RCA occlusion. Under these conditions, global RV
function is determined by LV septal contractile contributions that
stretch the dyskinetic RVFW and generate an active, albeit depressed,
RV systolic waveform through septal-mediated systolic ventricular
interactions.
Nevertheless, as shown in the present study, the responses to reperfusion differ, depending on the presence or absence of a lytic state. Mechanical recanalization in the absence of a systemic lytic state results in prompt improvement of RVFW contraction and consequently global RV performance. In contrast, reperfusion by thrombolysis of coronary thrombi results in RVFW swelling by ultrasound, with interstitial and myocyte edema, contraction band necrosis, and intramyocardial hemorrhage, evident microscopically, all associated with impaired recovery of RVFW function. After balloon deflation to induce reperfusion of nonthrombotic occlusions in the absence of a systemic lytic state or direct angioplasty of thrombotically occluded vessels, these changes were not seen. However, they did occur in a similar, although less severe, pattern when mechanical recanalization was performed in association with an induced systemic lytic state.
In the present study, reperfusion in the presence of a systemic lytic state improved global RV performance, which is attributable to reduction in the extent of mechanically disadvantageous RVFW dyskinesis associated with reperfusion-induced increments in RVFW thickness. The fact that reperfusion-induced regional wall swelling and stiffening can substantially improve global ventricular performance is consistent with previous results after antegrade32 and retrograde collateral33 reperfusion of an ischemic right ventricle and antegrade reperfusion of the left ventricle.36 37 38 39 40 The biphasic response of regional RVFW contraction in the present study, characterized by acute improvement followed by rebound deterioration associated with thrombolytic reperfusion-induced increments in wall thickness, is consistent with previous results in studies of reperfused RV and LV segments.32 41
Deleterious Effects of a Systemic Lytic State
Reperfusion
injury is thought to result from direct and indirect
effects on myocardium attributable to both reperfusion and
ischemia
itself10 14 15 26 42
mediated through
their combined effects on microvascular perfusion and
permeability,1 27 42 43 44 45
generation of oxygen-derived free
radicals,46 47 48 49
activation of neutrophils and
complement,50 51 and increased intracellular
calcium.15 The abrupt wall swelling, interstitial edema,
and intramyocardial hemorrhage observed are characteristic of
reperfusion-induced alterations of microvascular
permeability.1 13 14 15 27 32 36 37 38 39 40 41 42 43 44 45
The abrupt derangements
in RVFW structure and function seen in this study when reperfusion was
induced in the presence of a systemic lytic state are consistent with
previous observations implying that a systemic lytic state can, in and
of itself, increase vascular permeability.52 The increases
have been attributed to the direct and indirect effects of plasmin on
the vessels themselves and on blood cell
elements.52 53 54 55
Such effects may be the consequences of (1) nonspecific protease
activity degrading essential components that disrupt the endothelial
barrier; (2) activation and adherence of neutrophils; (3) complement
activation; (4) fibrinogenolysis, resulting in the generation of
fragments that can increase permeability; (5) platelet activation with
the consequent release of vasoactive substances; and (6) alterations in
plasma viscosity.
Although previous studies in experimental animals have shown that pharmacological coronary thrombolysis in animals reduces infarct size,30 neither initial nor long-term functional impacts of thrombolysis have been well delineated, nor has the potential impact of reperfusion injury associated with a systemic lytic state been elucidated. Furthermore, the response of ischemic myocardium to recanalization of thrombotically occluded vessels induced by primary angioplasty in animals has received little attention.31 In the present study, although the thrombolytic milieu contributed to reperfusion injury even in the absence of intracoronary thrombus, reperfusion induced by pharmacological lysis of thrombotic occlusions was more adverse, with increased microvascular leakage and myocardial damage. Contraction band necrosis, an indicator of irreversible myocyte damage, was seen only under those conditions. In contrast, the lack of reperfusion injury and the remarkable early recovery of RVFW contraction in animals in which direct angioplasty was applied to thrombotically occluded vessels indicate that dissolution of intracoronary thrombus does not induce the deleterious effects typical of thrombolysis with a systemic lytic state. The combination of clot lysis and a systemic lytic state, however, may be particularly deleterious. We can only speculate as to the mechanisms responsible for the distinctive pattern of injury seen with clot lysis. Potential additional culprits include distal microemboli, fibrin split products, vasoactive humors released by platelets and/or vascular endothelium, and other factors.
Clinical Implications
In both experimental animals and
humans, important differences
exist between the ventricles with respect to myocardial structure and
function, coronary anatomy, oxygen supply and demand, and responses to
ischemia and reperfusion.32 33 Therefore, caution
must be used when the present experimental results are extrapolated
to reperfusion interventions in patients with myocardial infarction in
general and to the responses of the ischemic left ventricle in
particular. Nevertheless, our observations may have clinical
implications for patients with acute myocardial infarction. Although
the incidence, mechanisms, and impact of reperfusion injury in human
subjects are unclear, its existence is
not.10 15 18 19 20 26 56 57 58 59
Reperfusion injury may contribute
to myocardial stunning. Although ischemia itself undoubtedly
delays the recovery of myocardial function after thrombolysis, PTCA,
and coronary bypass surgery, reperfusion injury is thought to play a
pathogenic role.26 Delayed recovery is particularly
prevalent after
thrombolysis.7 8 9 16 17 18 19 20
The systemic lytic
state may contribute to stunning through effects mediated by
reperfusion injury. Results in autopsy studies document an association
between thrombolysis and hemorrhagic
infarction,60 61 62 63 a
phenomenon that reflects severe mircrovascular injury that results in
extravasation of erythrocytes into reperfused
myocardium.14 27 28 29
Intramyocardial hemorrhage is not seen
when occlusion occurs without reperfusion1 14 and is
notably absent when reperfusion is induced by direct angioplasty
(rather than by thrombolysis).63 However, successful
rescue angioplasty in patients unresponsive to thrombolysis, which
thereby reestablishes perfusion in the presence of a systemic lytic
state, can result in hemorrhagic infarction.63 Regardless
of whether hemorrhage occurs exclusively in regions of myocardium
already irreversibly injured and predestined to necrosis, its presence
is a marker of a unique kind of reperfusion injury. Taken together with
findings from the present study, such observations support the
concept that a systemic lytic state may be deleterious with respect to
exacerbating reperfusion injury.
Compared with successful thrombolysis, recanalization of coronary thrombi by primary angioplasty may confer specific benefits.21 22 23 24 25 Although such salutary effects, if confirmed by further studies, may depend on more rapid or complete reperfusion, they may reflect avoidance of injury associated with a systemic lytic state. Even if direct angioplasty has unique attributes related to our observations, logistical and economic limitations will limit its widespread application. Accordingly, treatment strategies designed to maximize the well-documented salutary effects of thrombolysis by minimizing potentially deleterious effects of a systemic lytic state on reperfused myocardium are promising. Because the adverse effects of a systemic lytic state are largely attributable to plasmin,52 development of novel thrombolytic agents that are even more clot selective than those presently available should facilitate not only more rapid but also enhanced salvage of jeopardized myocardium. However, determination of whether the method of recanalization of coronary thrombi influences the nature of the response of ischemic myocardium to reperfusion in patients, as in this experimental study, requires clinical validation.
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Acknowledgments |
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This research was supported in part by NIH grant HL-17646, SCOR in Coronary and Vascular Diseases, and RO1-HL-32257. We wish to express our appreciation to Linda Gallo for secretarial support, Advanced Cardiovascular Systems, Inc and Cordis Corp (Miami, Fl) for interventional equipment, and Johnson & Johnson Interventional Systems for unpolished stents.
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Footnotes |
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Reprint requests to James A. Goldstein, MD, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073-6769.
Received July 25, 1994; revision received January 18, 1995; accepted January 28, 1995.
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