Ann Thorac Surg 2005;80:1408-1416
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Multiple Treatment Approach to Limit Cardiac Ischemia-Reperfusion Injury
James E. Davies, MD
a
,
Stanley B. Digerness, PhD
a
,
Cheryl R. Killingsworth, DVM, PhD
b
,
Corinne Zaragoza, MS
a
,
Charles R. Katholi, PhD
c
,
Robert K. Justice, PhD
b
,
Steven P. Goldberg, MD,
William L. Holman, MD
a
,
*
a Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
b Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
c Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama
Accepted for publication April 14, 2005.
* Address reprint requests to Dr Holman, University of Alabama at Birmingham, Birmingham, AL35294-0007 (Email: wholman{at}its.uab.edu).
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Abstract
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BACKGROUND: This study evaluates a multiple treatment approach (ie, pharmacologic preconditioning [diazoxide], sodium-proton exchange inhibition [cariporide], and controlled reperfusion) to improve the outcome from severe cardiac ischemia-reperfusion injury that occurs during a cardiac operation.
METHODS: Five groups of 10 pigs (group 1: control, group 2: diazoxide, group 3: cariporide, group 4: controlled reperfusion, and group 5: combination of diazoxide and cariporide-controlled reperfusion) underwent 75 minutes of left anterior descending occlusion, 1 hour of cardioplegic arrest, and 2 hours of reperfusion. Prior to occlusion, each group received an infusion of vehicle alone (ie, dimethylsulfoxide for the control and the controlled reperfusion groups) or vehicle with drug (ie, diazoxide or cariporide, or both for all other groups). Infarct size (primary outcome) was measured and was normalized to the region at risk. Regional function (secondary outcome) was measured using preload recruitable work area.
RESULTS: Infarct size as a function of area at risk was decreased by cariporide-controlled reperfusion, and combination treatment compared with the control group (14 ± 6%, 15 ± 8%, and 9 ± 4% vs 24 ± 9%; p < 0.02), and variation in infarct size was decreased by combination treatment compared with the controlled reperfusion group alone (p < 0.02). Recovery of systolic function during reperfusion significantly improved in the left anterior descending region in the cariporide and combination groups compared with the control, controlled reperfusion, or diazoxide groups (group-time effect, p < 0.05).
CONCLUSIONS: Combined use of controlled reperfusion, cariporide, and diazoxide decreases myocyte necrosis and loss of systolic function compared with an untreated control group. Combination treatment has the potential to improve the results of cardiac surgery, however further improvements are needed before clinical application.
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Introduction
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Perioperative myocardial infarction, defined as infarction due to ischemia that begins at some time after initiating anesthesia, is a major problem in cardiac surgery [1]. Studies that included large numbers of patients have shown unequivocally that perioperative myocardial infarction has an adverse effect on survival. In these studies, immediate survival is decreased by perioperative infarction and long-term survival is lower, especially in those patients who have a more extensive myocardial infarction or worse preoperative myocardial function [2–4]. A recent post-hoc analysis of data from the Warm Heart Trial confirmed the importance of perioperative myocardial infarction as an adverse influence on long-term survival [5], as did a post-hoc analysis of the Arterial Revascularization Therapy Study, which found elevations of CK-MB isoenzymes in a substantial proportion of patients after coronary artery bypass grafting for multivessel coronary artery disease. In this analysis, CK-MB isoenzyme elevation was an independent risk factor for late adverse events including death [6].
Our laboratory is defining a multi-treatment method to provide protection from perioperative ischemia-reperfusion injury that is additively greater than the protection afforded by any one of the treatments alone. The components of this therapy were chosen for their ability to improve intra-myocyte ion homeostasis and protect mitochondria from ischemia-reperfusion injury. A previous study from this laboratory demonstrated that cariporide (a Na+-H+ exchange inhibitor that improves intra-myocyte ion homeostasis during ischemia and reperfusion) and diazoxide (a mitochondria-specific adenosine triphosphate (ATP)-sensitive potassium channel [K+ ATP] opener that increases resistance of myocyte mitochondria to ischemia-reperfusion injury) used together additively improved mechanical function and decreased infarct size in an isolated perfused rat heart model of severe ischemia-reperfusion injury [7]. Another study from this laboratory found that improved recovery of intra-myocyte ion homeostasis is a mechanism for the benefit of controlled post-ischemic reperfusion with a warm hyperkalemic-hypocalcemic blood cardioplegia solution [8], and this finding was confirmed in a porcine model of severe regional ischemia-reperfusion injury [9].
These previous experiments led to the hypothesis that pre-ischemic treatment with a mitochondria-specific K+ ATP channel opening drug and a drug that blocks sarcolemmal Na+-H+ exchange, together with controlled post-cardioplegia reperfusion using a hypocalcemic and hyperkalemic blood-based solution provides myocardial protection from severe ischemia-reperfusion injury that is additively greater than the protection provided by the treatments used individually. The primary outcome measurement for this study was infarct size, with contractile function serving as a secondary outcome variable.
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Material and Methods
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Fifty adult pigs of both sexes (n = 10 pigs per group), ranging in weight from 37 to 68 kg were used in this study. The University of Alabama at Birmingham Institutional Animal Care and Use Committee approved the experimental protocols. This protocol met the requirements of the National Institutes of Health standards defined by the United States Department of Agriculture Animal Welfare Act. The pigs were anesthetized with intramuscular atropine (0.4 mg/kg), tiletamine HCL/zolazepam HCL (4.4 mg/kg), and xylazine (4.4 mg/kg). Anesthesia was maintained with sodium pentobarbital (0.05 mg/kg/hr) by continuous intravenous infusion. Animals were given intravenous lactated Ringer's solution, were intubated, and were mechanically ventilated with 100% oxygen. Skeletal muscle paralysis was achieved with a single dose of intravenous pancuronium (0.11 mg/kg) that prevented involuntary movement due to electrocautery use during exposure of the heart. Heart rate and blood pressure were continuously monitored to ensure that anesthesia was adequate, and additional doses of muscle relaxants were not given.
The right carotid artery and external jugular veins were cannulated for measurement of arterial blood pressure and infusion. Arterial blood gas values and electrolyte levels were maintained within the normal range during the experiment.
A median sternotomy was performed, and all animals were given heparin (10,000 units initially and 5,000 units every hour during cardiopulmonary bypass [CPB]). Aortic and right atrial cannulas were placed, and then snares were placed around the superior and inferior vena cava. Two pairs of piezoelectric crystals (Sonometrics Corporation, London, Ontario, Canada) were inserted into the wall of the left ventricle (one in the left anterior descending (LAD) coronary distribution [test region] and one in the left circumflex distribution [control region]). Each pair of crystals was 2 cm apart in the axis perpendicular to the specified coronary artery. A high-fidelity pressure tipped transducer (Millar Instruments, Inc, Houston, TX) was inserted into the left ventricle through the apex. Finally, an aortic root cannula and a pulmonary artery vent catheter were placed.
An initial preload recruitable work area (PRWA) measurement with the piezoelectric crystals was performed prior to the initiation of CPB. The technique was based on that described by Glower and colleagues [10] in 1988. Measurements were taken continuously over a 1-minute time interval (10 seconds baseline, 20 seconds with superior and inferior vena cava snares engaged, and 30 seconds recovery to baseline). Next, CPB was initiated at 2.2 L/min/m2 and 37° C. Dimethylsulfoxide ± drug intervention (ie, diazoxide or cariporide, or both) was given over a 10-minute period at a constant aortic root pressure of 70 mm Hg. At the conclusion of this 10-minute period, CPB was discontinued. A second PRWA measurement was taken in the same manner as previously described. Cardiopulmonary bypass was then reinstituted at 1.8 L/min/m2 and a suture ligature (0 silk) was placed around the proximal LAD artery (approximately 1.0 to 1.5 cm distal to the left main coronary artery). After 45 minutes of proximal LAD ischemia, the aorta was cross-clamped and cold (4°C) hyperkalemic, hypocalcemic blood cardioplegia solution was infused over a 3-minute period at a constant aortic root pressure of 70 mm Hg. Supplemental 1-minute cardioplegia doses were given every 15 minutes thereafter for a total of four doses of cold blood cardioplegia. The LAD occlusion was released after the third dose of cardioplegia to mimic surgical revascularization of an acutely ischemic region.
Reperfusion was initiated after 60 minutes of cardioplegic arrest and continued for a 2-hour period. All groups had infusion of blood or blood cardioplegia ([Na+] = 135 to 145 mM; [K+] = 20 to 25 mM [initial dose], or 8 to 10 mM [all other doses]; [Ca++;] = 0.1 to 0.2 mM; pH = 7.7 to 7.8) into the aortic root at a mean pressure of 70 mm Hg for the initial 5 minutes of reperfusion, which is explained as follows.
Three subsequent PRWA measurements were taken at 30, 60, and 120 minutes after initiation of reperfusion. As previously performed, the animals were weaned from CPB and were allowed to stabilize prior to each measurement. After 2 hours of reperfusion, the fifth and final PRWA measurement was made, then CPB was resumed, and the aortic cross-clamp was reapplied. The coronary vessels were cleared with 60 mL of normal saline infused into the aortic root. Left ventricular fibrillation was induced and the LAD snare was engaged again. Fast green dye (30 mL; 1% [Sigma, St. Louis, MO]) was infused directly into the aortic root. The heart was harvested and was immediately placed into an iced normal saline solution, and was then stored overnight. After 24 hours the heart was sliced in 1 cm transverse sections and incubated for 5 minutes in 1% triphenyltetrazolium. Tracings were made of the slices using a digitizer (SigmaScan, [SPSS, Chicago, IL]) to measure the total left ventricular wall area, the region at risk for ischemia, and the region of infarction.
The five groups of 10 pigs included the control group, a cariporide only group, a diazoxide only group, a controlled reperfusion group, and a group that received a combination of all three treatments. The control and controlled reperfusion groups received only dimethylsulfoxide during the initial aortic root infusion (vehicle control). Cariporide was infused into the aortic root at a concentration of 40 mol/L for 10 minutes at a constant pressure of 70 mm Hg. Diazoxide was infused into the aortic root at 50 mol/L for 10 minutes at a constant pressure of 70 mm Hg. The combination group received identical doses of cariporide and diazoxide as did the individual groups. At the onset of reperfusion, the controlled reperfusion and combination groups were given 5 minutes of hyperkalemic, hypocalcemic 37°C blood cardioplegia infused into the cross-clamped aortic root at 70 mm Hg. The control, cariporide, and diazoxide groups were given 5 minutes of normokalemic 37°C blood at the onset of reperfusion with identical conditions.
Preload Recruitable Work Area Analysis
Left ventricular pressure, surface electrocardiogram, and segment length data were recorded and then analyzed using custom algorithms based on PV-WAVE programming language (RKJ) (Visual Numerics, San Ramon, CA). The analysis methodology is based on the PRWA concept [10]. Stroke work and end-diastolic segment length were calculated for all cardiac cycles in a specified interval of as much as 1 second. This process began with an investigator (JED) examining the raw data to define acceptable beats and delete spurious beats (eg, premature ventricular contractions) from the analysis. Based on the waveforms chosen for analysis of each specific time point, the slope, x-intercept, and correlation coefficient for the stroke work–end-diastolic segment length relationship were computed using a linear regression function (Figs 1, 2).
From all the waveforms for time points 1 through 5, the maximum value for end-diastolic length (xmax) was identified for each experimental animal. Once the x-intercept, xmax, and slope values had been determined, the area of the triangle representing the PRWA was calculated using the equation below, with the upper value for the x-axis calculation arbitrarily set at 1.2*xmax [10]:
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Fig 1. (A) Data (pre-drug/pre-ischemia, left anterior descending region) used to calculate preload recruitable work area (PRWA) are shown. Complexes marked by an "X" on the zero line of the first derivative of left ventricular pressure with respect to time (DPDT) channel were used for analysis. (B) Loops depicting segment length (x-axis) versus left ventricular pressure (y-axis). (C) Pressure at end diastole was chosen by an automated process and displayed as a function of end-diastolic length (EDL). The maximum EDL identified during the experiment was identified as the xmax. The slope, xmax, and intercept were used to calculate PRWA. (3–4 and 7–8 = channels recording sonomicrometry crystal excursion; ECG = electrocardiogram; LVP = left ventricular pressure; SW = stroke work.)
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Fig 2. (A–C) Data from sample time number 2 (post-drug/pre-ischemia) are shown. (3–4 and 7–8 = channels recording sonomicrometry crystal excursion; DPDT = first derivative of left ventricular pressure with respect to time; ECG = electrocardiogram; EDL = end-diastolic length; LVP = left ventricular pressure.)
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The absence of recovery resulted in akinesis (PRWA = 0) or systolic bulging (PRWA < 0). The zero and negative values are meaningless as measurements of systolic function; therefore all values for PRWA 
0 were treated as missing values for the purposes of statistical comparisons.
Statistical Analysis
For analysis of the PRWA data, a mixed model analysis of variance was used. The observations were transformed by taking the natural log to stabilize the variance across groups. The correlation structure of observations during time within a subject was modeled as compound symmetry. The model contained factors for group, time, and the group-time interaction. Selected multiple comparisons within a single group during time and between groups at fixed times were made on the least squares means.
For the analysis of the infarct area data, the areas of the ventricle at risk for infarction and the infarct areas for each 1 cm slice were added. The percent infarcted area as a function of the area at risk was calculated as the ratio of infarction area divided by area at risk times 100. The infarct areas for the five groups were compared by means of a one-way analysis of variance. Multiple comparisons were made on the least squares means.
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Results
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Analysis of the excised hearts indicated that the areas of the left ventricle put at risk by LAD occlusion were similar for all groups (control group, 51 ± 9%; cariporide group, 49 ± 10%; controlled reperfusion group, 55 ± 9%; diazoxide group, 52 ± 9%; combination group, 51 ± 6%; p = not significant between all groups). Measurements of infarct area as a percentage of the area at risk show that combination therapy, cariporide alone, and controlled reperfusion alone significantly decrease infarct size compared with the control group in this model of severe regional ischemia and reperfusion (Table 1, Fig 3). The infarct area in the diazoxide treated animals was similar to the vehicle-only (control) group. The smallest infarct area was seen in the combination therapy group; however, the infarct area for this group was statistically similar to the infarct areas for the cariporide and controlled-reperfusion groups.
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Fig 3. The area of left ventricular infarction expressed as a percentage of the area at risk is shown for each heart, together with the group mean and standard deviation. • = individual/animals;  = group mean ± standard deviation. (Cont Rpf = controlled reperfusion.)
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Within group variance for the infarct area was compared between experimental groups (Table 1, Fig 3). The variance in the combination group was less than the variance in all the other groups. This difference in variance was statistically significant in all groups, except the cariporide group in which the variance was greater than in the combination group but did not attain statistical significance (p < 0.09).
Comparisons of PRWA showed substantial decreases in systolic function after ischemia and reperfusion in all the groups. Of note, the initiation of bypass and infusion of the test substances into the aortic root resulted in a decrease of systolic function that was uniformly spread across the experimental groups (ie, there were no significant differences between groups for PRWA measurement number 2) (Tables 2
, 3
and 4
, Figs 4, 5
showing pre-ischemic and post-ischemic PRWA measurements).
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Table 4. Comparison in Left Circumflex Region of Pre-Load Recruitable Work Area Versus Untreated Control Group at Time Number 2 (Post-Drug/Pre-Ischemia) and Time Number 5 (Post-Reperfusion), and Versus Combination Group at Time Number 5 (Post-Reperfusion)
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Comparisons with PRWA in the left circumflex distribution (Table 2, Fig 4) showed that recovery of PRWA was similar for all groups, and that the values for PRWA during reperfusion were similar for all groups. This was reflected by an analysis for group-time interaction that yielded p = 0.60.
Comparisons with PRWA in the left anterior descending distribution are shown in Table 3 and Figure 5. In contrast to the left circumflex region, the group-time interaction for the LAD region was statistically significant (p = 0.007). Statistical comparisons between all of the experimental groups for the LAD distribution at the end of the study (ie, comparisons at sample time 5 in table 5
and 6
) failed to achieve significance after accounting for the large number of comparisons.
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Table 5. Comparison in Left Anterior Descending Region of Pre-Load Recruitable Work Area Versus Untreated Control Group at Time Number 2 (Post-Drug/Pre-Ischemia) and at Time Number 5 (Post-Reperfusion), and Versus Combination Group at Time Number 5 (Post-Reperfusion)
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Table 6. Comparison of Pre-Load Recruitable Work Area at Time Number 2 (Post-Drug/Pre-Ischemia) Versus Time Number 5 (Post-Reperfusion) in Left Anterior Descending Region
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Comment
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As summarized in the introduction, perioperative myocardial infarction remains an important problem that limits short and long-term survival in cardiac surgery. The increasing challenging patient population that is referred for surgery suggests that the problems posed by perioperative myocardial ischemia and infarction will only grow in magnitude, and that development of methods to increase the resistance of the heart to severe ischemia-reperfusion injury is warranted [11].
Our laboratory is focusing on methods that protect mitochondria and improve intra-myocyte ion homeostasis after severe ischemia-reperfusion injury. The goal is to define a group of treatments with independent mechanisms of action that when used together provide a degree of protection that is additively greater than the protection from the treatments used individually. The choice of methods is based on previous research that produced the following findings. First, maintaining intra-myocyte ion homeostasis is one mechanism for the benefit of controlled post-cardioplegia reperfusion [8]. Second, protection of mitochondria from ischemia-reperfusion injury by opening mitochondrial K+ ATP channels results in improved intra-myocyte ion homeostasis after ischemia-reperfusion injury [9]. Third, pharmacologic blockade of sarcolemmal Na+-H+ exchange limits the gain in intra-myocyte Na+ that otherwise occurs after ischemia and reperfusion [12] and is protective against ischemia-reperfusion injury. The treatments used in this study were based on this information and include: controlled post-ischemic reperfusion with normothermic hypocalcemic and hyperkalemic blood cardioplegia, pre-ischemic treatment with diazoxide (ie, a drug that is specific to mitochondrial K+ ATP channels), and pre-ischemic treatment with cariporide (ie, a drug that is specific to the Na+-H+ exchanger).
The animal model for regional ischemia was chosen based on our prior research [[7, 9]. The aim was to cause an ischemia-reperfusion injury severe enough to create regional myocardial infarction and post-ischemic contractile dysfunction, but not so severe that the regional infarction and contractile dysfunction could not be improved by any means. The myocardium perfused by the left circumflex artery provided an internal control in this study that defined the injury caused by cardiopulmonary bypass and cardioplegic arrest.
In the present study, left ventricular infarct size (expressed as a percent of the left ventricle at risk) was decreased by Na+-H+ exchange inhibition, controlled post-cardioplegia reperfusion, and combined use of all three treatments. Diazoxide did not decrease the size of the left ventricular infarct compared with the vehicle-only control group, which is contrary to prior experiments in crystalloid-perfused isolated rabbit hearts [13]. The mean left ventricular infarct size was the smallest in the combination treatment group, but the infarct size in this group was statistically similar to those for controlled reperfusion and cariporide (range for p values: 0.13 to 0.18).
On examining the left ventricular infarct size data, it was apparent that the values for combination therapy were grouped in a relatively tight array. This suggested a protective effect that was more consistent than in the other groups. Statistical evaluation found that infarct size variance in the combination therapy was significantly lower (p < 0.05) for the combination group than the control group, the controlled reperfusion group, and the diazoxide group. Variance of infarct size was lower in the combination group than in the cariporide group, but this difference did not attain statistical significance (p = 0.09).
Recovery of systolic function in the left circumflex region during the course of reperfusion was similar for all of the experimental groups (ie, group-time interaction did not attain significance). The absence of improvement in the combination group for this region is consistent with our prior finding that a less severe ischemic injury obscures the additive benefits of multiple therapies, whereas a more severe ischemic injury displays the limits for single agent treatment as well as the benefits of multiple agent treatment [7]. It is important to note that at some point ischemic injury becomes so severe that multiple agent treatment becomes ineffective. Thus, a realistic goal is to increase myocardial resistance to ischemia-reperfusion injury and reduce the incidence and severity of perioperative myocardial infarction, but it is impossible to eliminate morbidity and mortality from a sufficiently severe ischemia-reperfusion injury.
Within the left anterior descending region, the combination therapy and cariporide groups displayed a better pattern for recovery of systolic function (ie, PRWA) than the other groups during the course of reperfusion (Fig 3). The effect of cariporide on myocardial contractile function (ie, myocardial stunning) remains controversial; however, this study and another recent one [14] indicate that blockade of the sodium-proton exchange mechanism improves post-ischemic stunning.
This study shows that myocardial infarction size and post-ischemic loss of contractile function can be favorably influenced in a model mimicking clinical cardiac surgery and suggests that increased protection can be achieved against severe ischemia-reperfusion injury by combining the three treatments used in this study. Nevertheless, the outcome of pre-ischemic treatment with diazoxide was disappointing in view of our prior research [7] as well as the research of others [13, 15–19]. The reasons for this finding are unclear, but it may reflect a competing preconditioning effect due to the anesthetic drugs or the surgery itself, or possibly the effect of sanguineous perfusion. In order to be effective, this arm of the multiple treatment plan may require a different dose of diazoxide, a different drug to open the mitochondrial K+ ATP channel, or another intervention to augment the effect of mitochondrial K+ ATP channel modulation (perhaps stabilizing the mitochondrial transition pore [20–22]).
Studies by other groups that evaluated combined treatments for cardiac ischemia-reperfusion injury have not reached consensus, and the concept of achieving additively greater protection from ischemia-reperfusion injury with multiple treatments remains controversial. In 2000, Hale and Kloner [23] failed to show an additive effect from cariporide and diazoxide on infarct size in rabbit hearts subjected to 30 minutes of regional ischemia. However, the smallest infarcts in this experiment were seen in the combined treatment group, and there were large variations of infarct size for the control and diazoxide groups. It is important to note that independent mechanisms have been demonstrated for preconditioning and sodium-proton exchange inhibition [24–27], which is a necessary condition for an additive combination effect to be possible. Furthermore, additive protection with the combined use of sodium-proton exchange inhibition and ischemic preconditioning has been achieved [28], and other investigators have successfully used pharmacologic preconditioning mediated by adenosine or diazoxide in combination with cariporide to provide superior protection [29, 30].
In the present study, sodium-proton exchange inhibition with cariporide decreased infarct size and improved post-ischemic contractile function. This is similar to the effects noted in clinical trials; this was also an important component for the benefit from combination therapy at least in this experimental model. The beneficial effect of controlled reperfusion on contractile function was less than the benefit of cariporide, but controlled reperfusion has the distinct advantage of being used after rather than before ischemia.
The problem of perioperative myocardial infarction remains an important one in cardiac surgery. It is encouraging to achieve reductions in infarct size together with improved systolic function in this model of severe ischemia-reperfusion injury. Furthermore, evidence that combination therapy provides a more consistent infarct reducing effect than treatment with any of the three methods used alone suggests that further refinements to this approach in ameliorating perioperative myocardial ischemia-reperfusion injury will improve morbidity and mortality in a severely ill group of cardiac surgical patients.
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R. M. Mentzer Jr
Invited commentary
Ann. Thorac. Surg.,
October 1, 2005;
80(4):
1416 - 1416.
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Top
Abstract
Introduction
= diazoxide; 
= controlled reperfusion; 
= combination; measurement events: 1 = prior to cardiopulmonary bypass; 2 = after aortic root infusion of test drug or vehicle, or both dimethyl sulfoxide; 3, 4, 5 at 30, 60, and 120 minutes after initiation of reperfusion.