© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration
Laboratory for Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, Rotterdam, Netherlands
* Corresponding author. Tel. (+31-10) 408 8029; Fax (+31-10) 436 5607; E-mail: verdouw@tch.fgg.eur.nl
Received 30 June 1997; accepted 25 August 1997
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: To test the hypothesis that mild hypothermia potentiates the cardioprotection afforded by ischaemic preconditioning so that infarct size limitation can be obtained after coronary artery occlusion (CAO) durations which exceed the cardioprotective range (>90 min) of either hypothermia or ischaemic preconditioning alone. Methods: Four groups of anaesthetized rats were subjected to different durations of CAO: (i) normothermia (N, 36.5–37.5°C, n = 29), (ii) normothermia+ischaemic preconditioning (N+IP, 15 min CAO followed by 10 min of reperfusion, n = 35), (iii) hypothermia (H, 30–31°C, n = 31) and (iv) hypothermia+ischaemic preconditioning (H+IP, n = 24). Infarct size (IA/AR) was determined after 3 hours of reperfusion using trypan blue to delineate the area at risk (AR) from non-risk region and nitroblue tetrazolium to delineate infarcted area (IA) from viable myocardium. Results: In N the CAO duration versus infarct size relation had a sigmoid shape with virtually no infarction occurring at 15 min CAO and 56±5% of the area at risk being infarcted at 30 min CAO reaching a plateau of 71±2% at 60 min CAO. Hypothermia produced a rightward shift of the relation resulting in an approximately 15 min delay in onset of infarction. Ischaemic preconditioning produced a similar reduction in infarct size (23±4%) at 30 min CAO compared to hypothermia (13±3%) but also limited infarct size at 45 min to 36±3% and at 60 min CAO to 50±3% suggesting a slowing of infarct progression. Neither intervention limited IA/AR produced by 120 min CAO. In H+IP, combined hypothermia and ischaemic preconditioning resulted in synergistic infarct size reduction so that at 45 min and 60 min CAO IA/AR was reduced to 17±3% and 23±3%, respectively, and even at 120 min CAO to 58±5%, which was significantly smaller than during normothermic control conditions (p<0.05 vs. N). Conclusion: Mild hypothermia limited IA/AR modestly but markedly enhanced the cardioprotection afforded by ischaemic preconditioning in the in situ rat heart so that irreversible damage produced by even prolonged coronary artery occlusions was limited.
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Several groups of investigators have recently reported that irreversible myocardial damage by a coronary artery occlusion can be limited by modest reductions in body core temperatures. For instance, Chien et al. [1]reported a steep relation between body core temperature in the temperature range between 35°C and 42°C and myocardial infarct size in rabbits subjected to a 30-min coronary artery occlusion, so that an increase of 1°C resulted in a 12% increase in infarction of the area at risk. Duncker et al. [2]observed an even steeper relation between body temperature and infarct size produced by a 45-min coronary artery occlusion in swine as infarct size increased with 20% of the area at risk with a 1°C increase in temperature in the range of 35°C to 39°C. Recently, Schwartz et al. reported that in dogs infarct size was modulated by epicardial temperature after coronary artery occlusions of 60 min [3]. Unexpectedly, we found similar infarct sizes in rats subjected to a 60-min coronary artery occlusion either at 30–31°C or to 36.5–37.5°C [4].
Ischaemic preconditioning is an alternative approach to limit myocardial infarct size produced by coronary artery occlusions, but it is ineffective for coronary artery occlusions exceeding 60–90 min [5, 6]. We have shown that ischaemic preconditioning exerts greater cardioprotection during 60 min coronary artery occlusions at 30–31°C than at 36.5–37.5°C [4], but information on the interaction of cardioprotection by mild hypothermia and ischaemic preconditioning and in particular its dependency on the duration of coronary artery occlusion, is lacking. In the present study we therefore investigated the cardioprotection by ischaemic preconditioning for coronary artery occlusions of different durations in anaesthetized rats with modest reductions in body temperature. Specifically, we tested the hypothesis that hypothermia potentiates the protection afforded by ischaemic preconditioning, so that cardioprotection could be obtained after durations of coronary occlusion that exceed the 60–90 min which have been described in normothermic animals [5, 6].
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Experiments in ad libitum fed male Wistar rats (
300 g) were performed in accordance with the Guiding Principles in the Care and Use of Animals as approved by the Council of the American Physiological Society and under the regulations of the Animal Care Committee of the Erasmus University Rotterdam.
2.1 Experimental groups
Fig. 1 depicts the 4 animal groups (comprising a total of 16 protocols) investigated in this study. Nine protocols were performed at normothermia (N, body temperature of 36.5–37.5°C) of which in 4 protocols rats were preconditioned with a 15-min coronary artery occlusion and 10 min of reperfusion (IP). Infarct sizes were determined after coronary artery occlusions varying between 15 and 120 min. Of the 7 protocols that were performed at hypothermia (H, body temperature of 30–31°C), ischaemic preconditioning was performed in 3 protocols. In all animals area at risk (AR) and infarcted areas (IA) were determined after 3 hours of reperfusion. Because lowering of body temperature was accompanied by a decrease in heart rate, we included an additional group of hypothermic animals (n = 7) in which heart rate was raised by atrial pacing to match that of the normothermic animals in order to exclude differences in heart rate as a confounding factor. Since hypothermia exerted its greatest protection during a 30-min coronary artery occlusion (30 min CAO), atrial pacing was performed only in the 30-min CAO protocol. The results of the 60-min CAO groups have in part been reported earlier [4]. In all groups body temperatures were maintained in the designated range throughout the entire experimental protocol, including preconditioning stimulus, sustained coronary artery occlusion and the 3 hours of reperfusion.
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2.2 Surgical and experimental procedures
Full details of the experimental procedures have been reported previously [4]. Briefly, rats were anaesthetized with pentobarbital (60 mg/kg) and intubated for positive-pressure ventilation (Harvard rodent ventilator, Hilliston, Mass, USA) with room air. A PE-10 catheter was positioned in the thoracic aorta for measurements of arterial blood pressure and heart rate (Baxter Diagnostic Inc.). A PE-50 catheter was positioned in the inferior caval vein for infusion of Haemaccel (Behringwerke AG, Marburg, FRG) a polygeline containing 145 mmol/l Na+, 6.25 mmol/l Ca2+, 5.1 mmol/l K+, and 145 mmol/l Cl– with a pH of 7.3±0.3 to compensate for blood loss during surgery. After intercostal thoracotomy, the pericardium was opened and a silk 6–0 suture was looped under the coronary artery for later production of coronary artery occlusion. Following laparotomy, a catheter was positioned in the abdominal cavity to allow intraperitoneal infusion of pentobarbital for maintenance of anaesthesia.
Rectal temperature was continuously measured with an electronic thermometer (Electromedics Inc.) and was maintained in the designated range by either heating pads or ice-filled packages. Except during production of coronary artery occlusion and reperfusion, the thoracotomy site was covered with aluminum foil to prevent heat loss from the thoracic cavity. In an earlier study [4]we verified the adequacy of this procedure in five rats in which simultaneous measurements of rectal and intrathoracic temperature showed no differences at baseline and at the end of a 60-min coronary artery occlusion.
Rats that fibrillated during ischaemia or reperfusion were allowed to complete the protocol when conversion to normal sinus rhythm occurred spontaneously within 1 min, or when resuscitation by gently thumping on the thorax or defibrillation with a modified battery of nine volts was successful within 2 min after onset of fibrillation. Occlusion and reperfusion were visually verified by appearance and disappearance of myocardial cyanosis.
2.3 Measurement of area at risk and infarcted area
At the end of each experiment, the heart was quickly excised and cooled in ice-cold saline before it was mounted on a modified Langendorff apparatus and perfused retrogradely via the aorta with 10 ml saline to wash out blood. After the coronary ligature was tightened, the heart was perfused with 3 ml Trypan Blue (0.4%, Sigma Chemical Co.) to stain the normally perfused myocardium dark blue and delineate the nonstained area at risk (AR). The heart was then frozen for 10 min at –80°C and cut into slices of 1 mm from apex to base. From each slice, the right ventricle was removed and the left ventricle was divided into the AR and the remaining left ventricle, using microsurgical scissors. The AR was then incubated for 10 min in 37°C Nitro-Blue-Tetrazolium (Sigma Chemical Co.; 1 mg per 1 ml Sörensen buffer, pH 7.4), which stains vital tissue purple but leaves infarcted tissue unstained. After the infarcted area (IA) was isolated from the noninfarcted area, the different areas of the LV were dried and weighed separately. Infarct size was expressed as a percentage of the AR. Animals in which AR was below 20% of left ventricular weight were excluded.
2.4 Data analysis and presentation
After the normality of the distribution of the data was established using the Kolmogorov–Smirnov test, the effect of temperature and ischaemic preconditioning on infarct size (IA/AR) were analyzed using parametric two-way ANOVA with IA/AR as dependent variable, and temperature and preconditioning as independent factors (Sigmastat, Jandel Scientific Software, San Rafael, CA, USA). When a significant effect was observed, post-hoc testing was performed using the unpaired t test. Haemodynamic variables were compared by two-way ANOVA for repeated measures followed by the paired or unpaired t test. Statistical significance was accepted if p<0.05. Data are presented as mean±SEM.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Mortality
Fourteen (2 in N, 1 in H, 3 in N+IP and 8 in H+IP) of the 149 rats that entered the study were excluded because of sustained ventricular fibrillation, while nine animals (1 in N, 3 in H, 5 in N+IP and 0 in H+IP) were excluded because of technical failure. In Fig. 1 the number of the animals in the individual groups that completed the study or had to be excluded have been presented.
3.2 Haemodynamics
Table 1 shows that at the onset of the sustained coronary artery occlusion there were no differences between the mean arterial blood pressures of N, N+IP, H and H+IP. On the other hand, hypothermia caused a 25% reduction in heart rate of both H and H+IP compared to N and N+IP. Consequently, the product of heart rate and systolic arterial blood pressure (double product) was approximately 25% lower in H and H+IP than in N and N+IP. The differences in heart rate and the double product between normothermic and hypothermic groups were maintained during the experimental protocol. Atrial pacing in the hypothermic animals, which was performed at 360 bpm, had no significant effect on mean aortic blood pressure (81±4 mmHg at spontaneous sinus rhythm versus 90±8 mmHg during pacing, p = NS). Consequently the double product of these animals (34 400±2400 beatsxmmHg/min) which underwent a 30-min CAO was not different from that of the comparative normothermic animals at spontaneous sinus rhythm (37 300±1700 beatsxmmHg/min).
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3.3 Infarct size
There were no significant differences between AR of the 16 experimental protocols (N, 58±2%; H, 53±2%; N+IP, 63±3%; H+IP, 58±3%). In N the relation between IA/AR and the duration of the coronary artery occlusion (CAO) followed a sigmoid curve with a sharp increase in IA/AR when CAO increased from 15 to 30 min (Fig. 2). A similar sigmoid relation with the same plateau was observed in H, but was shifted to longer coronary occlusion durations by approximately 15 min.
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=normothermia (36.5–37.5°C); 
=hypothermia (30–31°C); 
=preconditioning at normothermia; 
=preconditioning at hypothermia; IA=infarcted area; AR=area at risk. Data are mean±SEM. *p<0.05 vs. 
p<0.05 vs. The same figure (Fig. 2) also shows that ischaemic preconditioning limited IA/AR at both temperatures. However, it appeared that in the preconditioned animals there was a linear relationship between IA/AR and CAO over the CAO-range tested. For both IP+N and IP+H the slope was considerably less than for the steep part of N and H. Another striking feature was that hypothermia and ischaemic preconditioning at normothermia had no effect on infarct size produced by a 120-min CAO, but that ischaemic preconditioning in hypothermic animals limited IA/AR of IP+H compared to N (p<0.05). After 30 min CAO IA/AR of the 7 hypothermic animals that were paced at 360 bpm was 13±2% which was not different from the animals in H with spontaneous sinus rhythm which underwent the same CAO duration (13±3%).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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4.1 Temperature and infarct size
Previously we reported [4]that a decrease in body temperature to 30–31°C did not affect infarct size produced by a 60-min coronary artery occlusion in rats, which at first glance appeared to be at variance with observations in rabbits [1]and swine [2]that used 30 min and 45 min occlusion periods, respectively. We hypothesized that this could be due to the longer duration of occlusion in our study. The present study demonstrates that also in rats a decrease in body temperature of 6°C can profoundly decrease infarct size (at 30 min coronary artery occlusion) but that the delay in infarction (the time window of tissue salvage) is only 15 min. As a result the protective effect of hypothermia is lost when the coronary occlusion is maintained for 60 min. The present data therefore demonstrate that the duration of the coronary artery occlusion is an important determinant of the magnitude of protection by hypothermia, so that hypothermia is no longer effective when the infarct size–coronary occlusion duration relation has reached its plateau. In dogs, which have an extensive collateral circulation, infarct size still progresses at 60 min of ischaemia [8]and has therefore not reached its plateau, which may explain why hypothermia can reduce infarct size produced by a 60-min coronary artery occlusion in this species [3].
Hypothermia produced significant decreases in heart rate and hence the product of heart rate and systolic blood pressure. Earlier studies in dogs [9]have suggested that this double product at the onset of coronary occlusion is an important determinant of infarct size but more recent studies have failed to find such a role for the double product [2, 10, 11]. Nevertheless, in the present study we increased the heart rates of hypothermic animals subjected to a 30-min CAO (because hypothermia was most effective at this coronary occlusion duration) so that the double product was no longer different from that of the normothermic rats and observed that infarct size was still identical to that in hypothermic rats with bradycardia. These findings clearly show that other mechanisms must have been responsible for the hypothermia-mediated protection.
The mechanism by which temperature influences infarct size is uncertain. Cellular determinants of myocyte viability distal to a coronary artery occlusion are not fully understood but may include depletion of high-energy phosphate pools below a critical level (ATP<10% of normal) or damage to mitochondrial membranes and sarcolemma with altered ion homeostasis. Because many enzyme systems in mammalian membranes (including adenosinetriphosphatases) are temperature sensitive, a decrease in temperature might decrease infarct size through reduction of energy utilization with consequent slowing of high-energy phosphate depletion. In support of this hypothesis, Jones et al. [12]reported that a decrease in temperature of 3°C markedly slowed the rate of ATP depletion and lactate production in globally ischaemic isolated dog hearts. Furthermore, Ichihara et al. [13]reported that glucose utilization in both nonischaemic and ischaemic hearts was significantly reduced at 20°C and accumulation of lactate was reduced from that seen at 37°C, suggesting that the metabolic demand of hypothermic hearts is less than that of normothermic hearts. In addition, there is evidence that a decrease in temperature can decrease fluidity and, consequently, ion permeability of membranes [14, 15]. The latter mechanism has been implicated in the protective effect of hypothermia against calcium overload associated with the calcium paradox [15]and during reoxygenation following hypoxia in isolated perfused rodent hearts [16]. Finally, hypothermia also inhibits the Na+/Ca2+ exchanger by both a phase transition of membrane lipids [17]and by the temperature dependence of the exchanger protein [18], so that cooling may have reduced ischaemia-related calcium overload. Thus, potential mechanisms through which mild hypothermia decreases infarct size likely include decreased energy utilization, reduced acidosis, and/or maintained ion homeostasis during ischaemia and reperfusion.
4.2 Modification of ischaemic preconditioning by hypothermia
In contrast to hypothermia which only induced a modest rightward shift of the infarct size coronary occlusion duration relation, ischaemic preconditioning also decreased the slope of the relation. Thus, at 30 min CAO hypothermia and ischaemic preconditioning produced similar reductions in infarct size, whereas at 45 and 60 min CAO only ischaemic preconditioning resulted in significant infarct size limitation which was no longer present after 120 min of myocardial ischaemia. Interestingly the combination of hypothermia and preconditioning resulted in a synergistic cardioprotection, so that at 45 and 60 min CAO hypothermia potentiated the protection afforded by preconditioning. Moreover, at 120 min CAO infarct size was still smaller compared to normothermic control conditions, while either hypothermia or preconditioning alone failed to limit infarct size. The different effects of hypothermia and preconditioning on the slope of the occlusion time infarct size relation suggests a difference in mechanism of protection. However, the mechanism of potentiation is not readily explained. A contribution of activation of a neural pathway is unlikely because hexamethonium did not affect the enhanced protection of ischaemic myocardial preconditioning by hypothermia [4]. McClanahan et al. [7]reported that either mild hypothermia or adenosine deaminase inhibition alone had no effect on infarct size. In contrast, when these stimuli were combined, a significant reduction in myocardial infarct size was observed. Their findings are in agreement with the present study and suggest that body temperature, even when it does not alter infarct size by itself, can significantly modify the cardioprotective effects of other physiological or pharmacological interventions.
The present study was designed to investigate whether hypothermic and ischaemic preconditioning would result in a greater degree of cardioprotection than either modality alone. However, in the group in which ischaemic preconditioning and hypothermia were combined not only the prolonged coronary artery occlusion but also the preconditioning stimulus was applied under hypothermic conditions which may have blunted the intensity of this stimulus. This is supported by Dote et al. [19]who reported that ischaemic preconditioning was less effective at 25°C than at 38°C in reducing infarct size produced by a 45-min coronary artery occlusion in the rabbit heart. Their findings suggest that in the present study the synergistic action of hypothermia and ischaemic preconditioning may actually have been underestimated and would have been even more pronounced when the preconditioning stimulus would have been applied at normothermia.
4.3 Conclusions
The present study showed that lowering body temperature with 6–7°C limits infarct size produced by coronary artery occlusions in the rat heart but that limitation depends critically on the duration of the coronary artery occlusion. In contrast, ischaemic preconditioning resulted in cardioprotection over a larger range of coronary occlusion durations. Despite its modest effects on infarct size, 6–7°C hypothermia markedly potentiated the cardioprotection afforded by ischaemic preconditioning, so that a reduction in infarct size was still observed after a 120-min coronary occlusion.
Time for primary review 22 days.
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Acknowledgements |
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M.A. v.d. Doel is supported by grant (D96.024) of the Netherlands Heart Foundation. The research of Dr. D.J. Duncker has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences.
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