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Right arrow Myocardial protection

Eur J Cardiothorac Surg 2007;32:493-500. doi:10.1016/j.ejcts.2007.05.020
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved

Adenosine instead of supranormal potassium in cardioplegic solution improves cardioprotection

Øyvind Jakobsen*, Stig Muller, Erling Aarsæther, Tor Steensrud, Dag G. Sørlie

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

Received 28 August 2006; received in revised form 18 May 2007; accepted 23 May 2007.

* Corresponding author. Address: Surgical Research Laboratory, Institute of Clinical Medicine, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway. Tel.: +47 970 63 949; fax: +47 776 28 298. (Email: oyvind.jakobsen{at}fagmed.uit.no).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objective: To determine whether adenosine instead of supranormal potassium in cold crystalloid cardioplegia gives satisfactory cardiac arrest and improved cardioprotection. Cold crystalloid cardioplegia with adenosine, procaine and magnesium (A) was compared with standard cold crystalloid hyperkalemic cardioplegia (K). Methods: Sixteen pigs were randomized to receive either cold K (n = 8) or A (n = 8), where hyperkalemia was substituted with 1.2 mM adenosine. The cold (6 °C) cardioplegia was given intermittently and antegradely, with an aortic cross-clamp time of 1 h. Hemodynamic data was continuously measured and pressure–volume conductance catheters were used to determine global left ventricular systolic and diastolic function. Coronary flow and O2 content differences allowed determination of left ventricular energetics. Blood samples, and left ventricular microdialysis were used to measure parameters of ischemia. Measurements were done at 1 and 2 h after cross-clamp release. Results: Mean arterial pressure was reduced with 55 mmHg (standard deviation, SD: 19) in the K group versus 30 mmHg (SD: 14) in the A group 2 h after cross-clamp release (p = 0.030). Left ventricular contractility expressed as slope of the preload recruitable stroke work index (Mw) was reduced to 53% (SD: 14) in the K group versus 78% (SD: 23) in the A group 2 h after cross-clamp release (p = 0.046). Reduction of maximum of first derivate of pressure with respect to time (dP/dt max) was 804 mmHg/s (SD: 189) in the K group versus 538 mmHg/s (SD: 184) in the A group (p = 0.033). The slope of the myocardial oxygen consumption–pressure volume area was at 2 h reperfusion increased from 1.37 (SD: 0.64) to 2.86 (SD: 1.27) in the K group, whereas no shift was detected in the A group (p = 0.019). Cardiac troponin T measured in the coronary sinus 1 h after cross-clamp release was 1.25 µg/l (SD: 0.64) in the K group versus 0.73 µg/l (SD: 0.31) in the A group (p = 0.046). Conclusion: Adenosine instead of supranormal potassium in cold crystalloid cardioplegia gives satisfactory cardiac arrest, improves post cardioplegic left ventricular systolic function and efficiency, and attenuates myocardial cell damage.

Key Words: Adenosine • Cardioplegia • Energetics • Myocardial protection


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Since the days of induced ventricular fibrillation, administration of hyperkalemic cardioplegic solutions has induced cardiac arrest during cardiac surgery. By giving hyperkalemic cardioplegia the myocytes become depolarized, and the contractions stop. Although extensively used, hyperkalemic crystalloid cardioplegia has its limitations, both in surgery on failing hearts and in long lasting procedures [1]. Patients at high risk of low cardiac output syndrome therefore need a better intraoperative myocardial protection than afforded by the hyperkalemic cardioplegia.

Studies have shown that supranormal potassium per se gives ionic unbalance and intracellular calcium overload, which subsequently may cause contracture and myocardial injury, together with the need for more energy to restore ion balance during recovery [2]. It has also been shown that intravascular exposure of high potassium plays a critical role in causing functional endothelial damage [3].

Adenosine is an endogenous substance with well-documented cardioprotective properties [4]. Several studies have shown promising results with adenosine as an adjunct to hyperkalemic cardioplegia, both in large animal models [5], and in clinical trials [6]. Studies in isolated heart models have shown that cardioplegia with adenosine alone or in a combination with lidocaine, but without supranormal concentrations of potassium, achieves faster cardiac arrest and improved cardioprotection compared to hyperkalemic cardioplegia [7,8]. However, investigation of cardioplegia containing adenosine, without supranormal potassium concentrations, in models close to the human situation is, however, lacking. Corvera et al. [9] used the combination of adenosine and lidocaine in warm and cold blood cardioplegia in a large animal model, showing equal post cardioplegic cardiac function compared with the hyperkalemic cardioplegia. The problem with the use of adenosine in blood cardioplegia is, however, the rapid catabolism of adenosine in blood (half life of 0.6 s [10]). Also the concentration is important; Corvera et al. [9] used only 400 µM adenosine, whereas Mentzer et al. [6] showed in a clinical trial that a high concentration of adenosine (2 mM) as an adjunct to hyperkalemia in blood cardioplegia gives better protection than a low concentration (500 µM), without any problems with systemic hypotension. Corvera et al. [9] also employed a model with only a modest reduction of post cardioplegic function in their dogs. In contrast to these studies, we therefore wanted to test higher doses of adenosine in crystalloid cardioplegia, without supranormal concentrations of potassium, with a more reduced post cardioplegic function using pigs as a better experimental animal as close to the human situation as possible. Since we used crystalloid cardioplegia with negligible breakdown of adenosine we decided to use a lower concentration than 2 mM to avoid systemic hypotension. The same concentrations of procaine and magnesium as in the hyperkalemic cardioplegia were used, rendering a direct comparison of adenosine versus hyperkalemia possible.

We used an open-chest pig model with global myocardial ischemia on full cardiopulmonary bypass (CPB), and hypothesized that adenosine (1.2 mM), together with magnesium (16 mM) and procaine (1 mM) would give satisfactory cardiac arrest and less cardiac dysfunction compared to the standard hyperkalemic cardioplegia (St. Thomas’ Hospital Solution No. II).


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1 Animal care
The experimental protocol was approved by the local steering committee of the Norwegian Animal Experiments Authority. The study was conducted in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ published by the US National Institute of Health (National Institutes of Health Publication No. 85 to 23, revised 1996). Sixteen locally bred domestic pigs (Norwegian landrace) of either sex with mean weight 60 kg (standard deviation (SD) ± 7 kg) were fasted over night, but had free access to water before the surgical procedure.

2.2 Anesthesia
The pigs were premedicated with intramuscular ketamine (20 mg/kg, Warner Lambert Nordic, Sweden) and atropine (2 mg/kg, Nycomed Pharma, Norway). They were transported to the operation room where anesthesia was induced by an intravenously (ear vein) bolus of pentobarbital (10 mg/kg, Nycomed Pharma, Norway) and fentanyl (0.02 mg/kg, Pharmalink, Sweden). The pigs were tracheostomized and mechanically ventilated (Servo Ventilator 900D, Elema-Schønander, Sweden) with 60% oxygen (100% during reperfusion and weaning of cardiopulmonary bypass). Repeated arterial blood gas analyses (Rapidlab 860, Chiron, USA) were performed throughout the experiment to control tidal volume. Anesthesia was continuously maintained throughout the experiment with pentobarbital (4 mg/kg/t), fentanyl (0.02 mg/kg/t) and midazolam (0.3 mg/kg/t, Alpharma, Norway). The doses of the anesthetics were investigated to give a steady state blood concentration throughout the experiment in pilot studies. Glucose enriched sodium chloride for fluid replacement (1.25 g glucose/l sodium chloride) was given together with the anesthetics into the left external jugular vein.

2.3 Surgical preparation
The bladder was drained by a cystostomy. Central venous pressure (CVP) was measured in the right external jugular vein. Mean arterial pressure (MAP) was measured in the descending aorta through the right femoral artery. After a median sternotomy the pericardium was incised and the left hemiazygos vein ligated. Transit time flow probes (Cardio-Med CM 4000, Medi-Stim AS, Norway) were applied snugly around the three main coronary arteries and the pulmonary trunk, to measure myocardial blood flow (MBF) and cardiac output (CO). The pigs then received 2500 IE heparin intravenously. A band was placed around the inferior caval vein for snaring it (preload reductions), and a 7 Fr, 12-electrode, dual field, combined pressure–volume conductance catheter (Sentron, AC Roden, The Netherlands) was placed in the left ventricle through the left carotid artery. Two microdialysis catheters (CMA 70 and CMA 71, CMA Microdialysis, Sweden) were positioned intramurally in the left ventricle, and controlled by a CMA 400 microdialysis pump (CMA Microdialysis, Sweden). Myocardial venous blood was obtained from a catheter (Blue Flex Tip, Arrow, USA) in the great cardiac vein, and a catheter (Pediatric Jugular Vein Catheter, Arrow, USA) was inserted in the pulmonary trunk for monitoring mean pulmonary artery pressure (MPAP). Baseline measurements were done after 20 min of stabilization.

2.4 Experimental protocol
The pigs were randomized in two rounds (equal number of pigs in both groups after eight and sixteen pigs) to receive either standard St. Thomas Hospital No. II cardioplegia (hyperkalemic group (K)) or adenosine–procaine–magnesium cardioplegia (adenosine group (A)). The compositions of the cardioplegic solutions are given in Table 1 . The solutions were made at The Hospital Pharmaceutical Department (University Hospital of North Norway, Tromsø) and blinded for the researchers. After baseline measurements (T0) and before cannulation the pigs received 380 IE/kg heparin, giving an activated clotting time (ACT) >480 s. The pigs were cannulated through the right carotid artery with a pediatric arterial cannula (18 Fr, Jostra Arterial Cannula, Maquet, Germany), and venous drainage was obtained from a cavoatrial cannula (32/40 Fr, Dual Stage Venous Drainage Cannula, Edwards Lifescience, Canada). Normotherm cardiopulmonary bypass (CPB) was initiated with a flow similar to baseline CO, using a roller pump (Stockert/Shiley Caps Roller Pump, Soma Technology, USA) and a membrane oxygenator (Synthesis, Sorin Biomedica, Italy). A non-heparin coated polyvinylchloride tubing was employed. A standard cardioplegic cannula (9 Fr, dlp-CB20012, Aortic root cannula, Medtronic, USA) with a side branch for venting of the left ventricle was placed in the ascending aorta. The aorta was then cross-clamped for 1 h. The cardioplegia (6 °C) was given antegradely and intermittently, the first dose of 500 ml immediately after cross-clamping the aorta, the second and third of 200 ml following 20 and 40 min after cross-clamping the aorta. Infusion rate was 200 ml/min. Ice-slush was applied, and an isolation pad was put behind the heart to prevent rewarming between the infusions. After 1 h of cold ischemic arrest the aortic cross-clamp was released. Weaning from CPB was tried 20 min after cross-clamp release. If necessary, animals were allowed another 20 min of support before CPB was terminated, but no inotropic agents were used. Sampling and measurements were done 1 h (T1) and 2 h (T2) after cross-clamp removal. If necessary the animals received bicarbonate (Tribonat®, Fresenius Kabi AB, Sweden) to adjust negative base excess after the arrest period. Animals were sacrificed after T2 with an overdose of intravenous pentobarbital.


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  		Table 1 Composition of the cardioplegic solutions in final concentration (mmol/l)
 
2.5 Microdialysis technique
Two microdialysis catheters (CMA 70 and CMA 71, CMA Microdialysis, Sweden) were placed intramurally in the left ventricle free wall, and the perfusate was infused with a CMA 400 pump (CMA Microdialysis, Sweden). After a 30 min period of washing, the dialysate was collected in three periods; before ischemia, during ischemia, and for the first hour of reperfusion. The CMA 70 catheter was infused with Ringer solution (in mM: NaCl 147, CaCl2 2.3 and KCl 4, pH 7.4) at a flow rate of 0.4 µl/min. This catheter was used to collect glucose, pyruvate, lactate and glutamate. The CMA 71 catheter was infused with Ringer solution containing 0.5 nM/µl/min salicylic acid. This is an indirect method to quantify the production of hydroxyl free radicals in the left ventricle, as described by Obata et al. [12]. The microvials collecting the dialysate from the CMA 71 catheter contained 1 µl 0.1 M HClO4/1 µl dialysate to prevent amine oxidation. The collecting microvials from both catheters were immediately frozen at –20 °C (microvials from CMA 70 catheter) and at –70 °C (microvials from CMA 71 catheter). The samples were later analyzed by high performance liquid chromatography (HPLC) at the Clinical Pharmacological Department at the University of Tromsø.

2.6 Drugs used
St. Thomas’ Hospital Solution No. II cardioplegia was purchased from Ullevål University Hospital, Norway, which provides for all cardiac centers in Norway. All other chemicals were purchased from Sigma Chemical Co. (St. Louis, USA).

2.7 Intraventricular measurements and calculations
The conductance catheter method is based on measuring time-varying electrical conductances of five segments of blood in the left ventricle as described in detail elsewhere [13]. 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 2000 V0150.0 (Leycom). Conductance derived pressures and volumes were assessed at baseline and following 1 and 2 h after cross-clamp release, where the measurements following 1 h after cross-clamp release did not include any preload reductions. Preload reductions were obtained by snaring the inferior caval vein. The slope factor {alpha} was calculated from the ratio between conductance and transit time derived cardiac outputs, using the basal preload (no reduction of preload) at each time of assessment.

Variably loaded beats were obtained by transient (12–15 s) stepwise preload reductions during disconnection of the respirator. Pressure–volume (PV) recordings with concomitant myocardial oxygen consumption (MVO2) were performed at five different steady state preloads (including the basal preload) in order to assess the myocardial oxygen consumption–pressure volume area relationship (MVO2–PVA) [14]. Calculation of MVO2 was based on the differences in oxygen content between arterial and coronary sinus samples multiplied by the coronary flow and corrected with regard to left ventricular (LV) weight, heart rate, and a pig-specific constant in ml O2/g Hb (1.39). When calculating LV mechanoenergetics, MVO2 was converted to joules (1 ml O2 = 20.2 J). PVA was calculated as the sum of stroke work (SW) and potential energy (PE), where SW is the area within the pressure volume loop and PE is represented as the area bounded by the end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR), bordered by the PV loop. The preload-varied steady-state MVO2 and PVA points assessed at each sampling period were used to obtain the MVO2–PVA relationship by linear regression.

Preload independent contractility indexes and EDPVR were calculated on a beat-to-beat basis from pressure–volume data during 12 s of total inferior caval vein occlusions (VCO). The slope index (Mw) of the preload recruitable stroke work (PRSW) has been described in details elsewhere [14], and was used to assess global left ventricular systolic function. EDPVR was fitted by the logarithmical equation P ed = {alpha}e(Ved ß), and end diastolic stiffness was expressed by the slope coefficient (ß, dimensionless) of the logarithmical EDPVR.

2.8 Statistics
Data are presented as mean ± SD. Data was analyzed in a statistical software package, SPSS 11.0 (SPSS, Chicago, USA). Analyses of within group differences were done by using one sample T-test for the differences between the times of measurements. Analyses of between group differences were done by using ANOVA for differences ({Delta}) between the actual time of measurement and baseline, or for recovery (%) from baseline values (Mw). Significance level was set to p less than 0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Sixteen pigs were included from 23 experiments. Three pigs were excluded because of ventricular fibrillation during the preparation, one because of a major bleeding episode during preparation and one because of pericarditis. In addition, two pigs were excluded because of sustained MAP below 40 mmHg during CPB, due to technical problems with the CPB, thus making it impossible to maintain adequate flow. Time to complete cardiac arrest was within 1 min after administration of the cardioplegia in the hyperkalemic group. In the adenosine group left ventricular contractions stopped within 1 min, but small waves of contraction were observed in the right ventricle for some more minutes, 4 min at most. No reanimation was observed in any of the groups. Six pigs in the hyperkalemic group and five pigs in the adenosine group had to be electroconverted to regain sinus rhythm. Four pigs in the hyperkalemic group and two pigs in the adenosine group needed an extra 20 min of CPB support after cross-clamp release before they could be weaned from CPB. Two pigs in each group died between T1 and T2 measurements, due to a progressive loss of heart function during the reperfusion period. Measurements of contractility were made while in a stable sinus rhythm.

3.1 Hemodynamic results
Hemodynamic data are summarized in Table 2 . Except from a higher MPAP in the hyperkalemic group the pigs were similar at baseline. Both groups had a significant decrease in MAP and systemic vascular resistance (SVR) and a significant increase in MPAP and CVP, both 1 and 2 h after cross-clamp release compared to baseline values, but the adenosine group had a significantly smaller reduction of MAP compared to the hyperkalemic group (p = 0.030). Adenosine hearts had a significant increase in heart rate (HR) both at 1 and 2 h after cross-clamp release and an increased myocardial blood flow index 1 h after cross-clamp release compared to baseline values, while the hyperkalemic group had no significant change in these parameters. However, there were no statistically significant differences between the two groups. The hemodynamic data showed a tendency towards baseline values between 1 and 2 h after cross-clamp release in the adenosine group, while the unfavorable tendency persisted in the hyperkalemic group. When the cardioplegic solution was given we observed a significantly higher drop in MAP in the adenosine group compared to the hyperkalemic group (A: 18 ± 8 mmHg, K: 5 ± 2 mmHg, p = 0.002), but MAP recovered within 1 min in both groups.


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  		Table 2 Hemodynamic variables at baseline and at 1 and 2 h after cross-clamp release in 16 pigs, following 1 h of ischemia with hyperkalemic (K, n = 8) or adenosine (A, n = 8) cardioplegia
 
3.2 Contractility, diastolic properties and left ventricular measurements
Recovery (%) from baseline values of the parameters of left ventricular contractility is displayed in Fig. 1 . The adenosine group had a significantly better recovery of the preload independent parameter Mw 2 h after cross-clamp release. Also, the first derivate of pressure with respect to time (dP/dt max, in mmHg/s) was significantly less reduced in the adenosine group 2 h after cross-clamp release compared with the hyperkalemic group (Baseline: K: 1676 ± 168, A: 1634 ± 166 and 2 h after cross-clamp release: K: 914 ± 90, A: 1031 ± 237, p = 0.033). The diastolic parameters including the stiffness constant (ß), the time constant of relaxation (tau), and the first derivative of pressure decay with respect to time (dP/dt min), revealed no significant differences between groups; data not shown.


Figure 1
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  		Fig. 1. Left ventricular parameters of contractility. Percent recovery from baseline values 2 h after cross-clamp release following 1 h of ischemia with hyperkalemic (n = 6) or adenosine (n = 6) cardioplegia. dP/dt max: maximum of the first derivate of pressure with respect to time; SWI: stroke work index; Mw: slope of the preload recruitable stroke work index; p: probability for a between group difference (ANOVA).

 
3.3 Myocardial energetics: MVO2–PVA relationship
The MVO2–PVA relationship is depicted in Fig. 2 . Both groups were similar at baseline for both y-intercept (A: 0.20 ± 0.30, K: 0.21 ± 0.25) and slope (A: 1.32 ± 0.62, K: 1.37 ± 0.64). There was no y-intercept difference between or within groups 2 h after cross-clamp release. The slope was significantly steeper (p = 0.019) in the hyperkalemic group (r 2 = 0.88) compared with the adenosine group (r 2 = 0.84).


Figure 2
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  		Fig. 2. Cardiac energetics, myocardial oxygen consumption–pressure volume area (MVO2–PVA) data at baseline for all 16 pigs, and 2 h after cross-clamp release following 1 h of ischemia with hyperkalemic (n = 6) or adenosine (n = 6) cardioplegia. Lines indicate mean values. p: probability for a between group difference (ANOVA).

 
3.4 Troponin T and microdialysis
Levels of troponin T measured in the coronary sinus and in the superior caval vein and results from microdialysis are displayed in Table 3 . Both groups had a significant increase of troponin T after cross-clamp release compared to baseline. At T1, 1 h after cross-clamp release, there was also a significant difference between the two groups, with a lower release of troponin T into the coronary sinus in the adenosine group (p = 0.046). Results from the microdialysis showed significant changes from baseline values, but without differences between the two groups (Table 3).


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  		Table 3 Cardiac troponin T measured in venous samples and samples from the coronary sinus (CS) at baseline and at 1 and 2 h after cross-clamp release, and results from microdialysis collected during a period of 40 min before ischemia, during the ischemic period and during the first hour of reperfusion, in 16 pigs, following 1 h of ischemia with hyperkalemic (K, n = 8) or adenosine (A, n = 8) cardioplegia
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The aim of this study was to investigate whether adenosine instead of supranormal potassium in cold crystalloid cardioplegia would give satisfactory cardiac arrest and whether the cardioplegic solution consisting of adenosine, procaine and magnesium could give better post cardioplegic recovery compared with a standard hyperkalemic cardioplegia (St. Thomas’ Hospital Solution No. II). Substitution of hyperkalemia with adenosine gave satisfactory cardiac arrest, and a significantly improved preservation of left ventricular energetics, left ventricular systolic function and mean arterial pressure, together with a significantly lower release of cardiac troponin T.

Four subtypes of adenosine receptors (A1, A2a, A2b, A3) are known [15]. Adenosine was chosen because it induces rapid cardioplegic arrest by inhibiting sinus and atrioventricular node function [16], and because of its well-documented cardioprotective properties [4]. The cardioprotective effect is shown to be due to both A1 receptor [17] and A3 receptor activation [18], and the mitochondrial ATP sensitive K+ channel (mitoKATP) activation downstream of Protein Kinase C (PKC) activation is shown to be involved in the signal transduction pathway from adenosine receptor activation [19]. It is however demonstrated that the cardioprotective effect of adenosine markedly exceeds that of A1 receptor activation [20]. This indicates that the beneficial effect on functional recovery also could be mediated by adenosine's role as a substrate for nucleotide resynthesis and as a precursor for (high energy phosphates (HEP); adenosine monophosphate (AMP), diphosphate (ADP), and triphosphate (ATP)), and it is shown that adenosine is important for the preservation of postischemic ATP [21]. Adenosine is also shown to prevent cardioplegic/ischemic-induced calcium loading in cardiac cells [22], which also can contribute to the improved recovery seen in the adenosine group. Activation of the A2a and the A2b receptor leads to rapid vasodilatation. We also observed a rapid drop in MAP in the adenosine group when the cardioplegic solution was delivered, but because of the rapid turnover of adenosine in blood, MAP recovered in all pigs within 1 min.

According to Suga [14], an increase in the slope of the MVO2–PVA relationship represents a decrease in contractile efficiency, and a fall in the contractile efficiency was found in the hyperkalemic group after the cardioplegic period, while unchanged in the adenosine group, (Fig. 2). The slope increase represents a reduction in chemomechanical conversion efficiency, either because of a decrease in the conversion of O2 to ATP, or due to a decrease in the conversion of ATP to mechanical energy. The involvement of mitoKATP downstream of adenosine receptor and PKC activation indicates a preservation of mitochondrial function during ischemia/reperfusion which partly can explain the improved mechanoenergetic efficiency observed in the adenosine group. Since ATP is almost exclusively hydrolyzed in the mitochondria, a postischemic mitochondrial dysfunction in the hyperkalemic group would decrease the efficiency in conversion of O2 to ATP.

Cardiac troponin T is positively correlated to histologic evidence of necrosis in pigs [23]. In addition to the ischemic insult, the early reperfusion after a period of ischemia leads to opening of mitochondrial permeability transition pores (MPTP) which further leads to necrotic cell death [24]. Activation of PKC, both through ischemic preconditioning, and by administering adenosine, is an effective way to protect the heart against reperfusion injury and may explain the lower release of cardiac troponin T in the early reperfusion period, and possibly also the better preserved ventricular function observed in the adenosine group. Results from microdialysis showed an expected tendency during the experiment concerning changes in metabolic and ischemic parameters. We could however not detect any significant differences between groups, so while this method did detect ischemic and metabolic changes as expected it did not add sensitivity to our endpoint measurements.

We used similar concentrations of procaine and magnesium in both solutions. Briefly, procaine was chosen because of its Na+ channel blocking property and thereby arresting ability, together with its antiarrhythmic properties. Magnesium is an important ion in both crystalloid and blood cardioplegia. It is shown that addition of magnesium in cardioplegic solutions improves myocardial protection and prevents substrate derangement during the arrest period [25]. Since both procaine and cooling have cardioplegic properties we cannot conclude that adenosine can be used as sole cardioplegic agent, but when given instead of supranormal potassium the cardioplegic arrest was satisfactory.

Earlier experiments in our laboratory with the same pig model have revealed that 1 h of ischemia with cold crystalloid cardioplegia gave an appropriate reduced cardiac function; both to allow for representative measurements, and to detect any improvements of post-cardioplegic left ventricular function (pig hearts are more susceptible to ischemia than human hearts). Two hours after cross-clamp release we had an overall mean recovery of dP/dt max of 59.5 ± 11.5% compared to baseline values. Since preload reductions in itself are a significant trauma to a troubled heart, we experienced that we had to abandon the first set of measurements with preload reductions. Therefore, in order to detect differences during early reperfusion a similar study with a milder ischemic injury could be of interest. It might be argued that including more animals would have increased the statistical power of the study. When, after block randomization, we reached the planned number and found that recovery of all parameters of contractility was better in the adenosine group we stopped, albeit not all of the parameters were statistically significant. We also used intact adolescent healthy pigs, and since responses can vary both between species and be age-related our observations can not be transferred directly to the senescent, diseased human heart, although the model now has been established for studying cardioprotection for over a decade, and is a good alternative for testing prior to clinical trials.

Adenosine has in many years been investigated as a possible beneficial agent in cardioplegic solutions. The cardioprotective effect is well documented in studies on isolated hearts, and several studies are performed with adenosine as an adjunct to hyperkalemic cardioplegia both in large animal models, and in some clinical series, but then with more varied results. Adenosine has probably, therefore, not yet become as popular as it deserves. In the present study we present promising results with adenosine instead of potassium, in contrast to using it as an adjunct, which has been the case in the clinical studies. Both the possible unfavorable effects of supranormal potassium were avoided, and the cardioprotective effect of adenosine fully present. Our results show that the idea of using adenosine in cardioplegic solutions should not be put aside.

The use of blood versus crystalloid cardioplegia has been debated for decades, and there is probably consensus that blood cardioplegia is superior to crystalloid cardioplegia in long lasting operations, and in patients at high risk of low cardiac output syndrome. We wanted to exclusively explore adenosine versus hyperkalemia, and hence used crystalloid cardioplegia in the present study. Use of adenosine in blood cardioplegia represents some extra challenges because of the rapid catabolism of adenosine in blood, but this is probably just a question of doses, as pointed out by Mentzer et al. when they combined adenosine with blood and hyperkalemia [6]. The instability of adenosine in blood cardioplegia can therefore also partly explain the varied results seen in clinical trials where adenosine was used in combination with blood cardioplegia. The problem can, however, be partly solved by using different input tubes of delivery for adenosine and blood into the aortic root. The investigation of higher doses of adenosine in blood cardioplegia without supranormal concentrations of potassium is therefore warranted.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In conclusion, adenosine instead of supranormal potassium in cold crystalloid cardioplegia can be used to arrest the heart during open chest heart surgery in the intact pig. Both left ventricular systolic function and efficiency were improved when adenosine was used instead of supranormal potassium, possibly due to less reperfusion injury and cell damage. The improved functional recovery is consistent with other reports on the cardioprotective properties of adenosine, and indicates that adenosine not only can be used as an additive to hyperkalemia, but even as a substitute in a normokalemic solution


   Acknowledgments
 
We greatly appreciate the skilful technical assistance at the Surgical Research Laboratory at the University of Tromsø.


   Footnotes
 
\#9734; This study was supported with a grant from the Norwegian Council on Cardiovascular Diseases.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

  1. Chambers DJ. Mechanisms and alternative methods of achieving cardiac arrest. Ann Thorac Surg 2003;75:S661-S666.[Abstract/Free Full Text]
  2. Chambers DJ, Hearse DJ. Developments in cardioprotection: ‘polarized’ arrest as an alternative to ‘depolarized’ arrest. Ann Thorac Surg 1999;68:1960-1966.[Abstract/Free Full Text]
  3. Mankad PS, Chester AH, Yacoub MH. Role of potassium concentration in cardioplegic solutions in mediating endothelial damage. Ann Thorac Surg 1991;51:89-93.[Abstract]
  4. Vinten-Johansen J, Thourani VH, Ronson RS, Jordan JE, Zhao ZQ, Nakamura M, Velez D, Guyton RA. Broad-spectrum cardioprotection with adenosine. Ann Thorac Surg 1999;68:1942-1948.[Abstract/Free Full Text]
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