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Ann Thorac Surg 1998;65:1690-1697
© 1998 The Society of Thoracic Surgeons
a Departments of Surgery, Pathology, Pharmacology and Therapeutics, and Anesthesia, The University of British Columbia, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada
Accepted for publication February 3, 1998.
Address reprint requests to Dr Qayumi, Department of Surgery, Room 3100, 910 W 10th Ave, Vancouver, BC, Canada V5Z 4E3
e-mail: (qayumi {at}unixg.ubc.ca)
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Abstract |
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Methods. In groups 1 and 2 (n = 12 each), the left anterior descending coronary artery was ligated for 60 minutes to induce regional myocardial ischemia followed by 6 hours of reperfusion. Group 1 received the platelet-activating factor antagonist TCV-309 before ischemia, whereas group 2 did not. Group 3 (n = 3) had a sham operation.
Results. Animals in group 2 exhibited significant (p < 0.05) hemodynamic instability and myocardial depression during the reperfusion period. Despite preventive measures, 7 of the 12 animals experienced severe dysrhythmias in the form of atrial and ventricular fibrillation leading to cardiac arrest. In contrast, animals in group 1 in whom the effects of platelet-activating factor were blocked by the specific platelet-activating factor receptor antagonist TCV-309 were hemodynamically stable and had significantly (p < 0.05) better myocardial function. This significant difference in global myocardial function between the groups was observed in the presence of similar morphologic findings and regional myocardial function.
Conclusions. These results suggest that platelet-activating factor has a definite influence on global myocardial dysfunction associated with regional myocardial ischemia-reperfusion injury.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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In terms of the effects of PAF on the cardiovascular system, both the endogenous release of PAF [4] and the exogenous administration of PAF [5] have been associated with decreased cardiac output, cardiac filling pressure (preload), myocardial depression, coronary vasoconstriction, and dysrhythmias. Experimental studies [6] have shown that PAF antagonists reverse the adverse cardiovascular effects of PAF. It is well known that these dysfunctions, observed in the presence of exogenous or endogenous PAF, are also seen in patients with severe regional myocardial ischemia followed by the reintroduction of oxygenated blood (reperfusion) to the ischemic tissue. Several investigators [7, 8] have also demonstrated in various animal models that the release of PAF into the circulation during regional myocardial ischemia-reperfusion injury (RMIRI) is associated with cardiac dysfunction.
Despite all currently available evidence, the role of PAF in the pathophysiology of RMIRI remains controversial [8–16]. This is likely why the use of PAF antagonists in the treatment of myocardial infarction is delayed. The present experimental protocol was designed to help clarify the role of PAF in the pathophysiology of RMIRI using the specific PAF antagonist TCV-309, a synthetic open-chain phospholipid analogue of PAF, in a swine model of RMIRI.
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Material and methods |
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At the termination of the experiment, animals were killed using an overdose of sodium pentobarbital. All animals used in this study were maintained in accordance with the "Guidelines of the Canadian Council on Animal Care" under the supervision of the Animal Care Committee of The University of British Columbia.
Rationalization of experimental design
Because the controversies surrounding the role of PAF in RMIRI may be methodologically driven, we found it important to rationalize our methodologic approach in specific terms. To approximate the human condition for the involvement of PAF in RMIRI, careful consideration was given to the animal model. Large animal models are preferred for preclinical studies because of their hemodynamic and anatomic similarities to humans. When considering a large animal model, it is important to recognize that there are substantial differences in the formation of collateral circulation between species. Under normal conditions, humans and swine have very sparse collateral circulation, so that after acute occlusion of a coronary artery, the regional myocardial blood flow rapidly decreases transmurally to almost zero [17]. Humans and swine form collateral beds only during chronic ischemic conditions such as congestive heart failure and severe atherosclerosis. In comparison, other animal species such as the dog have a well-developed collateral circulation that more closely resembles the chronic ischemic condition in humans. We chose to model the large proportion of myocardial infarctions that take place clinically without previous ischemic heart disease and therefore used swine as a model to investigate the role of PAF in RMIRI. Further, swine and humans share a major biochemical similarity in that they both lack the enzyme xanthine oxidase, which plays a crucial although controversial role in oxygen free radical generation in some situations [18]. Given these considerations, swine appear to be a novel and appropriate model for preclinical experiments studying the pathophysiology of PAF in relation to RMIRI.
One hour of ischemia was chosen on the basis of histologic changes that occur in the swine heart during regional ischemia followed by reperfusion. Indices of ischemic damage, such as contraction band necrosis, coagulation necrosis, and infarct size, increase markedly with reperfusion after a 60-minute period of LAD ligation [17]. Postischemic reperfusion has been shown to be protective in the swine heart if initiated within 1 hour after the onset of acute myocardial infarction [17]. Durations of ischemia of less than 45 minutes cause severalfold less damage than periods of 60 minutes or longer of ischemia, and periods of ischemia longer than 90 to 120 minutes invariably cause irreversible damage despite extensive reperfusion [17]. Consequently, we chose an ischemic interval that would produce substantial damage to the heart, but that might be amenable to some degree of salvage by reperfusion or pharmacologic interventions. A 6-hour reperfusion period was chosen and is considered the length of time by which coagulation or contraction band necrosis, leukocyte (PMN) infiltration, edema, and hemorrhage become visible and are readily measurable variables [19].
TCV-309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbonyloxy) ethyl]carbamoyl] ethyl]carbamoyl]-1-propylpyridium nitrate) is a potent and long-acting specific PAF antagonist. It was chosen for this study for two main reasons. First, this drug has been highly successful in antagonizing the effects of PAF in ischemia plus reperfusion of many organs but has not yet been investigated in an in vivo model of RMIRI. Second, we wanted to test a PAF antagonist that has potential for use in humans. TCV-309 is a synthetic open-chain analogue of PAF that has been proposed for clinical application. In our studies, TCV-309 was given 1 hour before coronary ligation at a dose of 0.1 mg/kg. The duration of the effect of TCV-309 on platelet aggregation at this dose is approximately 4 to 6 hours. Therefore, by administering TCV-309 1 hour before coronary artery ligation, PAF receptors were antagonized throughout the duration of ischemia and much of the reperfusion phase.
Operative techniques
Animals were given an intramuscular injection of ketamine hydrochloride (20 mg/kg), and anesthesia was maintained with isoflurane given by inhalation (0.5% to 2.0%). Body temperature was maintained at 38.5°C with a heating pad. Blood gas measurements were made frequently throughout the operation, and values were maintained within predetermined ranges: oxygen tension, 150 to 250 mm Hg; carbon dioxide tension, 35 to 42 mm Hg; and pH 7.40 to 7.45. Tidal volume and respiratory rate were modified to maintain blood gases within these ranges. Respiratory rate was kept within 10 to 12 breaths/min and tidal volume within 10 to 12 mL/kg; animals were ventilated with 45% oxygen. The electrocardiogram and heart rate were monitored continuously.
Initially, a 20F catheter was placed into the right carotid artery for monitoring arterial blood pressure and to serve as an access port for blood withdrawal. A Swan-Ganz catheter was inserted into the pulmonary artery for monitoring pulmonary artery, pulmonary capillary wedge, and right atrial pressures. Then a median sternotomy was performed. The pericardium was opened, and a Millar catheter was inserted into the left ventricle through the left atrial appendage for measurement of left ventricular pressure. A volume catheter was also inserted into the left ventricle through the aortic root to measure left ventricular volume by means of impedance ventriculography. A pediatric Foley catheter was inserted into the coronary sinus for collection of blood samples.
The LAD was dissected free from surrounding tissue for a length of 1 to 1.5 cm. A flow transducer was placed on the dissected LAD distal to the proposed area of occlusion. An crystal to measure epicardial wall thickening was placed on the target ischemic region. Acute regional myocardial ischemia was induced by clamping the LAD with a noncrushing clamp for 60 minutes, after which time the clamp was released and the myocardium reperfused for 6 hours. Complete occlusion of the coronary artery was verified when LAD flow distal to the site of occlusion reached 0 mL/min.
Indices of assessment
Intraoperative physiologic variables were monitored in real time using a Pentium 90 computer with DataFlow software (Northboro, MA). These variables were continuously monitored and recorded. Specific measurements were made at the following intervals: before ischemia; 10 minutes after the onset of ischemia; 50 minutes after the onset of ischemia; and 10 minutes, 30 minutes, 2 hours, and 6 hours after the onset of reperfusion.
Regional myocardial function
Left ventricular wall thickening is a widely used index of regional myocardial function in experimental animals and in humans. In this study, regional myocardial function was assessed by a single-crystal pulsed Doppler epicardial wall thickening probe (supplied by Crystal Biotech, Northboro, MA). The percent thickening fraction (TF) is determined from the following formula: 
, where SE = systolic excursion in millimeters and R = range-gait depth. Validation of this technique is reported by Zhu and associates [20].
Regional blood flow was assessed before, during, and after occlusion of the LAD. Flow transducers were placed on the dissected LAD distal to the area of occlusion. The transducer was connected with PD-10 or PD-20 modules (Crystal Biotech).
Global myocardial function
Global myocardial function was assessed by the following calculated cardiac indices: cardiac index, stroke index, left and right ventricular stroke work index, ejection fraction, systolic volume, end-diastole volume, end-systole volume, end-systolic pressure–volume relationship, internal diameter shortening, left ventricular wall stress, myocardial performance, systolic function, diastolic function, and diastolic work. Of these variables, assessment of changes in myocardial contractility by the end-systolic pressure–volume relationship has been shown to most accurately represent global function, primarily because this relationship is considered to be independent of preload and afterload [21]. The end-systolic pressure–volume relationship is characterized by its slope (Emax) and by its volume intercept (V0) at end-systole. To determine how well the myocardium was functioning, pressure–volume loops were obtained during preload reduction by vena cava occlusion at two time intervals: before ischemic induction and after 6 hours of reperfusion. The volume challenge was not performed during ischemia or immediately after reperfusion because of the hypersensitivity of infarcted hearts to these sorts of stressful conditions. The slope (Emax) at end-systole between pressure–volume loops during the preload reduction provided an assessment of global myocardial function.
Morphologic analyses
After 6 hours of reperfusion, the hearts were flushed in antegrade fashion through the aortic root with 100 to 200 mL of Ringer’s lactate solution followed by 500 mL of 10% neutral-buffered formalin at room temperature and then stored overnight in formalin. The hearts were serially sectioned in a plane parallel to the atrioventricular groove in slices approximately 5 mm thick. The myocardial slices were fixed in formalin for another 24 hours, dehydrated in a series of ethanol solutions, and embedded in paraffin blocks. Large whole-mount 5 µm-thick sections of each intact ventricular slice were cut on a sledge microtome and stained with hematoxylin and eosin and the phosphotungstic acid–hematoxylin method for myofibrils.
Areas of infarction, as manifested by staining characteristics of ischemic myocytes, were traced from projections of the phosphotungstic acid–hematoxylin–stained whole mounts to assess the degree of myocardial damage in each group. The hematoxylin and eosin–stained sections were examined for histologic changes associated with ischemia-reperfusion injury, notably coagulation or contraction band necrosis, PMN infiltration, edema, and hemorrhage [22]. Nonoverlapping microscopic fields of the infarct areas at 200x original magnification were used to assess the variables just listed in the following fashion: PMN infiltration: 0 = no increase in leukocytes within capillaries relative to normal, 1+ = occasional PMNs identified within capillaries, 2+ = frequent clusters or linear aggregates of PMNs marginating within capillaries, 3+ = obvious extravasation of PMNs into the perivascular space, 4+ = extensive, diffuse PMN extravasation; interstitial edema: 0 = no increase in interstitial widening, 1+ = patchy, mild increase in perivascular spaces between muscle bundles, 2+ = diffuse, mild interstitial widening or very focal severe widening of interstice, 3+ = generalized severe interstitial widening; and interstitial hemorrhage: 0 = no hemorrhage, 1+ = focal identification of small clusters or scattered individual red blood cells within the interstices, 2+ = patchy deposits of space-expanding red blood cell aggregates, and 3+ = diffuse interstitial hemorrhage.
Indications for initiating cardiovascular support
Animals in this experiment were treated as similarly as possible to humans undergoing RMIRI. Consequently, inotropic support, antiarrhythmic drug therapy, and defibrillatory and resuscitative measures were given based on the individual needs of each animal. The criteria for the administration of inotropic support were a 30% decrease in global myocardial function and a 30% decrease in arterial blood pressure. Inotropic support was provided by dopamine hydrochloride and epinephrine administered by Harvard pumps and individual intravenous lines. Occasional bolus doses were also given when required. Dopamine was the first choice, and administration was initiated at an infusion rate of 5 µg · kg-1 · min-1 and regulated to effect (regaining the 30% loss in arterial blood pressure). If the animal did not respond to dopamine, the second drug, epinephrine, was administered by slow intravenous infusion to restore arterial blood pressure.
Lidocaine hydrochloride was given prophylactically as an antiarrhythmic drug in both groups 1 and 2 with the onset of ischemia; the administration was initiated with a 5-mL bolus dose of 1% lidocaine (50 mg) followed by a continuous infusion of 3 to 6 mg/min, as required. Additional bolus doses (20 mg intravenously) were given if indicated by persistent dysrhythmias. The criteria for discontinuation of lidocaine were 60 minutes of normal sinus rhythm with lidocaine infusion and 10 minutes of sinus rhythm after the infusion was stopped.
Data analysis
The semiquantitative results of morphometric analysis were compared using the Kruskal-Wallis 
2 test. A Mann-Whitney test for pair-wise comparisons was used only if the overall Kruskal-Wallis test was significant at the 5% level. The statistical analysis of functional variables was determined by a repeated-measures model of one-way analysis of variance to evaluate time-dependent variations in each group, and comparison of groups at each time was performed with a group t test.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Inotropic support was required by all group 2 animals, typically starting immediately after LAD occlusion and extending to the end of the 6-hour reperfusion period (mean dose of dopamine, 22 µg per animal; mean dose of epinephrine, 0.9 mg per animal). In contrast, animals in group 1 did not require any inotropic support (see Table 1).
Dysrhythmias occurred in all group 2 animals. The alterations in conduction or pacemaker activity resulted in dysrhythmic events in the form of atrioventricular dissociation, paroxysmal tachycardia, and atrial and ventricular fibrillation. These events usually occurred within 5 to 10 minutes after the initiation of LAD occlusion and became progressively more severe during the first 2 hours of reperfusion. The mean dose of lidocaine given to group 2 animals was 3.13 g per animal. In contrast, the mean dose for group 1 animals was 1.4 g per animal. In group 1, lidocaine was used only for prophylaxis, and the dose required was significantly (p < 0.05) lower than that for animals not receiving the PAF antagonist (see Table 1).
Systolic arterial blood pressure in group 2 decreased significantly (p < 0.05) after the onset of reperfusion and returned to preischemic values after the administration of inotropic agents (Fig 1). In contrast, animals in group 1, which received the PAF antagonist TCV-309, were hemodynamically stable and did not require any inotropic support. Pulmonary artery blood pressure was significantly (p < 0.05) increased after 30 minutes of reperfusion only in group 2 (Fig 2).
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Morphologic analyses
Hearts of animals that underwent coronary ligation consistently demonstrated large transmural infarcts involving the anteroseptal myocardium in the apical third of the heart with areas of necrosis extending well into the middle third of the left ventricle. Demarcation of the necrotic areas was grossly obvious on whole-tissue mounts using the phosphotungstic acid–hematoxylin staining method, which also allowed for more detailed microscopic confirmation of infarct margins (Fig 6A). All hearts showed histologic features characteristic of early myocardial infarction: fiber eosinophilia, contraction band necrosis, capillary congestion within infarcted areas, interstitial edema, and PMN infiltration (Fig 6B). The semiquantitative histopathologic analyses revealed equivalent injury scores in both groups 1 and 2. There were no significant differences in degree of contraction band formation, edema, or interstitial hemorrhage. There was variability in PMN infiltration, ranging from 1+ to 3+, but this was seen in both groups. Polymorphonuclear leukocytes were seen as a diffuse infiltrate throughout the infarcted zone, mainly within capillaries and postcapillary venules, with early extravasation into the edematous interstitial space, all these features being consistent with reperfusion injury. Polymorphonuclear leukocyte margination confined to or prominent at the periphery of the infarcts was not observed. The sham-operation group demonstrated small areas of necrosis in the anterior subepicardial and apical zones that were associated with placement of the coronary ligature and the ventriculotomy site for the interventricular pressure transducer, respectively.
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Comment |
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The role of PAF in the pathophysiology of RMIRI has been the object of controversy for the past decade. Our findings that PAF plays a role in cardiovascular dysfunction during RMIRI, particularly dysrhythmias, hemodynamic instability, and myocardial depression, are supported by the findings of a number of other investigators. First, dysrhythmia occurrence during RMIRI has been reduced by PAF antagonist administration in the majority of published studies [9, 10]. Other investigators [12, 13], however, did not find any reduction in the incidence of arrhythmias with PAF antagonists. One factor contributing to the variable results may relate to differences in the chemical structure of PAF antagonist classes. Three of four in vivo RMIRI studies that found no protective effects of PAF antagonists against dysrhythmias used the WEB class of PAF antagonists [11, 13, 14]. In comparison, all studies that found protective effects of PAF antagonists against dysrhythmias, including this one, used a variety of natural and synthetic PAF antagonist agents, none of which were from the WEB class. It has been suggested that there may be more than one PAF receptor subtype in the body [23], which, if prevalent in the cardiovascular system, could be responsible for the differing cardiovascular effects of structurally diverse PAF antagonists.
Second, the role of PAF in hemodynamic instability during RMIRI remains controversial, despite the observations that exogenous administration of PAF and endogenous release of PAF are consistently associated with severe hemodynamic instability. Animal species may be a major source of variability. Studies showing that PAF antagonism blocks the systemic hypotensive effects of RMIRI have used an in vivo rabbit model [15, 16]. Conversely, most of the reports finding no protective effect of PAF antagonists against systemic hypotension during RMIRI have used a canine model [12, 13]. Similarities between the rabbit, swine, and human heart in other areas of research have been established. For example, rabbit, swine, and human hearts do not have xanthine oxidase activity, whereas canine and rat hearts have shown a high level of xanthine oxidase activity [18]. The finding in the present study that PAF causes hemodynamic instability during RMIRI in an in vivo swine model is consistent with results in the rabbit [15, 16]. Third, in regard to myocardial depression, our findings are consistent with those in the majority of studies, which also have found that PAF antagonist protects against myocardial depression during RMIRI [8, 9].
Our study also suggests that PAF may contribute to the high incidence of cardiac arrest in patients sustaining RMIRI. Despite the extensive preventive measures against cardiac arrest in group 2, 7 of the 12 animals had cardiac arrest. Resuscitative measures were able to revive 4 of the 7 animals. In contrast, in the group that received TCV-309, none of the animals sustained cardiac arrest or died. Furthermore, preventive measures in the form of lidocaine and inotropic support were also significantly (p < 0.05) less. These results are supported by the majority of studies [9, 10, 15], which have shown that PAF antagonist administration reduces the incidence of ventricular fibrillation and subsequent arrest during reperfusion after regional myocardial ischemia. The majority of deaths in humans that are due to acute myocardial infarction followed by reperfusion occur within the first 24 hours of the event and result from the acute cardiovascular dysfunctions associated with RMIRI, specifically dysrhythmias, myocardial depression, and hemodynamic instability. Our studies suggest an important role for PAF in influencing the severity of these factors that contribute toward reperfusion-induced cardiac arrest and ultimately death.
In considering possible mechanisms of global myocardial dysfunction caused by RMIRI, it has generally been accepted that tissue ischemia, necrosis, and regional dysfunction in the ischemic and then reperfused region of the myocardium are solely responsible for global cardiac dysfunction that may lead to hemodynamic instability and death. However, it has been shown that during ischemia and reperfusion, possibly under the influence of oxygen-derived reactive substances, mediators of the inflammatory cascade (PAF, thromboxane, leukotrienes, endothelins, and others) are triggered. Therefore, it can be speculated that the inflammatory mediators generated in the ischemic and reperfused region diffuse to the intact, nonischemic part of the myocardium, particularly during the immediate reperfusion period, thereby inducing global myocardial dysfunction. Production of mediators such as PAF has been shown to increase in the immediate postreperfusion period [8]. Thus, we hypothesize that the global myocardial dysfunction caused by RMIRI may not be dependent solely on the loss of viable tissue and contractile function in the infarcted region but also to the global dysfunction caused by inflammatory mediators [24].
The effects of PAF on cardiovascular dysfunction have been proved to be multifactorial. First, PAF has been shown to have a direct negative inotropic effect on isolated cardiomyocytes [25] and heart tissue preparations. Second, PAF has been shown to induce coronary artery vasoconstriction [26]. Further, these effects of PAF were blocked with the use of PAF receptor antagonists. Third, PAF may also act on vascular endothelium, PMNs, and platelets to induce microvascular injury and promote the production of other mediators, such as thromboxanes and leukotrienes [27], that can enhance global myocardial dysfunction and hemodynamic instability.
In summary, considering the controversies surrounding the role of PAF in RMIRI, the results of our study support the contribution of PAF to myocardial depression, hemodynamic instability, dysrhythmias, and ventricular fibrillation leading to cardiac arrest. In the presence of equal regional dysfunction occurring in the ischemic and reperfused region in our treated and untreated groups, the reduced global function in the group that was not given the specific PAF antagonist suggests that PAF plays a role in the global dysfunction of the heart during RMIRI. It can be speculated that PAF along with the other mediators generated in the ischemic and reperfused region reach the nonischemic region of the myocardium during the reperfusion period and cause severe global myocardial distress. Further, the results of this study suggest that by antagonizing the effects of inflammatory mediators such as PAF, it may be possible to greatly ameliorate the detrimental effects of these mediators in the postischemic interval. Results of this study may open new avenues in the management of patients with myocardial ischemia and infarction.
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Acknowledgments |
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We thank Kris Gillespie, Joanna Sniderman, and Betty Pearson for their technical support.
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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