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Ann Thorac Surg 2004;77:1391-1397
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Replacing potassium with nicorandil in cold St. Thomas' Hospital cardioplegia improves preservation of energetics and function in pig hearts

Tor Steensrud, MDa*, Dag Nordhaug, MDa, Kjell V. Husnes, MDa, Ebrahim Aghajani, MDa, Dag G. Sørlie, PhD, MDa

a Department of Cardiothoracic and Vascular Surgery, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway

Accepted for publication September 22, 2003.

* Address reprint requests to Dr Steensrud, Department of Cardiothoracic and Vascular Surgery, PO Box 102, N-9038 Tromsø, Norway
e-mail: tors{at}fagmed.uit.no


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 
BACKGROUND: To determine whether the adenosine triphosphate-sensitive potassium channel opener nicorandil, instead of potassium in cold crystalloid cardioplegia, may enhance cardioprotection, crystalloid cardioplegia with nicorandil, magnesium, and procaine was compared with standard crystalloid cardioplegia in terms of left ventricular performance and efficiency.

METHODS: Sixteen pigs were randomly assigned to receive cold hyperkalemic crystalloid cardioplegia (n = 8) or nicorandil in cold saline (n = 8). Cold (4°C) cardioplegic solutions were given antegradely and intermittently, with a cross-clamp time of 60 minutes. The preload recruitable stroke work relationship (PRSW), pressure-volume area (PVA), and myocardial oxygen consumption (MVO2) were calculated at baseline and at one and two hours following cross-clamp release, using combined pressure-volume conductance catheters, coronary flow probes, and O2-content differences.

RESULTS: The left ventricular contractility expressed in PRSW was reduced to 58% (standard deviation [SD]: 20) of baseline in the crystalloid group and to 89% (SD: 20) in the nicorandil group two hours after cross-clamp release (p = 0.044). The slope of the MVO2-PVA relationship increased in the crystalloid group from 1.59 (SD: 0.22) before cardioplegia to 2.55 (SD: 0.73) afterwards, significantly more than in the nicorandil group, where the slope changed from 1.69 (SD: 0.30) to 1.95 (SD: 0.47) (p = 0.027).

CONCLUSIONS: Nicorandil in a crystalloid cardioplegic solution was easily employed and contractility was significantly better than after standard hyperkalemic cardioplegia. The smaller shift of the slope in the MVO2-PVA relationship in the nicorandil group shows improved efficiency in oxygen to mechanical transfer compared with the crystalloid group.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 
Cardioplegia during surgery is most commonly achieved by elevation of the extracellular potassium concentration. This usually offers adequate myocardial protection and good working conditions for the surgeon. However, prolonged hyperkalemic arrests have been linked to calcium overload, contractures, and decreased myocardial adenosine triphosphate (ATP) levels [1]. Cardioplegic solutions without potassium may counteract the ionic imbalance and prevent arrhythmias associated with hyperkalemia. Adenosine triphosphate sensitive potassium channel (KATP) openers are cardioprotective, and have cardioplegic effects thought to be caused by lowering the membrane potential to more negative values [2, 3]. Using KATP openers instead of potassium in cardioplegic solutions, may thus combine the benefits of avoiding high levels of potassium with the added cardioprotection of a KATP opener.

Several experiments have shown improved postischemic contractile recovery after the use of KATP channel openers as cardioplegic agents, using both blood [4] and crystalloid solutions as vehicles [2]. In 1997, Jayawant [5] showed that nicorandil as cardioplegic agent improved functional recovery in a rabbit model, and in 1999 [6] he demonstrated that pinacidil as cardioplegic agent sustained ventricular function compared with St. Thomas' Hospital solution in a porcine model. We have found no reference to the use of KATP channel openers as a cardioplegic agent in humans. Hayashi and colleagues [7] and Li and colleagues [8] have used nicorandil as an additive and a pretreatment, respectively, in patients having standard, cold crystalloid hyperkalemic cardioplegia during heart surgery. Both studies suggest enhanced myocardial protective effects of nicorandil administration against ischemia-reperfusion damage.

We have previously shown improved cardiac performance and energetics after nicorandil, magnesium, and procaine in cold blood. We wanted to investigate if nicorandil offered similar protection in an asanguineous solution. Although blood cardioplegia offers better cardioprotection, crystalloid cardioplegia is still commonly used for routine heart surgery with expected aortic occlusion times less than 90 minutes, probably due to its feasibility. A crystalloid cardioplegic solution with improved cardioprotective properties could be clinically useful.

We used an open-chest pig model with global ischemia on full cardiopulmonary bypass, simulating a clinical setting as a prelude to a planned clinical study. The left ventricular oxygen consumption and pressure-volume relationship were analyzed in the myocardial oxygen consumption-pressure-volume area (MVO2-PVA) framework, as developed by Suga [9], to determine ventricular energetics. We hypothesized that nicorandil, in an asanguineous solution with added magnesium and procaine, would preserve functional recovery and mechanoenergetic efficiency better than hyperkalemic cardioplegia.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Conclusion
 Acknowledgments
 References
 
Preparation
The experimental protocol was approved by the local steering committee of the Norwegian Animal Experiments Authority and was conducted in compliance with the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (National Institutes of Health Publication No. 85 to 23, revised 1996). Domestic pigs of either sex, with mean weight 55 kg (standard deviation [SD] 7 kg), were fasted overnight and premedicated with intramuscular ketamine (20 mg/kg, Warner Lambert Nordic, Sweden) and atropine (2 mg, Nycomed Pharma, Norway). Anesthesia was induced by intravenous pentobarbital (10 mg/kg, Nycomed Pharma, Norway) and fentanyl (0.02 mg/kg, Pharmlink, Sweden) and maintained with an hourly infusion of fentanyl (0.02 mg/kg), midazolam (0.3 mg/kg, Alpharma, Norway), and pentobarbital (4 mg/kg). The pigs were tracheostomized and ventilated with 60% oxygen. Glucose enriched sodium chloride (1.25 g glucose/L sodium chloride) was given for basal fluid replacement. Body temperature was recorded from a rectal probe and urine was drained through a cystostoma. Mean arterial pressure (MAP) was measured in the descending thoracic aorta. Central venous pressure (CVP) was measured and infusions were given in the jugular veins. After a median sternotomy, the pericardium was incised and the left hemiazygos vein was ligated, and transit-time flow probes (Cardio-Med CM-4000, Medi-Stim AS, Norway) were placed on the three main coronary arteries and the pulmonary trunk for determination of coronary flow (myocardial blood flow, MBF) and cardiac output (CO). For preload reduction, a 7F balloon catheter (Sorin Biomedica, Canada) was placed in the inferior caval vein. A 7F, 12 electrode, dualfield combined microtip and conductance catheter (Sentron, CD Leycom, The Netherlands) for continuous measurements of left ventricular pressures and volumes was introduced into the left ventricle through the left carotid artery. Myocardial venous blood was obtained from a catheter in the great cardiac vein. A catheter was placed in the pulmonary artery for monitoring of mean pulmonary artery pressure (MPAP) and for parallel volume measurement by injection of 4 mL hypertonic (10%) saline [10]. Animals were stabilized for 20 minutes before baseline measurements. The myocardial temperature was measured with a myocardial probe connected to a thermistor (COM-1, American Edwards Laboratories, Canada).

Experimental protocol
After baseline measurements, 19 pigs were randomized to receive either standard potassium-magnesium crystalloid cardioplegia (Modified St. Thomas' Hospital solution No.1) [11] or a cold saline solution composed of 0.1 mmol/L nicorandil, 16 mmol/L magnesium and, in the bolus dose only, 2.5 mmol/L procaine (Table 1). The left axillary artery was cannulated after full heparinization (activated clotting time > 480 seconds); venous drainage was obtained from a cavoatrial cannula. Normotherm cardiopulmonary bypass (CPB) was initiated with a flow of 75 to 90 mL/kg, using a centrifugal pump (Biomedicus, MN), a heater/cooler (Stoeckert-Shiley, Germany) and a membrane oxygenator (Monolyth, Sorin Biomedical, Italy). A standard cardioplegic cannula (dlp CB20012, MI), with a side branch for pressure monitoring, was placed in the ascending aorta. The aorta was cross-clamped for 60 minutes and the left ventricle vented through the aortic cannula. Both forms of cardioplegia were given antegradely and intermittently, cardiac arrest was initiated with 500 mL followed by 200 mL cardioplegia every 20th minute. The infusion pressure measured at the aortic root was kept between 50 and 80 mm Hg and the infusion time was between 2 to 6 minutes. Ice-slush was applied when necessary to maintain myocardial temperature between 15 to 18°C. All hearts underwent 60 minutes of cold ischemic arrest before the aortic cross-clamp was released. Weaning from CPB was tried 20 minutes after cross-clamp release. If necessary, animals were allowed another 20 minutes of support before CPB was terminated. The first sampling was made one hour after cross-clamp release. Only pigs that were successfully weaned from CPB without use of inotropic agents were included in the study. Animals were killed after the experiment with intracardiac injection of KCl and intravenous pentobarbital. Transmural (tru-cut) biopsies were taken from the left ventricle at baseline and after the second measurements of energetics, and immediately cooled on liquid nitrogen for later analyses of high energy phosphates.


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  		Table 1. Composition of Cardioplegic Solutions in Final Concentration/mmol/L

 
Calculations
The conductance catheter technique has been described in detail elsewhere [10]. Variable loaded beats were obtained by transient (12 to 15 seconds) preload reductions with the balloon in the caval vein during disconnection of the respirator. Pressure-volume recordings with concomitant MVO2 determinations were performed at six different steady state preloads in order to assess the MVO2-PVA relationship [12]. Pressure and conductance signals were processed using a conductance conditioner (Leycom, Sigma 5DF, Cardiodynamics, the Netherlands) and displayed on a computer using the software Conduct PC, CPC V3.15 (Leycom). The slope factor {alpha} was calculated from the ratio between conductance and transit time derived cardiac outputs. Parallel conductance was calculated by analyzing beats with increasing conductance after injection of 4 mL 10% NaCl in the pulmonary artery [10]. Pressure-volume area represents total mechanical work [12] and was calculated as: PVA = [SW + (Pes · (Ves − V0)/2) − (Ped · (Ves − V0)/2)] (J mm Hg−1 mL−1), where stroke work (SW) is the area within the pressure-volume loop, and Pes and Ves are end systolic pressure and volume, respectively. The V0 is the extrapolated x-intercept of the end-systolic pressure-volume relationship (Ees) and Ped is end diastolic pressure. Global left ventricular function was assessed by the regression coefficient (Mw) of the preload recruitable stroke work relation (PRSW). The end-diastolic pressure-volume relationship (EDPVR) was assessed from consecutive beats during VCO, and fitted by the exponential equation Ped = {alpha} · e(ß · Ved). End-diastolic stiffness was evaluated by the slope coefficient (ß, dimensionless) of the exponential EDPVR. Left ventricular coronary blood flow (LVCBF) was calculated as left ventricular weight/total heart weight times total coronary blood flow. Left ventricular oxygen consumption (MVO2) was calculated as: MVO2 = (LVCBF · avdO2 · Hb · 1.39)/HR · 20.2, where avdO2 is the difference between aortic and myocardial venous oxygen saturation, Hb is hemoglobin in g/mL, 1.39 is a pig specific constant (in mL O2/g Hb), and HR is heart rate. The MVO2 was converted to joules with the factor 20.2 Joule/mL O2. Myocardial samples were crushed in a nitrogen-cooled mortar, pulverized in a pestle, and lyophilized. High performance liquid chromatography analyses were performed on the precipitate following preparation and the adenosine triphosphate pool determined [13].

Statistics
Data are presented as mean ± 1 SD. Normality of data distribution was analyzed with normal score plots of residuals. Data were analyzed using analysis of variance for repeated measures (GLM procedure, RANOVA) using a statistical software package (SPSS10.0, SPSS Inc., IL). Where appropriate, nonrepeated variables were compared by ANOVA. Significance level was set to p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Conclusion
 Acknowledgments
 References
 
Of nineteen pigs used in the study, sixteen animals completed the protocol; eight in each group. Three animals were excluded after cardioplegia; two in the crystalloid group due to failure of weaning from cardiopulmonary bypass and one in the nicorandil group due to a technical malfunction. Three animals in the crystalloid group needed an extra 20 minutes of CPB support after cross-clamp release before they could be weaned from CPB. Three animals in the nicorandil group regained sinus rhythm spontaneously during reperfusion, all other animals had to be electroconverted. Measurements of contractility were made while in a stable sinus rhythm.

Hemodynamic data are summarized in Table 2. Apart from a lower dP/dtmin (p = 0.02) at baseline in the nicorandil group, the groups were similar at baseline.


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  		Table 2. Hemodynamic Variables at Baseline and at 60 and 120 Minutes After Cross-Clamp Release for All Pigsa

 
Variables of systolic function are given in Table 3. The slope (Mw) of PRSW was significantly reduced in the crystalloid group (p = 0.044) after cross-clamp release compared with the nicorandil group (Fig 1). There was a significant increase in the stiffness coefficient ß two hours after cardioplegic arrest in the crystalloid group compared with the nicorandil group (p = 0.032), indicating increased diastolic stiffness in the crystalloid group (Fig 2). All other mechanical variables dP/dtmax, stroke work, tau, and dP/dtmin were reduced after cross-clamp release, but no significant group differences were observed in these measures. Global ischemia made it possible to use the relatively load and heat rate insensitive index PRSW as a more reliable index of ventricular contractility than the load and heart rate dependent indexes dP/dtmax, stroke work, tau, and dP/dtmin [14] (Tables 3 and 4).


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  		Table 3. Left Ventricular Contractility at Baseline and at 60 and 120 Minutes After Cross-Clamp Releasea

 


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  		Fig 1. Left ventricular contractility in Mw, the slope of the preload-recruitable stroke work index, in percentage of baseline values. Sixteen pigs, n = 8, in each group compared after different cardioplegia. Error bars are standard deviation. p = 0.015 nicorandil group versus St. Thomas' Hospital solution group 60 minutes after cross-clamp release; p = 0.044 nicorandil group versus St. Thomas' Hospital solution group 120 minutes after cross-clamp release.

 


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  		Fig 2. End-diastolic pressure-volume relationship, or diastolic stiffness expressed in ß, at baseline, after one, and after two hours after cross-clamp release in 16 pigs, n = 8 in each group. * p = 0.049 between the nicorandil group and St. Thomas' Hospital solution group 120 minutes after cross-clamp release.

 

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  		Table 4. Left Ventricular Diastolic Properties at Baseline and at 60 and 120 Minutes After Cross-Clamp Releasea

 
Analyses of left ventricular biopsies revealed no statistical difference between the groups at baseline or at the end of the experiment in the levels of the energy phosphates creatine, creatine phosphates, nicotinamide adenine dinucleotide (NAD), adenosine monophosphate (AMP), adenosine diphosphate (ADP), or ATP.

Myocardial energetics: MVO2-PVA relationship
The slopes and y-axis intercepts of the MVO2-PVA relationships at baseline and at two hours after cross-clamp release are shown in Table 5. These values were comparable between groups at baseline.


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  		Table 5. Changes in Left Ventricular Energetics 120 Minutes After Cross-Clamp Release in 15 Pigsa

 
According to Suga [12], the reciprocal of this slope is the contractile efficiency; that is, an increased slope represents a decrease in contractile efficiency. The slope was significantly increased in the crystalloid group compared with the nicorandil group after ischemia, demonstrating a reduced contractile efficiency in the crystalloid group (Fig 3). The y axis intercept of the MVO2-PVA relationship (unloaded MVO2) represents oxygen consumption for noncontractile purposes, consisting of basal metabolism and Ca2+ handling in excitation-contraction coupling. There were no significant changes in unloaded MVO2.



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  		Fig 3. MVO2–PVA (pressure-volume area) data 120 minutes after cross-clamp release for the nicorandil group (n = 8) and the St. Thomas' Hospital solution group (n = 7). Lines indicate mean values for the nicorandil group (dashed) and the St. Thomas' Hospital solution (solid) group. There was no difference between slopes or y intercepts at baseline. Significant (p = 0.012) increase in slope in the St. Thomas' Hospital solution group ({circ}) compared with the nicorandil group ({diamondsuit}).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Conclusion
 Acknowledgments
 References
 
The aim of this study was to determine whether a cardioplegic solution, consisting of nicorandil, magnesium, and procaine in cold saline, could give improved cardioprotection over a modified St. Thomas' Hospital solution No. 1. We have demonstrated significantly improved preservation of left ventricular energetics and functional recovery with nicorandil in the cardioplegic solution.

The KATP channel openers have previously been reported to induce "hyperpolarized (polarized) arrest" by opening sarcolemmal KATP channels and thereby increasing outward movement of potassium, generating a lower resting membrane potential rendering the cell inexcitable [2]. According to Sato and colleagues [15], 100 µmol/L nicorandil activated mitochondrial but not sarcolemmal KATP in rabbit myocytes, so that the nicorandil concentration used in our study (100 µmol/L) was probably mito KATP channel selective. Any effect of nicorandil on the sarcolemma might, in this setting, be unimportant both for inducing cardiac arrest and for myocardial protection during ischemia and reperfusion.

A lowered temperature also contributes to cardiac arrest and myocardial protection. Indeed, cooling the heart to about 20°C induces arrest on its own but significantly slower and affords less protection than chemical cardioplegia [16]. The first bolus of cardioplegia contained 2.5 mmol/L procaine in this study because it has been reported that sodium-channel blockade counteracts persistent electromechanical activity otherwise experienced with KATP channel cardioplegia [6, 17], and sodium channel blockade acts synergistically with sarcolemmal KATP channels. Procaine, although present in both forms of cardioplegic solutions, could also contribute to cardiac arrest as well as myocardial protection. The cardioplegia in both groups contained elevated concentrations of magnesium, which enhance myocardial protection [18], and at higher concentrations (160 mmol/L) may arrest the heart [19]. However, the main arresting principle in the St. Thomas' Hospital solution is hyperkalemia, and when potassium was replaced with nicorandil the arrest was at least as fast and complete.

In the present study, we could not differentiate between the roles the mitochondrial or the sarcolemmal KATP channels have as effectors or determine at which cellular level nicorandil acted. Also, we were not able to rule out the nitrate-like action on coronary vessels as an explanation for the improved postischemic performance. However, there were no significant group differences in myocardial blood flow or systemic vascular resistance (Table 2) indicating either an effect on the heart or systemic effects of nicorandil's NO moiety. In addition, nicorandil was given directly into the heart and only after cross-clamp release any remains of the drug were distributed systemically.

The increase of the slope of the MVO2-PVA relationship in the crystalloid group represents a reduction in chemomechanical conversion efficiency. This either reflects a decrease in the efficiency of conversion of O2 to ATP or a decrease in the conversion of ATP to mechanical energy. If the opening of mito KATP channels in the nicorandil group preserved mitochondrial function, this would partly explain the improved mechanoenergetic efficiency observed in this group. Since ATP is almost exclusively hydrolyzed in the mitochondria, a postischemic mitochondrial dysfunction in the crystalloid group would decrease the efficiency in conversion of O2 to ATP. Another possible explanation for the increased slope of the MVO2-PVA relationship in the crystalloid group is a decrease in the conversion of ATP to mechanical energy, which again could be due to inefficient excitation-contraction coupling or decreased function of myofilament ATPases [20].

We did not observe any group difference in high-energy nucleotide levels (HEPS) and this could support that a decreased ATP to mechanical energy conversion, not a reduced O2 to ATP conversion, gives the reduced cardiac efficiency. However, there are methodological concerns in the measurements of HEPS since biopsies were not taken immediately after ischemia, when the highest differences might be expected, but after two hours of reperfusion. This is a period in which the postischemic heart is fragile and we chose not to take biopsies in this period due to the risk of disturbing the measurements of function and energetics. A similar lack of correlation between postischemic adenosine triphosphate levels and functional recovery has also been observed by others [6, 21].

Nicorandil is a hybrid KATP channel opener and a NO-emitter that acts on both sarcolemmal and mitochondrial KATP channels. Although the mitochondrial KATP channel has not yet been isolated, it has been suggested to be the key player in the cardioprotection offered by ischemic preconditioning rather than the sarcolemmal KATP channel [22]. Activation of the mitochondrial KATP channels is cardioprotective in ischemia-reperfusion [23], but by which mechanism so far is unknown [24, 25]. It has been proposed that opening of mito KATP maintains the architecture of the intermembrane space and preserves the functional coupling between mitochondrial creatine kinase and adenosine nucleotide translocase [26, 27]. Mitochondrial function may thus be protected using a KATP channel opener during an ischemia-reperfusion injury by upholding ATP production [28]. This mechanism, independent of sarcolemmal membrane potential changes, could have greater impact on the myocardial protection than what happens during induction of cardiac arrest.

Enthusiasm for KATP channel openers has been tempered by reports of proarrhythmic effects [29]. In the present study, three animals in the nicorandil group converted spontaneously to sinus rhythm during the reperfusion phase and no arrhythmias were observed later in this group. All animals in the crystalloid group needed electroconversion to regain sinus rhythm.

We studied intact healthy "adolescent" pigs and these experimental observations may not be directly transferable to the senescent, diseased human heart, although this has now been an established model for studying cardioprotection for over a decade. Elderly may have a lower response to ischemic preconditioning but nicorandil mimics this protection also in this patient group [30]. It is uncertain if diabetic patients taking the drug glibenclamide (a KATP channel blocker) also gain from KATP channel openers in cardioprotection [31, 32].


   Conclusion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Conclusion
Acknowledgments
 References
 
In conclusion, nicorandil in the cardioplegic solution was used in the same way as potassium and gave immediate cardiac arrest in a cold, asanguineous solution in the intact pig. The improved functional recovery is consistent with other studies that have demonstrated cardioprotective properties of nicorandil. The efficiency of the left ventricle analyzed in the MVO2–PVA model was considerably improved by using nicorandil instead of KCl, possibly due to improved mitochondrial protection.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Conclusion
 Acknowledgments
References
 
This study was supported with a grant from the Norwegian Council on Cardiovascular Disease and the Odd Berg Research Fund, Norway. The staff at the Surgical Research Laboratory, Institute of Clinical Medicine, University of Tromsø is greatly acknowledged for technical assistance.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Conclusion
 Acknowledgments
 References
 

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