INO-1001 A NOVEL POLY(ADP-RIBOSE) POLYMERASE (PARP)... : Shock (original) (raw)
INTRODUCTION
To date the major part of routine cardiac surgery is performed using extracorporal circulation with cardioplegic arrest. Independent of the technique of cardioplegia, temporary cardiac dysfunction can frequently be observed as a consequence of ischemia/reperfusion injury. Even if cardiac dysfunction is not clinically evident, a reduction of myocardial contractility may occur as described in a human study using pressure–volume relationships (1). In addition, coronary endothelial and peripheral vascular dysfunction may further complicate the postoperative course (2). Extracorporal circulation is also known to induce a systemic inflammatory reaction (3–5) with free radical release (6) leading to secondary organ injury. There is evidence (7) that pulmonary injury occurs in the context of cardiac surgery as a consequence of extracorporal circulation–induced inflammatory reaction and reduced pulmonary perfusion. Postoperative pulmonary dysfunction is a significant clinical problem ranging from subclinical functional changes in most patients to full-blown ARDS in up to 2% of cases after extracorporal circulation (7). Significantly increased alveolar–arterial oxygen pressure difference and pulmonary shunt fraction together with decreased functional residual capacity and carbon monoxide transfer factor have frequently been observed in patients after extracorporal circulation.
Poly(ADP-ribose) polymerase is an abundant nuclear enzyme of eukaryotic cells. DNA single-strand breaks have been shown to induce the activation of PARP. Activated PARP catalyzes an energy-consuming cycle by transferring ADP ribose units to nuclear proteins. The results of this process are rapid depletion of the intracellular NAD+ and ATP pools, which slows the rate of glycolysis and mitochondrial respiration, leading to cell necrosis (8–11). Both the genetic disruption of the PARP pathway and the pharmacologic blockade of PARP effectively protect against oxygen radical and nitric oxide toxicity in different cell cultures (8, 10, 11).
PARP has recently been proposed to play a role in the pathogenesis of myocardial reoxygenation injury. Myocardial reperfusion injury in vitro and in vivo have been shown to be ameliorated by genetic disruption or pharmacological blockade of PARP (8–13). It was also demonstrated that PARP inhibition leads to a significant improvement of endothelial function ex vivo in peroxynitrite-treated thoracic aortic rings (14) and in isolated mesenteric arteries in the setting of splanchnic ischemia/reperfusion (15). In our previous rat heart transplant study (16), we showed that hypothermic cardiac arrest and reperfusion leads to PARP activation and energy depletion. In this setting, the blockade of PARP with the PARP inhibitor PJ34 improved both myocardial and endothelial functional recovery. Furthermore, it has been demonstrated that PARP is activated in various forms of inflammatory conditions (8, 17), including lung injury (18–21). PARP inhibition significantly attenuated lung injury in different rodent models of pulmonary inflammation (17, 18) and in a murine model of asthma (20).
Because PARP inhibition is a successful therapeutic concept in both cardiac ischemia/reperfusion and acute inflammatory lung injury, we tested the hypothesis that INO-1001, a novel PARP inhibitor (22, 23), improves cardiac and pulmonary function in a clinically relevant canine model of extracorporal circulation and cardioplegic arrest.
MATERIALS AND METHODS
Animals and experimental groups
Twelve dogs (foxhounds) weighing 23–32 kg (25 ± 4 kg) were used in this experiment. All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1996). The experiments were approved by the Ethical Committee of the Land Baden-Württemberg for Animal Experimentation. Six animals received 1 mg/kg INO-1001 (Inotek Pharmaceuticals, Beverly, MA), a novel, water-soluble PARP inhibitor with isoindoline structure (22, 23) as a short infusion starting 5 min before aortic declamping and continued during the first 25 min of reperfusion. Six vehicle-treated animals served as controls. The applied dose of INO-1001 is based on previous dose–response and pharmacokinetic studies.
General management and cardiopulmonary bypass
The dogs were premedicated with propionylpromazine and anesthetized with pentobarbital (15 mg/kg initial bolus and then 0.5 mg/kg/h i.v.), paralyzed with pancuronium bromide (0.1 mg/kg as a bolus and then 0.2 mg/kg/h i.v.), and endotracheally intubated. The dogs were ventilated with a mixture of room air and O2 (FiO2 = 60%) at a frequency of 12–15/min and a tidal volume starting at 15 mL/kg per minute. The settings were adjusted to maintain arterial partial carbon dioxide pressure levels between 35 and 40 mmHg. The femoral artery and vein were cannulated to record aortic pressure (AoP) and to take blood samples for biochemical analysis. Basic intravenous volume substitution was carried out with Ringer solution (1 mL/min/kg). According to the values of potassium, bicarbonate, and base excess, substitution included administration of potassium chloride and sodium bicarbonate (8.4%). Neither catecholamines nor other hormonal or pressor substances were administered.
After left anterolateral thoracotomy in the fourth intercostal space and pericardiotomy, the great vessels were dissected. After systemic anticoagulation with sodium heparin (300 U/kg), the left subclavian artery was cannulated for arterial perfusion. The venous cannula was placed in the right atrium. The extracorporeal circuit consisted of a heat exchanger, a venous reservoir, a roller pump, and a membrane oxygenator primed with Ringer lactate solution (1000 mL) supplemented with heparin (150 U/kg) and 20 mL sodium bicarbonate (8.4%). After initiation of CPB, the body temperature was cooled to 28°C. After crossclamping of the aorta, the heart was arrested with 25 mL/kg HTK solution (in mmol: 15 NaCl, 9 KCl, 4 MgCl2·6H2O, 18 histidine hydrochloride monohydrate, 180 histidine, 2 tryptophan, 30 mannitol, 0.015 CaCl2, 1 potassium-hydrogen-2-oxopentandioate, H2O). During cardiac arrest the pump flow was set at 100 mL/kg/min to maintain perfusion pressure above a value of 35–40 mmHg at any time point, and alpha-stat management was applied. Twenty minutes before cross-clamp removal, rewarming was initiated. After 60 min of cardiac arrest, the aorta was declamped, and the heart was reperfused with normothermic blood in the bypass circuit. If necessary, ventricular fibrillation was counteracted with DC cardioversion of 40 J. Ventilation was restarted with 100% oxygen. All animals were weaned from CPB without inotropic support 20 min after the release of the aortic cross clamp. Each animal underwent 90 min of CPB with 60 min of cardiac arrest.
Cardiac function
Left and right ventricular systolic and diastolic pressures and volumes were measured by combined 6F Millar pressure-conductance catheters with 6 mm spacing, which were inserted via the apex and the pulmonary artery, respectively. Stroke volume (SV) was calculated from the integrated flow signal measured by an aortic ultrasonic flow probe and was used to calibrate the volume signal from the conductance catheter. Parallel conductance was estimated by rapid injection of 1 mL of hypertonic saline into the pulmonary artery or superior vena cava, respectively. Vena cava occlusions were performed to obtain a series of pressure–volume loops. The slope (Ees) and intercept (V0) of the left and right ventricular end-systolic pressure–volume relationships and preload recruitable stroke work (PRSW) were calculated as load-independent indices of myocardial contractility. Myocardial relaxation was characterized by the relaxation time constant (τ) of the left and right ventricular pressure fall, respectively. τ was calculated from time-expanded recordings of left and right ventricular pressure. Pressure records were digitized at 1-ms intervals beginning at peak negative dP/dt; P began returning monophasically toward zero and terminating at an isovolumetric pressure (P) of 10% of peak systolic pressure. The coordinates were fitted by a monoexponential equation, P = P0e−t/τPB, where P0 is the left ventricular pressure at peak negative dP/dt and PB is the baseline pressure towards which the monoexponential decays.
Coronary blood flow was measured on the left anterior descending artery with a perivascular ultrasonic flow probe. Coronary endothelium-dependent vasodilatation was assessed after intracoronary administration of a single bolus of acetylcholine (ACH, 10−7 M) and endothelium-independent vasodilatation after sodium nitroprusside (SNP, 10−4 M). The vasoresponse was expressed as percentage change of baseline coronary vascular resistance.
Pulmonary function
In addition to routine blood gas analysis, blood gases were determined before and 1 h after weaning from CPB at room air ventilation. Pulmonary function was characterized by the alveolar–arterial oxygen difference, which was calculated according to the standard formulas. In addition, the left lower lobar pulmonary artery was dissected, blood flow was measured by a 4-mm-diameter ultrasonic flow probe, and pulmonary vascular resistance was calculated. Pulmonary endothelium-dependent vasodilatation was assessed after intra-arterial administration of a single bolus of acetylcholine (ACH, 10−7 M) and endothelium-independent vasodilatation after sodium nitroprusside (SNP, 10−4 M). The vasoresponse was expressed as percentage change of baseline pulmonary vascular resistance.
Poly(ADP-ribose) immunohistochemistry
Poly(ADP-ribose) (PAR), the product of PARP, was detected to assess the activation of PARP (24). Heart and lung biopsy specimens were taken at baseline and after 60 min of reperfusion, fixed in formalin, and embedded in paraffin. After section of the probes, slides were deparaffinized, antigen was retrieved by incubation in boiling 0.1 M sodium citrate (pH 6), then slides were rinsed in water. Slides were incubated in 10% (w/v) trichloroacetic acid (TCA) for 10 min to prevent catabolism of the polymer by poly(ADP-ribose) glycohydrolase. Slides were rinsed in PBS, and then endogenous peroxidase activity was quenched with 1.5% (vol/vol) hydrogen peroxide in methanol for 15 min. Nonspecific binding sites were blocked using 2% (vol/vol) normal goat serum in PBS for 1.5 h at 37°C. Preliminary experiments determined optimal antibody concentrations. Chicken antibody against PAR was a generous gift from Dr. John R. Simon (Tulip BioLabs, Inc., West Point, PA), and it was used in 1:250 or 1:500 dilutions; slides were incubated overnight at 4°C and then washed in PBS, and, as a secondary antibody, biotinylated goat anti–chicken IgG (Vector Laboratories, Burlingame CA) was used for 30 min at 30°C. After PBS washes, slides were incubated with Vectastain Elite ABC (peroxidase) standard kit (Vector Laboratory) for 30 min at 30°C and developed using diaminobenzidine substrate. Slides were counterstained with nuclear fast red.
Data analysis
All measurements were performed before cardiopulmonary bypass and after 60 min of reperfusion.
All values were expressed as mean ± standard error (SEM). Paired t test was used to compare two means within groups. Individual means between the groups were compared by one-way analysis of variance followed by an unpaired t test with Bonferroni correction for multiple comparisons and the post-hoc Scheffe’s test. A probability value less than 0.05 was considered statistically significant.
RESULTS
Hemodynamic parameters
Hemodynamic variables are shown in Table 1. Baseline parameters did not differ between the groups and were within the physiological range. HR did not change either in the control or in the INO-1001 group. Mean blood pressure (MAP) during cardiopulmonary bypass was 55 ± 3 and 58 ± 7 mmHg in the control and in the INO-1001 group, respectively (n.s.). After 60 min of cardioplegic arrest and 60 min of reperfusion, MAP decreased significantly (P < 0.05) in the control group while it remained unchanged in the INO-1001 group. CO did not differ significantly between the groups. However, it should also be noted that CO showed a clear decreasing tendency within the control group without reaching the level of significance (Table 1).
Hemodynamic variables before cardiopulmonary bypass and after 60 min of reperfusion
Left and right ventricular function
Left and right ventricular function were identical in both groups at baseline (Tables 2 and 3). Myocardial contractility—characterized by dP/dtmax and the load-independent slopes Ees and PRSW (Figs. 1 and 2) —showed a significant decrease (P < 0.05) after extracorporal circulation and reperfusion in the control group while it remained unchanged in the INO-1001–treated group. Representative pressure–volume loops are shown in Figure 1. Left ventricular dP/dtmin was significantly (P < 0.05) lower in the control group at 60 min of reperfusion while right ventricular dP/dtmin showed only a decreasing tendency without reaching the level of significance. Myocardial relaxation constant τ increased significantly (P < 0.005) in the control group at 60 min of reperfusion, but it remained at baseline level in the INO-1001 group.
Left ventricular function before cardiopulmonary bypass and after 60 min of reperfusion
Right ventricular function before cardiopulmonary bypass and after 60 min of reperfusion
Representative left ventricular (left panels) and right ventricular (right panels) pressure–volume loops in a control (top panels) and in an INO-1001–treated animal (bottom panels). Straight lines indicate end-systolic pressure–volume relationships. LVV, left ventricular volume; LVP, left ventricular pressure; RVV, right ventricular volume; RVP, right ventricular pressure.
Contractile function. The slope of the left ventricular (LV) end-systolic pressure–volume relationship (Ees, right, top) and preload recruitable stroke work (PRSW, left, top) before and after cardiopulmonary bypass (CPB) at 60 min of reperfusion. The slope of the right ventricular (RV) end-systolic pressure–volume relationship (Ees, right, bottom) and preload recruitable stroke work (PRSW, left, bottom) before and after cardiopulmonary bypass (CPB) at 60 min of reperfusion. All values are given as mean ± SEM, °P < 0.05 versus baseline, *P < 0.05, INO-1001 versus control.
Coronary blood flow and vascular function
Coronary blood flow was similar in both groups before cardioplegic arrest. After 60 min of reperfusion, coronary blood flow decreased significantly (P < 0.05) in the control group, but it remained unchanged in the INO-1001 group (Table 1). Endothelium-dependent vasodilatation after ACH was significantly (P < 0.05) reduced in the control group after 60 min of reperfusion in comparison to values before extracorporal circulation (Fig. 3) but remained unchanged in the INO-1001 group. Endothelium-independent vasodilatation after SNP showed no significant differences over time or between groups (Fig. 3).
Coronary (top) and pulmonary (bottom) vascular function. Endothelium-dependent vasodilatation after acetylcholine (ACH, 10−7 M, left) and endothelium-independent vasodilatation after sodium nitroprusside (SNP, 10−4, right) expressed as percentage change of coronary (CVR) and pulmonary vascular resistance (PVR) before and after cardiopulmonary bypass (CPB) at 60 min of reperfusion. All values are given as mean ± SEM, °P < 0.05 versus baseline, *P < 0.05 INO-1001 versus control.
Pulmonary function
PAP and PBF measured at the left lower lobar pulmonary artery were similar in both groups at baseline and remained stable after extracorporal circulation. Vascular responses to ACH and SNP did not differ between the groups at baseline. Pulmonary resistance showed a significantly (P < 0.05) attenuated response to injection of ACH after extracorporal circulation in the control group while it remained unchanged in the INO-1001 group (Fig. 3). Endothelium-independent vasodilatation after SNP did not differ between groups or over time.
Figure 4 shows blood gas levels and alveolar–arterial oxygen difference before and after extracorporal circulation. Partial oxygen tension, oxygen saturation, and alveolar–arterial oxygen difference decreased significantly in the control group, and they were significantly lower in comparison to the INO-1001 group. Partial carbon dioxide tension showed a similar increasing tendency in both groups without reaching the level of significance.
Pulmonary function. Oxygen saturation (SaO2, left, top), partial oxygen (pO2, right, top) and carbon dioxide (pCO2, left, bottom) tension and alveolar–arterial oxygen difference (A-aDO2, right, bottom) at room air ventilation before and after cardiopulmonary bypass (CPB) at 60 min of reperfusion. All values are given as mean ± SEM, °P < 0.05 versus baseline, *P < 0.05 INO-1001 versus control.
Poly(ADP-ribose) immunohistochemistry
There was no detectable PAR at baseline in the heart and lungs (Fig. 5). After 60 min of cardioplegic arrest and CPB, no PAR staining was found in the heart. In contrast, the lungs showed marked PAR staining. After 60 min of reperfusion, extensive PAR staining was observed in both the heart and the lung in controls, and this staining was markedly abrogated in the INO-1001–treated group.
Immunohistological staining for poly(ADP-ribose), a marker of poly(ADP-ribose) polymerase activation in the heart and lungs. (A) Representative poly(ADP-ribose) negative heart stainings before cardiopulmonary bypass. After 60 min of cardioplegic arrest (B), poly(ADP-ribose) staining was still negative in the heart. (C) Strong positive poly(ADP-ribose) staining is present in the cell nuclei of control heart after cardiopulmonary bypass (CPB) at 60 min of reperfusion, which indicates poly(ADP-ribose) polymerase activation. (D) Representative heart specimen of the INO-1001–treated group after CPB at 60 min of reperfusion. The poly(ADP-ribose) negative staining is indicative of the inhibition of poly(ADP-ribose) polymerase by INO-1001 treatment. (E) Representative poly(ADP-ribose)–negative lung stainings before cardiopulmonary bypass. After 60 min of cardioplegic arrest (F), poly(ADP-ribose) staining was positive in the cell nuclei of the lungs. (G) Strong positive poly(ADP-ribose) staining is present in the control lungs after CPB at 60 min of reperfusion, which indicates poly(ADP-ribose) polymerase activation. (H) Representative lung specimen of the INO-1001–treated group after CPB at 60 min of reperfusion. The poly(ADP-ribose)–negative staining is indicative of inhibition of poly(ADP-ribose) polymerase by INO-1001 treatment (×400 magnification).
DISCUSSION
In this study, the benefits of the application of the novel ultrapotent PARP inhibitor INO-1001 during reperfusion were assessed after cardioplegic arrest in a canine model of extracorporeal circulation and cardiac arrest. In accordance with the literature (1, 2), hypothermic cardioplegic arrest and reperfusion resulted in a decline in biventricular contractile and endothelial function. We have shown that PARP inhibition improves biventricular and endothelial functional recovery after cardioplegic arrest. In addition, pulmonary function was significantly improved in terms of pulmonary endothelial function and oxygenation after treatment with the PARP inhibitor INO-1001.
Cardiac injury with temporary myocardial dysfunction is a well-described phenomenon in the context of cardiac surgery. Hearts undergoing coronary bypass surgery or other surgical procedures requiring cardiopulmonary bypass and elective cardioplegia undergo repetitive episodes of ischemia and reperfusion, which leads to endothelial injury as well as contractile dysfunction and morphological injury despite the use of cardioprotective cardioplegic solutions and other strategies of myocardial protection (2). In cardiac surgery, as in coronary occlusion, myocardial and endothelial injury seems to occur on reperfusion with unmodified blood. Even blood cardioplegia, which is supposed to be the most protective cardioplegic approach, does not prevent this surgical reperfusion injury.
Previous studies have shown PARP activation in the reperfused heart (10–12, 16) and reduced reperfusion injury in PARP-knockout animals (10) or after PARP inhibition (12, 16). This is the first study that shows the effectiveness of PARP inhibition in clinically relevant large animal model of cardiopulmonary bypass. The mechanisms of INO-1001’s protective action are multiple. Ischemia/reperfusion injury initiates a pathophysiological cascade including an inflammatory response with liberation of cytokines and free radicals. Triggered by peroxynitrite-induced DNA single-strand breaks, PARP catalyzes an energy-consuming polymerization of ADP-ribose, resulting in NAD+ depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high-energy phosphates in the reperfused heart (8, 12, 16). Indeed, immunhistologic studies demonstrated that PARP rapidly activated in the reperfused myocardium (16, 23, 24). Most of poly(ADP-ribose) staining was seen in cardiac myocytes, indicating that the heart’s tissue itself, rather than the infiltrating mononuclear cells, is the main site of PARP activation. In addition, we showed previously (16) that PARP activation occurs in cardiac endothelial cells after cardioplegic arrest and reperfusion. These findings are in accordance with the immunhistologic findings of the present study. We could also demonstrate that PARP activation occurs during the reperfusion but not during cardioplegic ischemia. In various types of ischemia/reperfusion, the prevention of PARP activation results in a better preservation of the high-energy phosphate content, resulting in an improved energy status (8, 10–12, 16). In addition to its direct effects on myocardial metabolism, PARP-activation contributes to the expression of P-selectin and ICAM-1 during cardiac ischemia/reperfusion (10, 16) and consequently to the recruitment of neutrophils into the jeopardized tissue. It is likely that both an inhibition of the energetic component of PARP-mediated cell dysfunction and the suppression of proinflammatory pathways contribute to cardioprotective effects (8). Furthermore, Yang et al. (9) showed that myocardial ischemia/reperfusion results in a systemic increase of inflammatory cytokines and that PARP inhibition reduces the production of these mediators.
Because pulmonary dysfunction is common after cardiac surgery [reviewed by Ng et al. (7)], we assessed pulmonary function in terms of blood gas analysis and alveolar–arterial oxygen gradient as well as pulmonary vascular function. According to the literature (4, 5, 7, 25–27), we observed impaired gas exchange and pulmonary endothelial dysfunction after extracorporal circulation in the control group. Massoudy et al. (25) showed in a clinical study that proinflammatory cytokines are increased in pulmonary venous blood and, at the same time, activated blood cells are retained in the pulmonary circulation. This indicates an inflammatory response of the lung to extracorporal circulation. Schlensak et al. (26) clearly demonstrated that cardiopulmonary bypass caused a reduction in bronchial arterial blood flow that was associated with injury to the lung. Recent histologic studies described interstitial edema, leakage of erythrocytes into the alveolar space, and swelling of endothelial cells after cardiopulmonary bypass (28, 29) in relation with free radical generation. To summarize the recent literature, pulmonary dysfunction after extracorporal circulation is the result of multiple insults, which include general anesthesia, thoracotomy, and breach of the pleura as well as blood contact with artificial material, hypothermia, pulmonary ischemia, and lung ventillatory arrest (3, 7). Many of these factors may induce an inflammatory cascade with subsequent free radical production and PARP activation. There are only a few studies that describe the effects of PARP inhibition in lung injury. Cuzzocrea et al. (18) reported a reduction of lung injury and attenuated expression of P-selectin and ICAM-1 as well as recruitment of neutrophils into injured lung in after intrathoracic application of zymosan. In the study of Liaudet et al. (19), after intratracheal application of lipopolysaccharide, lung injury was reduced by genetic deletion or pharmacological inhibition of PARP. The absence of functional PARP reduced the increase of cytokines and chemokines, alveolar neutrophil accumulation, lung permeability, and lipid peroxidation. In a murine model of acute septic peritonitis, genetic depletion of PARP significantly attenuated lung injury (30). It was also shown that PARP activation mediates pulmonary microvascular dysfunction in endotoxin shock (31). In rabbit pneumocytes, PARP inhibition preserves surfactant synthesis after hydrogen peroxide exposure (20). Finally, in human A549 pulmonary epithelial cells, PARP inhibition attenuates peroxynitrite-induced epithelial hyperpermeability (32). While previous studies focused on histologic and biochemical changes, the present study demonstrates a functional improvement by PARP inhibition after lung injury in a model of cardiopulmonary bypass.
The present study has some limitations. Similarly to the clinical situation, in the present in vivo model, different types of patholophysiological stimuli counteract others, such as cardiac ischemia/reperfusion and systemic inflammatory response to extracorporal circulation. The systemic inflammatory reaction may worsen reperfusion injury, and in turn, reduced myocardial function may worsen the hemodynamic consequences of the systemic inflammatory reaction. Similarly, reduced coronary perfusion/reactivity may contribute to reduced myocardial function, and in turn, reduced myocardial function may interact with impaired gas exchange. Therefore, it remains unclear whether improved pulmonary function reflects improved cardiac function in the INO-1001 group or the local effects of PARP inhibition. Even if load-independent indices showed a marked difference between the groups, cardiac output, arterial pressure, and pulmonary blood flow showed, if any, only small differences. Therefore, we can assume that the observed improved pulmonary function is caused by at least partly by the local effects of PARP inhibition. It was also shown that ischemia/reperfusion injury or local inflammation (30) alone may cause PARP activation in remote organs (i.e., lung, liver) (33), and PARP inhibition may reduce tissue injury in these organs. Furthermore, immunohistologic staining clearly demonstrates PARP activation in the lungs, which was abolished by INO-1001 during the reperfusion phase. The fact that PAR positivity occurs earlier in the lungs than in the heart (during aortic crossclamp) indicates a direct injury from extracorporeal circulation in the lungs independent of cardiac ischemia/reperfusion and postischemic cardiac function.
In summary, in the present study INO-1001, a novel PARP inhibitor, was able to markedly attenuate reperfusion injury, resulting in a better functional cardiac recovery and improved pulmonary function in a clinically relevant large animal model of cardiopulmonary bypass. Based on the present data and our previous studies (16), clinical studies with PARP inhibitors are warranted to reduce reperfusion injury and to improve postoperative cardiac function.
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Keywords:
Poly(ADP-ribose) polymerase; cardioplegia; cardiopulmonary bypass; heart surgery; reperfusion injury; pulmonary dysfunction
©2004The Shock Society