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Ann Thorac Surg 2001;72:1457-1464
© 2001 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, Mount Sinai School of Medicine/New York University, New York, New York, USA
b Department of Neurology, Mount Sinai School of Medicine/New York University, New York, New York, USA
c Department of Neurosurgery, Mount Sinai School of Medicine/New York University, New York, New York, USA
* Address reprint requests to Dr Hagl, Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Pl, New York, NY 10029, USA
e-mail: chagl{at}hotmail.com
Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.
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Abstract |
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Methods. Twenty-one pigs (27 to 31 kg) underwent 90 minutes of HCA at 20°C and were electively sacrificed at 6, 24, 48, and 72 hours, and at 7, 10, and 12 days after HCA, and compared with unoperated controls. In addition, 3 animals that had HCA at 10°C, and 3 treated with cyclosporine A (CsA) in conjunction with HCA at 20°C, were examined 72 hours after HCA. After selective perfusion and cryopreservation, all brains were examined to visualize apoptotic DNA fragmentation and chromatin condensation on the same cryosection of the hippocampus: fluorescent in situ end labeling (ISEL) was combined with staining with a nucleic acid-binding cyanine dye (YOYO).
Results. In addition to apoptosis, which was seen at a significantly higher level (p = 0.05) after HCA than in controls, two other characteristic degenerative morphological cell types (not seen in controls) were characterized after HCA. Cell death began 6 hours after HCA and reached its peak at 72 hours, but continued for at least 7 days. Compared with the standard protocol at 20°C, HCA at 10°C and CsA treatment both significantly reduced overall cell death after HCA, but not apoptosis.
Conclusions. The data establish that significant neuronal apoptosis occurs as a consequence of HCA, but at 20°C, other pathways of cell death, probably including necrosis, predominate. Although preliminary results suggest that the neuroprotective effects of lower temperature and of CsA are not a consequence of blockade of apoptotic pathways, inhibition of apoptosis nevertheless seems promising as a strategy to protect the brain from the subtle neurological injury that is associated with prolonged HCA at clinically relevant temperatures.
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Introduction |
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There is also increasing evidence that blocking apoptotic pathways pharmacologically can reduce neurologicalinjury after hypoxic-ischemic insults, including HCA [5]. To study the potential of this approach for use in cardiothoracic surgery, we undertook to examine the morphological changes in the hippocampus after prolonged HCA, and the time course of both apoptotic and necrotic cell death. We also did some preliminary studies to assess whether two strategies previously shown to reduce postischemic cerebral injury (use of lower temperature and treatment with cyclosporine A) would affect apoptosis or necrosis after HCA. These results should help us to understand better the mechanisms of cerebral injury after HCA, and may influence protocols for the use of potentially neuroprotective interventions in the future.
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Material and methods |
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Each animal underwent preoperative behavioral assessment, intraoperative hemodynamic and metabolic monitoring, as well as recording of quantitative electroencephalogram and somatosensory-evoked potentials (SSEP). Daily behavioral/neurological assessment was performed until elective sacrifice according to the protocol. To evaluate the time course of histological cerebral injury, 3 animals were sacrificed at each of seven time points: 6, 24, 48, and 72 hours, and 7, 10, and 12 days after HCA. For histopathological assessment, all brains were selectively perfused and analyzed by two different methods for a quantitative evaluation of the amount of neuronal cell loss and evaluation of cell morphology.
Perioperative management and anesthesia
Pigs were pretreated with intramuscular ketamine (15 mg/kg) and atropine (0.03 mg/kg) and were anesthetized with intravenous pentobarbital (20 mg/kg). After endotracheal intubation, they were ventilated with 50% oxygen and anesthetized with isoflurane (1% to 2%); ventilation was adjusted to maintain pCO2 at 40 mm Hg. Paralysis was achieved with intravenous pancuronium (0.1 mg/kg). All animals received cephazoline (15 mg/kg) intravenously.
Urine output was measured via a bladder catheter (Foley 8–10 F), and temperature probes were placed in the esophagus, rectum, and in the brain (via a small burr hole). A femoral arterial line was placed for pressure monitoring and blood sampling (pH, oxygen tension, carbon dioxide tension, oxygen saturation, base excess, hematocrit, hemoglobin, glucose, and lactate [Blood Gas Analyzer; Ciba Corning 865; Chiron Diagnostics, Norwood, MA]). A thermodilution catheter (Baxter Healthcare Corp, Irvine, CA) in the pulmonary artery allowed assessment of cardiac output.
Cardiopulmonary bypass and hypothermic circulatory arrest
After heparinization (300 IU/kg), nonpulsatile cardiopulmonary bypass (CPB) was instituted via a single cannula (26–28 F) in the right atrium, with return to the ascending aorta. The left ventricle was vented via the right superior pulmonary vein. Surface cooling was used in all animals, and the head was packed in ice in the 10°C group during HCA. For CPB, a membrane oxygenator (VPCML Plus; Cobe Cardiovascular Inc, Arvada, CO) was primed with a bloodless solution consisting of 1,000 cc 0.9% NaCl, furosemide (1 mg/kg), heparin (5,000 IU), and KCl (1.5 meq/kg). CPB was continued for 45 minutes to reach a deep brain temperature of 20°C or 10°C; pH during cooling was maintained at 7.4 ± 0.1, and pCO2 at 35 to 45 mm Hg, uncorrected for temperature (alpha-stat management). The CPB flow rate (initially 100 mL/kg) was adjusted to maintain a pressure of approximately 50 mm Hg during cooling. Before HCA, all animals received 0.5 g of methylprednisolone intravenously.
Myocardial protection during HCA was afforded by topical iced saline (approximately 4°C). Core and surface rewarming were continued to an esophageal temperature of approximately 35°C to 36°C, avoiding a temperature gradient exceeding 10°C between the perfusate and core temperature. During weaning from CPB, 3 to 5 mg/kg/min dobutamine was frequently utilized, and norepinephrine was occasionally necessary.
All pigs received intramuscular cephalosporine (15 mg/kg) as well as pain killers (buterophenol 0.1 mg/kg) for the first 3 postoperative days, and were kept in separated pens for the entire observation period. Animals that refused liquids orally during the first 24 hours were treated with intravenous fluids.
Low temperature and drug treatment protocols
HCA at 10°C
Three pigs underwent HCA at 10°C rather than 20°C for 90 minutes. All were sacrificed at 72 hours for histological evaluation.
Cyclosporine A
Three pigs were pretreated with 2.5 mg/kg cyclosporine A (CsA) (Novartis Pharmaceuticals Corp, East Hanover, NJ) before CPB, diluted in 100 mL 0.9% NaCl, administered over a 10-minute interval before HCA for 90 minutes at 20°C. Another 2.5 mg/kg CsA was given intravenously 1 hour after CPB. Postoperatively, all drug-treated animals received daily doses of 5 mg/kg CsA subcutaneously until elective sacrifice at 72 hours.
Behavioral score
From postoperative day 1 until elective sacrifice, all animals were scored on a gross behavioral grading scale by a physician blinded to the experimental protocol, as described in earlier reports [6, 7]. Daily scores were determined after inspections in the morning, at noon, and in the evening. A score of 9 is normal, and 0 indicates coma or death.
Cerebral perfusion/fixation
Cerebral perfusion was performed in anesthetized, ventilated pigs after systemic heparinization (300 IU/kg) and cannulation of the ascending aorta (16 F). The descending aorta was cross-clamped, and the right atrium opened. The aortic arch was initially flushed with 500 mL of ice-cold saline (perfusion pressure 120 to 150 cm H2O) over 3 to 5 minutes, followed by 1 L of ice-cold buffered formalin (4%) (Fisher Scientific, Fair Lawn, NJ) over 10 minutes. A second liter of ice-cold formalin was infused over 45 minutes, and a third liter over another 20 minutes. The brain was removed 30 minutes later and stored at 4°C in buffered formalin for 48 hours. During the whole perfusion procedure, the head was packed in ice to minimize postmortem metabolic changes and autodigestion.
Histopathological preparation
All brains were bisected in the sagittal plane, and a tissue block encompassing the left hippocampus was infiltrated with sucrose and processed for subsequent histological analysis as previously described [8].
ISEL/YOYO staining for detection of neuronal degenerative changes
Serial 10-µm-thick frozen sections were cut through the main body of the hippocampus to provide a representative survey of the CA1, CA2, and CA3 subfields. The details of histological preparation can be found elsewhere. Approximately 80 slides were prepared; every 10th section was taken for ISEL/YOYO staining, for a total of eight sections per animal. Sections from HCA animals were run simultaneously with sections from a normal, age-matched control pig. All sections were examined first by epifluorescence microscopy (Olympus AX-70, U-MFI/TRITC filter; Olympus, Melville, NY) to determine the number of apoptotic or other degenerative nuclei per section. Slides were then examined by laser confocal microscopy (Leica, TCS 4D; Leica Microsystems, Bannockburn, IL) to obtain high-resolution digital images of individual nuclei.
Identification of apoptotic and nonapoptotic neuronal degeneration in the hippocampus
Apoptotic nuclei were identified by bright green fluorescence of the nucleic acid-binding cyanine dye (YOYO) in a typical chromatin condensation pattern, combined with bright red in situ end labeling (ISEL) fluorescence, indicating DNA fragmentation. In general, apoptotic nuclei are small and highly condensed masses of YOYO-bright DNA, sometimes associated with a remnant of the cytoplasm, with some variability in the pattern of DNA condensation [9].
Two other degenerative neuronal phenotypes were also seen in the pig hippocampus after HCA, and arbitrarily designated as type 1 and type 2: these cells appear to maintain their normal size or are slightly enlarged, in contrast to the shrunken appearance of typically apoptotic cells. In general, type 1 cells also frequently displayed faint ISEL signals, while ISEL signals in type 2 cells were not detectable. In contrast to apoptosis, these two degenerative morphologies were never observed in the control hippocampus. All three degenerative neuronal cell types were counted for each individual hippocampal section as described below.
Quantitation of degenerative hippocampal neurons as identified by ISEL/YOYO staining patterns
An ocular grid was centered on the CA1–3 neuron lamina, and apoptotic, Type 1, and Type 2 degenerative nuclei found within or touching the grid were counted as previously outlined in detail. Data were averaged from the eight slides counted per animal and plotted for each time point.
Confocal microscopy
ISEL/YOYO-stained sections were examined by confocal microscopy using two independent channels to detect specific ISEL (BODIPY-TR-14-dUTP emission maximum, 625 nm) and YOYO (emission maximum, 509 nm) fluorescence, as previously described [8].
Animal care
All animals received humane care in compliance with the guidelines of "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH Publication No. 88-23, revised 1996). The Mount Sinai Institutional Animal Care and Use Committee approved the protocols for all experiments.
Statistical analysis
ISEL/YOYO counts of degenerative nuclei were carried out by observers blinded with regard to the treatment groups. The nonparametric Mann-Whitney U test was used to analyze the data. A value of p 
0.05 was considered significant. Analyses were performed with Statistica software (Statsoft, Tulsa, OK) for Windows.
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Results |
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Apoptotic cells
The first type of dying cell we observed is shown in Figures 2A1 and 2A2, and is a classic picture of apoptosis. Apoptotic neurons were defined by simultaneous YOYO and ISEL staining of a highly condensed nucleus. In general, apoptotic cells were characterized by small, round nuclei, sometimes with an accompanying remnant of a highly condensed cell soma. This cell type was the only one found in control pigs (who had not undergone circulatory arrest), consistent with the concept that apoptosis is involved in the homeostasis of tissues under normal circumstances.
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Type 1 degenerative cells began to appear at 6 hours, and continued to increase until 72 hours, but were only rarely seen thereafter (Fig 3). The level of Type 1 cells was significantly higher than normal at 6, 24, and 72 hours (p = 0.05), and marginally higher at 48 hours (p = 0.19).
Type 2 cells
The third cell type (Fig 2C), arbitrarily designated Type 2, also displayed YOYO-bright condensation. Typically, the condensed bodies in Type 2 cells displayed irregular or rough edges, and no detectable ISEL signal. The rough-edged condensed bodies within Type 2 cells were of similar size, and were organized into an area reminiscent of the cell nucleus, filling much of the cell. Usually (in more than 90% of cells examined), the nuclear membrane no longer appeared intact.
Type 2 cells, which may represent orthodox necrosis, began to appear in samples occasionally at 6 hours (Fig 3), but reached a peak at 72 hours. Type 2 cells were still seen 7 days after HCA and even later; their density was significantly above normal throughout the period of observation (p = 0.05).
Summary of the effect of 90-minute HCA at 20°C on all degenerative hippocampal neurons)
It is important to note that while there is a baseline level of apoptotic cell death normally observed in the hippocampus, there was no evidence of Type 1 or Type 2 neurodegenerative changes in control pigs in the absence of HCA. From Figure 3, it can be seen that there was an increase in the number of all three categories of cells in the first 72 hours after HCA at 20°C; all neurodegenerative cell types were significantly higher than controls but for the two exceptions previously noted. In the second week after HCA, only the Type 2 cells remain elevated; there was no significant difference in the number of apoptotic or Type 1 degenerative neurons at 7, 10, or 12 days compared with baseline control values (p = 0.19 to 0.51).
In Figure 4, we have plotted histograms of each individual type of cell death on a linear time scale. By calculating the area under each curve, extrapolating between known time points, we can estimate the overall contribution of each kind of cell death to the total. In the case of apoptosis, we have subtracted the control level of apoptosis from each measurement. If one includes all 12 days of surveillance, this calculation suggests that apoptosis accounts for 21% of total cell death, with an estimated 39% contributed by each of the other two patterns. If one looks only at the first 3 days (when most of the cell death occurs and during which one would hope to intervene) apoptosis accounts for about 29% of the whole, Type 1 cell death for 45%, and Type 2 degeneration for 25%.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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In addition to new or modified perfusion techniques, a number of pharmacological agents have been tested in small animal models of focal and global ischemia, and have revealed promising neuroprotective properties. Although behavioral testing [1] and functional outcome are obviously important, histopathology is still considered the gold standard for showing the benefit of neuroprotective strategies on the brain. During the last few years, such studies have evolved from simply counting dead cells in a defined area to a more sophisticated description and analysis of the way in which a neuronal cell is damaged after ischemia. Delayed cell death via apoptotic pathways is of special interest because of the potential for intervening in this process.
In the past, we were able to demonstrate that our chronic model of prolonged HCA revealed a good correlation between behavioral scores, neurophysiological recovery [7], and the presence or extent of histological damage in the brain [15]. However, histopathology was only analyzed semiquantitatively and therefore was not always sensitive enough to show subtle damage. More recently [9], using improved methods of perfusion-fixation and more sophisticated analysis, we have observed that HCA initiates a series of events that ultimately leads to neuronal death via a typical apoptotic pattern. Current analysis is performed using ISEL or TUNEL to detect DNA fragmentation and concomitant staining with the nucleic acid-binding dye YOYO to allow visualization of apoptotic chromatin condensation in the same nucleus [8]. Chromatin condensation is a reliable marker of apoptosis, whereas DNA fragmentation can be observed in both apoptosis and necrosis [16].
But although classic evidence of apoptosis is undeniably present after HCA, further analysis in the current study has revealed a variety of chromatin condensation patterns, ranging from typical examples of classic highly condensed apoptotic nuclei to cells with a large nuclei containing multiple, smooth-surfaced chromatin condensations, and including cells with multiple rough-edged condensation patterns. Other observers of experimental hypoxic-ischemic damage (in neonatal pigs [3], as well as after HCA in a canine model [17]) have also noted multiple different patterns of cell damage and death in the brains they have analyzed (looking for evidence of apoptosis) by a multiplicity of methods, including electron microscopy. A consensus seems to be developing that cerebral injury after HCA results from at least two different pathways, corresponding to orthodox descriptions of necrosis and of classic apoptosis. In addition, most observers have seen some seriously damaged cells that fall into neither pattern.
For the purpose of trying to characterize our observations in the current study, we have classified the moribund cells as apoptotic, Type 1, and Type 2. At present, we are reluctant to further classify the Type 1 and Type 2 neurodegenerative patterns as ischemic or necrotic or apoptotic-necrotic because ISEL/YOYO staining alone does not allow us to draw conclusions regarding the involvement of specific gene expression programs or the lack of such involvement. However, we speculate that Type 1 may bear some resemblance to the ischemic death morphology described in a comprehensive review by Lipton [18], and Type 2 cells seem to have chromatin condensation patterns similar to those described by Wyllie and colleagues in necrotic cells [19]. We are convinced that all three types of neuronal degeneration can contribute to functional impairment after HCA, and our estimates of their relative contribution to total cell death indicate that these other neurodegenerative mechanisms may play a major role and therefore deserve further scrutiny.
From the results of our analyses, it would seem that the brain starts to exhibit serious cell injury as early as 6 hours after HCA, and that this process continues for at least 72 hours. At least some of the cell death observed in this model of HCA is unequivocally via an apoptotic pathway. If more subtle injury results in a greater proportion of damaged cells being shunted into apoptosis (as others have suggested), these experimental conditions may actually underestimate the contribution of apoptosis to cerebral sequelae after HCA: the 90-minute 20°C model was designed to result in more severe cerebral injury than is usually seen in clinical practice, in which HCA is carried out at lower (and presumably more neuroprotective) temperatures, and for shorter intervals.
The idea that lower temperature during prolonged HCA is more neuroprotective derives from experimental studies that show more complete suppression of metabolism and electrophysiological activity at more profound levels of hypothermia, better functional recovery in survival models, and fewer conventional histological changes in the brain. Clinical studies [10] also support the use of temperatures colder than the 15°C to 18°C range commonly considered adequate, but surgeons have been reluctant to use colder temperatures in part because of concern about possible counterproductive cold injury to the brain. The current study adds convincing albeit preliminary data to suggest that a temperature of 10°C is better than 20°C from the standpoint of neuronal cell death. These data also support the idea that milder cerebral injury is associated with a higher proportion of apoptosis than necrosis: 72 hours after HCA at 10°C, the density of apoptotic cells was essentially undiminished from levels after HCA at 20°C, but dying cells of the other two types were significantly less prevalent, and, in fact, were only rarely seen.
In contrast to findings from the comparison of HCA at two different temperatures, the results of the studies with CsA were surprising. We initially chose to explore the use of CsA because of evidence that it might inhibit apoptosis. In an earlier study of long-term survivors of the same 90-minute 20°C HCA protocol, CsA improved behavioral recovery [6]. But when we looked for apoptosis 7 days after HCA, we saw no differences between CsA pigs and untreated controls [9]. We speculated that we had missed the peak of apoptosis, and anticipated that we would find a reduction in apoptosis with CsA treatment if we looked at an earlier time point.
But in the current study, the level of apoptotic cells remained significantly above baseline levels in CsA-treated animals even 3 days after HCA compared with untreated controls. There was, however, a significant overall diminution of hippocampal cell death in CsA-treated animals. As with lower temperature during HCA, the chief impact of CsA seems to have been in preventing Type 1 and Type 2 cell death; such cells were rare in CsA-treated animals after HCA. Therefore, although CsA was chosen because of its reported ability to interfere with apoptosis, it seems likely to have exerted its neuroprotective effect by some other (possibly antiinflammatory) mechanism. We have previously shown that CsA can reduce intracranial pressure during reperfusion and rewarming after HCA, and this may have played a positive role. So although our results with CsA are encouraging and support the idea that pharmacological strategies may hold out considerable promise for improving cerebral recovery after HCA, the evidence suggests that it is unlikely that CsA acts specifically by inhibiting apoptosis.
Logic dictates that any drug aimed at improving cerebral recovery should be administered before HCA, and this study suggests that treatment with antiapoptotic drugs should continue for at least 72 hours. Although the peak of apoptosis seems to occur earlier, histological assessment at 72 hours allows evaluation and inclusion of the other types of cell death involved in cerebral injury after HCA. The 3-day time point also permits assessment of behavioral recovery after HCA in this survival model, reinforcing histological evidence of the success or failure of different neuroprotective strategies.
Other investigators have been more successful than we in demonstrating that reduction of apoptosis is associated with enhanced functional recovery after HCA. Baumgartner and his group, in a canine model involving HCA for 2 hours at 18°C [17], have shown that inhibitors of glutamate excitotoxicity and subsequent nitric oxide activation can reduce apoptosis after HCA and enhance cerebral recovery. Our finding of undiminished apoptosis despite improvement in outcome after HCA (both with lower temperature and with cyclosporine A treatment) suggests that the optimal hope for the future may involve combining inhibition of apoptosis with other strategies that act on different pathways leading to neuronal injury.
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