Eur J Cardiothorac Surg 2001;19:493-499
© 2001 Elsevier Science NL
Differential effect of preconditioning on post-ischaemic myocardial performance in the absence of substantial infarction and in extensively infarcted rat hearts
A. Efstathiou,
S. Seraskeris,
C. Papakonstantinou,
A. Aidonopoulos,
A. Lazou
Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece
Received 20 November 2000;
received in revised form 19 January 2001;
accepted 24 January 2001.
Corresponding author. Tel.: +30-31-99-83-81; fax: +30-31-99-83-31
e-mail: lazou{at}bio.auth.g
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Abstract
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Objectives: There is controversy concerning the beneficial effects of ischaemic preconditioning during short periods of ischaemia (stunning). The aim of the study was to investigate post-ischaemic myocardial performance after various periods of ischaemia in both non-preconditioned and preconditioned hearts and to compare these results with infarct volume estimation. Methods: Isolated perfused rat hearts were subjected to various periods of sustained ischaemia (15, 20, 30, and 45 min). Haemodynamic parameters, infarct size and lactate dehydrogenase (LDH) leakage were recorded in both preconditioned and non-preconditioned hearts. Results: After 15 min of ischaemia, preconditioned hearts revealed significantly lower developed pressure than non-preconditioned hearts (80±4.1 vs. 95±0.3%, P=0.02). In the 20 min ischaemia group, preconditioning resulted in non-significantly lower developed pressure (76±3.1% in preconditioned hearts vs. 87±5.3% in non-preconditioned hearts, P=0.11). In these groups infarct volume was small and not different between non-preconditioned and preconditioned hearts. After 30 min of ischaemia, preconditioning significantly improved developed pressure (66±3.1% in preconditioned and 44±5% in non-preconditioned hearts, P=0.002). LDH leakage was significantly higher in non-preconditioned hearts compared with preconditioned hearts (16±2.3 vs. 9.0±1.3, P=0.04), whereas infarct volume was not (12.5±0.8 and 9.8±1.5, respectively, P=0.1). Non-preconditioned hearts of this group, subjected to inotropic stimulation at the end of reperfusion, responded poorly. Significantly higher developed pressure was attained by preconditioned hearts (150±3.1 vs. 123±7.5%, P=0.01). After 45 min of ischaemia, preconditioning resulted in 69% limitation of infarct volume (P<0.0001) and 53% reduction in LDH release (P=0.009). Developed pressure was 57±8.5% in preconditioned hearts and 32±4.5% in non-preconditioned hearts (P=0.02). Conclusions: When ischaemic insult results in minimally lethal injuries, preconditioned hearts do not have the advantage of not being prone to stunning rather than non-preconditioned. If ischaemic insult is potentially able to produce extensive infarction, improvement in post-ischaemic myocardial function is mainly due to infarct size limitation evoked by preconditioning.
Key Words: Ischaemic preconditioning • Stunning • Infarct size • Rat heart
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1. Introduction
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Brief transient ischaemic episodes not capable of producing myocardial cell necrosis protect the heart against a subsequent more sustained ischaemic insult. This phenomenon is called ischaemic preconditioning [1]. The hallmark of this phenomenon is the reduction of infarct size observed in preconditioned hearts compared with that found in non-preconditioned hearts. This has been shown in a variety of experimental models and in many species [1–4]. In experimental models of regional ischaemia, the beneficial effects of preconditioning, in relation to the reduction of infarct size, were evident when the duration of ischaemic insult was about 30–90 min and disappeared when this time exceeded 3 h [1]. However, in models of global ischaemia, this period seems to be shorter [2]. Thus, myocardial ischaemic preconditioning does not prevent cell necrosis but rather protects the heart by delaying myocyte death. The delay time varies among different experimental models and species from 10 to 20 min [2,3]. Irreversible injuries of myocardium appear approximately after 20 min of ischaemia [3,5].
Whereas diminution of infarct size by ischaemic preconditioning is well accepted, protection against stunning is controversial. For example, P
rez et al. [6] demonstrated that preconditioning reduces myocardial stunning in isolated rat heart. This is in contrast to the results obtained from other experimental models of global ischaemia [2,7]. Furthermore, in in vivo models, preconditioning failed to improve recovery of regional contractile function of viable but stunned myocardium [8–10]. Thus, the question of whether preconditioning improves post-ischaemic contractile function both when the infarct size is negligible and when severe irreversible damage of myocardium is present still remains.
One experimental approach that could clarify this issue includes assessment of post-ischaemic myocardial performance accompanied by infarct size estimation. For that purpose we used a model of global ischaemia of isolated rat heart where different periods of sustained ischaemia were applied. The haemodynamic performance of the heart during reperfusion was determined and correlated with the extent of infarct. The latter was assessed using both the determination of lactate dehydrogenase (LDH) leakage and the triphenyltetrazolium chloride (TTC) staining method.
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2. Material and methods
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2.1. Isolated perfused heart preparation
All animals received humane care in accordance with the Guidelines for the Care and Use of Laboratory Animals published by the Greek Government (160/1991) based on EU regulations (86/609). Male Wistar rats (250–300 g body weight) were anaesthetized by intraperitoneous injection of sodium pentothione (100 mg/kg). The chests of the rats were opened after intravenous administration of heparin (300 IU/kg) through the femoral vein. The hearts were rapidly excised and placed immediately in ice-cold perfusion buffer (0°C) before being mounted on a Langendorff apparatus. The ischaemic time between excision and mounting was less than 1 min. Hearts were retrogradely perfused in a non-working isovolumetric Langendorff mode at a constant hydrostatic pressure of 100 cm H2O during the entire duration of the experiments. Coronary flow varied during the reperfusion period according to left ventricular compliance alterations and to ischaemia-induced microvascular injuries and/or tone disturbances [11]. The perfusion medium was a non-recirculating oxygenated (95% O2/5% CO2) normothermic (37°C) Krebs–Henseleit bicarbonate (KHB) buffer. KHB buffer had the following ion concentrations (in mM): 25 NaHCO3, 4.7 KCl, 118.5 NaCl, 1.2 MgSO4, 1.2 KH2 PO4, 2.5 CaCl2 and 10 glucose (pH 7.4). The perfusion apparatus was water-jacketed to maintain a constant perfusion temperature of 37°C while during prolonged ischaemic periods the hearts were bathed in KHB buffer at 37°C.
To determine left ventricular pressure, a catheter with a latex balloon on its tip was inserted into the left ventricle through an incision in the left atrial appendage. The balloon was tied securely into place and filled with water to give an end diastolic pressure between 6 and 10 mmHg. The adjusted volume remained constant throughout the experiment. This allowed continuous measurement of left ventricular pressures and recording of their alterations on a fixed preload. The balloon was connected to a pressure transducer via water-filled polyethylene tubing. Left ventricular pressure and heart rate (HR) were monitored continuously and recorded on a computer. Coronary flow rate was determined by collecting the coronary effluent in a graduated cylinder.
2.2. Perfusion protocol
All hearts were allowed to stabilize for 20 min before undergoing any treatment. Baseline measurements were recorded during this period. Hearts were allowed to beat spontaneously throughout the experiment. Lethal arrhythmias, like ventricular fibrillation (VF) at the onset of reperfusion following the sustained ischaemic insult, were converted to normal rhythm by tapping the ventricle. Left ventricular function was assessed by end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP) and the product HRxLVDP. Developed pressure is defined as peak systolic minus end diastolic pressure. Functional recovery was expressed as a percentage of the individual stabilization values. Zero flow ischaemia was induced by clamping of the arterial line.
Preconditioned hearts underwent one cycle of 5 min of ischaemia and 10 min of reperfusion before the sustained ischaemic insult while the control hearts were perfused for another 15 min. Four series of experiments were performed using different periods of sustained ischaemia (15, 20, 30, and 45 min). The reperfusion time was 45 min for all series.
2.3. Infarct volume measurement
At the end of the reperfusion period, hearts were frozen in liquid nitrogen to facilitate slicing into 2 mm thick transverse sections across the long axis. All hearts were approximately the same size (1.2 cm, the atria and great vessels excluded) and therefore six slices were taken. Slices were incubated in 1% TTC in phosphate buffer (pH 7.4) for 30 min at 37°C. Tissue stained brick red was taken as viable and pale or white tissue was taken as necrotic. After the stained slices were photographed, photos were magnified (x4) and used for the estimation of infarcted tissue. The slices were also viewed under a stereoscope and traced on acetate paper. The area of left ventricle and the area of infarcted tissue were measured by planimetry from both the photographs and tracings independently and compared. Volumes were calculated by multiplying by the slice thickness.
2.4. LDH determination
The effluent during the first 15 min of reperfusion was collected and samples were taken for the determination of LDH activity. LDH activity was determined spectrophotometrically by the method of Ward et al. [14]. Results were expressed as units of LDH released per 15 min.
2.5. Inotropic stimulation
After 45 min of reperfusion, both non-preconditioned and preconditioned hearts from the 30 min ischaemia group were further reperfused for additional 10 min with Krebs solution plus 100 µM adrenaline. LVDP was recorded continuously during the adrenaline administration.
2.6. Analysis of data
Values are expressed as the mean±SEM. A one-way ANOVA was first performed to test for any differences between mean values from all groups. If a significant value of F was obtained, values were compared using Dunnet's test. Comparison of VF incidences between non-preconditioned and preconditioned hearts of each group was done in contingency tables with Fisher's exact test. A difference was considered statistically significant if P<0.05.
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3. Results
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3.1. Pre-ischaemic data
Baseline haemodynamic values were comparable among the experimental groups (Table 1). Ischaemic preconditioning (5 min of ischaemia followed by 10 min of reperfusion) induced a small decrease in LVDP resulting mainly from the slight reduction of peak systolic pressure rather than from the elevation of LVEDP. Pre-treatment values of LVEDP were attained at the end of the 10 min reperfusion period. There was no correlation between pre-ischaemic LVDP and post-ischaemic recovery of function in preconditioned hearts (data not shown).
3.2. Recovery of contractile function
In total, 52 hearts were entered into the study; one control heart from the 20 min ischaemia group was excluded due to sustained VF which exceeded the first 5 min of reperfusion. Generally, restoration of cardiac activity was uneventful in the 15 and 20 min ischaemia groups and no lethal arrhythmias were presented. Similarly, after 30 min of ischaemia, hearts started beating immediately at the onset of reflow. Manifestation of VF was slightly more frequent in preconditioned hearts but lasted for a few seconds, being converted to normal rhythm automatically or by tapping the ventricles. After 45 min of ischaemia, preconditioned hearts revealed VF at the onset of reperfusion with the same characteristics as in the 30 min group. These short periods of arrhythmias did not deteriorate the final mechanical activity of the hearts. On the contrary, in non-preconditioned hearts there was a lower incidence of VF. Instead these hearts became bradycardic shortly after restoration of reflow. Bradycardia in these hearts was accompanied by functional impairment. The model was not designed to allow electrocardiographic recording. VF is an easily recognized arrhythmia (with reasonable confidence) from the characteristic alteration that is produced in the force tracing. However, supraventricular and ventricular tachycardias could not be distinguished. Incidences of VF are presented in Table 2. It would appear that ischaemic preconditioning does not confer protection against the occurrence of reperfusion VF in our model but this observation requires confirmation using a model specifically designed to assess electrocardiographic changes.
Post-arrest data are summarized in Table 3 and Fig. 1
. In the 15 min ischaemia group, LVDP at the end of reperfusion was significantly higher in non-preconditioned hearts and nearly the same as stabilization values (95±0.3%). LVEDP was similar between non-preconditioned and preconditioned hearts, reaching the stabilization values. Coronary flow and HR remained unaffected in this short period of ischaemia. After 20 min of ischaemia non-preconditioned hearts attained 87±5.3% of LVDP compared with stabilization values, whereas preconditioned hearts attained 76±3.1%. The difference between these values was not significant. Diminution of coronary flow during reperfusion in this group was similar and possibly caused by alterations in microvascular tone induced by ischaemia/reperfusion since LVEDP values almost reached pre-ischaemic levels. HR achieved stabilization values in both non-preconditioned and preconditioned hearts. As ischaemic insult became more severe, preconditioning resulted in a significant improvement of myocardial performance. This was demonstrated by the significantly greater LVDP and lower LVEDP observed in preconditioned hearts, both in 30 and 45 min ischaemia groups. Lower LVDP obtained in non-preconditioned hearts is the result of both a greater reduction of peak systolic pressure and a higher elevation of LVEDP. Myocardial ischaemia and infarction alter not only the contractile systolic properties of the heart but also its diastolic properties [12]. Elevation of LVEDP against fixed preload is an indication of enhanced wall stiffness of the heart. In crystalloid perfused hearts, this enhanced stiffness is attributed to the increase of myofibrillar tone and the so-called erectile or garden hose effect whose relative magnitude is dependent on the severity of myocardial damage induced by ischaemia [13]. Thus, LVEDP elevation observed in non-preconditioned hearts appears to be related to a more severe degree of myocardial damage. Furthermore, this decrease in compliance, appearing in almost all hearts of 30 and 45 min ischaemia groups early at the onset of reperfusion, was irreversible when extensive lethal damage existed and finally resulted in a higher LVEDP at the end of reperfusion. Even though coronary flow is decreased in these two groups of enhanced ischaemic periods no differences were obtained between preconditioned and non-preconditioned hearts. Non-preconditioned hearts of the 45 min ischaemia group exhibited a high incidence of bradycardia to which a lower HRxLVDP product is attributed.
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Table 3. Recovery of myocardial function and release of LDH in non-preconditioned and preconditioned hearts at the end of reperfusiona
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Fig. 1. LVDP expressed as a percentage of pre-ischaemic values in four different experimental groups. (A) 15 min of ischaemia; (B) 20 min of ischaemia; (C) 30 min of ischaemia; (D) 45 min of ischaemia. Each point represents the mean±SEM of three to ten different experiments. #P<0.01 and *P<0.05 vs. non-preconditioned hearts.
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3.3. Infarct volume measurements
Four hearts (two non-preconditioned and two preconditioned) from the 30 min ischaemia group were excluded. One of them was broken during immersion in liquid nitrogen while the staining of the other three hearts was not satisfactory, making the separation between viable and necrotic tissue very difficult. One preconditioned heart from the 20 min ischaemia group was also excluded for the same reason. Quantification of infarct volume was made both in photographs and sketches. The results obtained from the application of these two methods were similar for each heart measured. Infarction is first evident in subendocardium, next involves mid myocardium and finally the whole area of the left ventricle. Fig. 2
shows the infarct volume of preconditioned and non-preconditioned hearts of all groups except the first one where no necrotic tissue was detected by TTC. In the 20 min ischaemia group, the infarct volume was almost equal in non-preconditioned and preconditioned hearts (7.8±1.3 and 6.0±1.2%, respectively, P=0.3). The infarct volume of hearts subjected to 30 min of ischaemia was not quite significantly different between non-preconditioned and preconditioned groups (12.5±0.8 and 9.8±1.5%, respectively, P=0.1). However, after the prolonged ischaemic insult of 45 min, preconditioning significantly reduced the infarct volume from 54±4.9% in non-preconditioned hearts to 16.6±2.4% in preconditioned hearts (P<0.0001).
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Fig. 2. Infarct volume as a percentage of left ventricular volume for non-preconditioned (NPC) and preconditioned (PC) hearts in three different experimental groups (20, 30, and 45 min of ischaemia). Open circles represent the individual heart infarct volume. Closed squares signify the group mean±SEM. *P<0.0001 vs. non-preconditioned hearts.
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3.4. Enzyme release
No significant differences in LDH leakage were observed in the 15 and 20 min ischaemia groups (Table 2). These results are in accordance with the respective measurements of infarct volume, suggesting that the degree of necrosis induced by these short periods of sustained ischaemia is small. In the 30 and 45 min ischaemia groups, however, non-preconditioned hearts released significantly more LDH compared with preconditioned hearts (Table 3).
3.5. Inotropic stimulation
Although LDH release was significantly different between non-preconditioned and preconditioned hearts in the 30 min ischaemia group, the extent of necrotic tissue, as demonstrated by the TTC staining method, was not significantly different. This discrepancy restrained us from attributing the significant functional recovery of preconditioned hearts strictly to infarct size limitation. We considered that by evaluating the magnitude as well as the profile of the response to inotropic stimulation, we could acquire further evidence to clarify this discrepancy. It is known that stunned hearts respond to catechol administration, whereas irreversibly injured myocardium cannot [15,16].
For that purpose we subjected non-preconditioned and preconditioned hearts of the 30 min ischaemia group to inotropic stimulation with 100 µM adrenaline at the end of the reperfusion period. Elevation of LVDP after adrenaline administration in four non-preconditioned and four preconditioned hearts is shown in Fig. 3
. LVDP reached a peak at the first 30 s which was significantly greater in preconditioned hearts (150±3.1 vs. 123±7.5% with respect to LVDP values at the end of reperfusion, P=0.01). LVDP decreased thereafter and was stabilized to a plateau 2–5 min later. However, it remained at higher levels in preconditioned hearts for the rest of the administration period.
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Fig. 3. Response to inotropic stimulation (100 µM adrenaline) at the end of reperfusion in the 30 min ischaemia group. An arrow shows the onset of adrenaline administration. Values are expressed as a percentage of LVDP at the end of reperfusion before adrenaline administration. Each point represents the mean±SEM (n=4). *P=0.015 vs. non-preconditioned hearts.
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4. Discussion
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Several experimental and clinical studies have shown that ischaemic preconditioning reduces myocardial infarct size and the incidence of ventricular arrhythmias after ischaemia/reperfusion. However, its effects on post-ischaemic contractile function are not uniform but rather vary according to the severity of myocardial damage. It is not clear if preconditioned hearts show better haemodynamic performance compared with non-preconditioned after any period of ischaemic insult where the infarct size is either small or large. Description of the beneficial effect of preconditioning on post-ischaemic contractile function should include the demonstration of the extent of myocardial damage in which this beneficial effect was achieved. This appears to be essential since it is known that different degrees of necrosis are produced by the same period of ischaemia in different experimental protocols.
It is generally accepted that a 15 min ischaemic period is not able to produce severe irreversible damages to myocardium. This period of ischaemic insult has been used in in vivo models of regional ischaemia in order to study the effects of preconditioning on stunned myocardium [8–10]. In our study, after 15 min of ischaemia, no necrotic tissue was detected by the TTC staining method. Furthermore, measurements of LDH leakage in this group, compared with those obtained in 30 and 45 min ischaemia groups, indicated that lethal injuries must be minimal (Table 3). Small infarcted volumes were observed in the hearts of the 20 min ischaemia group with the respective values being approximately equal between the preconditioned and non-preconditioned hearts. These results combined with the LDH values determined in the effluent suggest that infarcted tissue must be small and similar between the preconditioned and non-preconditioned hearts. In these short periods of ischaemia that caused minimal infarction, preconditioning resulted in lower recovery of LVDP compared with that observed in non-preconditioned hearts (Table 3). It is obvious that preconditioned hearts do not have the advantage of not being prone to stunning, when ischaemic insult results in minimally lethal injuries. In support of our results, Jenkins et al. [2], working in a model of global ischaemia in rabbit heart, demonstrated that after 30 min of ischaemia, ventricular function during reperfusion, as measured by LVDP, was significantly better in preconditioned than control hearts. However, there was no improvement in post-ischaemic recovery when the ischaemic insult was reduced to 20 or 15 min, suggesting that in short ischaemic periods where the irreversibly damaged myocardium is minimal, preconditioning fails to improve post-ischaemic recovery of function. In addition, in a study of crystalloid-perfused rabbit hearts subjected to 60 min of normothermic potassium arrest and 60 min of reperfusion, Faris et al. [7] showed the inability of preconditioning to relieve stunning in the absence of substantial infarction. In the same study there were no significant differences in creatine kinase wash out during the first 5 min of reperfusion and on infarct size as determined by TTC staining after 60 min of reperfusion between control and preconditioned hearts. The amount of infarction hardly averaged 10% of the left ventricle.
As ischaemic time is prolonged and irreversible injuries become more pronounced, preconditioning markedly improves post-ischaemic functional recovery. After 30 and 45 min of ischaemia, there was a significant difference in LVDP and LVEDP between preconditioned and non-preconditioned hearts (Table 3). In the 45 min ischaemia group post-ischaemic left ventricular function was strongly correlated with a significant reduction of the infarct size induced by preconditioning. In the 30 min ischaemia group the infarct volume estimated by TTC staining was not significantly different while the amount of LDH released was significantly higher in non-preconditioned hearts, indirectly suggesting the presence of more lethally injured tissue. It is generally accepted that progression from ischaemia-induced reversible dysfunction to frank necrosis and cell lysis is a spectrum. Methods routinely used as diagnostic of myocellular infarction, such as enzyme release and TTC staining, require cell lysis. It seems likely that multiple changes occur within the cell prior to lysis and these tests may be relatively insensitive to detect early, yet irreversible myocardial damage. Furthermore, TTC staining may not be good at detecting significant differences where infarct volumes are small and the reperfusion time is not long enough [17,18]. Thus, it can be suggested that functional protection achieved by preconditioning in this group is due to reduced cell death which TTC staining fails to demonstrate. However, a reduction in myocardial stunning cannot be excluded. Furthermore, the significant elevation of LVDP observed in preconditioned hearts after inotropic stimulation does not reflect directly significant differences in infarct size. Results obtained from this intervention could not also exclude attenuation of stunning by preconditioning. However, this appears to be of limited value if one considers results from the 45 min ischaemia group where there is a strong correlation between infarct size limitation and contractile function improvement. In addition, the significantly increased LVEDP observed in non-preconditioned hearts of the 30 min ischaemia group provides further evidence for the existence of more lethal injuries in these hearts. We conclude that the effects of preconditioning on post-ischaemic myocardial functional recovery vary according to the degree of myocardial damage. Its effects seem to be more beneficial when the severity of ischaemic insult is able to produce remarkable lethal injuries. This beneficial effect is exercised mainly by delaying myocytes necrosis and therefore attenuating infarct size.
Cardiac surgery is a discipline, where preconditioning can be used as an adjunct for myoprotective strategies [19,20]. However, mechanical interventions, such as cross-clamping and opening the aorta before cardioplegic arrest, which have been suggested as a preconditioning protocol, could possibly cause some additional damage [21]. Therefore, the routine use of these interventions in cardiac surgery remains questionable. It is important to ascertain whether preconditioning is expected to improve the functional recovery of the heart when the ischaemic time is too short to produce severe irreversible injuries. On the other hand, the fact that preconditioning delays myocardial necrosis amplifies arguments supporting its application when ischaemic insult is expected to be aggravating for myocardial viability. Taking into account differences between clinical conditions and the model used in the present study, our results support this hypothesis.
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Acknowledgments
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This work was supported by a grant from the Greek General Secretariat of Research and Technology (PENED 95).
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Abstract
1. Introduction
