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Ann Thorac Surg 2003;75:1238-1245
© 2003 The Society of Thoracic Surgeons
a Department of Surgery, Division of Cardiothoracic Surgery, University of California, Los Angeles, School of Medicine, Los Angeles, California, USA
Accepted for publication September 19, 2002.
* Address reprint requests to Dr Buckberg, Division of Cardiothoracic Surgery, 62-258 Center For the Health Sciences, Los Angeles, CA 90095-1701, USA.
e-mail: gbuckberg{at}mednet.ucla.edu
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Abstract |
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METHODS: Control studies tested the safety of glutamate-aspartate–enriched blood cardioplegic solution in 4 Yorkshire-Duroc pigs undergoing 30 minutes of aortic clamping without prior unprotected ischemia. Twenty-four pigs underwent 30 minutes of unprotected normothermic global ischemia to create a jeopardized heart. Six of these hearts received normal blood reperfusion, and the other 18 jeopardized hearts underwent 30 more minutes of aortic clamping with cardioplegic protection. In 12 of these, the Na+/H+ exchanger inhibitor cariporide was used as intravenous pretreatment (n = 6) or added to the cardioplegic reperfusate (n = 6).
RESULTS: Complete functional, biochemical, and endothelial recovery occurred after 30 minutes of blood cardioplegic arrest without preceding unprotected ischemia. Thirty minutes of normothermic ischemia and normal blood reperfusion produced 33% mortality and severe left ventricular dysfunction in survivors (preload recruitable stroke work, 23% ± 6% of baseline levels), with raised creatine kinase MB, conjugated dienes, endothelin-1, myeloperoxidase activity, and extensive myocardial edema. Blood cardioplegia was functionally protective, despite adding 30 more minutes of ischemia; there was no mortality, and left ventricular function improved (preload recruitable stroke work, 58% ± 21%, p < 0.05 versus normal blood reperfusion), but adverse biochemical and endothelial variables did not change. In contrast, Na+/H+ exchanger inhibition as either pretreatment or added during cardioplegic reperfusion improved myocardial recovery (preload recruitable stroke work, 88% ± 9% and 80% ± 7%, respectively, p < 0.05 versus without cariporide) and comparably restored injury variables.
CONCLUSIONS: Na+/H+ exchanger blockage as either pretreatment or during blood cardioplegic reperfusion comparably delays functional, biochemical, and endothelial injury in jeopardized hearts.
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Introduction |
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Our prior studies of both regional and global ischemia have consistently used a profoundly jeopardized heart, and this model allowed us to define how amino acid–enriched blood cardioplegic solutions can resuscitate hearts from the severe injury that normally follows normal blood reperfusion [1, 2]. This current study addresses the limitations of our conventional techniques, by extending the safe ischemic duration, and evaluates whether either pretreatment or supplementing the controlled reperfusate with Na+/H+ exchanger (NHE) inhibition improves recovery in an otherwise profoundly damaged heart.
One central mechanism of damage, especially in the jeopardized heart, is abnormal ionic balance, with sodium and calcium accumulation in the myocytes, with resultant hypercontracture and membrane disruption that joins with endothelial damage, leukocyte adherence, and oxygen radical injury that can progress to cell death after normal blood reperfusion [3]. We previously improved mechanical and endothelial function after reperfusion by using a blood cardioplegic solution, and defined the limits of controlled cardioplegic reperfusion, by showing (1) that myocyte recovery is not accompanied by endothelial improvement unless elements related to nitric oxide synthesis (L-arginine) or endothelin production were added [4], and (2) that extending the interval of normothermic ischemia from 20 to 30 minutes reduces mechanical recovery to 50%, from 100%, and fails to prevent biochemical and endothelial injury [5]. We suspect that an important limitation of our prior methods was failure to deal with NHE activation during ischemia and reperfusion, which can accentuate the adverse effects of sodium and calcium accumulation [5].
Na+/H+ exchanger inhibition has emerged, experimentally, as an innovative strategy to prevent water and calcium overload during ischemia-reperfusion, by blocking the entrance of sodium. The two surgical avenues of management with NHE inhibition include pretreatment, and adding the agent to the cardioplegic solution. Experimentally, pretreatment with cariporide (HOE 642) delays myocardial damage and reduces ischemic-induced arrhythmias [6], and clinically lowers mortality and incidence of infarction in high-risk patients undergoing coronary artery bypass grafting with varied methods of protection [7]. Although NHE inhibition pretreatment is possible in a broad spectrum of high-risk patients with open vessels, pretreatment is not used in low-risk patients who may unexpectedly require an unanticipated interval of prolonged aortic clamping. Furthermore, NHE inhibition delivery only during reperfusion has had varied effects [8, 9].
Prior reperfusion studies with cariporide studies may have been limited because reoxygenation was with normal blood, and the heart was allowed to beat during the initial phase of reflow [10]. In contrast, the heart can be kept arrested during reperfusion in the surgical setting, and warm-blood cardioplegic reperfusion is now used more commonly before unclamping. Consequently, control of the aortic reperfusate may allow a unique mechanism for NHE inhibition delivery and permit testing of Piper’s suggestion that asystole during initial reoxygenation may avoid sudden hypercontraction and sarcolemmal damage [11].
The objective of this study is to contrast the myocardial and endothelial effects of reperfusing severely ischemic tissue with either normal blood or our tested amino acid–enriched reperfusate without cariporide, and either adding an NHE inhibitor during pretreatment or using this agent only as a supplement to the cardioplegic reperfusate. Our findings will establish the limits of substrate blood cardioplegia alone in profoundly damaged hearts and show a comparable and marked functional, biochemical, and endothelial benefit of either pretreatment with NHE inhibitor or only supplementing the blood cardioplegic reperfusate with this drug.
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Material and methods |
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Twenty-eight Yorkshire-Duroc pigs (27 to 34.5 kg) were premedicated (ketamine, 15 mg/kg; diazepam, 0.5 mg/kg intramuscularly) and anesthetized with pentobarbital, 30 mg/kg, intravenously and subsequent bolus injections of sodium pentobarbital. Support with a volume-controlled ventilator (Servo 900C; Siemens-Elema, Solna, Sweden) was started after tracheostomy and endotracheal intubation. The femoral artery and vein were cannulated, and arterial blood gases were measured to keep oxygen tension, carbon dioxide tension, and pH values within the normal range. A balloon-tipped catheter (model 132F5; Baxter Healthcare Corp., Irvine, CA) was advanced into the pulmonary artery through a jugular vein to measure cardiac output (thermodilution technique) and pulmonary artery pressure before and after cardiopulmonary bypass.
The pericardium was incised after median sternotomy, and a solid-state pressure transducer–tipped catheter (model MPC-500; Millar Instruments, Inc., Houston, TX) was inserted through the apex to monitor left ventricular (LV) pressure. Left ventricle dimensions were measured with 2-mm ultrasonic microtransducer crystals (Sonometrics, London, Ontario, Canada) placed into the subendocardium. One pair of crystals was oriented across the minor axis diameter, and the other was positioned in the major axis direction. Left ventricular volume was assessed using an ellipsoid-based formula. Pressure-volume loops were recorded digitally by means of acquisition hardware and software (Sonometrics). Measurements were made 15 minutes before starting bypass and 30 minutes after bypass was discontinued.
After systemic heparinization (300 U/kg), a 12F aortic cannula was inserted in the ascending aorta and a dual-lumen 29F venous cannula in the right atrium through the right atrial appendage. Extracorporeal circulation was achieved with a membrane oxygenator (Affinity NT 541; Medtronic, Inc., Minneapolis, MN) and an extracorporeal pump (Sarns, Ann Arbor, MI) with the circuit primed with 1000 mL of Plasma-Lyte solution (Baxter Healthcare Corp.), 700 mL of stored porcine packed blood, and calcium chloride for normocalcemia (1.0 to 1.2 mmol/L). Cardiopulmonary bypass was started at an oxygen tension of 300 mm Hg and an aortic pressure of 50 to 70 mm Hg, adjusting flow by monitoring mixed venous oxygen saturation to approximately 70%. Potassium, calcium, and pH were kept at normal levels. A dual-lumen aortic cannula measured delivery of blood cardioplegic solution and aortic root pressure. The blood cardioplegic solution was hyperkalemic (20 mg KCl/L), hypocalcemic (0.2 mEq/L Ca2+), alkalotic (pH 7.7) and enriched with glutamate and aspartate as reported previously [1]. The solution was obtained from Central Admixture Pharmacy Services, and mixed with blood from the extracorporeal circuit.
The coronary sinus was cannulated through the atrium for blood sampling, and the left ventricle was vented. Rectal temperature was kept at 35°C to 37°C during extracorporeal circulation. All cases were performed and analyzed by the same surgeon.
Experimental protocol
Control studies
Cardioplegia without ischemia
Four hearts underwent 30 minutes of arrest with glutamate-aspartate–enriched blood cardioplegic solution without ischemia. The cardioplegia protocol included warm induction (2 minutes), cold maintenance for 2 minutes (repeated at 15 minutes), and warm reperfusion (3 minutes) before unclamping [1].
Normothermic ischemia
Normal blood reperfusion
Six pigs underwent 30 minutes of normothermic aortic clamping followed by reperfusion with normal blood, achieved by removing the aortic cross-clamp.
Blood cardioplegic reperfusion
In 6 pigs undergoing 30 minutes of normothermic ischemia, 30 more minutes of cardioplegic arrest was added, following the above protocol of cardioplegic delivery, to simulate time needed for a surgical procedure.
Cariporide plus blood cardioplegia
Pretreatment
Six pigs received 5 mg/kg of HOE 642, as the agent was added to the prime of the extracorporeal circuit 15 minutes before 30 minutes of normothermic ischemia. Each pig underwent 30 more minutes of arrest, using the same blood cardioplegia protocol.
Reperfusion only
In 6 pigs undergoing the same interval of normothermic aortic clamping and 30 more minutes of blood cardioplegic arrest, cariporide was added to the cardioplegic solution to achieve a concentration of 10-4 mol/L (40 mg/L). Cariporide was administered in only the reperfusate cardioplegic dose, approximately delivering 16 mg directly into the heart.
Measurements
Cardiopulmonary bypass was continued 30 minutes after unclamping the aorta. Global LV function before and 30 minutes after cardiopulmonary bypass was assessed by pressure-volume analysis. Left ventricular pressure and volume were recorded during transient inferior vena cava occlusions to obtain a series of evenly declining pressure-volume loops. Global stroke work and end-diastolic volume were calculated through a video graphics program (Sonometrics). Preload recruitable stroke work (PRSW) for each series was identified as the relation between stroke work and end-diastolic volume, and quantified by a slope (MW) and x-intercept (LW). The slope (erg · cm-3 · 103) has been described as a reliable measure of intrinsic myocardial performance independent of loading, geometry, and heart rate [12]. Postbypass LV performance was expressed as percent of recovery from prebypass values.
Coronary sinus blood analysis
Myocardial injury was determined from analysis of coronary sinus blood samples taken 5 minutes after initiating (baseline) and previous to the end of cardiopulmonary bypass (reperfusion). Coronary samples were taken during aortic root infusion of normal blood, administered at 100 mL/min, proximal to the clamp.
Conjugated dienes
As a marker of oxidant-mediated lipid peroxidation, conjugated diene levels were determined spectrophotometrically in coronary sinus plasma after chloroform-methanol 2:1 (vol/vol) extraction. Conjugated diene concentration was expressed as absorbance at a wavelength of 240 nm per 0.5 mL plasma. Myocardial protein or deoxyribonucleic acid were not measured.
Creatine kinase MB
Myocardial damage was determined by measuring creatine kinase fraction MB (units per liter) in coronary sinus plasma by an ultraviolet spectrophotometric method (Sigma Chemical Co., St. Louis, MO) as recommended by the German Society for Clinical Chemistry.
Endothelin-1
Endothelin-1 levels (pg/mL) in coronary sinus plasma were determined after sample purification (Ethyl C2 Amprep minicolumns; Amersham Pharmacia Biotech, Piscataway, NJ) by an enzyme immunometric assay (ACE EIA kit; Cayman Chemical Company, Ann Arbor, MI) based on a double antibody "sandwich" technique.
Myocardial biopsy
At the end of the experiment, the pigs were killed by bolus injections of pentobarbital 5 mg followed a minute later by 15 mL of cold hyperkalemic blood (KCl, 30 mEq/L). Hearts were harvested for water component and myeloperoxidase activity.
Myeloperoxidase activity
Final transmural samples of LV myocardium (approximately 0.5 g) from the anterior free wall were immediately frozen in liquid nitrogen until analyzed. Samples were analyzed for neutrophil-specific myeloperoxidase activity as previously described [13]. Myeloperoxidase activity is expressed in units per gram of tissue.
Water component
Myocardial tissue of the free wall of the LV was weighed before and after desiccation. The relation, in percent of weight loss, was considered the water percent content in the tissue.
Statistical analysis
Statistical analysis of data within and between groups was performed using multiple analysis of variance followed by application of the Student’s t test with Tukey-Kramer’s correction for multiplicity. Changes within and between groups were considered statistically significant when the p value was less than 0.05. All data are expressed as mean ± standard deviation.
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Results |
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Evidence of oxidant-mediated lipid peroxidation, evaluated by conjugated dienes, was absent in the control group, but rose comparably to approximately 50% above resting levels after either normal blood or blood cardioplegic reperfusion, without cariporide (Table 1). In contrast, adding cariporide to the cardioplegic solution, as either pretreatment or only into the reperfusate, yielded levels comparable to nonischemic levels (p < 0.05 versus normal blood or blood cardioplegic groups). Leukocyte accumulation, measured by tissue myeloperoxidase activity, did not change without ischemia, but increased fourfold after normothermic ischemia and normal blood reperfusion. Blood cardioplegia without cariporide did not limit the increased activity (approximately threefold rise), but adding cariporide to the cardioplegic solution by pretreatment or only into the reperfusate markedly reduced this increase (approximately 40% above baseline), yielding levels different (p < 0.05) from the normal blood and blood cardioplegic groups.
Water component was measured in the blood-donor pigs, as a baseline control reference (Table 1 and Fig 2). Only mild (<1%) water gain followed blood cardioplegia without normothermic ischemia. In contrast, normal blood reperfusion after normothermic ischemia resulted in an approximately 3% increase in water content, with limited improvement (approximately 2% water gain) after blood cardioplegia. Pretreatment, or supplementation of the blood cardioplegic reperfusate with cariporide resulted in water content similar to blood cardioplegia without normothermic ischemia, and values were different (p < 0.05) from normal blood and blood cardioplegia methods.
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Comment |
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The combination of pretreatment with NHE inhibitor cariporide before ischemia and controlled cardioplegic reperfusion caused marked improvement of a spectrum of indicators of damage, including PRSW, oxygen radical damage, myocardial cellular and endothelial damage (including less leukocyte adherence and endothelin-1 release), and water accumulation. Comparable results were obtained when NHE inhibition was introduced only during the reperfusion period by adding cariporide to the amino acid–enriched blood cardioplegia. These findings of similar benefit of NHE inhibition before ischemia, yet improvement only during reperfusion, differ from prior reports showing the limitation of cariporide when restricted to the reperfusate [9], and led to our evaluation both of the benefits and limitations of our tested reperfusion solution and of why cariporide was a useful supplement.
Our first end point showed that controlled cardioplegic reperfusion (without NHE inhibition) allowed complete survival, and improved functional recovery when compared with normal blood without added aortic clamping. The severity of the 30-minute normothermic ischemic model was defined by these findings, because complete recovery followed 20 minutes of unprotected ischemia when reperfusion was controlled by our enriched blood cardioplegia [4]. These data suggest a limitation of calcium-related injury by our noncariporide-containing cardioplegic solution, but not its prevention. We speculate that the near complete recovery after NHE inhibition was related to more advantageous management of sodium and calcium loading. Unfortunately, measurements of calcium and sodium flux are needed to confirm this speculation, but their absence does not diminish the importance of the measured functional, biochemical, and endothelial recovery.
Our prior reperfusion work did not analyze the adverse sodium and calcium pumping mechanisms developed during severe ischemia; the energy-dependent Na+/K+ adenosine triphosphate pump becomes impaired, reactions that do not need adenosine triphosphate generation for action, like the Na+/H+ antiporter, become activated, and the Na+/Ca2+ pump becomes reversed to unload sodium and facilitate intracellular calcium accumulation [1]. We believe the mechanism of NHE inhibition by cariporide is to presumably restrict sodium and thereby calcium accumulation [14]. Our data show that this can occur both as pretreatment, and as an amplification method during warm-blood cardioplegic reperfusion. We suspect the reduced water accumulation becomes a secondary event in this mechanism, closely related to sodium overload.
These interrelated actions of NHE inhibition to prevent further sodium accumulation are blended with the protective affects of our blood cardioplegic protocol, used during the added 30-minute ischemic interval to simulate a surgical period for repair in jeopardized hearts undergoing prior unprotected ischemia. Prior studies have demonstrated that cariporide prevents realkalinization during reperfusion by limiting hydrogen ion flux [14]. Maintenance of low pH during reperfusion delays enzymatic activity and has been described as a beneficial factor to limit early contraction during a period of ionic and energetic instability [15]. Although we did not measure pH, cariporide allows a level of acidosis during reperfusion that can inhibit calcium injury by delaying enzymatic activity, thereby combining with the reduced calcium flux caused by asystole and hypocalcemia conferred by the cardioplegic reperfusate. We also provide new information that the NHE inhibitor can be useful in the reperfusate, in the event that a single preischemic dose may become less effective, as the 30-minute half-life (personal communication from Aventis labs on dissipation of dose in experimental studies) is exceeded by a longer duration of normothermic and hypothermic aortic clamping. The half-life in humans is not yet known.
Delivery of the NHE inhibitor was more than 15 minutes before ischemia in this study, so that part of its 30-minute half-life occurred before the cardioplegic solution was administered. Consequently, its role as a part of the cardioplegic solution and the reperfusate is uncertain in the pretreatment group, other than through recognition that some amount was present. Furthermore, we restricted additional aortic clamping to only 30 minutes in these profoundly damaged hearts, and longer periods are routinely used in practice. This may be remedied in the future by adding an ongoing dose into the pump or the cardioplegic solution, but the role with hypothermia must be evaluated.
Insight into the perioperative advantages of limiting sodium-related and calcium-related damage are drawn from prior studies of surgical ischemia-reperfusion injury. We did not study cariporide without cardioplegia in this report, but have done this previously, and found inferior results to supplementing the cardioplegic solution with NHE inhibition [16]. Previous cardioplegic strategies reduced calcium overload by delaying anaerobic metabolism, buffering acidosis, and controlling ionic blood calcium with citrate addition to the reperfusate [17]. The limitations of our substrate cardioplegic solution to confer complete protection may relate to its inability to deal with the profound damage of ongoing activity of the NHE antiporter that is modified positively by NHE supplementation.
The capacity to pretreat the heart, and thus supplement our prior solution, is available to a broad range of high-risk patients with open arteries. However the duration of benefit will relate to the half-life of cariporide when there is no ongoing delivery. Consequently, a short ischemic interval, as in off-pump coronary artery bypass grafting, would be satisfactory, but longer intervals of aortic clamping will need additional doses either intravenously (in the systemic prime) or in the cardioplegic solution.
Until our study and that of Martin and coworkers [18], the value of supplementation during cardioplegic reperfusion was not clear, in contrast to consistent favorable effects after cariporide pretreatment before the ischemic insult [19]. We suspect the explanation for reperfusion advantages relates to cardioplegic asystole that pharmacologically impairs sudden hypercontraction and limits resultant structural damage, as suggested by Piper and Garcia-Dorado [11]. Arrest during the short interval of induced blood cardioplegic reperfusion may provide a time-related mechanism that allows ionic balances to regain competence, so that contraction can restart more properly when normal blood is then restored.
Prior studies of cariporide, an NHE inhibitor, were restricted to isolated use after a spectrum of ischemic injuries with and without cardiopulmonary bypass. Our study differs because we complemented cariporide by controlling the reperfusate with the addition of many cardioplegic components that provide the time and protection needed to recover metabolism, whereas cariporide restricted sodium and calcium accumulation. We suspect that this integration with a tested cardioplegic method is critical, and that cariporide augments the controlled reperfusion process.
Several components are altered during controlled blood cardioplegic reperfusion and together may improve transmembrane ion balance restoration during the early phase of reperfusion, including (1) maintenance of arrest to avoid the sudden calcium accumulation, disruption of the sarcolemma, and hypercontraction if reoxygenation allows premature shortening to resume, (2) low calcium concentration within the solution to limit calcium loading during conditions of impaired ionic balance in the early period of reperfusion, (3) substrate enrichment to enhance oxygen utilization in the arrested heart to hasten ionic recovery, (4) normothermia to provide a correct temperature environment for enzymatic function, (5) hyperosmolarity to reduce edema, and (6) alkalosis with trihydroxymethylaminomethane to provide a buffer to hasten enzymatic recovery; simultaneously this limits acidosis, as carbonic acid is yielded by breakdown of bicarbonate buffers [20]. Such acidification, probably intracellular, by adding carbonic acid will further accentuate sodium-hydrogen exchange and can magnify subsequent calcium accumulation.
Protection against the endothelial response to ischemia and reperfusion was evident by comparisons between the normal blood and blood cardioplegia, with and without cariporide. Cardiac myocytes also release endothelin-1 so that we cannot conclude that reduction of this marker is related to only the endothelium. Myeloperoxidase activity was used to reflect leukocyte accumulation on the endothelium, and the activity after cariporide supplementation mirrored findings in control subjects with protected ischemia, in which the blood cardioplegic solution was used without preceding normothermic ischemia. Leukocyte penetration beyond the endothelium usually requires approximately 4 hours. We interpret the reduced conjugated diene levels to support our contention of improved endothelial protection, yet recognize we did not fully evaluate the extent of oxygen radical damage. Cariporide is very selective for isoform 1, which is also present in neutrophils, so that direct inhibition of neutrophil function may have occurred [21].
Na+/H+ exchange inhibition with cariporide amplifies the usefulness of a tested cardioplegic reperfusion solution. Our results in jeopardized hearts closely mirror the advantages of cariporide cardioplegic supplementation in previously arrested hearts prepared for transplantation after 30 minutes of normothermic ischemia [18]. A broad range of experimental reports show that cariporide delivery before ischemia reduces infarct size, LV dysfunction after myocardial infarction, apoptosis, and auricular and ventricular arrhythmias during reperfusion, and these findings have been confirmed during cardiac surgery [22]. In contrast, these effects were not so evident during reperfusion [8].
The aforementioned considerations may explain how our study of NHE inhibition in a specific cardioplegic solution developed for reperfusion contrasts with marginal results in other studies. The clinical limitations of cariporide alone after normal blood reperfusion are clear from its failure to reduce myocardial infarction or death in patients with unstable angina or non-ST elevation myocardial infarction, and its limited results (lowering myocardial infarction or death from 17% to 12%) in high-risk patients undergoing coronary artery bypass grafting in the GUARDIAN study [7] were obtained with a spectrum of crystalloid and blood cardioplegic methods. Furthermore, prior hemodynamic changes were not evaluated. In contrast, testing of this agent in our study was with a focused technique, rather than broad cardioplegic methods, and we define several hemodynamic, biochemical, and endothelial benefits that amplify our blood cardioplegic reperfusate.
The clinical implications of this study suggest that cariporide can be given both as pretreatment and during controlled reperfusion. When used for pretreatment, we suggest including an ongoing intravenous cariporide delivery, to ensure a satisfactory serum level to ensure its presence in the blood used for the cardioplegic solution. We did not measure cariporide levels in blood cardioplegic solution in animals subjected to cariporide pretreatment and cardioplegic reperfusion, or the effects of hypothermia in NHE inhibition, but recognize that cariporide may have been present during the interval of cardioplegic delivery after the supplemental aortic clamping was added to this study. Of equal importance, these findings show cariporide is useful when delivered only into the reperfusate.
This observation has important potential implications, as NHE inhibition can be used when an unexpected interval of prolonged ischemia is encountered in elective low-risk patients, or if there is a completely occluded vessel, in which case the cardioplegic solution becomes the only delivery option, as exists after use of coronary artery bypass grafting to treat acute myocardial infarction or percutaneous transluminal coronary angioplasty closure. Functional recovery likely represents diminution of stunning, so that the interval of postreperfusion management with cariporide may become limited to the operating room, although validation of this concept was not tested.
In conclusion, NHE blockage by cariporide amplifies the benefits of aspartate-glutamate–enriched blood cardioplegia in ischemia-reperfusion injury, presumably by limiting sodium and calcium accumulation, thus preserving myocardial and endothelial function to improve the outcome variables we measured in this study. These actions can be achieved by use of cariporide as either pretreatment or by adding NHE inhibition to the blood cardioplegic reperfusate.
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