Ann Thorac Surg 2004;77:651-657
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Sodium-hydrogen exchange inhibition attenuates in vivo porcine myocardial stunning
Randy M. Stevens, MDa,
M. Salik Jahania, MDa,
Robert M. Mentzer, Jr, MDa,
Robert D. Lasley, PhDa*
a Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, USA
Accepted for publication June 6, 2003.
* Address reprint requests to Dr Lasley, Department of Surgery, University of Kentucky College of Medicine, MN276, Chandler Medical Center, 800 Rose St, Lexington, KY 40536-0298, USA
e-mail: rlasley{at}uky.edu
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Abstract
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BACKGROUND: Inhibition of the sodium-hydrogen exchanger isoform 1 with HOE-642 (cariporide) has been shown to protect against ischemia-reperfusion injury and to decrease myocardial cell death in numerous animal preparations; however the effects of cariporide in stunned myocardium are not as well understood. We sought to determine whether cariporide attenuated myocardial stunning in vivo.
METHODS: Open chest anesthetized pigs (22–33 kg) were subjected to 15 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Regional ventricular function was assessed by segment shortening. Contractility was measured by stroke work and by load-insensitive preload recruitable stroke work and preload recruitable stroke work area. Vehicle or HOE-642 (1 mg/kg, IV) was administered 10 min before LAD occlusion.
RESULTS: Cariporide treatment significantly improved postischemic segment shortening, stroke work, preload recruitable stroke work, and preload recruitable stroke work area and had no systemic hemodynamic effects. After 3 h of reperfusion, control animals recovered 33% ± 4% and 33% ± 3% of preischemic LAD segment shortening and preload recruitable stroke work area values, respectively, whereas animals treated with HOE-642 recovered 59% ± 6% and 57% ± 6%, respectively (p < 0.05). Seven (39%) of 17 control animals exhibited ventricular fibrillation during reperfusion; none of the cariporide-treated pigs fibrillated.
CONCLUSIONS: Sodium–hydrogen exchange inhibition can attenuate postischemic myocardial stunning in addition to its well-described anti-infarct properties. Inhibition of the sodium–hydrogen exchanger may be beneficial in patients susceptible to postischemic myocardial dysfunction associated with cardiac surgery.
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Introduction
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Intracellular calcium overload is one of the primary mediators of both reversible and irreversible myocardial ischemia–reperfusion injury. Although the results of initial experimental studies indicated that calcium-channel blockers may reduce this injury [1] more recent findings indicate that the calcium overload is caused, in large part, by reverse sodium–calcium exchange [2–4]. The reversal of this exchange process, which normally extrudes intracellular calcium, is caused by the increases in intracellular sodium and hydrogen ions during ischemia and early reperfusion and the increased activity of the sodium–hydrogen exchanger (NHE) [4]. Recognition of this latter pathway has led to numerous investigations of selective NHE inhibitors.
One such NHE inhibitor is HOE-642 or cariporide. This agent has been shown to be a selective inhibitor of NHE-1, the primary isoform expressed in the sarcolemma of cardiac myocytes [4, 5]. Under normal conditions the major stimulus that regulates NHE-1 activity is an acidic intracellular pH [6, 7]. The agent has been shown to decrease intracellular calcium overload in cardiac myocytes and to decrease myocardial ischemia–reperfusion injury in isolated myocytes, isolated hearts, and in vivo preparations [5, 8–22]. Inhibition of NHE-1 with cariporide has also been shown to decrease the incidence of ischemic arrhythmias and reperfusion-induced ventricular fibrillation [23, 24].
The vast majority of studies examining the cardioprotective properties of cariporide have however been conducted in models of prolonged ischemia in which the primary endpoint has been infarct size reduction. Isolated heart studies examining cariporide's beneficial effects on postischemic ventricular function have utilized prolonged ischemia times which are associated with necrosis. There have been substantially fewer reports on the effects of cariporide on reversible postischemic cardiac dysfunction (ie, myocardial stunning) and these studies have yielded conflicting findings on cariporide's beneficial effects [14, 21, 22, 25, 26]. Two groups reported that cariporide improved regional segment shortening following multiple brief (
5 min) occlusions [14, 21] whereas the results of two other studies indicated no beneficial effects of cariporide in myocardial stunning models [25, 26]. In addition no studies have assessed the effects of cariporide on load insensitive measurements of regional contractility in stunned myocardium. Thus, the purpose of this study was to determine whether cariporide attenuates myocardial stunning in an in vivo porcine preparation of reversible cardiac dysfunction.
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Material and methods
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All animals in this study received humane care according to the guidelines set forth in "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 (National Institutes of Health Publication No. 86 to 23, revised 1996). In addition animals were used in accordance with the guidelines of the University of Kentucky Institutional Animal Care and Use Committee.
Animal preparation
Studies were conducted in domestic farm pigs weighing 22–33 kg. Ketamine (20 mg/kg, IM) and sodium pentobarbital (15 mg/kg, IV) were administered for induction of anesthesia. Pentobarbital (3–5 mg · kg-1 · h-1) in combination with fentanyl (0.02 µg · kg-1 · h-1) was infused continuously for maintenance of anesthesia. A tracheostomy was performed and ventilation was maintained with a large-animal ventilator (Harvard Apparatus, Holliston, MA). Tidal volume, respiratory rate, and fraction of oxygen-inspired air were adjusted to maintain normal arterial blood gas and pH values. Core body temperature was monitored via an esophageal temperature probe and maintained at 38°C with heating pads. A femoral artery catheter was used to monitor arterial blood pressure and to obtain blood samples to measure arterial blood gases.
A midline sternotomy was performed to expose the heart which was suspended by a pericardial cradle. Left ventricular pressure was measured with a 5F high-fidelity pressure-sensitive tip transducer (Millar Instruments, Houston, TX) placed into the left ventricular cavity through the apex and secured with a purse-string suture. A segment of left anterior descending coronary artery (LAD), distal to the origin of the first diagonal branch, was carefully dissected free of surrounding tissue. The area at risk was delineated by a brief ( < 20 s) occlusion of the LAD with a vascular occluder. A ligature was placed around the artery to be used for occlusion. A transit time perivascular flow probe (Transonic Systems Inc, Ithaca, NY) was placed distal to the occluder to measure coronary blood flow. Pairs of piezoelectric segment shortening crystals (Crystal Biotech, Houston, TX) were placed in the perfused beds of the LAD and the left circumflex coronary artery to measure regional segment shortening. Crystals were placed in the midmyocardium (approximately 4–6 mm deep and perpendicular to the epicardium) 5–15 mm apart and aligned in a manner such that the intercrystal axis was parallel to the direction of myocardial fiber shortening.
Measurement of regional ventricular function and contractility
All hemodynamic and sonomicrometry signals were sent through a 32-bit analog digital converter to an online data acquisition computer with customized software (Augury, Coyote Bay Instruments, Manchester, NH), continuously displayed on a computer monitor, and recorded.
End-diastole was defined as the onset of a positive rate of pressure rise (+LV dP/dt), and end-systole was defined as 20 ms before peak -LV dP/dt. Segment shortening (SS) was defined as end-diastolic length (EDL) minus end-systolic length (ESL) and percent SS (%SS) was calculated as
Regional stroke work (SW) was calculated by quantifying the area within the pressure–segment length loops generated during each cardiac cycle. Regional preload recruitable SW (PRSW) and PRSW area (PRSWA) were generated from the segment length and left ventricular pressure data collected during brief vena cava occlusions. The procedure of vena cava occlusion was performed by gradually tightening an umbilical tape around the supradiaphragmatic portion of the inferior vena cava. During data acquisition ventilation was held at end-expiration to minimize the effects of varying venous return on preload. PRSW and PRSWA were calculated according to the original methods of Glower and associates [27] as previously done by our laboratory [28, 29]. PRSW was based on linear regression of the relationship between SW and end-diastolic segment length calculated by the equation
where Msw is the slope of PRSW and Lw is the x-axis intercept. PRSWA was determined by the formula
where Lw max is the maximum x-axis intercept during the entire experiment. Base line and caval occlusion data were saved at specific time points in the protocol for offline analysis. An average of 9–11 heartbeats were used in each calculation.
Experimental protocols
When instrumentation was completed, the animals were treated with heparin (100 U/kg body weight, IV) and allowed to stabilize for 30 min before coronary occlusion. Ten minutes before LAD occlusion cariporide (1 mg/kg, via the femoral vein) or the cariporide vehicle was administered. Subsequently all animals underwent a 15-min LAD occlusion and 3 h of reperfusion. Lidocaine (2 mg/kg, IV) was administered immediately before releasing the occluder. We have previously reported that this model of myocardial stunning does not produce irreversible myocardial injury [28, 29]. At the conclusion of the protocol the ischemic area at risk was identified by reoccluding the LAD and by infusing 1.0% Evan's blue solution into the left ventricle while occluding the aorta. Each animal was euthanized by an intracardiac bolus of potassium chloride and sodium pentobarbital. Crystal placement in the midmyocardium of the ischemic and nonischemic regions was confirmed after the heart was excised.
Determination of the region at risk
The left ventricle was isolated from the rest of the heart. The region at risk (devoid of Evans's blue staining) was then separated from the remainder of the left ventricle and each section was weighed. The region at risk was then sliced parallel to the atrioventricular groove into equal thicknesses and the slices were incubated in 1% 2,3,5-triphenyltetrazolium chloride solution in phosphate-buffered saline solution at 37°C for 15 min. Brick-red stain indicated viable tissue; infarcted tissue appeared pale. The region at risk was calculated by dividing the area at risk by the total left ventricular area (eg the sum of the area at risk and the area of the remainder of the left ventricle).
Statistical analysis
Results are expressed as mean ± the standard error of the mean. Reperfusion SS, SW, PRSW, and PRSWA are expressed as percent recovery of preischemic values. Differences between the groups were determined with two-way analysis of variance for treatment and time. Significant differences between the groups were determined using the Dunnett post hoc test. A p value of less than 0.05 was accepted as statistically significant.
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Results
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A total of 17 pigs were studied in the control group. Seven animals were excluded from analysis because they exhibited ventricular fibrillation at the time of reperfusion. Three pigs were excluded because placement of the piezoelectric crystals was determined to be on the edge or outside the region at risk at the conclusion of the experiment. The treated group consisted of 8 pigs. None of these animals fibrillated during the protocol; however, 1 pig was excluded because of a broken crystal wire. Thus, 7 control pigs and 7 treated animals were available for analysis.
The systemic hemodynamic and ventricular function data for control and treated animals are summarized in Table 1.
The mean arterial pressure (MAP), heart rate (HR), +LV dP/dt, and LAD blood flows at base line, during ischemia, and during reperfusion were similar for both groups. Before the onset of ischemia, cariporide had no effect on LAD %SS or LAD PRSWA (Fig 1).
The areas at risk were similar in both groups and there was no evidence of necrosis by triphenyltetrazolium chloride staining in either group.
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Fig 1. The effects of cariporide treatment (1 mg/kg, IV) on left anterior descending coronary artery segment shortening (SS) and preload recruitable stroke work area (PRSWA) before ischemia. Baseline SS and PRSWA measurements were made 30 minutes after completion of instrumentation. Responses to cariporide were recorded 5 minutes after administration of cariporide.
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Effect of cariporide on %SS recovery and regional SW
Preischemic LAD SS values in the two groups were 15.0% ± 1.0% in the control group and 20.9% ± 1.1% in the cariporide group. Regional SW values in the LAD beds before ischemia were 225 ± 19 mm Hg · mm in the control group and 282 ± 33 mm Hg · mm in the cariporide group. Cariporide pretreatment significantly improved recoveries of regional SS and SW, both parameters of regional ventricular function, at each time point measured, as shown in Figs 2 and 3,
respectively.
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Fig 2. The recovery of segment shortening (SS) during reperfusion following 15 minutes of left anterior descending coronary artery occlusion. Results are expressed as percent of preischemic (PreISC) values. Values are mean ± the standard error of the mean (*p < 0.05 versus control group).
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Fig 3. The effects of cariporide treatment before ischemia on the recovery of left anterior descending coronary artery stroke work (SW). Results are expressed as percent of preischemic (PreISC) values. Values are mean ± the standard error of the mean (*p < 0.05 versus control group).
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Effect of cariporide on PRSW and PRSWA
Presichemic LAD PRSW and PRSWA values in the control group were 103 ± 13 mm Hg/mm and 606 ± 132 mm Hg · mm3/mm. Respective values in the cariporide-treated pigs were 94 ± 6 mm Hg/mm and 632 ± 88 mm Hg · mm3/mm. Cariporide treatment before ischemia was associated with a significantly greater recovery of PRSW at 1 h of reperfusion (82% ± 5%) compared with control pigs (54% ± 5%). Although LAD PRSW values in the cariporide group tended to be higher at 2 and 3 h of reperfusion these differences were not statistically significant (Fig 4).
As shown in Fig 5
recovery of PRSWA was significantly greater in the cariporide group throughout reperfusion.
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Fig 4. Reperfusion recovery of left anterior descending coronary artery bed preload recruitable stroke work (PRSW). Results are expressed as percent of preischemic (PreISC) values. Values are mean ± the standard error of the mean (*p < 0.05 versus control group).
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Fig 5. The effect of 15 minutes of coronary occlusion and 3 hours of reperfusion on left anterior descending coronary artery bed preload recruitable stroke work area (PRSWA). Results are expressed as percent of preischemic (PreISC) values. Values are mean ± the standard error of the mean (*p < 0.05 versus control group).
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Comment
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The results of this study indicate that the preischemic administration of the NHE inhibitor cariporide significantly improved the recovery of regional ventricular function and load-insensitive parameters of regional contractility in stunned in vivo porcine myocardium. Cariporide treatment, which was associated with no hemodynamic effects, improved reperfusion regional SS, SW, PRSW, and PRSWA. These results suggest that this agent may be a promising new treatment modality for improving myocardial protection during off-pump cardiac surgery.
The NHE has been shown to be an important extrusion pathway for intracellular protons in cardiac myocytes [8, 16, 30]. This exchange mechanism is activated during ischemia and early reperfusion because of the accumulation of intracellular H+ associated with adenosine triphosphate catabolism and anaerobic glycolysis. The removal of intracellular H+ is associated with the antiport of extracellular Na+ down its concentration gradient. As ischemia is prolonged the sarcolemmal sodium–potassium adenosine triphosphatase becomes inhibited resulting in a further accumulation of intracellular Na+. These exchange mechanisms are accelerated during early reperfusion in an attempt to restore intracellular pH. However, the increased intracellular Na+ concentration reverses the normal Na+/Ca2+ exchanger resulting in increased intracellular calcium and potential calcium overload and cellular injury.
The beneficial effects of NHE inhibitors in cardiac models of ischemia–reperfusion injury have been recognized for years. However, initial agents such as amiloride and related compounds exerted nonspecific effects at the doses needed to effectively inhibit Na+/H+ exchange [4]. Cariporide, a selective inhibitor of NHE-1 [4, 5, 8], has been shown to reduce intracellular Na+ accumulation during simulated ischemia in guinea pig ventricular myocytes [15] and to reduce rebound increases in intracellular pH following anoxia in rat cardiac myocytes and acidosis in human ventricular myocytes [8, 30]. Cariporide can improve postischemic ventricular function in isolated perfused heart studies [11, 17, 19, 20] and can reduce myocardial infarct size in vivo [10, 12, 13, 21, 31].
In contrast to the numerous reports on cariporide's beneficial effects following prolonged ischemia, there are fewer studies reporting the beneficial effects of cariporide in reversible postischemic ventricular function (ie, myocardial stunning). The five studies published to date in in vivo models of stunning have yielded conflicting results [14, 21, 22, 25, 26]. Symons and associates [14] reported that cariporide delayed the onset of regional dysfunction in conscious pigs undergoing 25 cycles of 2 min of coronary artery occlusion. More recently it was reported that cariporide attenuated regional myocardial contractile dysfunction assessed by single crystal measurements of wall thickening in intact rabbits [21] and sheep [22]. In contrast cariporide did not attenuate stunning in a canine model [25] or following regional ischemia in rats [26]. The reasons for these discrepant results are not clear but they may be due to differences in species and the models of myocardial dysfunction studied.
The results of the present study indicate that cariporide attenuates myocardial stunning in pigs under conditions similar to those that may occur clinically during off-pump cardiac surgery. Treatment with a single bolus of the NHE inhibitor 10 min before a 15-min coronary artery occlusion significantly improved postischemic SS, SW, PRSW, and PRSWA. Although SS and SW are load-sensitive parameters of contractility cariporide treatment did not exert any hemodynamic effects, and there were no differences in systemic hemodynamics between the groups at any time point. Postischemic PRSW and PRSWA, both of which are load-insensitive markers of ventricular contractility, were also significantly improved in the cariporide-treated animals. Because by definition myocardial stunning is reversible postischemic dysfunction these results suggest that cariporide accelerates the recovery of function in stunned myocardium.
The beneficial effect of cariporide in the present study is likely due to a direct effect on the cardiac myocytes. This hypothesis is based on the fact that NHE-1 is the primary isoform expressed in the cardiac myocyte sarcolemma [4, 8] and NHE inhibitors have been shown to protect myocyte function in vitro as well as in vivo. NHE-1 is also expressed on neutrophils [32], however, and NHE inhibition has been shown to reduce the neutrophil oxidative burst and the accumulation of neutrophils during reperfusion following prolonged ischemia [33]. It has also been reported that cariporide inhibits neutrophil adhesion following ischemia and reperfusion [34]. However it is unlikely that modulation of neutrophil function contributes to cariporide's beneficial effects in the present study because we used a model of stunning in which neutrophils are thought to play a negligible role [35].
An additional beneficial effect observed in the present study was the ability of cariporide to significantly reduce reperfusion-related ventricular fibrillation. None of the pigs pretreated with cariporide experienced the ventricular fibrillation that often occurs at the onset of reperfusion in this model. In this study, 7 of the original 17 pigs in the control group were excluded from further analysis because of ventricular fibrillation. Our observations are similar to other reports documenting the antiarrhythmic effects of cariporide [23, 24].
The significant antistunning effect of cariporide documented in this study combined with cariporide's potent infarct size-reducing effect [10, 12, 13, 21, 31] and antiarrhythmic properties [23, 24] appear to make cariporide an attractive agent for use in myocardial protection in humans. Clinically cariporide has been shown to provide significant benefit to patients undergoing coronary artery bypass graft (CABG) surgery and in the GUARD During Ischemia Against Necrosis (GUARDIAN) trial [36]. Although the trial did not show a significant benefit of cariporide over placebo in the overall population of patients who underwent high-risk percutaneous coronary intervention, who had unstable angina, or who underwent CABG surgery, the subgroup of patients pretreated with 120 mg of cariporide before CABG surgery had a significant 25% relative reduction in the risk of death or myocardial infarction when compared with the placebo group.
In summary, these data provide evidence that cariporide administration before an ischemic insult can protect against the development of myocardial stunning in vivo. Although these studies are promising more studies are required to prove that NHE inhibition is protective against myocardial stunning and/or other forms of myocardial dysfunction in patients undergoing cardiac surgery.
| Dr Mentzer discloses that he has a financial relationship with Aventis.
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Acknowledgments
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The authors would like to thank Brandon Klar and Ruth Oremus for their technical assistance. This work was supported by a National Institute of Health Grant (NHLBI 34579) and a grant from Aventis Pharmaceuticals.
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Abstract
Introduction
