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J Thorac Cardiovasc Surg 2003;125:1499-1509
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Sodium-hydrogen exchange inhibition preserves ventricular function after ventricular fibrillation in the intact swine heart

David G. Rabkin, MDa, Santos E. Cabreriza, MBAa, Jared C. LaCorte, MDb, Alan D. Weinberg, MSc, Lindita Çoku, MDa, Rowan Walsh, MDa, Ralph Mosca, MDa, Henry M. Spotnitz, MD*

From the Departments of Surgery,a Pediatrics,b and Biostatistics,c Columbia College of Physicians and Surgeons, New York, NY.

Supported in part by Department of Surgery Attending-Resident Start-up Grant and in part by the National Heart Lung, and Blood Institute of the National Institutes of Health (NRSA F32 HL69641-01).

Received for publication June 3, 2002. Revisions requested July 11, 2002; revisions received Aug 6, 2002. Accepted for publication Aug 15, 2002. Address for reprints: Henry M. Spotnitz, MD, Department of Surgery, Columbia College of Physicians and Surgeons, 622 West 168th St, PH 1422, New York, NY 10032 (E-mail: hms2{at}Columbia.edu).


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background: We tested the hypothesis that sodium-hydrogen exchange inhibition attenuates ventricular dysfunction after ischemia-reperfusion injury in the intact porcine heart.
Methods: Twelve pigs (weight, 30-45 kg) were evenly divided into 2 groups. Baseline ventricular function studies were based on echocardiography, conductance, aortic flow, and left ventricular pressure. Animals were given vehicle (control) or benzamide-N-(aminoiminomethl)-4-(4-[2-furanylcarbonyl]-1-piperazinyl)-3-(methylsulfonyl)methanesulfonate (BIIB 513; 3 mg/kg administered intravenously). Ten minutes later, hearts were subjected to 75 seconds of ventricular fibrillation. After reperfusion for 40 minutes, function studies were repeated. Hearts were arrested and excised. Postmortem data included passive pressure-volume curves and myocardial water content.
Results: Preload recruitable stroke work was significantly decreased from baseline after ischemia and reperfusion in the control group (27.7 ± 2.5 vs 48.0 ± 5.6 mm Hg [± SEM], P = .001) but not in the BIIB 513 group (43.0 ± 5.8 vs 45.5 ± 4.1 mm Hg, P = not significant). In vivo diastolic and postmortem passive left ventricular compliance were reduced after ischemia and reperfusion for control animals but remained unchanged for animals receiving BIIB 513. Time required to recover baseline blood pressure after ventricular fibrillation was significantly longer for control animals (159 ± 15 vs 88 ± 14 seconds [± SEM], P = .008). Myocardial water content (78.97% ± 0.94% vs 77.86% ± 0.46% [± SEM]) and normalized left ventricular mass (137.24 ± 6.17 vs 128.41 ± 1.96 g [± SEM]) were insignificantly increased in control animals.
Conclusions: Sodium-hydrogen exchange inhibition attenuates ventricular dysfunction after 75 seconds of ventricular fibrillation and 40 minutes of reperfusion. This family of agents might prove useful in patients with severe left ventricular dysfunction undergoing ventricular fibrillation for implantable cardioverter defibrillator testing.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Implantable cardioverter-defibrillators (ICDs) are effective treatment for refractory malignant arrhythmias, decreasing the incidence of sudden arrhythmic death to 1% to 2% per year.Go Go 1-3 Insertion requires induction of ventricular fibrillation (VF) to measure defibrillation thresholds (DFTs). ICD recipients often have markedly decreased ventricular function caused by cardiomyopathy, infarct-related scars, or left ventricular (LV) aneurysms.Go 1 Although perioperative mortality for routine ICD insertion is low (0.5%-5%), eligibility has been expanded to patients formerly thought to be too ill (eg, patients with ventricular arrhythmias awaiting heart transplantation or patients with ejection fractions [EFs] of ≤10% or less).Go Go 3,4 DFT testing in some of these patients is considered too hazardous and is deferred. A small study from our laboratory revealed no mean change in intraoperative EF after ICD testing,Go 5 but there was considerable individual variation between patients. Also, cardiovascular collapse has been reported during ICD insertion and can occur without warning.Go Go 6-8 Animal studies have demonstrated significant decreases in cardiac output after repeated short intervals of VF,Go 9 whereas longer periods of VF resulted in profound heart failure.Go 10

A considerable body of literature supports the capacity of the sodium-hydrogen ion exchange inhibitors to attenuate ischemia-reperfusion injury after regional or global ischemia by using energy metabolites or infarct size as indices of ischemic damage. However, the ability of sodium-hydrogen exchange (NHE) inhibition to attenuate ventricular dysfunction after iatrogenic VF has not been reported. Inhibition of NHE during ischemia and reperfusion has been shown to attenuate myocardial damage,Go Go 11,12 reduce infarct size,Go Go 13,14 limit regional dysfunction,Go 15 and attenuate arrhythmias.Go 16 NHE protection after global ischemia has been studied as well in isolated heart preparationsGo Go 17-19 and in the setting of orthotopic transplantation of hearts harvested after normothermic ischemia.Go Go 20-22 Cariporide, a selective NHE inhibitor, has been shown to improve regional LV function in patients with acute myocardial infarction undergoing percutaneous transluminal coronary angioplastyGo 23 and was well tolerated by patients in the GUARDIAN trial,Go 24 which concluded that NHE inhibition could be beneficial in patients undergoing bypass surgery after infarction.

Consequently, we explored the possibility of pharmacologic protection from ventricular dysfunction in the setting of iatrogenic VF. We investigated the use of one of the newer members of the NHE family, benzamide-N-(aminoiminomethl)-4-(4-[2-furanylcarbonyl]-1-piperazinyl)-3-(methylsulfonyl)methanesulfonate (BIIB 513), a selective NHE-1 inhibitor, untested in human beings. Reagents were obtained from Boehringer Ingelheim Pharma KG (Biberach, Germany). We used a pig model because of the similarity of the porcine myocardium to the human myocardium and its susceptibility to myocardial ischemia.Go 25


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Overview
All animals received humane care 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, National Research Council, and published by the National Academy Press, revised 1996.

Twelve male domestic pigs weighing 32 to 45 kg were anesthetized with atropine sulfate (1-2 mg administered intramuscularly), ketamine hydrochloride (20 mg/kg administered intramuscularly), and acepromazine (0.5 mg/kg). They were intubated, mechanically ventilated, and maintained on isoflurane (1.5%-2.5%) mixed with 100% oxygen. A heating pad was used to maintain body temperature. Arterial blood gases and serum electrolytes were periodically checked to monitor oxygenation and optimize ventilation. During the experiments, 0.9% saline solution was administered through an 18-gauge angiocatheter in the femoral vein at 10 mL · kg-1 · h-1 for the first hour and then decreased to 5 mL · kg-1 · h-1 for the duration of the study, a protocol developed in collaboration with laboratory veterinarians at Columbia University.

After preliminary studies were performed in 2 animals to determine an interval of VF that would produce reproducible changes in ventricular function after 40 minutes of reperfusion, animals were divided into 2 groups (control group, n = 6; BIIB 513 group, n = 6). Baseline hemodynamic indices were taken before and after 75 seconds of VF and 40 minutes of reperfusion. Hearts were subsequently arrested and excised, and postmortem studies were performed.

Study protocol
In vivo studies
While the electrocardiogram (ECG) and peripheral blood pressure were monitored with a fluid-filled catheter (model 7758, 8-channel recording system, Hewlett-Packard), a median sternotomy was performed. The hemiazygous vein (which drains directly into the coronary sinus in pigs) was ligated, and a longitudinal pericardiectomy was performed. A snare was placed around the inferior vena cava. After systemic heparinization (100 U/kg), a calibrated 5F micromanometer pressure catheter (Millar Instruments) and a 5F dual-field 12-electrode conductance catheter with reversed configuration allowing apical placement (Millar Instruments) were placed into the left ventricle through a 4-0 prolene purse-string suture in the LV apex. The position of the conductance catheter was verified by means of 2-dimensional epicardial echocardiography to ensure that the tip was through the aortic valve and that contact of the electrodes with the endocardium was avoided. Final position was adjusted by inspection of the individual segment pressure-volume loops. By using an oscilloscope x/y plotter (Hewlett-Packard), counterclockwise rotation of each of the 5 individual pressure-volume segment loops ensured that each was within the LV cavity. Before data collection, a 6-mL arterial blood sample was collected to measure blood resistivity with the rho cuvette by using the Leycom Sigma- 5 conductance module (Cardiodynamics DV). A pericardial well was created by sewing a plastic sheet to the pericardium. The free edges of the sheet were brought out and draped over the opened sternum. The well was used to hold water-soluble echocardiography gel (Ultraphonic scanning gel, Pharmaceutical Innovations, Inc) around the heart during echocardiographic measurements. The gel was removed during conductance measurements. A 16-mm A-series transit time ultrasonic flow probe (Transonic Systems, Inc) was filled with acoustic coupling gel and placed around the ascending aorta. The probe was connected to a dual-channel flowmeter (HT207, Transonic Systems, Inc). Finally, a pliable latex insulator was placed under the heart to limit parallel conductance.Go 26

Echocardiograms were obtained (Vingmed CFM 800, GE Medical) for LV cross-sectional short-axis measurements and for LV volume determination by using a hand-held 5.0-MHZ ultrasound transducer. The pericardial well was filled with scanning gel (Ultraphonic scanning gel, Pharmaceutical Innovations, Inc) to provide a standoff between the epicardium and the ultrasound transducer. Echocardiograms, LV pressure measurements, aortic flow measurements, and ECGs were obtained in the steady state. Display of the ECG and calibrated LV pressure on the echocardiography system facilitated synchronization of echocardiographic frames with physiologic events.

After collection of baseline hemodynamic data (Table 1), pressure-volume loops were generated during preload reduction through caval occlusion. Before inferior vena caval occlusion, a 1-V deflection mark was recorded on the echocardiogram and on the digital data acquired on the computer to allow the synchronization of the echocardiogram, ECG, LV end-diastolic pressure value, and aortic flow value. After recovery of baseline blood pressure, inflow occlusion was repeated during simultaneous LV pressure and LV short-axis echocardiography recording with the conductance catheter turned off. After collection of baseline hemodynamic data, epicardial pacemaker leads were connected to the anterior surfaces of the right and left ventricles. Animals were then given 50 mL of 0.9% saline solution with or without 3 mg/kg BIIB 513 according to protocols developed for this drug to provide adequate drug levels 10 minutes after bolus injection.Go 27 Ten minutes later, VF was induced for approximately 75 seconds with a 13-V 800-mA alternating current through a transformer (Archer AC adapter, Radioshack; Figure 1). VF was terminated on cardioversion with 50 J by using the internal paddles of a defibrillator module (Hewlett-Packard). If cardioversion resulted in asystole, animals were paced (Medtronic 5375) at 60 beats/min until hearts regained an independent organized rhythm. This occurred in 4 of the 12 animals evenly distributed between groups. One animal given BIIB 513 had a fine VF that was unresponsive to cardioversion or pacing. This animal could not be resuscitated and was excluded from the study. After cardioversion, animals were allowed to recover for 40 minutes, and hemodynamic data and echocardiograms were again collected. At the beginning and conclusion of the experiment, a 10 mL-bolus of hypertonic saline (5%) was infused directly into the pulmonary artery for measurement of parallel conductance, as described below.


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  		Table 1. Hemodynamic data before and after ischemia and reperfusion
 


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  		Fig. 1. Representative ECG, LV pressure tracing, and LV flow from a pig before and during induced VF.

 
Postmortem studies
Hearts were arrested by means of infusion of 3°C University of Wisconsin solution into the aortic root after aortic crossclamping and transection of the inferior vena cava and left inferior pulmonary vein. Hearts were rapidly excised and placed in a 3°C ice slurry of University of Wisconsin solution. Postmortem pressure-volume relationships were obtained as follows. An 18-gauge anigocatheter connected to one port of a 3-way stopcock was placed through the previously performed LV apex purse-string suture. The left ventricle was sealed by placing atraumatic clamps at the atrioventricular groove approximately 2 mm above the mitral annulus. The clamp was positioned to minimize annular compression or other distortions of LV geometry that could induce artifacts.Go 28 LV pressures were measured through a second port of the stopcock by using the same 5F micromanometer, as previously used after recalibration. The third port of the stopcock was used for volume infusion. Before pressure measurements, all air was eliminated from the system. Volume was infused into the left ventricle in 5-mL increments, and micromanometer pressure was recorded at a sampling rate of 200 points per second by using an analog-to-digital conversion recording system (MacLab, ADInstruments, Inc). Volume was infused until an LV pressure of 20 mm Hg was reached. The infused fluid was withdrawn and measured to determine whether leakage had occurred. In all animals, 95% or more of injected volume was recovered, and therefore no data were excluded from the pressure-volume analysis on this basis. This procedure was performed in duplicate for each excised heart.

After pressure-volume data were collected, the aorta, pulmonary artery, and atria were removed, and fat was trimmed. Excised hearts were placed on a preweighed piece of aluminum foil and weighed on an analytic balance (H16, Mettler Instruments Corp) to obtain heart wet weight (WW). The hearts were then dried to a constant weight in a 60°C oven for over 48 hours and reweighed to obtain heart dry weight (DW). The percentage of myocardial water content (MWC) was calculated as follows: (1)
MWC (%) = ([WW - DW/WW]) x 100%

Data acquisition and analysis
Amplified pressure, conductance, and aortic flow were sampled at 200 Hz and transferred through a 16-channel analog-to-digital converter (MacLab, ADInstruments Inc) to a personal computer (IMAC, Apple Computer). Data were analyzed with the use of IGOR software (Wavemetrics, Inc). The total conductance signal was generated and processed in a Sigma 5 DF unit. The principles of conductance measurement of volume are described elsewhere.Go Go 29,30 Cumulative ejected volume determined by means of conductance and recorded during caval occlusion was plotted against the integrated aortic flow probe signal at each time point during ventricular ejection; gain was derived as the gradient of the linear regression. Correlation coefficients of the linear regression greater than 0.95 with a slope of the regression line within 0.3 of the line of identity (0.7-1.3) were accepted. Parallel conductance was calculated by a modification of the hypertonic saline injection method developed by Baan and associates.Go 30

Calculation of systolic function
Calculation of indices of systolic function during brief caval occlusion was performed with more than 8 consecutive cycles free of ventricular ectopy. All data were recorded with the ventilator off and measured at end expiration. For each cycle during caval occlusion, LV stroke work was calculated as the area of the pressure-volume loop. This was plotted against the end-diastolic volume. Preload recruitable stroke work (PRSW) was derived as the slope of the linear regression between stroke work and end-diastolic volume.Go 31 The greatest slope of the pressure-volume relationship throughout the cardiac cycle defined end systole, and the end-systolic pressure-volume relationship (ESPVR) defined maximum systolic elastance.Go 32

Calculation of diastolic function
The in vivo end-diastolic ventricular compliance curves were calculated in two ways. In the first method we used the conductance catheter to generate ventricular volumes as described above to create LV end-diastolic pressure-volume relationship (LV EDPVR) curves. In vivo LV EDPVR was obtained by superimposing the peak of the R wave of the ECG on the LV pressure and volume tracings. To enable comparison of animals of different sizes, LV raw volumes (V) were normalized to an average dry heart weight (W) of 28.74 g by using the following relationship:
(2)
Vn = V(28.74/W).
In the second method of calculating in vivo end-diastolic ventricular compliance curves, we used echocardiography (as described below) to generate LV pressure-normalized LV area relationships.

Postmortem LV passive pressure-volume relationships were compared between groups by using methods previously described.Go Go 33,34 Briefly, a compliance curve was generated for each animal by plotting cumulative volume-injected and measured LV pressure. LV volumes were normalized to dry heart weight.

Echocardiographic analysis
Images were digitized during real-time data acquisition by using the Vingmed CFM 800 echocardiography machine. End-diastolic short-axis cross-sectional images were planimetered by hand to obtain LV end-diastolic area.

Statistical analysis
PRSW was compared within groups before and after ischemia and reperfusion by using the Student t test. Comparisons between groups for hemodynamic data both before and after ischemia and reperfusion were made by using the Student t test. Pressure-volume curves and equations were generated by using Proc Mixed (SAS) methodology for repeated measurements. This method estimates the SEs by modeling the covariance structure of the repeated measures.Go Go 35,36 These measures are inherently correlated within the subject. Three of the more common covariance structures include compound symmetry for correlations that are constant for any 2 points in time, autoregressive order one for correlations that are smaller for time points further apart, and unstructured, which has no mathematic pattern within the covariance matrix. It was found that the autoregressive order one covariance structure provided the best fit for the postmortem data. This was discerned by means of comparing log likelihoods and the respective degrees of freedom for a given 2 models at a time.

For the in vivo data, a logarithmic transformation of all pressures was performed to exponentiate the data and provide the best fit. A significant interaction term was the requirement for statistically significant difference among the groups. For the postmortem data, a cubic polynomial function was fitted. P values were not corrected (eg, Bonferonni) for the multiplicity of testing. All data were analyzed by using SAS system software (SAS Institute Inc).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Data for changes in PRSW are shown in Table 2 and Figure 2. PRSW for control animals was significantly reduced from baseline after ischemia and reperfusion (27.7 ± 2.5 vs 48.0 ± 5.6 mm Hg [± SEM]; P = .001, paired Student t test) but not in the BIIB 513 group (43.0 ± 5.8 vs 45.5 ± 4.1 mm Hg, P = not significant). PRSW after ischemia and reperfusion was significantly different between the 2 groups (P < .04, unpaired Student t test). The x intercept of the PRSW relationship did not change significantly after ischemia-reperfusion injury within or between groups. Data for changes in EF are shown in Table 2Go. Average baseline EF (36.8% ± 5.2% for the control group and 33.4% ± 4.3% for the BIIB 513 group [± SEM]) was insignificantly reduced by ischemia and reperfusion in both groups (31.2% ± 5.1% for the control group and 32.7% ± 2.7% the for BIIB 513 group [± SEM], P = not significant). The average percentage change in EF showed trends toward decreased EF in control animals that fell short of statistical significance (-15.54% for the control group and +2.63% for the BIIB 513 group; P = .178, Mann-Whitney test). ESPVRs are reported in Table 2Go; preischemic values for the control and BIIB 513 groups (2.44 ± 0.6 vs 1.85 ± 0.3 mm Hg/mL [± SEM]) are not significantly different than postischemic values (1.54 ± 0.2 vs 2.77 ± 0.8), although trends suggested a decrease in ESPVR in the control group and an increase in the BIIB 513 group.


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  		Table 2. Ventricular function before and after ischemia and reperfusion
 


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  		Fig. 2. Effect of BIIB 513 on PRSW after ischemia-reperfusion injury. The ordinate represents averaged PRSW in millimeters of mercury, and the abscissa represents the time point in the experiment: PRE, baseline levels; POST, 40 minutes of reperfusion after VF. Filled squares and the dotted line represent values for the control group, and open squares and the solid line represent values for the BIIB 513-pretreated group. SEs are represented by brackets. Differences in PRSW for control animals after 40 minutes of reperfusion are significantly different from those of control animals' baseline levels and BIIB 513-pretreated animals after 40 minutes of reperfusion (P = .005, analysis of variance).

 
Data for changes in baseline hemodynamics are presented in Table 1Go. The average time required to recover baseline systolic blood pressure after VF was significantly longer for the control group when compared with that of the BIIB 513 group (158.75 ± 15 vs 87.5 ± 14.5 seconds [± SEM]; P = .008, Student t test). The average heart rate was also significantly decreased in the control group (69.17 ± 4 vs 83.4 ± 5.2 beats/min [± SEM]; P = .03. Student t test). Differences between the control and BIIB 513 groups in postischemic early peak systolic pressure (110 ± 8 vs 134 ± 11 mm Hg [± SEM], P = .076), cardiac output (1.47 ± 0.46 vs 1.98 ± 0.39 L/min [± SEM], P = .18) and peak systolic blood pressure after 40 minutes (72.3 ± 4.3 vs 89.6 ± 10.4 mm Hg [± SEM], P = .18) all reflected trends in decreased myocardial function in the control group but fell short of significance.

Data for in vivo end-diastolic pressure-volume (calculated by means of conductance) relationships are represented by Figure 3, A, and Table 3. Compliance reflected by the slopes of the LV compliance curves was significantly diminished from baseline after ischemia-reperfusion injury in the control group (0.021 ± 0.044 pre vs 0.039 ± 0.066 post; P = .013) but remained unchanged after ischemia-reperfusion injury in the experimental group (0.032 ± 0.004 pre vs 0.034 ± 0.0029 post; P = .594).



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  		Fig. 3. A, Effect of sodium-hydrogen ion exchange inhibition on in vivo EDPVRs (by means of conductance) after ischemia-reperfusion injury. The ordinate represents end-diastolic LV pressure (in millimeters of mercury), and the abscissa represents average end-diastolic volume (in milliliters) generated by means of conductance and corrected for parallel conductance normalized to 28 g of dry heart weight (DHW). Filled symbols represent control animals, and open symbols represent BIIB 513-pretreated animals. Squares represent baseline compliance, and circles represent compliance after ischemia and reperfusion. Values of the average slopes and SEs of the compliance curves are represented in Table 3Go. Ischemia and reperfusion in the control group led to a statistically significant increase in slope (P = .0128), demonstrating a decrease in compliance (smaller volumes at any given pressure), whereas for the BIIB 513 group, ischemia-reperfusion injury led to a statistically insignificant shift to the right (greater volumes at any given pressure). B, Effect of sodium-hydrogen ion exchange inhibition on in vivo end-diastolic pressure-area (by means of echocardiography) relationship after ischemia-reperfusion injury. The ordinate represents end-diastolic LV pressure (in millimeters of mercury), and the abscissa represents averaged end-diastolic area generated by means of echocardiography normalized to 28 g of dry heart weight (DHW). Filled symbols represent control animals, and open symbols represent BIIB 513-pretreated animals. Squares represent baseline compliance, and circles represent average compliance after ischemia and reperfusion. Values of the average slopes and SEs of the compliance curves are represented by Table 4Go. Ischemia-reperfusion injury in the control group led to a statistically insignificant shift to the left (lesser volumes at any given pressure), whereas in the BIIB 513 group it led to a statistically insignificant shift to the right (greater volumes at any given pressure).

 

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  		Table 3. Slopes of in vivo LV compliance curves (LV volume by conductance)
 

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  		Table 4. Slopes of in vivo LV compliance curves (LV area by echocardiography)
 
Data for in vivo end-diastolic pressure-area (calculated by echocardiography) relationships are represented by Figure 3Go, B, and Table 4. These data demonstrate a similar phenomenon, as observed when volume was measured by means of conductance (diminished compliance in the control group after ischemia-reperfusion injury); however, differences in the slopes of these compliance curves were not statistically significant: control pre 0.266 ± 0.05 vs control post 0.332 ± 0.080; P = .475; BIIB pre 0.295 ± 0.050 vs BIIB post 0.280 ± 0.060; P = .850).

Data for postmortem end-diastolic pressure-volume relationships are presented in Figure 4 and Table 5. The difference in slopes of the compliance curves (control: y = -0.892 + 0.313 vol - 0.002 vol2 + 0.0000315 vol3 vs BIIB: y = -0.621 + 0.195 vol - 0.002 vol2 + 0.0000315 vol3) was statistically significant and indicated that the control group had significantly lower volumes at any given pressure demonstrative of a loss in ventricular compliance.



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  		Fig. 4. Effect of BIIB 513 on postmortem passive pressure-volume relationship after ischemia-reperfusion injury. The ordinate represents averaged end-diastolic LV pressure, and the abscissa represents averaged LV volume normalized to 28 g of dry heart weight (DHW). Filled symbols represent values for control animals, and open symbols represent values for BIIB 513-pretreated animals. Curves are fit as a cubic polynomial function. Control animals had an averaged postmortem compliance curve, with a statistically significantly steeper slope (P = .0001) representing a decrease in compliance.

 

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  		Table 5. Formulas of postmortem LV passive pressure-volume curves
 
Data for myocardial water content and normalized LV mass are presented in Table 6. Water content and normalized LV mass in the control group (78.97% ± 0.94% SEM and 137.24 ± 6.17 g SEM, respectively) was increased when compared with that in the BIIB 513 group (77.86% ± 0.46% and 128.41 ± 1.96 g, SEM) but did not reach statistical significance.


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  		Table 6. Animal and heart weights and myocardial water content
 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study indicates that NHE inhibition preserves LV myocardial contractility and attenuates loss in LV compliance after 75 seconds of VF. This is reflected by significant differences in both systolic (PRSW) and diastolic indices (in vivo and postmortem compliance curves) before and after ischemia-reperfusion injury for control animals, whereas experimental animals' indices were unchanged. The protective effect of NHE inhibition is also reflected by greater time to recovery of baseline systolic blood pressure in control animals after VF and trends toward diminished postischemic cardiac output and peak systolic blood pressure in control animals. Additionally, the protective effect is supported by statistically insignificant decreases in EF and ESPVR and increases in myocardial edema and normalized LV mass in control animals when compared with animals receiving BIIB 513.

This study was designed to assess the effects of ischemia and reperfusion. Although electrical defibrillation can cause direct myocardial cell injury, leading to postischemic myocardial dysfunction, significant injury only occurs at energy levels far exceeding those used to reverse VF in the current study.Go 37 Negligible or no injury has been reported after single countershocks at energy levels comparable with those used in our study.Go Go 38,39

Clinically, NHE inhibition has been tested unsuccessfully for the prevention of myocardial infarction and mortality during percutaneous transluminal coronary angioplasty or surgical revascularization.Go 24 The present results suggest NHE inhibition could prove valuable for prevention of ventricular dysfunction during ICD insertion. The duration of VF used in the present study is longer than that usually used during ICD insertion but not outside the range previously reported.Go 8 Furthermore, normal baseline ventricular function in the animals used here contrasts markedly with the diminished function commonly observed in ICD recipients.

Mortality and morbidity during ICD insertion can be due either to LV power failure or acute myocardial ischemia related to underlying coronary artery disease. Although not widely reported, DFT testing might be deferred in the highest-risk patients rather than risking death or serious injury as a result of testing. The present results suggest that NHE inhibition could provide increased safety for DFT testing in ICD recipients both by ameliorating power failure and limiting ischemic injury. In contrast to cariporide, BIIB 513 is a relatively novel agent that has not yet been used in clinical trials nor has its effect on DFT testing been investigated. This would need to be done experimentally before clinical use for this indication. We speculate that the observed protective effect of BIIB 513 is likely the result of limitations of increases of intracellular calcium concentration during ischemia, resulting in reduced reperfusion-induced calcium overload. Because animals were subjected to repeated episodes of limited ischemia during preload reduction from caval occlusions, it is worth considering the possibility of a role for ischemic preconditioning and/or myocardial stunning in our experiment, although significant differences between animals protected by NHE inhibition and controls suggests that the drug itself played an important role in observed differences in ventricular function after ischemia-reperfusion injury.

Our porcine model appears more vulnerable to myocardial ischemia than other experimental models. Variable degrees of potentially reversible systolic dysfunction have been reported after resuscitation from cardiac arrest in animalGo Go 40-42 and humanGo 43 models; however, these ischemic intervals were considerably longer than 75 seconds. For example KernGo 42 demonstrated severe ventricular dysfunction after 10 to 15 minutes of VF in intact swine hearts. Animals were resuscitated with dopamine and epinephrine. By 24 hours, invasive and noninvasive measures of systolic and diastolic LV function had begun to improve. At 48 hours, all measures of LV function had returned to baseline levels.

The present results confirm that load-dependent indices of systolic ventricular function, such as EF and ESPVR, are less sensitive indices than PRSW. Trends in EF and ESPVR in our study, however, reflect a pattern consistent with the PRSW data and together provide convincing evidence that there is a sustained decrease in systolic ventricular function after just 75 seconds of VF in the healthy pig heart.

Although ischemia and reperfusion generally results in impaired diastolic function in the intact heart,Go 42 some contradictory evidence has been described in isolated hearts and trabeculae.Go Go 41,44 A recent study in the isolated rat heart demonstrated that NHE inhibition ameliorated ischemic contracture, prevented postresuscitation diastolic dysfunction, and favored earlier return of contractile function after 25 minutes of iatrogenic VF.Go 45 Previous studies in pigs have suggested that diastolic dysfunction is worse immediately after resuscitation and improves throughout the reperfusion period.Go 42 Ischemic contracture has been reported as a cause of reduced diastolic compliance, but the duration of ischemia in our study is too short to support this mechanism.

A comparison of the EDPVR from the postischemic in vivo studies and postmortem studies reveals curves of different shapes; in vivo data were fit to exponential curves, whereas postmortem data fit cubic functions better. This might be the consequence of differences in volume measurements (the conductance catheter was used in vivo, and direct volume infusion was used postmortem), or it might be the result of ischemic contracture resulting from the arrest or the ischemic period during calculation of the EDPVR. However, all postmortem studies were done within 15 minutes of cardiac arrest, whereas ischemic contracture does not occur in the pig heart, even after considerably longer periods of time.Go 48 A similar relationship in EDPVRs between the control animals and animals pretreated with BIIB 513 was evident in the postmortem studies compared with in the in vivo postischemic studies, suggesting that postmortem EDPVR accurately reflects in vivo changes in compliance.

Baseline effects of BIIB 513 administration on hemodynamics included a higher peak systolic pressure and heart rate compared with that in control animals, but these were not statistically significant (Table 1Go). The heart rate of experimental animals was also higher after 40 minutes of reperfusion, with comparable derived averaged stroke volumes (21 mL/beat for the control group vs 24.5 mL/beat for the BIIB 513 group). This difference might reflect an attenuated response to catecholamine stimulation in stunned myocardium. It might also be related to pre-existing differences between the 2 populations; the control animals had an average baseline heart rate of 62 ± 6 beats/min compared with 75 ± 4.5 beats/min in the BIIB 513 group, a difference that approached significance (P = .10, Student t test).

The only animal in our study that could not be resuscitated after induction of VF had been given BIIB 513. As described above, the animal had a fine VF that was not terminated on multiple attempts at cardioversion and from which the animal could not be paced. This deserves further consideration, along with the effect of NHE inhibition on DFT testing.

Limitations of this study include the lack of documented serum drug levels (despite following protocols previously demonstrated to provide adequate drug levels) and the use of anesthesia not commonly used during ICD insertion. Additionally, this study was performed in healthy animals, while often in the clinical arena ICDs are inserted in patients with severe cardiomyopathies. Consequently, future studies should focus on enhancing clinical relevance of these data by using cariporide (HOE642), which has already been demonstrated to be safe in human subjects, and by better simulating the anesthetic conditions under which ICD insertion is performed.


   Acknowledgments
 
We thank Dr Randolph W. Seidler, Boehringer Ingelheim Pharma KG; Dr Lee Huang; Mrs Ivelisse Castro; Ms May Deutsch; Ms Caroline Pitney; and Dr Mauricio Dawgs Garrido.


   Footnotes
 
*George H. Humphreys, II Professor of Surgery. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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