Ann Thorac Surg 1999;67:1623-1629
© 1999 The Society of Thoracic Surgeons
Original Articles
Pretreatment with a potassium-channel opener before prolonged cardiac storage: an evaluation in an experimental brain death model
Matthias Kirsch, MDa,
Sylvie Bertrand, MDa,
Jean-Paul Garnier, MDb,
Christine Fernandez, PharmDa,
Christophe Baufreton, MD, PhDa,
Alain Astier, PharmDa,
Daniel Loisance, MDa
a Centre de Recherches Chirurgicales Henri Mondor and the Pharmacie Centrale, Hôpital Henri Mondor, Créteil, France
b Department of Biochemistry, Hôpital Saint-Louis, Paris, France
Accepted for publication November 13, 1998.
Address reprint requests to Dr Loisance, Centre de Recherches Chirurgicales Henri Mondor, Faculté de Médecine, 8 rue du Générail Sarrail, 94010 Créteil Cédex, France
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Abstract
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Background. Pretreatment with a potassium-channel opener has been shown to improve functional recovery after long-term cardioplegic arrest. We evaluated whether pretreatment with the potassium-channel opener cromakalim is beneficial in a more clinically relevant experimental model of brain death in the rabbit.
Methods. Four groups of rabbits were studied in a 2 x 2 factorial experiment (n = 8 per group). Rabbits were subjected to a sham operation or 90 minutes of brain death induced by inflating a subdurally placed balloon. Thirty minutes before heart explantation, rabbits received either no pretreatment or an intravenous injection of cromakalim, 30 µg/kg. Hearts then received 5 hours’ hypothermic storage in St. Thomas’ Hospital solution and were assessed on a buffer-perfused isolated heart preparation. Hemodynamic recovery, coronary flow, and creatine kinase release were determined after 60 minutes of reperfusion.
Results. Systolic function and diastolic function were significantly altered in hearts explanted from brain-dead rabbits compared with hearts from rabbits having a sham operation. Cromakalim pretreatment had no significant effect on poststorage systolic or diastolic function of hearts explanted from brain-dead or sham-operation rabbits. Further, cromakalim pretreatment did not affect coronary flow or overall creatine kinase release during reperfusion.
Conclusions. In vivo pretreatment of brain-dead rabbits or anesthetized rabbits with an intravenous injection of cromakalim had no significant effect on functional recovery of or enzymatic release from explanted hearts after 5 hours’ hypothermic storage and 60 minutes’ reperfusion. These findings underscore the importance of clinically relevant experimental models.
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Introduction
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Myocardial preservation for heart transplantation relies mainly on cardioplegic cardiac arrest and organ storage in a cold preservation solution. Numerous cardioplegic and storage solutions have been commercialized, varying both by their principle (extracellular versus intracellular) and by their additives. However, this exogenous approach to cardiac preservation provides only incomplete protection against ischemia-reperfusion injury, and early graft failure remains one of the most frequent causes of death after heart transplantation [1].
Ischemic preconditioning has been described as a powerful intrinsic adaptation of the cardiomyocyte to a brief ischemic insult that slows down the rate of cell death during a subsequent period of prolonged ischemia [2]. This concept was subsequently extended to protection against other deleterious effects of the ischemia-reperfusion sequence, such as myocardial stunning, arrhythmias, and endothelial lesions. Although hypothermia appears to increase the threshold for ischemic preconditioning [3], several recent studies [4–7] have reported that ischemic preconditioning provides additional protection during long-term hypothermic cardioplegic arrest. Similarly, hypoxic preconditioning has been reported to improve left ventricular function after prolonged hypothermic storage of hearts [8]. Du and associates [6] demonstrated that the adenosine triphosphate–sensitive potassium channels are at least partially involved in this protection, as the administration of the potassium-channel antagonist glibenclamide markedly reduced the beneficial effects of ischemic preconditioning before a period of prolonged hypothermic storage.
The administration of a preconditioning-mimetic drug to reproduce the beneficial effects of ischemic preconditioning but without the need of an ischemic or hypoxic preconditioning insult would be of particular interest in the clinical context of heart transplantation. Thus, in a previous report, we [9] found that intravenous pretreatment of awake rabbits with the potassium-channel opener (PCO) cromakalim allows additional protection to that provided by cardioplegic arrest and prolonged hypothermic storage in an extracellular solution.
However, one has to consider that in the clinical setting, donor hearts are excised from brain-dead patients. Brain death is a pathophysiologic condition associated with major myocardial alterations principally related to massive endogenous catecholamine release [10]. Because catecholamines have repeatedly been implicated in the biochemical cascade induced by ischemic preconditioning [11, 12], their massive release during brain death might interfere with the preconditioning response. Therefore, in the following series of experiments, we examined whether cromakalim pretreatment improves poststorage cardiac recovery of hearts excised from either anesthetized or brain-dead rabbits.
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Material and methods
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Adult New Zealand white rabbits weighing 3 to 4 kg were used. 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" published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Anesthesia
Animals were premedicated with intramuscular administration of acetylpromazine (1 mg/kg). Venous access was obtained through a 20-gauge intravenous catheter placed in a large marginal vein in the ear. Anesthesia was induced (20 mg/kg) and maintained with (120 mg · kg-1 · h-1) intravenous ketamine and hydrochloride. Animals were ventilated through a tracheotomy with an endotracheal tube at a rate of 60 strokes per minute and an oxygen fraction of 100%. Arterial pH and partial oxygen and carbon dioxide pressures were measured after equilibration. Body temperature was maintained between 37° and 38°C throughout the experiments by an automatically adjusted heating lamp connected to an intrarectal temperature catheter.
Induction and validation of brain death
We reproduced the experimental brain-death model in the rabbit previously described and validated by Biswas and co-workers [13]. After 30 minutes of equilibration, a craniotomy was performed on the midline of the skull at the fusion of the frontoparietal plates. In animals randomized to the brain-death groups, a 10-gauge Foley catheter was introduced into the subdural space. Brain death was induced by rapidly inflating the catheter balloon with 4 mL of saline solution, with the aim of acutely increasing the intracranial pressure. After brain-death induction, all anesthetic drugs were withheld, and animals received no hemodynamic pharmacologic support. Animals were considered to be brain dead when pupillary reflexes and spontaneous respiration became absent and when cerebral electrical activity ceased. Electroencephalographic changes were recorded by means of two unipolar electrodes planted in the temporoparietal regions of the scalp and connected to an MP 100 data-acquisition system using Acknowledge 3.0 software (Biopac Systems; Cerom SARL, Paris, France).
In vivo measurements
Hemodynamic data
A 20-gauge catheter connected to a quartz universal pressure transducer (model HP 1290C; Hewlett-Packard) was placed in the left common carotid artery for continuous monitoring of mean arterial pressure (MAP) and withdrawal of blood samples. Mean arterial pressure was calculated as follows: 
. A similar catheter was introduced into the left ventricle through the right common carotid artery. In vivo left ventricular contractility was assessed by the maximal positive and negative rates of rise of left ventricular pressure (+dP/dtmax and -dP/dtmax). Hemodynamic data were recorded at baseline (25 minutes after anesthesia) and at 1 minute, 5 minutes, 15, 30, 60, and 90 minutes after intracranial balloon inflation.
Plasma catecholamines
Arterial blood samples for catecholamine level determination were taken at baseline (25 minutes after anesthesia) and 1 minute and 30 minutes after intracranial balloon inflation. Blood samples were centrifuged in a cooling centrifuge at 3,000 rpm for 10 minutes. Plasma was removed and stored at -80°C until analysis. The plasma catecholamines norepinephrine and epinephrine were analyzed by high-performance liquid chromatography with electrochemical (coulometric) detection.
In vitro measurements
Heart explantation
After 90 minutes of brain death or anesthesia, the thorax was opened by sternotomy, the pulmonary veins and the venae cavae were ligated en masse, and the pulmonary artery was transected to vent the heart. Then the aorta was cross-clamped, and 40 mL of cold (4°C) St. Thomas’ Hospital cardioplegic solution (in millimoles per liter: NaCl, 110; KCl, 16; MgCl2, 16; NaHCO3, 10; CaCl2, 1.2) was infused into the ascending aorta until cardiac arrest. Meanwhile, the heart was cooled with topical cold saline solution. After explantation of the heart, the aorta was cannulated, and a thin-walled latex balloon was inserted into the left ventricle through a left atriotomy and sutured to the mitral annulus. The left atrium was closed with a pursestring suture. The compliance of this balloon was such that it did not produce any hydrostatic pressure until filled to 2 mL. The left ventricular balloon was connected to an HP 1290C pressure transducer by way of a 14-gauge catheter and to a calibrated syringe for administration of withdrawal of fluid. Then the heart was immersed in St. Thomas’ Hospital cardioplegic solution and stored at 4°C for 5 hours.
Isolated heart preparation
After cold storage, hearts were mounted on a standard crystalloid-perfused isolated heart preparation. Briefly, the circuit consisted of a venous reservoir that served also as an oxygenator, a roller pump, a heat exchanger (Buckberg-Shiley blood cardioplegic solution delivery set DP 23-1014 A), and a 40-µm arterial filter (Ultipor SQ40S; Pall Biomedical, Saint-Germain-en-Laye, France). Hearts were placed in an organ chamber that was maintained at 37°C. The circuit was primed with physiologic Krebs-Henseleit solution (in millimoles per liter: NaCl, 118; KCl, 4.7; MgSO4, 1.2; NaHCO3, 25; KH2PO4, 1.2; CaCl2, 2.5; glucose, 11). Oxygenation was achieved with a 95% oxygen–5% carbon dioxide mixture. The perfusion temperature was maintained at 37°C throughout the protocol and the pressure, between 80 and 90 mm Hg. Pacing wires were placed on the right ventricle and connected to a Medtronic 5375 pacemaker to allow measurements to be made at a constant heart rate (150 bpm).
Functional measurements
Cardiac functional recovery was assessed after 60 minutes of reperfusion. The left ventricular balloon and the pressure transducer were connected to an MP 100 data-acquisition system using Acknowledge 3.0 software (Biopac Systems). Initially the balloon volume was adjusted to produce a left ventricular end-diastolic pressure (LVEDP) between 0 and 2 mm Hg. Six increments of 0.1 mL were then added to obtain pressure–volume plots. Developed pressure (calculated as the difference between left ventricular peak systolic pressure and LVEDP) was recorded at an LVEDP between 0 and 2 mm Hg. Compliance curves were assessed by fitting by linear regression the LVEDP–volume plots to the equation 
is the slope, V is the left ventricular balloon volume, and 
is the balloon volume corresponding to an LVEDP of 0,or the x-intercept. Fremes and associates [14] previously demonstrated that linear regression provides a reasonable model for diastolic function curves. The +dP/dtmax and -dP/dtmax were calculated simultaneously by the computer. Coronary flow rate was obtained by collecting effluent from the pulmonary artery after 60 minutes’ reperfusion.
Metabolic studies
Cellular injury occurring during ischemia and reperfusion was assessed by measuring creatine kinase release in coronary effluent. Samples of coronary effluent were taken after 10, 15, 30, 45, and 60 minutes’ perfusion and stored at 4°C. Levels were measured by an enzymatic assay with Boehringer Mannheim kits on Progress version 8.1. (Koné Instruments, Paris, France) and expressed as international units per liter.
Experimental groups and study design
A 2 x 2 factorial study protocol was used to evaluate the main effects of brain death versus control and of cromakalim pretreatment versus no pretreatment. Thus, animals were randomized into four experimental groups: control, control+PCO, brain death, and brain death+PCO (n = 8 per group). The control group was subjected to 90 minutes of anesthesia (sham operation) before cardioplegic arrest and 5 hours’ cold storage in St. Thomas’ Hospital solution. In the control+PCO group, anesthetized rabbits received an intravenous bolus injection of 30 µg/kg of cromakalim 30 minutes before cardioplegic arrest and 5 hours’ cold storage in St. Thomas’ Hospital solution. The brain-death group underwent 90 minutes of brain death before cardioplegic arrest and 5 hours’ cold storage in St. Thomas’ Hospital solution. In the brain death+PCO group, brain-dead rabbits received an intravenous bolus injection of 30 µg/kg of cromakalim 30 minutes before cardioplegic arrest and 5 hours’ cold storage in St. Thomas’ Hospital solution. The dose of cromakalim chosen for these experiments was based on studies documenting improved cardiac protection after regional ischemia in rabbit hearts [15] and on previous studies performed in our laboratory [9]. The PCO cromakalim (supplied by Sigma Chemical, Saint-Quentin-Fallavier, France) was prepared with 0.96 water volume and 0.04 ethanol volume to obtain a final concentration of 0.3 µg/mL after dilution in saline solution.
Statistical analysis
All results were expressed as the mean ± the standard error of the mean. In vivo intragroup hemodynamic and hormonal changes were assessed by one-way analysis of variance for repeated measures followed by the Tukey post-hoc correction for multiple comparisons. Main effects of brain death and cromakalim pretreatment and their eventual interaction were analyzed by two-way analysis of variance. A p value of less than 0.05 was considered significant. All statistical procedures were performed with the use of SPSS 6.1 software (SPSS Inc, Chicago, IL).
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Results
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Brain death versus control
In vivo measurement
Intracranial balloon inflation rapidly abolished pupillary reflexes and spontaneous respiration in all animals. Electroencephalographic changes were characterized by immediate cessation of cerebral electrical activity after intracranial balloon inflation. Control rabbits showed a moderate but significant reduction in MAP during the last 30 minutes of the study period (Fig 1). In contrast, major and persistent hemodynamic changes were observed after brain-death induction. Intracranial balloon inflation produced an immediate and significant increase in MAP in the brain-death group (from 79.8 ± 3.9 mm Hg to 142.1 ± 7.5 mm Hg; p < 0.001) and in the brain death+PCO group (from 81.3 ± 6.2 mm Hg to 139.0 ± 7.1 mm Hg; p < 0.001). Thereafter, MAP decreased rapidly and remained significantly lower than baseline for the remainder of the study period. At explantation, MAP values were significantly lower in brain-dead rabbits than in control rabbits (F = 18.55, p = 0.0002).
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Fig 1. In vivo mean arterial pressure for the four experimental groups at baseline (BL) and for 90 minutes after intracranial balloon inflation. (BD = brain death; CTRL = control; PCO = potassium-channel opener; * = p < 0.05, BD and BD+PCO versus BL; # = p < 0.05, CTRL and CTRL+PCO versus BL.)
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Cardiac function, as assessed by pressure–time relationships, remained stable overall in control rabbits throughout the study period (Table 1). In contrast, intracranial balloon inflation caused a significant increase in +dP/dtmax and -dP/dtmax (see Table 1). Thereafter, +dP/dtmax and -dP/dtmax rapidly deteriorated to lower than baseline. At explantation, +dP/dtmax and -dP/dtmax were significantly lower in brain-dead rabbits than in control rabbits (F = 31.9, p < 0.0001 and F = 19.6, p = 0.0001, respectively).
Plasma catecholamine levels remained stable throughout the study period in control animals (Table 2). In contrast, a significant rise in plasma norepinephrine levels was observed 1 minute after intracranial balloon inflation. By 30 minutes after brain death, norepinephrine levels had returned to baseline. Epinephrine levels did not increase after intracranial balloon inflation but were significantly lower than baseline after 30 minutes of brain death.
In vitro measurements
After 60 minutes of ex vivo perfusion, hearts of brain-dead rabbits had significantly lower left ventricular developed pressures than did hearts of control rabbits (F = 9.58, p = 0.004) (Fig 2). Similarly, the +dP/dtmax was significantly reduced in hearts of brain-dead rabbits compared with hearts from control rabbits (F = 14.61, p = 0.0007) (Fig 3). In contrast, brain death had no significant effect on the values of the slope or the x-intercept of the LVEDP–volume relationship (Table 3). However, -dP/dtmax was significantly reduced in hearts of brain-dead rabbits compared with hearts from control rabbits (F = 12.03, p = 0.0017) (Fig 4). Although coronary flow tended to be lower in brain-dead animals (Table 4), the effect of brain death was not significant. No differences in overall creatine kinase release were noted between hearts explanted from brain-dead animals or from control animals (Fig 5).
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Fig 2. Left ventricular developed pressure (LVDP) after 5 hours of cold storage and 60 minutes of crystalloid reperfusion. Data are shown as the mean ± the standard error of the mean. (ANOVA = two-way analysis of variance; BD = brain death; CTRL = control; PCO = potassium-channel opener.)
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Fig 3. Maximal positive rate of rise of left ventricular pressure (+dP/dtmax) after 5 hours of cold storage and 60 minutes of crystalloid reperfusion. Data are shown as the mean ± the standard error of the mean. (ANOVA = two-way analysis of variance; BD = brain death; CTRL = control; PCO = potassium-channel opener.)
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Fig 4. Maximal negative rate of rise of left ventricular pressure (-dP/dtmax) after 5 hours of cold storage and 60 minutes of crystalloid reperfusion. Data are shown as the mean ± the standard error of the mean. (ANOVA = two-way analysis of variance; BD = brain death; CTRL = control; PCO = potassium-channel opener.)
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Fig 5. Creatine kinase (CK) release during 60 minutes of crystalloid reperfusion. Data are shown as the mean ± the standard error of the mean. (BD = brain death; CTRL = control; PCO = potassium-channel opener.)
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Cromakalim pretreatment versus no pretreatment
In vivo measurements
Intravenous injection of cromakalim significantly reduced MAP in control rabbits (from 61.4 ± 4.8 mm Hg to 48.6 ± 2.7 mm Hg; p < 0.01) and tended to reduce MAP in brain-dead animals without achieving significance (from 48.1 ± 3.0 mm Hg to 39.9 ± 2.6 mm Hg; p > 0.05) (see Fig 1). Cromakalim pretreatment had no significant effect on MAP (see Fig 1) or cardiac function at explantation (see Table 1).
In vitro measurements
Although cromakalim pretreatment tended to improve functional recovery in brain-dead rabbits and not in control rabbits, there was no significant interaction between the two factors brain death and cromakalim pretreatment for any of the variables studied. Cromakalim pretreatment, as assessed by two-way analysis of variance, had no significant effect on left ventricular developed pressure (F = 0.59, p = 0.45) (see Fig 2) or on the +dP/dtmax (F = 0.12, p = 0.73) (see Fig 3). Further, cromakalim pretreatment did not affect the values of the slope or x-intercept of the LVEDP–volume relationship (see Table 3), nor did it affect the -dP/dtmax (F = 0.36, p = 0.55) (see Fig 4). No differences in coronary flow were noted between the pretreated animals and those that were not given cromakalim (see Table 4). Overall creatine kinase release during reperfusion was unaffected by cromakalim pretreatment (see Fig 5).
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Comment
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The major finding of this study is that pretreatment of brain-dead or anesthetized rabbits with an intravenous injection of cromakalim, 30 µg/kg, 30 minutes before heart explantation had no significant effects on functional recovery or enzymatic release after prolonged hypothermic storage. However, our data confirmed that brain death induces major hemodynamic and hormonal modifications leading to persistent myocardial dysfunction.
Potassium-channel openers have been used in different ways in the field of cardiac surgery. Some authors [16] have reported that hyperpolarized cardiac arrest induced with a PCO is followed by a statistically significant better functional recovery than that seen after conventional depolarized cardiac arrest using hyperpotassic cardioplegia. Alternatively, other groups [17] have shown that PCO supplementation during hyperpotassic cardioplegic arrest improves functional recovery of hearts after short-term cardioplegic arrest. Finally, PCOs have been used as a preconditioning-mimetic drug to reproduce the beneficial effects of ischemic preconditioning without the need of a preceding ischemic insult. In an isolated rat heart model, Ménasché and associates [18, 19] administered a PCO (nicorandil) 5 minutes before global ischemia. They observed an improved functional recovery after 45 minutes of normothermic cardiac arrest [18] and 120 minutes of hypothermic cardioplegic arrest [19].
More recently, this concept of pharmacologic preconditioning has been applied to prolonged periods of cardioplegic arrest as encountered during heart transplantation. Du and colleagues [20] reported enhanced myocardial preservation during 12-hour hypothermic storage by a combination of PCO (pinacidil) pretreatment and storage in an antioxidant-enriched cardioplegic solution. Similarly, we [9] previously found that intravenous pretreatment of awake rabbits with 30 µg/kg of cromakalim significantly improved functional recovery after prolonged storage (6 hours) in an extracellular solution. However, these studies were limited by the fact that the PCO was administered either in vitro (while the heart was beating on the perfusion column) [18–20] or in vivo to awake rabbits [9]. These limitations preclude any extrapolation to the clinical setting, where hearts are explanted from brain-dead donors.
In the present study, although cromakalim pretreatment tended to improve functional recovery of hearts explanted from brain-dead rabbits, the main effect of cromakalim pretreatment was not significant. Brain death is known to be associated with major hemodynamic and hormonal changes [10]. The in vivo hemodynamic modifications observed after induction of brain death in our study corroborated the findings of previous studies involving experimental brain death in the rabbit [13] or other animal species [21, 22]. Like others, we could distinguish two successive phases. The first, lasting approximately 10 minutes from the moment of intracranial balloon inflation, was characterized by a hyperdynamic state with significant increases in MAP, heart rate, and the inotropic and the lusitropic state of the heart. The second phase was characterized by significant reductions in MAP and cardiac inotropism and lusitropism to lower than baseline. These hemodynamic changes were associated with a significant increase in plasma norepinephrine levels immediately after intracranial balloon inflation. After global hypothermic cardioplegic arrest and crystalloid reperfusion, left ventricular function remained significantly lower in brain-dead animals than in control rabbits.
These findings confirm those of a previous report [13] involving an experimental model in the rabbit, which showed that brain death induces a persistent myocardial injury that is additive to ischemia-reperfusion injury. Thus, it is possible that brain death–induced myocardial injury counteracted the beneficial effects of cromakalim pretreatment. Furthermore, catecholamine release has repeatedly been shown to be involved in the biochemical cascade induced by ischemic preconditioning in the rabbit [11, 12]. Their massive release during brain death might have activated the intracellular pathways associated with preconditioning, thereby rendering them unresponsive to a subsequent preconditioning stimulus such as cromakalim pretreatment.
In contrast to our previous study [9], cromakalim pretreatment was also ineffective in control hearts. However, our two studies differ on two major points. First, whereas hearts were mounted on a blood-perfused isolated heart model in our previous study, they were buffer-perfused in the present study. However, we note that Sandhu and coauthors [23] found that the protective effects of ischemic preconditioning are not significantly different in blood-perfused and buffer-perfused isolated heart models. Second, cromakalim was administered 30 minutes before induction of anesthesia in our previous study. In contrast, in the design of this study, cromakalim pretreatment was preceded by a prolonged period of anesthesia. Morita and co-workers [24] showed that cromakalim pretreatment elicits cardiac protection in rabbit hearts independently of anesthetic agents. However, it is possible that the complex neurohormonal and hemodynamic modifications associated with prolonged anesthesia (as shown by the significant reduction in MAP in control rabbits [control+PCO group] during anesthesia) interfered with the myocardial response to cromakalim pretreatment. These findings suggest that myocardium subjected to stressful conditions such as brain death or prolonged anesthesia might have a different response to a subsequent preconditioning stimuli. Thus, Dekker and associates [25] demonstrated that the cardioprotective effects of ischemic preconditioning are absent in failing rabbit hearts. Further research is warranted to investigate whether hearts of brain-dead donors can be preconditioned, and if so, whether the mechanisms involved are the same as in healthy hearts.
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Conclusions
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In vivo pretreatment of brain-dead rabbits or anesthetized rabbits with an intravenous injection of cromakalim, 30 µg/kg, 30 minutes before heart explantation had no significant effects on functional recovery or enzymatic release after 5 hours’ hypothermic storage and 60 minutes’ buffer reperfusion. These findings are in sharp contrast with those in our previous study [9] and underscore the importance of experimental models that are representative of the clinical setting. Our data confirm that brain death induces major hemodynamic and hormonal modifications that lead to persistent myocardial dysfunction on ex vivo reperfusion.
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References
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Abstract
Introduction
