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Circulation. 1995;92:500-510

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(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.

Yoshio Ohnishi, MD; Michelle C. Butterfield, PhD; Jeffrey E. Saffitz, MD, PhD; Burton E. Sobel, MD; Peter B. Corr, PhD; James A. Goldstein, MD

From the Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Mo.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Effects of Acute RCA Occlusion
At baseline, all hemodynamic and echocardiographic measurements were normal in all animals (Figs 1 through 6DownDownDownDownDownDown). 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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  		Figure 1. Echocardiographic two-dimensional and M-mode (MM) images with simultaneous cursor-timed ECG (arrow) in a group 1 animal subjected to balloon occlusion alone. Baseline study at end diastole (ED) and end systole (ES) documents normal right ventricular (RV) and left ventricular (LV) chamber size; the RV free wall (FW) thickens (arrows) and shortens toward the interventricular septum (IVS) and LV posterior wall (PW). After 1 hour of occlusion, in systole the IVS bulged paradoxically into the RV cavity (open arrow); the RVFW was dyskinetic (solid arrows), and the RV fractional area change (FAC) was depressed. At ED, RV area was increased, septal curvature was reversed (large arrows), and LV area was decreased. During early reperfusion and over 30 minutes, there was prompt improvement in RVFW thickening and shortening (small arrows), with increased RVFAC. RV diastolic area decreased, diastolic septal curvature was less flattened (arrows), and LV area increased. RVFW diastolic thickness (small arrows) did not increase. Paradoxical septal motion persisted (open arrow) but was diminished. These changes persisted over the 60-minute reperfusion interval.



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  		Figure 2. Echocardiographic images in a group 2 animal subjected to pharmacological lysis of thrombotic occlusion. At baseline, right ventricular (RV) and left ventricular (LV) chamber size and function were normal. After 1 hour of occlusion, RV free wall (FW) thickening and shortening were absent, the RVFW was dyskinetic (large arrows), and RV fractional area change (FAC) was depressed. In systole, the septum bulged paradoxically into the RV cavity (open arrow). At end diastole (ED), the RV was dilated, diastolic septal curvature was reversed (large arrows), and LV size was reduced. After acute reperfusion, RVFW contraction did not recover but became less dyskinetic in association with striking increases of RVFW ED thickness (small arrows). Despite a lack of RVFW thickening and shortening and diminished paradoxical septal motion, RVFAC was increased, RV diastolic size was decreased, septal curvature was less flattened, and LV area was increased. Over 60 minutes, RVFW diastolic thickness increased further, and although RVFW thickening and shortening were absent, RVFW dyskinesis was further reduced and RVFAC increased despite diminished paradoxical septal motion. RV diastolic size was decreased, septal curvature had normalized, and LV size was increased. ES indicates end systole; MM, M mode; IVS, interventricular septum; and PW, posterior wall.



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  		Figure 3. Echocardiographic images in a group 3 animal subjected to balloon deflation in the presence of a systemic lytic state. At baseline, right ventricular (RV) and left ventricular (LV) chamber size and function were normal. After 1 hour of occlusion, RV free wall (FW) thickening and shortening were absent, the RVFW was dyskinetic (large arrows) and RV fractional area change (FAC) was depressed; the septum bulged paradoxically (open arrow) into the RV cavity. At end diastole (ED), the RVFW was thin, the RV cavity was dilated, the septum was flattened, and LV size was reduced. After acute reperfusion, the dyskinetic RVFW became akinetic in association with a marked increase in RVFW diastolic thickness (small arrows). Despite a lack of RVFW thickening and shortening, RVFAC increased. RV diastolic area was reduced and septal curvature was less flattened. Over 30 to 60 minutes, RVFW diastolic thickness increased further, thereby further reducing the magnitude of RVFW dyskinesis, and although RVFW thickening and shortening were absent, RVFAC increased despite diminished paradoxical septal motion. ES indicates end systole; MM, M mode; IVS, interventricular septum; and PW, posterior wall.



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  		Figure 4. Echocardiographic images in a group 4 animal subjected to direct angioplasty (percutaneous transluminal coronary angioplasty, PTCA) of a thrombotic occlusion. Baseline study documents normal right ventricular (RV) and left ventricular (LV) function. After 1 hour of occlusion, the RV free wall (FW) was thin and dyskinetic (solid arrows), RV cavity was dilated, and RV fractional area change (FAC) was depressed. PTCA resulted in prompt improvement in RVFW thickening and shortening (small arrows) with increased RVFAC. RVFW diastolic thickness (arrows) did not increase. RV diastolic size decreased, diastolic septal curvature was less flattened (small arrows), and LV area was increased. Paradoxical septal motion persisted (open arrow) but was diminished. Over 60 minutes, there was further recovery of RVFW contraction and increased RVFAC. ED indicates end diastole; ES, end systole; MM, M mode; PW, posterior wall; and IVS, interventricular septum.



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  		Figure 5. Graphs comparing changes over time in right ventricular (RV) end-diastolic and peak systolic pressures and RV maximum negative (-) and positive (+) dP/dt. {circ}, group 1; {blacksquare}, group 2; {bullet}, group 3; and {square}, 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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  		Figure 6. Graphs comparing changes over time in right ventricular free wall (RVFW) end-diastolic thickness (top left), RVFW motion score (bottom left), RVFW systolic shortening (top right), and RV fractional area change (FAC) (bottom right). Legend as in Fig 5Up. *P<.05 with respect to significant changes over time within each group; significant differences between groups at any given time point are indicated (+ versus group 1 and group 4; - versus group 1).

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 6UpUpUpUpUpUp). 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 6UpUpUpUpUpUp). 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 4UpUpUpUp). 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 1Up, 5Up, and 6Up). 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 7Down and 8Down). In 1 animal, minimal contraction band necrosis was evident with some interstitial hemorrhage and neutrophil accumulation.



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  		Figure 7. Bar graphs comparing magnitude of quantitative histological changes in the middle segments of the right ventricular free wall. For each group, the mean histological scores for interstitial edema, contraction band necrosis (CBN), intramyocardial hemorrhage, and polymorphonuclear (PMN) cell infiltration are illustrated, as is mean myocyte cell width (in micrometers). PTCA indicates percutaneous transluminal coronary angioplasty. *P<.05 with respect to significant differences between groups.



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  		Figure 8. Histopathologic specimens, obtained from right ventricular free wall zones manifesting greatest wall thickness by ultrasound and gross inspection, stained with hematoxylin and eosin, and viewed at magnification x320. A, In an animal subjected to reperfusion by balloon release alone (group 1), myocardium was normal. B, Thrombolytic reperfusion of thrombotic occlusion in a group 2 animal led to diffuse widening of interstitial spaces (asterisks) consistent with edema, prominent contraction band necrosis (large open arrows), and intramyocardial hemorrhage (solid dark arrows). C, In an animal subjected to balloon release in presence of systemic lytic state (group 3), interstitial edema (asterisks) and vascular plugging (arrows) are evident. D, In an animal subjected to direct angioplasty of thrombotic occlusion (group 4), the myocardium was normal.

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 2Up and 6Up). 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 2Up) 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 2Up). 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 6Up).

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 7Up and 8Up). 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 7Up and 8Up). 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 7Up and 8Up). 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 3Up, 5Up, and 6Up). 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 3Up and 6Up). 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 3Up), 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 3Up and 6Up).

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 7Up and 8Up). 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 8Up), 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 6UpUpUp). 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 7Up and 8Up), with only mild interstitial edema, slight myocyte swelling, rare contraction bands, and no intramyocardial hemorrhage or neutrophil accumulation.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
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.


*    Acknowledgments
 
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.


*    Footnotes
 
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.


*    References
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