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Ann Thorac Surg 1998;66:417-424
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Preconditioning with cromakalim improves long-term myocardial preservation for heart transplantation

^a Centre de Recherches Chirurgicales Henri Mondor, Créteil, France
^b Pharmacie Centrale, Hôpital Henri Mondor, Créteil, France

Accepted for publication February 27, 1998.

Address reprint requests to Dr Loisance, Centre de Recherches Chirurgicales Henri Mondor, Faculté de Médecine, 8 rue du Général Sarrail, 94010 Créteil Cedex, France
e-mail: (loisance{at}univ-paris12.fr)

	Abstract

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Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arrest and hypothermic storage. Our study investigated whether pretreatment with a potassium-channel opener (cromakalim) before prolonged storage in an extracellular fluid improves left ventricular recovery.

Methods. Rabbit hearts were submitted to 6-hours’ cold storage and assessed on a blood-perfused isolated heart preparation. Hemodynamic recovery, enzyme release (creatine kinase and lactate dehydrogenase), and adenine nucleotide content were determined. Five groups were tested: control (n = 6), no ischemia; UW group (n = 7), hearts arrested with and stored in University of Wisconsin solution; STH group (n = 5), hearts arrested with and stored in St. Thomas’ Hospital solution; cromakalim group (n = 6), hearts pretreated with cromakalim (30 µg/kg) before arrest with and storage in St. Thomas’ Hospital solution; and glibenclamide group (n = 5), hearts pretreated with cromakalim followed by glibenclamide (a potassium-channel blocker) before arrest with and storage in St. Thomas’ Hospital solution.

Results. Hemodynamic recovery was improved and enzyme release was lower in the UW group than in the STH group. Compared with the STH group, the group pretreated with cromakalim had significantly decreased left ventricular end-diastolic pressures, increased left ventricular developed pressures, increased maximal values of positive and negative rates of rise of left ventricular pressure, and increased time constant of isovolumetric relaxation. Hemodynamic recovery was similar in the UW group and cromakalim groups. Glibenclamide did not abolish the effects of cromakalim. None of the protocols affected myocardial energy stores.

Conclusions. Pretreatment with cromakalim affords additional protection to that provided by cardioplegic arrest and prolonged cold storage using an extracellular solution. The intracellular mechanisms involved remain to be determined.

	Introduction

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Organ immersion in a preservative solution remains the cornerstone of myocardial protection for heart transplantation. Experimental research to lengthen the duration of cold ischemic time has been performed worldwide, and one result of this research has been the development of the University of Wisconsin solution (UW) [1]. Despite optimal recovery of left ventricular function, UW has been shown to be deleterious to the endothelial wall because of its high K⁺ concentration. Recently, clinical evidence has suggested the involvement of UW in the development of long-term allograft vasculopathy [2]. However, we previously found that turning the intracellularlike composition of UW into an extracellular lactobionate and adenosine–based solution to avoid K⁺ cytotoxicity was followed by impaired recovery of left ventricular function after prolonged ischemia. The goal of future research then became the development of an approach to myocardial protection that would improve functional recovery after prolonged storage using exogenous myocardial preservation with an extracellular fluid. In this setting, endogenous protection afforded by cardiac preconditioning would be of great interest.

Ischemic preconditioning has been described as a powerful protective adaptation of the cardiomyocyte to a brief ischemic insult that slows down the rate of cell death during a subsequent period of prolonged ischemia [4]. This concept was subsequently extended to protection against other deleterious effects of the ischemia-reperfusion sequence such as myocardial stunning, arrhythmias, and endothelial lesions. Recently, ischemic preconditioning has been shown to provide additional protection during long-term hypothermic cardiac preservation [5, 6]. Similarly, hypoxia has been reported to improve left ventricular functional recovery after long-term ischemia [7]. Adenosine triphosphate (ATP)–sensitive potassium (K_ATP) channels are generally believed to support the mechanisms of ischemic preconditioning, as administration of the K_ATP channel blocker glibenclamide can suppress this protective effect [8]. Further, the use of potassium-channel openers (PCOs) before or during hyperkalemic cardioplegic arrest can mimic ischemic preconditioning and improve functional recovery of hearts submitted to short-term ischemia [9, 10].

However, additional protection conferred by PCOs to that provided by cardioplegia for long-term ischemia as encountered in heart transplantation has never been studied. In this clinical setting, the use of PCOs would have an obvious advantage over hypoxia or ischemic preconditioning. Thus, the aim of our study was to assess whether pretreatment with a PCO before cardioplegic arrest and prolonged heart storage in an extracellular fluid improves left ventricular recovery as well as use of UW solution alone.

	Material and methods

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Animals
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 86-23, revised 1985).

Surgical preparation
Animals were premedicated with intramuscular administration of acetylpromazine (1 mg/kg), and anesthesia was induced (20 mg/kg) and maintained (120 mg · kg^-1 · h^-1) with intravenous administration of ketamine hydrochloride. After general anesthesia and heparinization (300 IU/kg), animals were ventilated through a tracheotomy. The thorax was opened by a sternotomy and the heart was isolated.

In blood-donor rabbits, the ascending aorta was immediately cross-clamped and cannulated for total blood collection into a heparinized recipient.

In heart-donor rabbits, pulmonary veins and venae cavae were ligated en masse, and the pulmonary artery was transected to vent the heart. In the control group, the aorta was cross-clamped and cannulated immediately to start retrograde perfusion in the open chest without ischemia. The heart was then rapidly excised and the pulmonary artery, cannulated. A thin-walled latex balloon was inserted into the left ventricle through the left atriotomy and sutured to the mitral annulus. The left atrium was closed with a pursestring suture. The compliance of the balloon was such that it did not produce any hydrostatic pressure until filled to 2 mL. The left ventricular balloon was connected to a HP 1290 C pressure transducer (Universal Quartz Transducer; Hewlett-Packard) by a 14-gauge catheter and to a calibrated syringe for administration or withdrawal of fluid. Then the heart was fixed to the isolated heart preparation. In the preservation groups, after the aorta was cross-clamped, 40 mL of cold cardioplegia (4°C) was infused into the ascending aorta until cardiac arrest while the heart was cooled with topical use of cold saline solution. The heart was rapidly excised and the aorta, cannulated. Then the heart was immersed in the preservative solution and stored at 4°C for 6 hours before it was prepared for fixation to the isolated heart apparatus.

Isolated heart preparation
Hearts were mounted on a simplified blood-perfused isolated heart preparation as described by Deng and associates [11]. 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; and glucose, 11) in combination with blood from a blood-donor rabbit to obtain a hematocrit of 20% (±5.6%). Oxygenation was achieved with a 95% oxygen–5% carbon dioxide mixture (pH 7.4). 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.

Cardioplegic solutions and experimental design
The composition of the UW (Viaspan; Du Pont Pharma SA, Paris, France) and the St. Thomas’ Hospital (locally prepared) solution (STH) is given in Table 1. 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. The K_ATP-channel blocker glibenclamide (supplied by Aldrich Chemie, Saint-Quentin-Fallavier) was solubilized with polyethylene glycol 400 (0.5 volume) and NaHCO₃ (0.5 volume at 50 mmol/L) to obtain a final concentration of 0.3 mg/mL.

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; Cerom SARL, Paris, France). Initially the balloon was filled with a volume sufficient to produce a left ventricular end-diastolic pressure (LVEDP) of 0 mm Hg. Six increments of 0.1 mL were then added, and for each volume, the left ventricular developed pressure was calculated from the difference between left ventricular peak systolic pressure and LVEDP at a heart rate of 150 beats per minute. The LVEDP pressure–volume plots were fitted by linear regression to the equation ), where m is the slope, V is the left ventricular balloon volume, and V₀ is the balloon volume corresponding to an LVEDP of zero, or the x-intercept. Maximal positive and negative rates of rise of left ventricular pressure (+dP/dt and -dP/dt, respectively) were calculated simultaneously by the computer. The rate of left ventricular relaxation was measured using the time constant of isovolumetric relaxation. After aortic valve closure, which corresponds to the maximum value of -dP/dt, the decrease in left ventricular pressure was adjusted to the monoexponential model , where P_t represents the instantaneous pressure, P₀ is the pressure at minimal dP/dt, t is the time, and is the time constant of left ventricular isovolumetric pressure decay [13]. Coronary flow rate was measured by collection of effluent overflow from the cannulated pulmonary artery after 60 minutes of reperfusion.

Metabolic studies
Cellular injury occurring during ischemia and reperfusion was assessed by measuring creatine kinase and lactate dehydrogenase. Blood samples were taken after 10, 15, 30, 45, and 60 minutes of perfusion and stored at 4°C. Levels were measured by enzymatic assay with Boehringer Mannheim kits on progress version 8.1. (Koné Instruments, Paris, France) and expressed as international units per liter.

The adenine nucleotide pool was measured in all groups to study myocardial cellular energy stores. At the end of the 90-minute reperfusion period, left ventricular apex samples were immediately placed in liquid nitrogen. The adenine nucleotide pool was determined from this frozen biopsy specimen by high-performance liquid chromatography using the method of Hull-Ryde and coworkers [14]. Values were standardized to the amount of protein measured using the method of Hartree [15] and expressed in nanomoles per milligram of protein. Energy charge (EC) was calculated with the formula , where ATP is adenosine triphosphate, ADP is adenosine diphosphate, and AMP = adenosine monophosphate.

Statistical analysis
All results were expressed as the mean ± the standard deviation. One-way analysis of variance was used to determine if there were any significant differences between treatment groups. If significance was indicated by one-way analysis of variance, the two-tailed unpaired Student t test was used to compare groups. 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).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Myocardial function
Diastolic function
The slopes of the diastolic pressure–volume relationships were compared between groups after 60 minutes of reperfusion. After STH preservation, the slope had a significantly higher value than in the control group and the UW group (Table 2). After cromakalim pretreatment, the slopes of the LVEDP–volume relationships were similar to those of control hearts and were significantly lower than that seen after STH preservation. When glibenclamide was used, the slopes tended to increase, but this partial loss of the protective effect on diastolic function was not significant. Figure 1 summarizes the maximal values of -dP/dt in the five groups. Diastolic function was better preserved after cardioplegia with and storage in UW than STH. Hearts receiving cromakalim before STH cardioplegia significantly improved the maximal -dP/dt. However, glibenclamide administration did not abolish the protective effect of cromakalim. The recovery of the time constant of isovolumetric relaxation paralleled the results of -dP/dt (Fig 2). A protective action against the development of left ventricular contracture was exerted by cromakalim pretreatment but was not abolished by glibenclamide.

View larger version (25K): [in this window] [in a new window]   Fig 1. Maximal negative rates of left ventricular pressure relaxation (-dP/dtmax.) after 6 hours’ cold storage and 60 minutes of blood reperfusion. Data are shown as the mean ± the standard error of the mean. (STH = St. Thomas’ Hospital solution; UW = University of Wisconsin solution; *p < 0.05, UW and STH versus Control; p < 0.01, STH versus UW; #p = 0.01, Cromakalim versus STH.)

View larger version (24K): [in this window] [in a new window]   Fig 2. Time constant of left ventricular isovolumetric pressure decay () after 6 hours’ cold storage and 60 minutes of blood reperfusion. Data are shown as the mean ± the standard error of the mean. (STH = St. Thomas’ Hospital solution; UW = University of Wisconsin solution; *p < 0.05, STH versus other groups.)

View larger version (22K): [in this window] [in a new window]   Fig 3. Left ventricular (LV) developed pressure as a function of LV volume after 6 hours’ cold storage and 60 minutes of blood reperfusion. Data are shown as the mean ± the standard error of the mean. (STH = St. Thomas’ Hospital solution; UW = University of Wisconsin solution; $p < 0.03, Cromakalim versus Control; #p < 0.05, UW versus Control; *p < 0.05, STH versus UW, Cromakalim, and Control.)

View larger version (24K): [in this window] [in a new window]   Fig 4. Maximal positive rates of left ventricular pressure development (+dP/dtmax.) after 6 hours’ cold storage and 60 minutes of blood reperfusion. Data are shown as the mean ± the standard error of the mean. (STH = St. Thomas’ Hospital solution; UW = University of Wisconsin solution; *p < 0.05, UW, STH, and Cromakalim versus Control; p < 0.01, STH versus UW; #p = 0.01, Cromakalim versus STH.)

View larger version (25K): [in this window] [in a new window]   Fig 5. (A) Creatine kinase (CK) and (B) lactate dehydrogenase (LDH) release during 60 minutes of blood reperfusion. Data are shown as the mean ± the standard error of the mean. Areas under release curves for University of Wisconsin solution (UW) and control (CTRL) groups are significantly smaller than areas under release curves for St. Thomas’ Hospital solution (ST), Cromakalim (Crom) or potassium-channel opener (cromakalim), 30 µg/kg (PCO30), and glibenclamide (Glib) groups.

	Comment

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Cromakalim is a PCO without nitrovasodilative effect that has been reported to exert pharmacologic cardioprotection during acute ischemia by reducing myocardial dysfunction and infarct size [12]. As opposed to ischemia-induced depolarization, opening K_ATP channels causes potential shortening and membrane potential hyperpolarization. This results in decreased electromechanical activity and more rapid diastolic arrest, thus saving energy stores. The action potential shortening is accelerated, leading to decreased amplitude of intracellular Ca²⁺ diffusion and Ca²⁺ overload [16].

The cardioprotective effects of PCOs have been studied in different ways in the field of cardiac surgery. Some authors [17] have demonstrated that hyperpolarized cardiac arrest induced by a PCO is followed by significantly better functional recovery after normothermic ischemia than that obtained after cardioplegia-induced depolarization. Other researchers have assessed the results of the administration of a PCO immediately before or simultaneously with hyperkalemic cardioplegia. Sugimoto and associates [18] reported that myocardial protection after short-term ischemia is improved when a PCO (nicorandil) is given immediately before cold crystalloid cardioplegia. Hosada and co-workers [19] found that the addition of a PCO (pinacidil) to a cardioplegic solution improved myocardial recovery after short-term hypothermic ischemia. However, the effects on membrane potential when a PCO is given simultaneously with hyperkalemic cardioplegia are not known. The PCO–induced hyperpolarization might be antagonized (at least partially) by the depolarization induced by the hyperkalemic cardioplegia. To mimic the effect of ischemic preconditioning, Menasché and colleagues [9, 10] administered a PCO (nicorandil) and then allowed 5 minutes of reperfusion before cardioplegic arrest. They observed an improved hemodynamic recovery after 45 minutes of normothermic ischemia [9] and 120 minutes of hypothermic ischemia [10].

In studies dealing with pharmacologic preconditioning, the antagonist usually is administered before or simultaneously with the agonist [9, 10]. However, PCOs have an extended duration of activity and when used to mimic preconditioning, are still present during the onset of ischemia to protect the heart [8]. One of the main issues of pharmacologic preconditioning experiments is to discriminate between the "memory effect" of preconditioning and the persistence of cardioprotective effects afforded by the drug [20]. Indeed, PCOs act on the cytoplasmic side of the membrane after penetrating the cell [21]. Thus, a short washout interval may not be sufficient to eliminate the drug from the intracellular compartment and to suppress its residual effects before the onset of ischemia [22]. An elegant approach to demonstrate that K_ATP channels are involved in adenosine preconditioning was reported by Toombs and coauthors [23]. They introduced adenosine 30 minutes before ischemia and thereafter blocked the K_ATP channels by giving glibenclamide immediately before ischemia. We used a similar agonist/antagonist administration sequence in our protocol, as reflected by the delivery of cromakalim 25 minutes before glibenclamide. The expected benefit of this sequence was to allow the discrimination between sustained cardioprotective effects of PCO administration and effects of preconditioning induced by PCO pretreatment.

The K_ATP channel target of glibenclamide is different from the K_ATP channel receptor triggered by PCOs, thereby leading to a strong inhibition of PCO effects when glibenclamide is administered after the PCO [24]. Thus, glibenclamide introduced 5 minutes before cardioplegia antagonized the opening of K_ATP channels on cardiac myocytes induced by cromakalim administration 25 minutes earlier. Therefore, a remaining effect of K_ATP-channel opening by cromakalim cannot be considered responsible for the cardioprotection afforded during ischemia, as glibenclamide did not abolish this cardioprotection. This suggests that the intravenous administration of cromakalim triggered a cascade of events generating some endogenous cardioprotection as ischemic preconditioning does.

Potassium-channel openers are potent vasodilators and cause transient systemic hypotension when administered intravenously [12]. Thus, a transient hypotension on administration of cromakalim might have led to transient coronary hypoperfusion or an acute catecholaminergic response, both of which are known triggers for myocardial preconditioning [25, 26]. Alternatively, recent studies [27] suggest that activation of K_ATP channels may lead to activation and subsequent translocation of protein kinase C. Activation and translocation of protein kinase C have been shown to be implicated in ischemic preconditioning of the rabbit myocardium [28]. However, our data do not allow us to discriminate between any of these suspected mechanisms.

The cardioprotection induced by ischemic preconditioning is known to decrease when the duration of ischemia is extended and is lost after 60 to 90 minutes of normothermic ischemia [4]. The present study shows that cromakalim pretreatment enhances myocardial recovery after long-term (6 hours) hypothermic storage. Our results parallel those previously published [5–7] in which myocardial dysfunction, after long-term hypothermic storage, was reduced by ischemic or hypoxic preconditioning. Thus, the duration of safe myocardial preservation afforded by PCO pretreatment may be lengthened under a condition of deep hypothermia and cardioplegic arrest. The pharmacologic preconditioning afforded by cromakalim might be useful for the prolonged cardiac storage encountered in heart transplantation programs, as such a drug would be more easily administered than ischemia, hypoxia, or heart shock in this setting.

The precise mechanism of preconditioning remains incompletely understood. It has been suggested that this endogenous protection might be related to the slowing rate of ATP depletion during ischemia [29]. This contrasts with our results because we found that cromakalim did not significantly affect the myocardial energy stores despite better functional recovery. This could be due to the experimental protocol, which was performed under profound hypothermic conditions. Our results are consistent with those of Engelman and associates [7], who found that hypoxia prior to hypothermic storage did not increase adenine nucleotide content. The ATP content has been reported to represent an important determinant of recovery only under conditions of severe depletion [30]. Thus, in our study, the remaining energy charge was probably sufficient to not become a limiting factor of recovery.

When compared with an extracellularlike fluid such as STH, the superiority of UW has generally been attributed to its intracellularlike composition, impermeant agents, hydroxyethyl starch, and oxygen free radical scavengers [1]. Adenosine, initially introduced as a precursor of intracellular ATP resynthesis, also contributes to the efficacy of UW [31]. Moreover, in rabbits, adenosine has been proved to be involved in the ischemic preconditioning process through specific membrane receptors [32]. However, we have to realize that with UW, the administration of adenosine simultaneously with the cardioplegia (and not by pretreatment) does not strictly reproduce a preconditioning phenomenon. Surprisingly, we found that the functional recovery was not paralleled by enzyme leakage. The cellular damage was reduced and the sarcolemmal integrity was better maintained after UW storage than STH storage even without preconditioning by cromakalim. This superior ability of UW to reduce the reperfusion injury may be explained by its composition supplemented with oxygen free radical scavengers such as reduced glutathione, allopurinol, and lactobionate anion [33]. This is particularly true in our blood reperfusion model where the major contributors to oxygen free radical production (neutrophils and Fe²⁺ in erythrocytes) are fully available.

In conclusion, in this study we demonstrated that PCO pretreatment with cromakalim provided additional protection to that given by cardioplegic arrest and prolonged cold storage using an extracellularlike fluid for heart transplantation. This endogenous approach coupled with a basic exogenous myocardial protection resulted in a myocardial functional recovery similar to that obtained with UW alone, which should be restricted to heart storage because of its endothelial cytotoxicity. However, the mechanisms involved intracellularly after such PCO preconditioning are unclear and might be different from membrane hyperpolarizing induced by K_ATP-channel opening. Further research is mandatory to determine these second messengers of cardiac myocyte resistance to ischemia [3].

	References

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