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Ann Thorac Surg 1996;62:31-38
© 1996 The Society of Thoracic Surgeons
Department of Surgery, Medical College of Virginia, Richmond, Virginia
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Myocardial protection was compared in the blood-perfused isolated parabiotic rabbit heart Langendorff model. Twenty-four hearts were protected with a 50-mL infusion of cardioplegia for a 30-minute global normothermic ischemic period followed by 30 minutes of reperfusion. Systolic function (percent recovery of developed pressure) and the diastolic properties of the left ventricle were measured. Coronary blood flow was measured throughout each experiment.
Results. The percent recovery of developed pressure (mean ± standard error of the mean) for St. Thomas' solution, pinacidil, and aprikalim was 53.1% ± 5.4%, 64.0% ± 3.0%, and 62.4% ± 3.2%, respectively. The time (minutes) until mechanical and electrical arrest was significantly longer in the pinacidil (4.82 ± 0.10 and 12.06 ± 1.07) and aprikalim (3.33 ± 0.28 and 11.12 ± 0.94) groups when compared with the St. Thomas group (1.84 ± 0.74, and 3.17 ± 1.44). Coronary blood flow upon reperfusion was significantly greater in the pinacidil (16.4 ± 2.1 mL/min) and aprikalim (19.4 ± 2.8 mL/min) groups compared with the St. Thomas' solution group (8.0 ± 1.0 mL/min), and this returned to baseline after 15 minutes of reperfusion.
Conclusions. Myocardial protection with pinacidil and aprikalim is comparable with that of St. Thomas' solution in the blood-perfused isolated rabbit heart despite prolonged mechanical and electrical activity during ischemia.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Since their initial description in guinea pig ventricular myocytes by Noma [1] in 1983, adenosine triphosphate (ATP)-sensitive potassium (KATP) channels have been the subject of extensive investigation because of their unique link to cellular metabolism. Opening of the KATP channel causes an outward potassium current that hyperpolarizes the ventricular cell membrane. This channel has been shown to be responsible for many of the cellular electrophysiologic responses to ischemia [2–4]. During ischemia, potassium efflux from the cell causes a marked shortening of the action potential duration that is mediated in a large part by this channel. To perform this function, the channel is closely coupled to cellular metabolism. It is inhibited by intracellular ATP and opens during ischemia and other conditions that result in ATP depletion [1].
Pharmacologic activation of the KATP channel has been demonstrated using a diverse group of chemical agents termed potassium-channel openers (PCOs). These agents have been shown to be cardioprotective in various animal models of myocardial ischemia [4–7]. These agents also have been demonstrated to preserve ventricular function and high-energy nucleotides after regional and global ischemia, to limit infarct size after ischemia, and to define the important role that KATP channels play in the phenomenon of ischemic preconditioning [5, 7–10].
In an effort to improve upon the shortcomings of traditional hyperkalemic cardioplegia, it has been hypothesized that PCOs would be excellent agents to provide myocardial protection during surgical ischemia because of their inherent cardioprotective properties. By opening potassium channels and causing a potassium efflux from the cell, these agents decrease the action potential duration, thereby decreasing the duration of the plateau phase portion of the action potential. It is during this phase that inward calcium transport occurs, and a decrease in this influx leads to contractile failure and therefore energy conservation during ischemia [1, 11, 12]. Because increased intracellular calcium has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury, the decreased calcium influx also may improve myocardial tolerance to ischemia. Potassium-channel openers also offer the benefit of arresting the myocyte at a more negative membrane potential (hyperpolarized), near its resting membrane potential. From the cellular standpoint, this is more physiologic than the depolarized arrest induced by hyperkalemic cardioplegia. Energy consumption is minimized at the resting membrane potential because fewer ionic fluxes occur and active ion transport is minimized [11, 13, 14].
Our laboratory previously has demonstrated the benefit of the PCO aprikalim during surgical global ischemia in a crystalloid-perfused [15] and in a blood-perfused [16] isolated rabbit heart model. Hyperpolarizing cardioplegia containing aprikalim (100 µmol/L) provided superior protection during a normothermic ischemic period when compared with hyperkalemic depolarizing arrest (Krebs-Henseleit solution with 20 mmol/L KCl) in both models. In addition, previous work from our laboratory has demonstrated the benefit of the PCO pinacidil (50 µmol/L) during normothermic ischemia in a blood-perfused model when compared with Krebs-Henseleit solution with and without 20 mmol/L KCl [17]. However, Krebs-Henseleit solution is not an ideal hyperkalemic cardioplegia delivery solution. In an effort to compare the efficacy of aprikalim (100 µmol/L) and pinacidil (50 µmol/L) with a more clinically relevant hyperkalemic cardioplegia, this study compared St. Thomas' solution, a superior and widely accepted hyperkalemic depolarizing cardioplegia, with PCOs in an isolated blood-perfused rabbit heart model.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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After support animal preparation, the donor animal was heparinized and ventilated via a tracheostomy. The animal then underwent rapid sternotomy and cardiectomy. The aorta was cannulated and coronary perfusion instituted via the Langendorff column. The support animal was given indomethacin (1 mg/kg) intravenously to promote blood pressure stability [18]. The systolic arterial blood pressure of the support animal was maintained greater than 65 mm Hg by transfusion with either Plasmalyte (Baxter Healthcare Corp, Deerfield, IL) or blood collected from the donor animal at the time of cardiectomy. Arterial blood gases, electrolytes, and the hematocrit of the support animal were monitored at regular intervals and maintained within physiologic limits. The support animal was given supplemental anesthesia intramuscularly as needed throughout the experiment. Heparin (500 U) was given to the support animal at hourly intervals.
After aortic cannulation, a left atriotomy was performed and a vent (polyethylene tubing, internal diameter = 0.86 mm; Clay Adams, Parsippany, NJ) was placed into the left ventricle. A fluid-filled latex balloon was placed into the left ventricle and secured with a pursestring in the mitral annulus. The balloon was connected to a pressure transducer (model 42559-01; Abbott Laboratories, North Chicago, IL) and to a Gould amplifier (model 13-4615-50; Gould, Inc). The zero pressure reference was set at the level of the aortic valve. Two right atrial electrodes were positioned and connected to a pacemaker (model DTU101; Bloom Associates Ltd, Reading, PA). The heart was paced at a constant rate (180 to 240 beats/min) throughout the study. Two left ventricular epicardial bipolar electrodes were positioned and connected to a preamplifier (model 11-G5407-58; Gould Inc) and to a universal amplifier (model MU13-4615-58; Gould Inc) and filtered between 0.05 and 1,000 Hz. The pressure and electrogram waveforms were displayed continuously on an oscilloscope (Gould ES1000) and digitized on-line using an AT-CODAS system (DATAQ Instruments, Akron, OH) at a sampling rate of 1,000 Hz.
The heart was enclosed in an air bath surrounded by a glass-jacketed water beaker. Myocardial temperature was monitored throughout the experiment using a temperature probe (model 0112; Shiley Inc, Irvine, CA) placed in the right ventricle. Myocardial temperature was maintained at 37°C by adjusting the water bath (model 71; Polyscience, Niles, IL) temperature. Coronary flow was monitored using an in-line flow probe (model 2N; Transonic Systems, Ithaca, NY) and an ultrasonic blood flow meter (model 101; Transonic Systems).
Experimental Protocol
Hearts were excluded from the study if they did not obtain a developed pressure (DP) of 80 mm Hg at an end-diastolic pressure of 10 mm Hg, or if the baseline DP did not remain stable during the 30 minutes after instrumentation.
After the 30-minute equilibration period, baseline electrolyte levels, hematocrit, and arterial blood gases were recorded for the support animal and any abnormalities were corrected. Left ventricular pressure-volume relationships were measured. A wide range of volumes were infused into the intraventricular latex balloon to generate end-diastolic pressures (EDPs) of 0, 2.5, 5, 10, 15, and 20 mm Hg. After baseline data acquisition, the amount of fluid in the latex balloon was adjusted to obtain an EDP of 5 mm Hg before the ischemic period.
Twenty-four hearts were randomly assigned to receive either hyperpolarizing or depolarizing cardioplegia for myocardial protection during a 30-minute period of global normothermic ischemia. Hyperpolarizing cardioplegia consisted of Krebs-Henseleit solution (in mmol/L distilled water: NaCl, 118.5; NaHCO3, 25.0; KCl, 3.2; MgSO4, 1.2; KH2PO4, 1.2; glucose, 5.5; CaCl2, 2.5) with either pinacidil (50 µmol/L; n = 8) or aprikalim (100 µmol/L; n = 8). Dose-response curves previously determined in our laboratory have defined 50 µmol/L and 100 µmol/L as the optimal concentrations for pinacidil and aprikalim, respectively [15, 17]. Depolarizing cardioplegia consisted of St. Thomas' solution (n = 8). Pinacidil was provided by Leo Pharmaceuticals, Ballerup, Denmark. Aprikalim was provided by Rhone-Poulenc Rorer, Antony, France. St. Thomas' solution (in mmol/L: NaCl, 110.0; CaCl2, 1.6; MgCl2, 16.0; KCl, 16.0) was provided by Abbott Laboratories (North Chicago, IL). Sodium bicarbonate (8.4%) was added to the St. Thomas' solution (0.5 mL/50 mL) to correct the pH to 7.8. The appropriate amount of pinacidil or aprikalim was added to the Krebs-Henseleit solution before each cardioplegia infusion. Heparin (12.5 U/mL) was added to each of the cardioplegia solutions.
At the start of the ischemic period, the Langendorff perfusion column was clamped and 50 mL of normothermic (37°C) cardioplegia was infused from a height of 80 cm H2O via a separate column. The cardioplegia effluent was collected and discarded. Both the time until cessation of mechanical activity and the time until electrical quiescence were recorded. Cessation of mechanical activity was defined as the absence of a DP.
After 30 minutes of normothermic global ischemia, the Langendorff column was unclamped and the heart reperfused for 30 minutes. If ventricular fibrillation persisted after reperfusion, the heart was defibrillated (model D84; Electrodyne Co, Inc, Westwood, MA). Measurements of electrolytes, hematocrit, and arterial blood gas of the support animal were repeated to ensure stability. After 30 minutes of reperfusion, data were collected at the identical balloon volumes used during baseline preischemic data acquisition. At the conclusion of the experiment, a sample of the left ventricle was excised, blotted, and weighed to obtain the wet weight. The sample was dried until a constant dry weight was achieved. Percent tissue water was determined using the following equation: percent tissue water = (wet weight - dry weight)/wet weight.
All animals received humane care in American Association for the Accreditation of Laboratory Animal Care accredited (#00036), United States Department of Agriculture registered (#52-R-007) facilities in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Data Analysis
Left ventricular systolic and diastolic pressures were determined from the digitized data files using software developed in our laboratory.
END-SYSTOLIC PRESSURE.
The end-systolic pressure (ESP) of a beat was defined as the maximum point of the digitized pressure waveform. The average ESP was calculated by averaging the ESPs of ten beats. Average ESPs were obtained for each balloon volume at baseline and after reperfusion. The ESP versus balloon volume data for baseline and postreperfusion data were fitted to the linear end-systolic pressure-volume relationship below using a least squares linear regression algorithm: ESP = Emax x (BV) + k, where Emax is the slope, k is the y-intercept, and BV is the balloon volume.
END-DIASTOLIC PRESSURE.
The EDP of a beat was defined as the point at which the increase in slope of the pressure waveform exceeded a threshold of 0.5 mm Hg/ms. This was visually confirmed for each beat. The average EDP was calculated by averaging the EDPs of ten beats, and was obtained for each balloon volume at baseline and after reperfusion. The EDP versus balloon volume data were fitted to the linear end-diastolic pressure-volume relationship below using a least squares linear regression algorithm: EDP = m (BV - BV0), where m is the slope and BV0 is the balloon volume corresponding to an EDP of zero, or the x-intercept [19, 20]. The mean linear regression coefficient for the diastolic pressure-volume curves was 0.98 ± 0.01, 0.99 ± 0.00, and 0.98 ± 0.00 for St. Thomas, 100 µmol/L aprikalim, and 50 µmol/L pinacidil, respectively. Thus, a linear representation of the diastolic pressure-volume relationships was appropriate over the limited range of end-diastolic volumes examined in this mode [21].
DEVELOPED PRESSURE.
The left ventricular DP was obtained by subtracting the end-diastolic pressure from the end-systolic pressure for each data point. An average of ten data points was used for each balloon volume. The DP versus balloon volume values for baseline and postreperfusion data were fitted to a linear pressure-volume relationship using the following linear regression algorithm: DP = ESP - EDP = (Emax x BV + k) - m (BV - BV0).
PERCENT RECOVERY OF DEVELOPED PRESSURE.
The percent recovery of DP was calculated as the percentage of the postreperfusion average DP compared with the baseline average DP at the same balloon volume. This was calculated for each of the postreperfusion matched balloon volumes. The average percent recovery of developed pressure was obtained using the trapezoidal rule [22] and the following equation:
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where BVmax is the maximum postreperfusion matched balloon volume and BVmin is the minimum postreperfusion matched balloon volume [16].
Statistical Analysis
Values are represented as the mean ± standard error of the mean. Analysis of variance (or Kruskall-Wallis when appropriate) was used for multiple comparisons of means with a Dunnett's test for individual comparisons. A Fisher's exact test was used to compare mutually exclusive data where appropriate. A Student's t test (or Mann-Whitney test when appropriate) was used to compare two means. A paired Student's t test was used to compare means before and after an intervention. Differences were considered statistically significant when p was less than 0.05. Statistical analysis was performed using Sigma Stat (Version 1.01; Jandel Corp, San Rafael, CA).
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Cardioplegia Delivery
The mean time to infuse the cardioplegia solution was 1.93 ± 0.24, 2.36 ± 0.22, and 1.86 ± 0.17 minutes for St. Thomas' solution, pinacidil, and aprikalim, respectively, and was not significantly different between groups.
Temporal Aspects of the Development of Electromechanical Arrest
The mean times until the cessation of both electrical and mechanical activity are represented in Table 1
for each group. Electrical quiescence and mechanical arrest were achieved most rapidly in the St. Thomas group, and this was significantly shorter than with either PCO (see Table 1).
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). The aprikalim group had a slightly greater incidence of ventricular fibrillation upon reperfusion compared with the pinacidil group (50% versus 38%, respectively). A statistically significant difference was only seen between the aprikalim and St. Thomas groups.
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). There was no significant difference between groups; however, there was a trend toward better recovery of function with the PCOs, particularly pinacidil (p = 0.09, St. Thomas versus pinacidil; and p = 0.16, St. Thomas versus aprikalim).
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). There was a statistically significant increase in slope compared with baseline after reperfusion in all groups. However, the x-intercepts were not significantly different between baseline and reperfusion in any group.
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). Coronary blood flow immediately upon reperfusion was significantly increased compared with baseline flow in all groups. The coronary blood flow was not significantly different immediately upon reperfusion between groups.
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).
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After 15 minutes of reperfusion, and for the remainder of the reperfusion period, the coronary blood flow in the St. Thomas group declined to a level significantly less than the baseline flow.
After 20 minutes of reperfusion, there were no statistically significant differences in coronary blood flow between groups.
Myocardial Tissue Water
The mean percent tissue water was 80.1% ± 0.5%, 80.3% ± 0.7%, and 79.2% ± 0.3%, for the St. Thomas, pinacidil, and aprikalim groups, respectively. There was no statistically significant difference in percent tissue water between groups.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Previous work from our laboratory has documented the effectiveness of aprikalim and pinacidil as cardioplegic agents when compared with hyperkalemic cardioplegia consisting of Krebs-Henseleit solution with 20 mmol/L KCl [15–17]. In an effort to compare the effectiveness of aprikalim and pinacidil with that of a more effective and widely accepted hyperkalemic cardioplegia, this study was undertaken using the blood-perfused isolated rabbit heart Langendorff model. St. Thomas' solution is both more clinically relevant and effective than Krebs-Henseleit solution with 20 mmol/L KCl and thus a more appropriate comparison can be made between depolarizing and hyperpolarizing (PCO) cardioplegia.
Postischemic Functional Recovery: Depolarized Versus Hyperpolarized Arrest
The best percent recovery of DP was seen in the hearts protected with 50 µmol/L pinacidil cardioplegia. There was a trend toward improved recovery with the PCOs, particularly pinacidil (p = 0.09), although this did not reach statistical significance. Hyperpolarized arrest with PCOs thus afforded myocardial protection comparable, if not superior, to the widely accepted St. Thomas' solution in this model of global normothermic ischemia.
The dose of 50 µmol/L was chosen as it provided the best percent recovery of DP during dose-response analysis previously performed in our laboratory [17]. This dose differs from that of other investigators using pinacidil in other animal models, indicating a possible species difference in response to these agents [4, 23, 24], which is likely due to differences in the hepatic oxidation of pinacidil and the renal excretion of active metabolites [25].
Postischemic Recovery of Diastolic Properties
The end-diastolic pressure-volume relationships were linear over the range of volumes tested in our experiments, as has been described by other investigators [19–21]. All three cardioplegia groups showed a significant increase in the slope of pressure-volume relationships after ischemia, indicating a decrease in ventricular compliance in all groups. The x-intercepts of the pressure-volume relationships were not different between baseline and reperfusion, probably reflecting the wide range of balloon volumes due to the variable heart sizes.
The Development of Electromechanical Arrest
The time until mechanical arrest in the PCO groups was significantly prolonged when compared with the St. Thomas group. This is in contrast to our previous work using Krebs-Henseleit solution with 20 mmol/L KCl, suggesting that St. Thomas' solution more rapidly and effectively arrests the heart. The time until electrical arrest was also significantly prolonged in the PCO as compared with the St. Thomas group, which is consistent with our previous work and the work of others [6, 15–17].
Despite the persistent electrical and mechanical activity, PCOs provided comparable myocardial protection. Previous work has demonstrated that persistent electrical activity does not adversely influence recovery of function, nor does it result in any significant depletion of high-energy nucleotides after ischemia [26]. This is due to the fact that isolated electrical activity comprises less than 1% of total myocardial oxygen consumption [27]. The slight delay in mechanical arrest appears to be of little consequence in this model as the PCOs provided protection comparable with that of the St. Thomas' solution. This suggests that the beneficial effects of the PCOs were able to compensate for the additional energy expenditure imposed by the persistent mechanical and electrical activity. However, this may present problems during more prolonged episodes of ischemia.
Reperfusion Coronary Blood Flow
Pinacidil and aprikalim were associated with increased reperfusion coronary blood flow when compared with St. Thomas' solution, which is similar to previous results from our laboratory [17]. The greatest increase in reperfusion coronary blood flow was seen in the aprikalim group, and this continued for the first 20 minutes of reperfusion. The increased coronary flow continued for 10 minutes of reperfusion in the pinacidil group before returning to baseline. This is similar to the findings of other investigators using PCOs before myocardial ischemia in various animal models [6, 24]. Fifteen to 20 minutes may reflect the time necessary for the drug to wash out of the coronary circulation.
Others have suggested that coronary hyperemia may be a positive predictor of recovery of cardiac function as increased blood flow may remove harmful metabolites [24]. Our results do not confirm this, as the group with the greatest increase in reperfusion coronary blood flow (100 µmol/L aprikalim) was not the group with the greatest percent recovery of DP. In addition, others have demonstrated that the administration of PCOs during reperfusion alone is not protective, and that PCOs can provide significant myocardial protection even when reperfusion coronary blood flow is not permitted to increase to more than baseline values [5, 28]. Thus, the cardioprotective effects of PCOs are likely to be unrelated to their vasodilatory effects.
An exaggerated hyperemic response to ischemia may be an explanation for the increased reperfusion coronary blood flow. However, this does not correlate with the better recovery of ventricular function provided by PCOs. Pinacidil-induced activation of KATP channels has been shown to be a mechanism underlying coronary hyperemia in a porcine cardiopulmonary bypass model [24]. However, these investigators demonstrated that the addition of adenosine to porcine microvessels pretreated with glibenclamide resulted in a smaller attenuation of the relaxation response compared with microvessels pretreated with glibenclamide and pinacidil. Thus, both KATP channels and adenosine play a role in reactive hyperemia [24]. It also is possible that PCOs may have an endogenous protective effect on endothelial cells. Further research is needed to determine the etiology of the increased reperfusion coronary blood flow associated with PCOs.
Incidence of Ventricular Fibrillation Upon Reperfusion
Potassium-channel openers have been demonstrated to be proarrhythmic [6–8, 10]. Our study supported these findings and revealed an increased incidence of reperfusion ventricular fibrillation in the hearts receiving PCOs. Potassium-channel openers result in a marked decrease in action potential duration and a resultant decrease in refractory period. This has been shown to promote reentrant ventricular arrhythmias, and represents a potential drawback of this class of drugs [8]. An increased incidence of ventricular fibrillation in the clinical setting is worrisome and would preclude the widespread use of these agents; however, its occurrence immediately after release of the aortic cross-clamp on cardiopulmonary bypass is readily treatable. Further research is necessary to delineate the time course of this proarrhythmic effect and to determine if the myocardium remains susceptible to reentrant arrhythmias after the drug washes out of the coronary circulation. In our model, ventricular arrhythmias have never occurred after the immediate reperfusion period, which is encouraging and suggests that their profibrillatory effect is short-lived.
Model Shortcomings
The advantages and disadvantages of the blood-perfused isolated rabbit heart Langendorff model have been previously described [16, 17]. This model provides a closer approximation to the clinical situation when compared with crystalloid-perfused models. There are many advantages of blood over crystalloid perfusion in the investigation of ischemia/reperfusion phenomenon. These include a higher oncotic pressure, improved oxygen carrying and buffering capacity, the presence of free radical scavengers, and improved capillary flow distribution [29]. The isolated rabbit model has been shown to be quite stable over 120 minutes of aerobic perfusion as compared with other animal species [30]. As always, care should be taken when extrapolating these data to the clinical situation.
Summary
Pinacidil (50 µmol/L) and aprikalim (100 µmol/L) are effective cardioplegic agents and provide myocardial protection comparable with that of St. Thomas' solution in the blood-perfused rabbit heart model. The best percent recovery was seen in the PCO groups as compared with the St. Thomas group. The PCO groups had prolonged mechanical and electrical activity and an increased incidence of ventricular fibrillation upon reperfusion when compared with St. Thomas' solution. This study is consistent with our previous work demonstrating an increase in reperfusion coronary blood flow in the PCO groups when compared with hyperkalemic cardioplegia. Despite several potential drawbacks, PCOs provide myocardial protection comparable with that of traditional hyperkalemic depolarizing cardioplegia. Potassium-channel openers remain a promising new class of agents that may play an important role in future myocardial protection strategies during surgical global ischemia.
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Acknowledgments |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Damiano, Hershey Medical Center, Penn State University, PO Box 850, Hershey, PA 17033.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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