EXPERIMENTAL STUDY
Platelet GPIIb/IIIa receptor blockade reduces infarct size in a canine model of ischemia-reperfusion
John G. Kingma, Jr., PhD, FACC*,
Sylvain Plante, MD, FACC*  and
Peter Bogaty, MD*
* Department of Medicine, Faculty of Medicine, Laval University, Sainte-Foy, Quebec, Canada
Quebec Heart Institute, Laval Hospital, Sainte-Foy, Quebec, Canada
Manuscript received July 14, 1998;
revised manuscript received August 9, 2000,
accepted August 11, 2000.
Reprints requests and correspondence: Dr. J. G. Kingma, Jr., Research Center, Laval Hospital, 2725, Chemin Sainte-Foy, Sainte-Foy, Quebec, G1V 4G5, Canada
john.kingma{at}med.ulaval.ca
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Abstract
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OBJECTIVES
We studied the effects of N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate (MK-0852) (platelet GPIIb/IIIa receptor blocker) on peak reactive hyperemia, distribution of blood flow, regional contractile function and infarct size in a canine model of acute ischemia-reperfusion injury.
BACKGROUND
Platelet activation and formation of platelet microaggregates in coronary vessels could contribute to ischemia-induced myocyte injury. Inhibition of platelet aggregation could reduce ischemia-reperfusion injury.
METHODS
Three groups of dogs (n = 10/group) were studied; group 1—heparin (HEP) (100 U/kg/h intravenously), group 2—MK-0852 (300 µg/kg intravenous bolus followed by 3 µg/kg/min for 3 h) and group 3—MK-0852 plus HEP. Infarct size after 60 min regional ischemia and 3 h reperfusion was evaluated by tetrazolium staining and normalized to risk area (Monastral blue dye).
RESULTS
Infarct size in HEP-treated controls was 32.4 ± 2.8%; in MK-0852 without or with HEP groups, infarct size was 17.4 ± 1.9% (p = 0.001) and 23.4 ± 3.0% (p = 0.04), respectively. Cardiac hemodynamics and rate-pressure product were comparable between groups. Multivariate analysis using collateral blood flow as the independent variable confirmed the cytoprotective actions of MK-0852. Postischemic peak reactive hyperemia in the infarct-related artery was depressed in all groups; during reperfusion, transmural distribution of myocardial blood flow returned to near control levels, but severe regional hypokinesia persisted.
CONCLUSIONS
Diminished infarct size with MK-0852 treatment suggests an additional mechanism of benefit for GPIIb/IIIa blockers beyond stabilization of a "culprit" acute coronary lesion. This cytoprotective effect was unrelated to preservation of coronary vasoreactivity (assessed by reactive hyperemia), restoration of blood flow across the myocardium or acute improvement in contractility.
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Abbreviations and Acronyms
| | GPIIb/IIIa | = platelet glycoprotein IIb/IIIa receptor | | HEP | = heparin | | LV | = left ventricle | | MI | = myocardial infarction | | MK-0852 | = N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate | | PRISM-PLUS | = Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial | | PRP | = platelet rich plasma | | REP | = coronary reperfusion |
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Early restoration of arterial patency during acute myocardial infarction (MI) with thrombolysis or angioplasty significantly limits myocardial necrosis. This beneficial effect may be blunted by acute or subacute reocclusion or by the more protracted process of postangioplasty restenosis. Activated platelets participate in intravascular thrombus formation; they may: 1) cause reocclusion of the "culprit" coronary artery lesion, 2) form embolic aggregates compromising myocardial perfusion thereby exacerbating the effects of ischemia and 3) release vasoactive substances that may adversely affect downstream perfusion as well as have deleterious electrophysiologic effects. A common pathway for all platelet agonists has recently been described (1); the platelet-glycoprotein IIb/IIIa complex (GPIIb/IIIa) in activated platelets binds the soluble adhesive proteins fibrinogen, von Willebrand factor, fibronectin and vitronectin.
Clinical studies using either monoclonal antibodies (2,3) or other selective GPIIb/IIIa receptor antagonists have shown promise in reducing the complications associated with acute coronary syndromes (4–7) and with percutaneous coronary interventions (8) including refractory angina, MI and mortality in unstable angina and non-Q wave myocardial infarct patients without significant increases in bleeding (6–8). Studies in whole animals have reported antinecrosis and antiarrhythmic effects of platelet activating factor blockers (9–13). In this study we examined whether blockade of GPIIb/IIIa receptors by N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate (MK-0852) would limit infarct size and modify the potentially deleterious consequences of increased intravascular platelet aggregation on coronary reactive hyperemia and regional myocardial contractile function.
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Methods
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All procedures used in this study are in accordance with the "Guide to the Care and Use of Experimental Animals" (Vols. 1 and 2) of the Canadian Council on Animal Care; the Laval University Animal Ethics Committee also approved these studies. Thirty-six adult mongrel dogs of either sex (weight 20 to 25 kg) were premedicated with diazepam (1 mg/kg intravenous) and fentanyl (20 µg/kg intravenous) and then anesthetized using sodium pentobarbital (25 mg/kg intravenous). Dogs were intubated and mechanically ventilated; end-expiratory pressure was maintained at 5 to 7 cm H2O. Saline was administered intravenously at 100 mL/h to replace fluid loss. A splenectomy was performed to prevent significant alterations in blood volume and hematocrit (14). Body temperature was kept between 37.5 to 38.5°C by a water-jacketed Micro-Temp heating unit (Zimmer, Dover, Ohio) since temperature-induced variability during ischemia-reperfusion may be an important predictor of myocyte necrosis (15).
A left thoracotomy was performed in the fifth intercostal space. Polyethylene catheters (7F) were inserted into the internal thoracic artery, the left atrium and in both femoral arteries and veins for administration of drugs and fluids. A 5F microtipped pressure transducer (Millar Instruments, Inc., Houston, Texas) was placed in the left ventricle (LV) cavity through the apex to measure LV pressure and its first derivative; a 7F pigtail catheter was advanced to the aortic root via the left femoral artery. A segment of the main circumflex artery was isolated proximal to its first major marginal branch. Coronary blood flow was measured by transit time flowmetry (T206, Transonic Systems Inc., Ithaca, New York). The Transonic flowmeter uses wide-beam ultrasonic illumination to provide a measure of volume flow in mL/min. A catheter (22 intracath) was inserted in the lumen of the left circumflex artery immediately distal to the snare occluder and flowmeter (16).
Ultrasonic crystals (Triton Technologies, San Diego, California) were positioned in the midmyocardium of the ischemic and nonischemic perfusion beds as previously described (17). The chest cavity was then covered with plastic film to prevent myocardial cooling.
Experimental design.
Dogs were allowed to stabilize for 20 min; under steady-state hemodynamic conditions (i.e., baseline and every 30 min during reperfusion) the left circumflex artery was occluded for 20 s to assess the reactive hyperemic response of the infarct-related artery as described previously (18,19).
Dogs were subjected to 60 min regional coronary occlusion, randomly divided (by rotation through the various treatments) to three study groups and given: 1) heparin (HEP; 100 U/kg/h intravenously), 2) MK-0852 (300 µg/kg intravenous bolus over 3 min followed by 3 µg/kg/min for 3 h) and 3) HEP plus MK-0852 (as per groups 1 and 2). Treatment was initiated at the onset of coronary reperfusion (REP) and continued for 3 h. This MK-0852 dosage schedule has previously been shown to be beneficial in canine thrombosis models (20). Dogs were also given lidocaine (10 mg intravenous bolus) at 30 min coronary occlusion, 5 min before and at 5 and 10 min of REP. Hearts that went into ventricular fibrillation were cardioverted (DC shock  50 J); when hearts could not be defibrillated after two attempts, the animal was euthanized and not entered into the data analysis.
Measurement of ex vivo platelet aggregation.
In a parallel study, dogs (n = 4) were given MK-0852 as described earlier. Blood (5 mL) was collected from an indwelling femoral vein catheter into Vacutainer tubes containing 0.5 mL of 3.8% sodium citrate; after collection (0, 10, 30, 60, 120 min) platelet aggregation in whole blood was assessed by the impedance method of Cardinal and Flower (21) using a whole blood aggregometer (Model 592, Chrono-Log, Pennsylvania).
Flow cytometric analysis of platelet aggregation and activation.
Flow cytometric measurements were done using a modification of the method recently described by Jy and coworkers (22); platelet activation was assessed in platelet rich plasma (PRP) prepared by centrifugation of citrated whole blood at 1,000 rpm for 10 min. To 50 µL PRP was added 5 µL FITC  -CD41 to label platelets; after 10 min orbital shaking at 120 rpm at room temperature, samples were incubated with collagen (final concentration 5 µg/mL) and further shaken for 5 min. The reaction was stopped by the addition of p-formaldehyde (2% final concentration), incubated for 10 min and diluted with 1.0 mL of PBS. The antibodies used were an antihuman CD41 (clone SZ22), a murine IgG1 monoclonal antibody that specifically binds to GPIIb receptors (Coulter-Immunotech, Burlington, Ontario) and antihuman CD 62P (clone CLB-Thromb/6; canine CD 62P was not available), a murine IgG1 monoclonal antibody that recognizes P-selectin; neither of these antibodies inhibited platelet aggregation induced by collagen. All antibodies were used at optimum concentration for maximum fluorescence and minimal nonspecific binding.
Samples were analyzed within 2 h of collection in a Coulter EPICS Elite ESP flow cytometer (Coulter Corp., Hialeah, Florida) equipped with a 100-mV argon laser to produce a laser beam at 488 nm, detecting FITC and PE fluorescence at band-pass filters of 525 and 575 nm, respectively. Five thousand platelets were analyzed by forward and side scatter; identity was confirmed using the anti-GPIIb monoclonal antibody, CD41. An electronic bit map was set around the platelet population and adjusted for each sample to ensure that >98% of the particles analyzed were positive for GPIIb.
Hemodynamic measurements.
Standard lead II of the scalar electrocardiogram was used to determine heart rate. Heart rate, arterial pressures, coronary flow and myocardial segment lengths were measured throughout the experimental protocol. All analog data were recorded on a 12-channel direct-writing oscillograph (Yokogawa OR1200A; Electro-Meters, Dorval, Canada) and on videotape using a TEAC XR-510 recorder.
Measurement of regional myocardial blood flow.
Regional myocardial blood flow was determined using 15 µm microspheres suspended in saline (NEN, Boston, Massachusetts) and labeled with 113Sn, 85Sr, 95Nb or 46Sc. Microspheres were agitated with a vortex agitator before injection through the left atrial cannula and flushed with 15 mL normal saline. Reference arterial blood was withdrawn from the internal thoracic artery cannula at a rate of 7.5 mL/min beginning 10 s before microsphere injection and continuing for 2 min. Myocardial blood flow was evaluated at baseline, 30 min coronary occlusion and 180 min REP.
Infarct and risk zone analysis.
At the end of each study the circumflex coronary artery was ligated at the site of previous occlusion, and 10 mL of Monastral blue dye was injected via the atrial catheter to delineate the area at risk. Under deep pentobarbital anesthesia, cardiac arrest was induced by intraatrial injection of saturated potassium chloride. A 1.5% solution of warmed (37°C) 2,3,5-triphenyltetrazolium chloride was infused into the ischemic region via the coronary artery cannula (distal to the snare occluder) for a period of 30 min. The heart was rapidly excised and rinsed in saline at room temperature; atria, large epicardial vessels and right ventricle were removed, and the LV was fixed in 10% buffered formaldehyde. The LV was cut from apex to base, and the outline of each slice, the necrotic area and risk area were traced onto acetates. The LV area, risk area and necrotic area were determined using a digitizing tablet (Summagraphics II Plus; Seymour, Connecticut) interfaced with a personal computer and analyzed with SigmaScan software (SPSS Inc., California). Results are expressed as the risk area indexed to total LV mass and the area of necrosis indexed to either risk area or total LV mass.
Regional myocardial blood flow and reactive hyperemic response.
Tissue samples from the central portion of the nonischemic and ischemic zones were subdivided into endocardial, midmyocardial and epicardial segments. Myocardial tissue from the lateral border zones was discarded to avoid potential cross-contamination. Radioactivity in myocardial tissue and blood reference samples was measured in a gamma-well scintillation counter (Cobra II, Canberra Packard Instruments, Montreal, Canada) with standard window settings. Tissue counts were corrected for background, decay and isotope spillover; regional myocardial blood flow was calculated with computer software (PCGERDA, Packard Instruments, Montreal, Canada) and expressed as mL/min/g of myocardium.
Control and peak hyperemia blood flow were directly determined from strip chart recordings. Peak flow is the maximum mean flow during the reactive hyperemia response; this value was normalized to baseline values using the equation: [peak flow-control flow/control flow] x 100%.
Cardiac hemodynamics and systolic fractional shortening.
Heart rate and arterial blood pressure were measured and averaged over five continuous beats during normal sinus rhythm. Left ventricular dP/dt was used to define the timing of the cardiac cycle for segment length measurements; systolic fractional shortening was calculated as previously described (23).
Data analysis.
Cardiac hemodynamic parameters, coronary blood flow and myocardial contractile function during control conditions and after administrations of the respective pharmacologic treatments were evaluated using analysis of variance for repeated measures. When a significant effect of treatment was obtained, comparisons within experimental groups were made using Scheffe’s post-hoc test. Myocardial blood flow and infarct size were compared by analysis of variance. The relation between infarct size and blood flow within the ischemic zone was initially analyzed by analysis of covariance for linear regressions; infarct size (normalized to risk area) was the dependent variable, and blood flow within the inner two-thirds of the LV wall was the covariate. Since we were unable to reproduce the classic inverse relation between infarct size and subendocardial blood flow due to the narrow range of blood flow values (0.03 to 0.10 mL/min/g), a multivariate analysis was done to ascertain possible differences in infarct size. All statistical procedures were performed using the SAS statistical software package (SAS Inc., Cary, North Carolina). A p value less than 0.05 was used to indicate a significant difference in mean values.
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Results
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Thirty-six dogs were entered into the study. One was excluded due to an absent reactive hyperemic response (possibly due to high coronary collateral blood flow levels in the ischemic zone). Five dogs could not be resuscitated after two attempts at cardioversion and succumbed to ventricular fibrillation. Data are reported for 30 dogs that completed the protocol.
Platelet aggregation and activation.
Platelet aggregation in whole blood was completely abolished by MK-0852. Flow cytometry was also used to examine platelet aggregation and activation of CD41, a pan-platelet marker, in PRP (Fig. 1). Before MK-0852 treatment (Fig. 1A) some spontaneous platelet aggregation occurred in the absence of collagen; addition of collagen increased both side-scatter and CD41 fluorescence indicating enhanced platelet aggregation (Fig. 1B). No spontaneous platelet aggregation could be detected after MK-0852 without (Fig. 1C) or with (Fig. 1D) collagen.
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Figure 1 Effects of MK-0852 on collagen-induced platelet glycoprotein IIb/IIIa receptor activation. Platelet rich plasma from venous blood (i.e., from the ischemic zone) was prepared as described in the Methods section. Some spontaneous platelet aggregation was observed before the addition of collagen (5 µg/mL) in vehicle treated dogs (A); this did not occur after administration of MK-0852 (C). Collagen induced significant platelet aggregation in vehicle treated dogs (B), but this reaction was significantly blunted with MK-0852 treatment (D). MK-0852 = N-acetyl-cys-asn-(5,5-dimethyl-4-thiazolidine-carbonyl)-4-amino-methyl-phe-gly-asp-cys, monoacetate.
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Cardiac hemodynamics.
Baseline heart rate, mean arterial pressure and diastolic coronary perfusion pressure were similar in all experimental groups; changes due to coronary occlusion and REP are summarized in Table 1. Hemodynamic profiles were similar for all groups; heart rate increased during coronary occlusion and then remained higher than baseline values during REP. Rate-pressure product, an indirect index of myocardial oxygen demand, was similar for each experimental group (Fig. 2); this suggests that myocardial oxygen demand did not influence intergroup infarct size results.
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Figure 2 Changes in rate-pressure product during the ischemia-reperfusion protocol. Controls (i.e., heparin; open circles), MK-0852 plus heparin (open squares), MK-0852 (open triangles); the same symbols are used to identify each treatment group in all figures. I = ischemia; R = reperfusion. Data are means ± standard error of the mean.
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During ischemia significant hypokinesia occurred within the ischemic zone (Fig. 3); during REP myocardial contractile function returned to ±50% of baseline levels but remained consistently lower afterwards. Fractional shortening in nonischemic myocardium remained constant; we did not observe a compensatory increase in LV function in this region as described previously (24).
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Figure 3 Systolic segment shortening (as % of baseline value) in the ischemic-reperfused myocardium during the experimental protocol (left panel); data for the nonischemic myocardium is also shown (right panel). Controls (i.e., heparin; open circles); MK-0852 plus HEP (open squares); MK-0852 (open triangles). Data are means ± standard error of the mean.
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In the infarct-related artery, peak reactive hyperemia before ischemia was four-fold greater than control blood flow levels; during REP it was attenuated by >50% (p 0.05 vs. baseline) in all groups. Resting blood flow in ischemic and nonischemic myocardium was similar as shown in Figure 4. At 30 min coronary occlusion, blood flow within the ischemic zone was 0.06 ± 0.03, 0.07 ± 0.05 and 0.08 ± 0.05 mL/min/g in HEP, MK-0852 and MK-0852 plus HEP treated dogs, respectively (p = NS between groups). At the end of REP mean blood flow levels were similar to baseline values for all experimental groups.
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Figure 4 Blood flow across the left ventricular wall from inner (End) to outer (Epi) layers at baseline, 30 min coronary occlusion and at 180 min coronary reperfusion in ischemic (upper panel) and nonischemic (lower panel) regions. Controls (open circles); MK plus HEP (open squares); MK (open triangles). Data are means ± standard error of the mean.
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Infarct size data.
Infarct size (normalized to risk area) is shown in Figure 5; risk zone size was comparable for each group. Infarct size was 32.4 ± 2.8% in HEP-treated dogs compared with 17.4 ± 1.9% in MK-0852 (p = 0.001 vs. HEP) and 23.4 ± 3.0% (p = 0.04 vs. HEP) in MK-0852 plus HEP treated dogs. As such, MK-0852 without/with concomitant HEP treatment provides significant cardioprotection in this model of ischemia-reperfusion injury. Since important variations in coronary collateral flow occur between dogs (25), we performed a multivariate analysis taking into account both infarct size and ischemic zone blood flow during coronary occlusion (Fig. 6); significant cardioprotection (i.e., downward shift of the data vs. untreated dogs) was observed for both the MK-0852 and MK-0852 plus HEP treated dogs.
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Figure 5 Infarct size normalized to risk zone (left panel) and risk area as percent of the left ventricle (right panel) for each treatment group; data (mean ± standard error of the mean) for individual hearts (open circles) and mean values (closed squares) are shown. HEP = heparin; MK = MK-0852.
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Figure 6 Effect of MK-0852 on infarct size (% risk area) in dogs treated with MK-0852 plus HEP (open square; p < 0.05 vs. CON) or MK-0852 (open triangle; p < 0.05 vs. CON). Coronary collateral blood flow (mL/min/g) at 30-min coronary occlusion is also indicated. MK = MK-0852.
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Discussion
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In this study we documented significant cytoprotection with MK-0852 administered at the onset of REP in a canine preparation of acute ischemia-reperfusion injury. Cardioprotection occurred independently of collateral blood flow within the risk region, risk zone size or cardiac hemodynamics (i.e., metabolic oxygen demand) and distribution of myocardial blood flow.
Pathophysiological role for platelet aggregation.
Platelet activation and resultant aggregation are associated with various cardio- and cerebrovascular thromboembolic disorders including unstable angina, MI, stroke and atherosclerosis (26–28). An ongoing pattern of platelet aggregation within the infarct-related vascular bed may account for progressive tissue injury during coronary reperfusion (29); as such, antiplatelet treatments in the ischemia-reperfusion setting could exert a protective influence at the level of the microvasculature. Potential actions of MK-0852 with receptors other than the GPIIb/IIIa receptor and leukocyte-endothelium adhesion interactions might also constitute a cytoprotective mechanism against ischemia-reperfusion injury.
Clinical studies.
In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study, combination therapy with tirofiban and HEP significantly reduced the thrombus burden of the culprit lesion; this resulted in less coronary artery obstruction and improved distal flow in the infarct-related artery (8,30). Whether concomitant thrombin inhibition with HEP is essential for optimal efficacy of MK-0852 is not clear. Heparin has been shown to directly affect leukocytes and expression of adhesion molecules (31). In this study the combination of therapy with MK-0852 and HEP, administered at the onset of reperfusion, provided significant benefit against tissue necrosis, but the observed protection was not greater than that obtained with MK-0852 alone.
Earlier studies (21,31,32) speculated that inhibition of platelet aggregation could favorably affect distribution of blood flow within ischemic myocardium. Recent findings document that combination therapy with abciximab plus low-dose alteplase results in a more rapid restoration of epicardial reperfusion and possibly improved perfusion of microvessels; this resulted in greater ST resolution for patients with Thrombolysis in Myocardial Infarction flow grade 3 (33). In this study we cannot rule out a cytoprotective mechanism of the benefit of platelet inhibition independent of any effect on myocardial perfusion.
Peak reactive hyperemia and LV contractile function.
The precise mechanisms responsible for reductions in postischemic coronary flow reserve and LV contractile function remain unknown but probably involve release of reactive oxygen metabolites, microvascular plugging by platelets or leukocytes and infiltration by neutrophils (34–36). Persistently abnormal flow reserve in reperfused, viable myocardium might be due to prolonged postischemic microvascular stunning (37). In this study MK-0852 treatment did not significantly improve either the peak reactive hyperemic response of the infarct-related artery or contractile function within the ischemic vascular bed.
Conclusions.
We report that MK-0852, a cyclic heptapeptide antagonist of the platelet GPIIb/IIIa receptor, reduces infarct size in a canine preparation of acute myocardial ischemia-reperfusion injury. This cardioprotective effect was unrelated to coronary collateral flow within the ischemic zone. These data support the concept that inhibition of platelet aggregation is cytoprotective; however, the specific mechanism(s) for this cytoprotection remains undefined. The findings of this study may be relevant to the clinical management of patients with acute MI who are candidates for reperfusion therapy.
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Acknowledgments
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The authors would like to thank Dr. Marc Bossé (Viridis Biotech Inc.) for his expert assistance in performing the flow cytometry assays.
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Footnotes
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Supported by a Medical School Grant from Merck Frosst Canada Inc.
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N. Mehta, K. Uchino, S. Fakhran, M. A. Sattar, B. F. Branstetter IV, K. Au, J. S. Navratil, B. Paul, M. Lee, K. M. Gallagher, et al.
Platelet C4d Is Associated With Acute Ischemic Stroke and Stroke Severity
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J. G. Kingma Jr., C. Vincent, J. R. Rouleau, and I. Kingma
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T. Sakuma, I. Sari, C. N. Goodman, J. R. Lindner, A. L. Klibanov, and S. Kaul
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J. A. Barrabes, D. Garcia-Dorado, M. Mirabet, J. Inserte, L. Agullo, B. Soriano, A. Massaguer, F. Padilla, R.-M. Lidon, and J. Soler-Soler
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J. N. Nanas, E. Tsolakis, J. V. Terrovitis, A. Eleftheriou, S. G. Drakos, A. Dalianis, and C. E. Charitos
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L. Molero, J. Farre, A. Garcia-Mendez, P. Jimenez Mateos-Caceres, C. Carrasco Martin, I. Millas, F. Navarro, M. Cordoba, S. Casado, and A. Lopez-Farre
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J. A. Barrabes, D. Garcia-Dorado, M. Mirabet, R.-M. Lidon, B. Soriano, M. Ruiz-Meana, P. Pizcueta, J. Blanco, Y. Puigfel, and J. Soler-Soler
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