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J Thorac Cardiovasc Surg 2003;125:155-164
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology (CSP) |
From the Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, Ga.
Supported in part by a Scientific Development Award (Z.Z.) and a Grant-in-Aid (J.V-J.) from the National American Heart Association. Cariporide was kindly donated by Aventis Pharma AG, Frankfurt am Main, Germany.
Received for publication Dec 3, 2001. Revisions requested Feb 14, 2002; revisions received April 9, 2002. Accepted for publication April 16, 2002. Address for reprints: Jakob Vinten-Johansen, MD, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, 550 Peachtree St, NE, Atlanta, GA 30308-2225 (E-mail: jvinten{at}emory.edu).
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Abstract |
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Introduction |
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Cardiac surgery is performed on hundreds of thousands of patients each year to alleviate coronary artery disease, valve problems, and other cardiac diseases. Although the operative outcomes with current formulations of cardioplegic solutions are generally acceptable, with low morbidity and mortality, patients at high risk, such as those with an evolving myocardial infarction, low ejection fraction, or cardiogenic shock, require additional strategies to adequately protect the vulnerable myocardium during cardiac surgery. Current strategies in on-pump myocardial protection advocate the use of cardioplegic solutions not only to arrest the heart but to act as a vector by which to introduce cardioprotective agents targeting specific mechanisms of ischemia-reperfusion injury.
Activation of the Na+-H+ exchanger (NHE) has been implicated in the pathogenesis of tissue ischemia-reperfusion injury.
1-3 Under normal conditions, the Na+-H+antiport mechanism operates in the forward direction, driven by the inwardly directed transmembrane sodium ion gradient and expelling a single intracellular hydrogen ion in exchange, thereby maintaining intracellular pH and regulating intracellular sodium level. 4 During ischemia, however, the accumulation of intracellular hydrogen provides the greater driving force for the antiporter, with a resulting efflux of hydrogen ion to the extracellular compartment and a net intracellular accumulation of sodium. The robust buildup of protons in the extracellular compartment during ischemia eventually reduces the transmembrane gradient, which in turn may inhibit NHE activity and increase sodium accumulation. At reperfusion, however, washout of protons in the extracellular compartment restores a transmembrane gradient favoring proton efflux. Thus the antiporter becomes reactivated during reperfusion, 5 with a resulting net influx and accumulation of intracellular sodium. The consequent accumulation in intracellular sodium stimulates calcium ion influx through the Na+-Ca2+ antiporter and accumulation of intracellular free calcium. Intracellular calcium ion accumulation has been implicated in the pathogenesis of systolic and diastolic dysfunction and in the transition to irreversible tissue injury after ischemia and reperfusion. 6,7 Accordingly, inhibition of the NHE mechanism has been advocated as a cardioprotective strategy. 8-10 Previous studies have consistently demonstrated that inhibition of the NHE mechanism results in decreased accumulation of intracellular sodium 4 and subsequently decreased calcium overload and myocardial damage during nonsurgical ischemia and reperfusion when administered before the ischemic event. 1,9,11 Indeed, the cardioprotection during coronary occlusion and reperfusion observed with NHE inhibition rivals that observed with ischemic preconditioning, and it may in fact be synergistic with preconditioning or may exceed the cardioprotection observed with preconditioning. 12 However, whether cardioprotection is exerted when the NHE inhibitor is administered at reperfusion remains controversial. 13-15
In cardiac surgery under cardiopulmonary bypass (CPB) and intermittent cardioplegia, potential injury may occur during intraoperative ischemia between multidose infusions of cardioplegic solution or as a result of maldistribution of solution distal to total coronary occlusions. This intraoperative injury may be additive to the antecedent injury caused by regional ischemia, heart failure, cardiogenic shock, and so on. In addition, there is potential for reperfusion injury during each infusion of cardioplegic solution and after removal of the aortic crossclamp. Neutrophils play an important role in the pathogenesis of ischemia-reperfusion injury, 16 particularly in cardiac surgery, where the extracorporeal circuitry amplifies the inflammatory response. 17
Several studies performed in isolated perfused-heart preparations have indicated that inclusion of amiloride analogs or other NHE inhibitors attenuates postischemic or postcardioplegia contractile dysfunction. 18,19 Moreover, in a clinical randomized trial (the GUARDIAN trial 20) the selective NHE type 1 isoform (NHE-1) inhibitor cariporide (HOE 642) was administered intravenously during the perioperative period to high-risk patients who underwent coronary artery bypass grafting. This study reported a significant reduction in combined infarction and mortality. However, few reports have tested the cardioprotective effects of NHE inhibitors with in vivo models of surgical revascularization in which neutrophils may participate in the inflammatory component of reperfusion injury. Neither have any studies to date tested the potential benefits of NHE inhibitors as an adjunct to blood cardioplegia in vivo. Accordingly, this study tested the hypothesis that the selective NHE inhibitor cariporide would attenuate postcardioplegia injury when given as an additive to blood cardioplegic solution in a canine model simulating on-pump surgical revascularization of evolving myocardial infarction.
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Material and methods |
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In vitro superoxide anion generation by activated neutrophils
Experiments were performed to determine the direct effects of cariporide or neutrophil function. To isolate neutrophils, peripheral canine blood (200 mL) was mixed with 45 mL of anticoagulating agents, which included 1.6% citric acid and 2.5% sodium citrate (pH 5.4), and 100 mL of 6% dextran solution in buffered Hanks balanced salt solution. Polymorphonuclear neutrophils were isolated with the Ficoll-Pacque (Sigma Chemical, St Louis, Mo) technique described in detail elsewhere. 21 The cells were adjusted to approximately 9 x 107 cells/mL. Final suspensions contained 94% ± 1% neutrophils, and cell viability averaged 99% ± 0.5%, as determined by trypan blue exclusion. Superoxide anion production by neutrophils stimulated by platelet activating factor (100 nmol) were determined by measuring the superoxide dismutase-inhibitable reduction of ferricytochrome C to ferrocytochrome C spectrophotometrically at 550 nm with a V-Max Microtiter Plate Reader (Molecular Devices Corporation, Sunnyvale, Calif). In addition, degranulation of platelet-activating factor-stimulated neutrophils was determined by analysis of myeloperoxidase activity.
In vivo study
Twenty healthy mongrel dogs of either sex weighing 22.4 to 31.6 kg (average weight 27.4 ± 1.0 kg) were initially anesthetized by intravenous administration of 2.5% thiopental (20 mg/kg) followed by constant infusion of fentanyl citrate (0.4 µg/[kg · min]) and diazepam (0.003 mg/[kg · min]) during the experiment. Each dog was endotracheally intubated and mechanically ventilated to maintain Pao2 at greater than 100 mm Hg, Paco2 between 35 and 45 mm Hg, and pH between 7.35 and 7.45. Metabolic acidemia was corrected with sodium bicarbonate infusion as needed. Polyethylene catheters were inserted into the femoral artery for arterial blood sampling and for monitoring systemic arterial blood pressure, and a catheter was inserted into the femoral vein for fluid administration. A rectal temperature probe was inserted to measure core body temperature. After median sternotomy, the superior and inferior venae cavae were loosely encircled with umbilical tapes, the azygos vein was ligated, and the heart was suspended in a pericardial cradle. Millar catheter-tipped pressure transducers (model MPC-500; Millar Instruments, Inc, Houston, Tex) were placed into the proximal aorta through the right internal thoracic artery and into the left ventricular cavity through an apical stab incision. A 1-cm portion of the left anterior descending coronary artery (LAD) distal to the first diagonal branch was dissected and loosely encircled with a 2-0 silk suture, which was later used to produce regional myocardial ischemia. A pair of 5-MHz piezoelectric ultrasonic crystals, 2.5 to 3.0 mm in diameter, was placed in the subendocardium of the myocardium perfused by the LAD (ischemic-reperfused segment) to measure instantaneous segmental dimensions with a sonomicrometer (model 120; Triton Technology, Inc, San Diego, Calif).
The dogs were systemically anticoagulated with sodium heparin at 300 U/kg, supplemented every 90 minutes with an additional 150 U/kg to maintain the activated clotting time at more than 400 seconds. The left subclavian artery was cannulated for aortic perfusion, and the superior and inferior vena caval cannulas were inserted through the right atrium for venous return. The cannula tips were kept in the atrium until the institution of CPB to avoid hemodynamic interference. A double-lumen cardioplegic catheter (Medtronic DLP, Grand Rapids, Mich) was inserted into the ascending aorta proximal to the aortic crossclamp for the simultaneous delivery of blood cardioplegia and measurement of cardioplegic infusion pressure. Venous blood was oxygenated with a membrane oxygenator (COBE Cardiovascular, Inc, Arvada, Colo) and passed through a 50-µm filter and bubble trap before it was returned to the arterial circulation. The rate of oxygenation was adjusted to maintain the systemic Pao2 at greater than 200 mm Hg and the Paco2 between 30 and 40 mm Hg. Metabolic acidosis was counteracted with sodium bicarbonate to maintain arterial blood pH between 7.35 and 7.45. The mean arterial blood pressure during CPB was maintained at 70 mm Hg by adjustment of the blood flow through the arterial cannula. A myocardial temperature probe was placed in the anterior wall of the left ventricle.
Experimental protocol
After all surgical instrument placement, hemodynamic data and blood samples were obtained at baseline. Each dog then received a bolus injection of lidocaine (1.2 mg/kg) followed by a continuous infusion (0.3 mg/[kg · min]), after which the LAD was ligated just distal to the first diagonal branch for 75 minutes. After 75 minutes of LAD regional ischemia, the cannulas were advanced and CPB was initiated. The left ventricle was vented by gravity drainage through a transmyocardial cannula, and the systemic blood temperature was reduced to 28°C. The dogs were randomly allocated into groups that received blood cardioplegia supplemented with either saline vehicle (vehicle group, n = 8) or 10 µmol/L of HOE 642 (cariporide group, n = 8) at equivalent volumes of diluent. The aorta was crossclamped, and cardioplegic arrest was induced with multidose, hypothermic, hyperkalemic blood cardioplegic solution (66 parts blood to 1 part crystalloid) of the following composition: 20.0-mEq/L (induction, terminal) or 10.0-mEq/L (intermittent) potassium ion, 1.0 mmol/L calcium ion, and 0.4-mmol/L magnesium ion, at pH 7.4 with tris(hydroxymethyl)aminomethane. The blood cardioplegic solution was delivered with the Myocardial Protection System cardioplegia and perfusion system (Quest Medical, Dallas, Tex). High-potassium blood cardioplegia (20-mEq/L potassium ion, 4°C) was delivered for 3 minutes during induction, and low-potassium blood cardioplegia (approximately 10-mEq/L potassium ion) was delivered for 2 minutes after 20 and 40 minutes of arrest at an aortic root pressure of 50 mm Hg. The LAD ligature was loosened before the second cardioplegic infusion to simulate revascularization of a target vessel. After 60 minutes of cardioplegic arrest, a hot-shot (20-mEq/L potassium ion, 27°C) infusion of blood cardioplegia was delivered for 3 minutes. Systemic blood was rewarmed to 37°C by the end of the hour of cardioplegic arrest, and the aorta was unclamped to initiate reperfusion. After cardiac electromechanical activity appeared, the mean arterial pressure was gradually increased from 50 to 80 mm Hg through a period of 5 minutes. The heart was maintained on total vented bypass for the first 30 minutes of reperfusion (beating empty reperfusion). Subsequently, all hearts were weaned from CPB and reperfusion was continued in the working state for an additional 90 minutes. The experiment was terminated with a bolus of intravenous sodium pentobarbital (100 mg/kg). The heart was immediately excised and placed in cold Krebs-Henseleit solution oxygenated with 95% oxygen and 5% carbon dioxide and with the following composition: 118.1-mmol/L sodium chloride, 4.7-mmol/L potassium chloride, 1.2-mmol/L monobasic potassium phosphate, 1.2-mmol/L magnesium sulfate, 2.5-mmol/L calcium chloride dihydrate, 25.0-mmol/L sodium hydrogen carbonate, and 11.1-mmol/L glucose at pH 7.4.
Data collection and analysis
Hemodynamic and segmental length data were acquired during a 10-second period of respiratory apnea. The data from each channel were digitized and processed by computer algorithms with an interactive videographics program (SPECTRUM; Wake Forest University, Winston-Salem, NC) as described previously elsewhere. 22 Percentage segmental shortening and segmental stroke work were determined as described previously elsewhere. 22 Measurements were taken before LAD occlusion (baseline), after 75 minutes of LAD occlusion, after 30 minutes of empty beating reperfusion, and every 30 minutes during the 90 minutes of reperfusion in the off-pump working state.
Determination of area at risk and infarct size
After postexperimental excision of the heart, a catheter was inserted into the aortic root. The LAD ligature was retied, and Unisperse blue pigment (Ciba Specialty Chemicals Company, High Point, NC) was injected under a perfusion pressure of 100 mm Hg to stain the normally perfused region blue and thereby demarcate the area at risk. The left ventricle was cut into 4- to 5-mm thick transverse slices. The area at risk was separated from the nonischemic zone and incubated for 15 minutes in 1% triphenyltetrazolium chloride (Sigma, St Louis, Mo) at 37°C to differentiate the necrotic zone (pale) from the ischemic nonnecrotic zone (red). The area at risk was calculated as the sum of the weights of the nonnecrotic and necrotic tissues within the ischemic zone, divided by the weight of the left ventricle and expressed as a percentage (area at risk percentage). The infarct size was calculated as the weight of necrotic tissue divided by the weight of the area at risk and expressed as a percentage (infarct percentage).
Plasma creatine kinase activity
Arterial blood samples (3 mL) were centrifuged at 2500g and 4°C for 10 minutes. The plasma was drawn off and analyzed spectrophotometrically for creatine kinase (CK) activity and for protein concentration (CK-10 kit; Sigma Diagnostics, St Louis, Mo). Plasma CK activity was expressed in international units per gram of protein.
Determination of myocardial edema
Postexperimental transmural myocardial tissue samples were taken from the nonischemic zone and from the area at risk. Each sample was further subdivided into subepicardial and subendocardial regions, blotted to remove surface moisture, weighed, and desiccated for 48 hours. Percentage myocardial water content was determined as follows: ([wet weight - dry weight]/wet weight) x 100%.
Cardiac myeloperoxidase activity
Postexperimental transmural myocardial tissue samples were taken from the nonischemic zone and from the nonnecrotic and necrotic areas of the area at risk for spectrophotometric analysis of myeloperoxidase activity as an assessment of neutrophil accumulation in myocardium, as described previously elsewhere. 23 MPO activity was expressed as the change in absorbence units per minute per gram of myocardial tissue.
Postexperimental coronary artery endothelial function
Both the ischemic-reperfused LAD and nonischemic left circumflex coronary artery (LCx) were carefully dissected from the heart, and endothelial function was quantified by relaxation responses to incremental concentrations of the endothelium-specific nitric oxide synthase stimulator acetylcholine in organ chambers, as described previously elsewhere. 24 The vascular rings were placed at the optimal point of their length-tension relationship and incubated with 10-µmol/L indomethacin to prevent vascular responses to endogenous prostacyclin. The coronary rings were then contracted with 10 nmol/L of the thromboxane A2 mimetic agent U46619 (Pharmacia & Upjohn, Bridgewater, NJ). The procedure was repeated for sodium nitroprusside (Sigma) to test endothelium-independent vascular smooth muscle relaxation. Relaxation was expressed as a percentage of U46619-induced constriction. Drug concentrations were expressed as the final concentration in the organ chamber.
Statistical analysis
The data were analyzed by 1-way or 2-way analysis of variance for repeated measures to identify group, time, and group-time interactions. If significant interactions were found, then further pairwise analysis was performed by post hoc analysis to locate the source of differences. Comparisons between the two groups in the area at risk, infarct size, MPO activity, myocardial edema, and percentage relaxation of postischemic coronary artery rings at each concentration were analyzed with the Student t test. Data are reported as mean ± SEM.
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Myocardial temperature and cardioplegia variables
There were no group differences in blood cardioplegia variables within each time point (Table 2). Anterior myocardial temperatures were not statistically different between the two groups during the initial, maintenance (20 minutes and 40 minutes of infusion), or terminal cardioplegia infusions (Table 2).
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), was significantly reduced by nearly half in cariporide-treated hearts (22.4% ± 0.04%) relative to the vehicle group (40.1% ± 0.05%).
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). The degree of reduction in CK activity in the cariporide group was qualitatively similar to the reduction in infarct size.
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, A, shows the percentages of relaxation with vasodilators in the vehicle group. The response to acetylcholine, an endothelium-dependent and muscarinic receptor-mediated vasodilator, was significantly (P = .04) blunted in the LAD rings (maximum 51.4% ± 8.0% relaxation with the highest concentration) relative to the nonoccluded LCx rings (maximum 79.4% ± 10.6%). In contrast, the responses to acetylcholine in the LAD (maximum 77.5% ± 7.3%) and LCx (maximum 85.4% ± 6.9%) rings were comparable in the cariporide group (Figure 5, B), with LCx rings in the two groups relaxing comparably. The endothelium-independent vasodilator sodium nitroprusside caused comparable relaxations in the two groups (Figure 5, A and B), with no significant difference between the LAD and LCx rings. These data indicate that cariporide-supplemented cardioplegia protected endothelial function from ischemia-reperfusion injury.
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Discussion |
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1,25 Lethal effects are seen when sodium ion influx in exchange for hydrogen ion efflux stimulates calcium ion accumulation through the Na+-Ca2+ antiporter. Accordingly, NHE inhibitors have been advocated as a cardioprotective strategy during nonsurgical myocardial ischemia and reperfusion. 4,8,10 Previous studies of ischemia-reperfusion have reported significant reductions in infarct size, 14,15,26,27 reduced incidence of arrhythmias, 26,28,29 and attenuation of apoptotic cell death 29,30 with NHE inhibitors. In contrast, the cardioprotective effects afforded by NHE inhibitors during surgical ischemia and reperfusion have to date been examined primarily in isolated perfused-heart studies that used crystalloid cardioplegic solutions, with systolic function as the major end point. 18,31 In this study we investigated the potential of the NHE inhibitor cariporide (HOE 642) as an adjunct to blood cardioplegia only to reduce postcardioplegia injury after normothermic regional myocardial ischemia. The model of antecedent ischemic myocardium created by coronary artery occlusion was chosen not only to simulate surgical revascularization of acutely ischemic myocardium but also as a model of regionally jeopardized myocardium vulnerable to ischemic and reperfusion injuries. In this model, cariporide in blood cardioplegia used at a concentration of 10 µmol/L did not directly inhibit neutrophil activities but did reduce postischemic infarct size, neutrophil accumulation, and tissue edema in the area at risk. It also reduced coronary artery endothelial dysfunction. This concentration of cariporide is higher than that used in previous studies with isolated crystalloid-perfused hearts (approximately 1 µmol/L).
Treatment with cariporide-enhanced blood cardioplegia did not, however, improve functional recovery in the area at risk. Although NHE inhibitors have been reported to be more effective when hearts are treated before the onset of ischemia (coronary artery occlusion) than after ischemia (at reperfusion), 14,15,32,33 this study clearly demonstrated that NHE inhibitor administration in hypothermic cardioplegia was cardioprotective, in agreement with other studies of crystalloid 18 or blood 34 cardioplegic solutions. Previous studies have shown that the NHE mechanism remains functional even under hypothermic conditions 31 and is therefore a potential target for inhibition when hypothermic conditions are used. Although cariporide attenuates neutrophil activities at higher concentrations, consistent with reports for other NHE inhibitors, 35 the concentration used in this study was below that which would directly inhibit neutrophil functions. Thus the cardioprotection was likely exerted on the myocardium directly rather than by antineutrophil mechanisms. In addition, there was no evidence that cariporide may have had a direct protective effect on the coronary artery endothelium. Attenuation of postischemic endothelial dysfunction may also have resulted from a reduction in ischemic injury and a subsequent inflammatory response to reperfusion involving the endothelium.
In the surgical setting used in this protocol, cariporide had no opportunity to intervene during the period of coronary occlusion. However, cariporide could intervene during the ischemia imposed between infusions of cardioplegic solution and could also reduce reperfusion injury. The delivery of blood cardioplegia to ischemic myocardium is, in fact, a form of reperfusion. Maddaford and Pierce 25 reported that the NHE mechanism was most active during the initial phase of reperfusion, and inhibition of the mechanism at that time could thereby attenuate subsequent calcium overload. 32 Calcium overload is a suspected mechanism of the transition from reversible to irreversible injury. The reduction in neutrophil accumulation in the area at risk with cariporide treatment is consistent with a generalized reduction in the inflammatory response to ischemia-reperfusion 16 rather than with a direct antineutrophil effect. Numerous studies have reported a correlation between attenuated neutrophil accumulation and reduced postischemic injury in both surgical and nonsurgical models of ischemia-reperfusion. 16
Previous studies have demonstrated that NHE-1 is the sole isoform detectable in the cardiac myocyte 36 and that the activity of the NHE is responsible for approximately 50% of extrusion of hydrogen ion equivalents in cardiac tissue. 37 Cariporide inhibits more than 95% of the NHE-1 activity at 1 µmol/L concentration. Inhibition of the NHE-1 mechanism during myocardial ischemia and reperfusion delays realkalinization to normal intracellular pH 9,38 and prevents subsequent calcium overload and its deleterious consequences in cardiomyocytes. 32,38 We did not measure intracellular pH or intracellular calcium in this study, but we speculate that the inhibition of calcium entry and accumulation occurred primarily at the time of aortic crossclamping and at reperfusion.
We found that recovery of postischemic segmental function was not significantly improved by cariporide, despite dramatic reductions in infarct size and myocardial edema. Segmental work at 90 and 120 minutes of reperfusion strongly tended to be greater in the group treated with cariporide blood cardioplegia, whereas there was no difference in segmental shortening. This suggests that there was still systolic bulging in the ischemic-reperfused myocardium, but shortening occurred during late systole. This failure to restore contractile function was also reported for previous studies in which the NHE inhibitor was administered after the onset of coronary occlusion. 14,15,39 However, models of global ischemia have reported salutary effects. Reversible global ischemia may involve myocardial stunning, as opposed to the infarction observed with more prolonged periods of regional occlusion. However, it is not clear whether long-term recovery would demonstrate benefit, because most studies were conducted in acute (hours of reperfusion) models.
In summary, the present study demonstrated that blood cardioplegia supplemented with the NHE inhibitor cariporide provided superior cardioprotection following normothermic regional myocardial ischemia when used as an adjunct to blood cardioplegia. The protective effect was likely exerted directly on the myocytes since the concentration used was less than concentrations that directly inhibit neutrophil function. However, the attenuation of neutrophil accumulation and endothelial dysfunction most likely represent a reduced inflammatory response to ischemia-reperfusion. The effectiveness of hypothermic blood cardioplegia supplemented with such purported cardioprotective agents is predicated on the ability of the agent of interest to exert its therapeutic effects during the cardioplegic period or thereafter on the end points measured. In previous clinical trials of NHE inhibitors, such as the GUARDIAN Trial, 20 cariporide was administered intravenously to high-risk patients before cardiac surgery and for as long as several days perioperatively. However, the greatest risk for the patient occurs in the immediate postoperative period, the events of which may be influenced by intraoperative events and the adequacy of myocardial protection. Incorporation of a NHE inhibitor only at the time of cardioplegia delivery is a strategy that has not been tested yet in clinical trials. This study provides a scientific foundation supporting the use of NHE inhibitors during the intraoperative period as an adjunct to clinical cardioplegia. However, it is not known whether continued postischemic administration would have resulted in further cardioprotection. In addition, further studies should be pursued to determine whether use of a higher concentration of cariporide to directly inhibit neutrophil superoxide radical generation would increase the degree of myocardial protection.
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