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Departments of 1 Pharmacology & Toxicology2 Pathology, Cardiovascular Research Institute Maastricht, Universiteit Maastricht, Maastricht, the Netherlands
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(Received 11 March 2004;
accepted after revision 29 June 2004; first published online 15 July 2004)
Corresponding author T. De Celle: Department of Pharmacology & Toxicology, Cardiovascular Research Institute Maastricht, Universiteit Maastricht, Maastricht, the Netherlands. Email: t.decelle{at}farmaco.unimaas.nl
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Introduction |
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The in vivo mouse model of cardiac ischaemia–reperfusion (IR) was first published by Michael et al. (1995). Following transient occlusion of the left anterior descending coronary artery (LAD), they described the histological appearance of leucocytes and contraction bands in the ischaemic region of the heart up to 24 h after reperfusion. It should be noted that in this model infarct size is dependent on the duration of the ischaemic period. Infarct size is smaller after 30 than after 60 min of ischaemia. However, when the ischaemic period is extended up to 2 h, infarct size is comparable to those resulting from permanent occlusion (PO) of the LAD (Michael et al. 1999).
The murine model of IR has been frequently used to study the molecular mechanism of cardiac reperfusion injury or to evaluate potential therapies (Jones & Lefer, 2000,; Yet et al. 2001; Chen et al. 2003; Jones et al. 2003). Most of these studies have focused on the short-term consequences of reperfusion with myocardial infarct size or neutrophil influx as parameters to describe the progression of cardiac tissue damage in the time frame of a few hours (Palazzo et al. 1998; Girod et al. 1999; Jones et al. 1999), 1 day (Hoffmeyer et al. 2000; Jones et al. 2001, 2002; Scalia et al. 2001) or 3 days (Briaud et al. 2001; Yang et al. 2003) after the initiation of reperfusion.
The long-term effects of IR injury, in terms of weeks or months, are less well examined in this mouse model. However, this is relevant for extrapolation to the clinical setting. The outcome of interventions that are beneficial shortly after initiation of reperfusion may be different when the evaluation takes place at later stages. For example, a study by Metzler and others (Metzler et al. 2001), showed that genetic disruption of intercellular adhesion molecule-1 was associated with a beneficial effect and reduced influx of neutrophils in the heart in the early phase following IR. However, at 3 weeks following IR, left ventricular scar size did not differ compared to values obtained in wild-type mice. In addition, long-term adaptations to IR may differ from those induced by permanent occlusion of the LAD.
As described by Michael et al. (1999), the degree of septal hypertrophy was smaller after IR than after permanent occlusion of the LAD, despite a comparable infarct size.
The goal of the present study was to characterize the long-term functional and morphological consequences of cardiac IR in the in vivo mouse model. The ischaemic period was set to 30 min because this interval is most commonly used in the literature. We examined cardiac function by direct ventricular pressure measurements and cardiac geometry by echocardiography at three time points after IR (1 day, 2 and 8 weeks). In addition, standard histological techniques were applied to describe the morphological adaptations of the injured heart over time. We noticed that the long-term histological adaptations to IR were associated with prominent calcification. To evaluate whether this latter effect was specific for the IR process, data were compared to those obtained in mice subjected to permanent occlusion of the LAD.
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Methods |
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Male outbred Swiss mice (8–11 weeks old, body weight of 35–40 g) were purchased from Charles River (Someren, the Netherlands). Experiments were performed according to the guidelines of the University of Maastricht and were approved by the institutional animal ethics committee. The animals were kept on a 12 h:12 h light:dark cycle in a temperature-controlled (21 ± 2°C) room. After surgery, animals were housed individually with ad libitum access to standard food pellets (type Ssniff, Soest, Germany) and water.
In vivo ischaemia–reperfusion (IR) and permanent occlusion (PO)
Mice were anaesthetized with ketamine (100 mg kg–1I.M.) and xylazine (5 mg kg–1S.C.). Body temperature was monitored with a rectal probe and maintained at 37°C using a warming pad and heating lamp. The trachea of each mouse was intubated perorally with a stainless-steel tube connected to a respirator (Hugo Sachs Electronic rodent ventilator type 845, March-Hugstetten, Germany) set at a stroke volume of 250 µl and a rate of 210 strokes min–1. After left thoracotomy and exposure of the heart, the left anterior descending coronary artery (LAD) was ligated with 6–0 (metric 0) polypropylene suture (Surgipro, Chicago, IL, USA) just proximal to its main branching point. The suture was tied around a 3 mm long polyethylene tube (PE-10) to induce ischaemia. In the IR group, blood flow was re-established after 30 min of ischaemia by removal of the tube. The occurrence of reperfusion was assessed by the observation of blood flow in the epicardial coronary arteries through a surgical microscope.
In the PO group, the suture was tied permanently. Sham procedures were identical, with the exception of the actual tying of the polypropylene suture. The chest was closed with 5–0 (metric 1) silk sutures. The animals were then weaned from the respirator, and the intratracheal tube was removed once they were breathing spontaneously. Then 0.2 mg kg–1 body weight buprenorphine hydrochloride (Buprenex; Reckitt and Colman Pharmaceuticals, Richmond, VA, USA) was injected subcutaneously as an analgesic.
Echocardiography
Echocardiographic measurements were performed under light isoflurane anaesthesia. One recording was taken before surgical procedures (week 0) and two recordings were taken 2 and 8 weeks thereafter. Postoperatively, animals were placed in an animal care unit under daily supervision from the investigator. Ill or distressed animals were excluded from the study. The in vivo transthoracic echocardiography of the left ventricle (LV) was performed using a Hewlett-Packard 15 MHz linear array transducer (15–6 l) interfaced with a Sonos 5500 echocardiography system (Philips, Eindhoven, the Netherlands). Two-dimensional B-mode echocardiograms were captured at a rate of 90–120 Hz from parasternal long-axis views as well as from midpapillary short-axis views of the left ventricle. The spatial resolution in the B-mode is 5 times higher than in the M-mode. Data were obtained from at least three different images taken in end diastole and systole using EnConcert software (Agilent Technologies, Andover, MA, USA). Representative examples of these images are given in Fig. 2 (control). From the long-axis B-mode echocardiograms, the LVAd and LVAs (the LV area in diastole and systole, respectively), as well as the LVLd and LVLs (the length of the LV lumen from base to apex in diastole and systole, respectively) were determined. The end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated from area and length measurements as 8(LVAd)2/3
LVLd and 8(LVAs)2/3LVLs, respectively. Stroke volume was determined as EDV – ESV and the ejection fraction was defined as 100(EDV – ESV)/EDV. From the short-axis B-mode echocardiograms we determined the left ventricular wall thickness at two sites. Given the anatomical location of the coronary arteries in a mouse heart (Janssen et al. 2003), the anterior wall contains the ischaemia-associated lesion, while the posterior wall represents the nonischaemic part of the LV wall. In addition to wall thickness, LV internal chamber diameters were determined in diastole (LVIDd) and systole (LVIDs). The LV percentage fractional shortening (FS) was calculated according to the following expression: 100(LVIDd – LVIDs)/LVIDd.
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LV contractility was evaluated at 1 day as well as 2 and 8 weeks after IR. For this purpose mice were anaesthetized with urethane (2.5 mg (g body weight)–1I.P., Sigma). Body temperature and respiration were controlled as described above. A high-fidelity catheter tip micromanometer (Mikro-tip 1.4F; SPR-671, Millar Instruments, Houston, TX, USA) was inserted through the right carotid artery into the left ventricular cavity. Ventricular pressure was measured and sampled at a rate of 2 kHz. Maximal positive pressure development (+dP/dt) and heart rate were determined on a beat-to-beat basis and 1 s averages were stored on disk. The heart was then stimulated by an I.V. ramp infusion of dobutamine (Sigma) using a microinjection pump (model 200 Series, KdScientific, Boston, MA, USA). Every 2 min the infusion rate of dobutamine was increased by 0.5 ng (g body weight)–1 min–1 up to 5 ng (g body weight)–1 min–1. Following recovery from dobutamine infusion (taking 10–20 min and assessed by restoration of +dP/dt and heart rate to baseline levels), hearts were additionally stressed by loading the circulation with an I.V. infusion of warmed (37°C) Ringer solution for 1 min at a rate of 2.5 ml min–1. Maximal values of +dP/dt were recorded and the changes of +dP/dt values from baseline were calculated. At the end of the experiment ventricles and lungs were excised, washed with isotonic saline and weighed. Ventricles were further incubated for 24 h in formalin and embedded into paraffin for histochemical staining and evaluation of infarct size as described below.
Evaluation of ischaemic area at risk (AAR) and infarct size
Twenty-four hours after IR, the infarcted area was measured on triphenyltetrazolium chloride (TTC)- stained tissue sections (Michael et al. 1995). In short, mice were anaesthetized with pentobarbitone (120 mg kg–1), the jugular vein was cannulated and the thorax was reopened, the LAD was re-occluded and 500 µl of 2.5% Trypan Blue was injected into the jugular vein to delineate the nonischaemic tissue and quantify the area at risk (AAR). The heart was then excised, briefly washed with isotonic saline and cut into two parts, along the frontal plane and centrally through the ventricles. These parts were each incubated for 20 min at 37°C in 5 ml of 1% 2,3,5-triphenyltetrazolium chloride solution (TTC; Sigma). Viable myocardium is stained red by TTC while the necrotic, infarcted area remains unstained (Vivaldi et al. 1985). The surface of the left ventricle, the AAR and the infarcted area were measured in both parts of the heart. The ratios of AAR:LV, infarct:AAR and infarct:LV, expressed as percentages, were calculated and expressed as the mean of both parts.
To determine infarct size 2 and 8 weeks after IR or PO, mice were anaesthetized with pentobarbitone (120 mg kg–1), hearts were excised, washed with isotonic saline, cut into two parts as described above and embedded in paraffin. One section (5 µm thick) from each of the two parts of the heart was stained with AZAN (Cleutjens et al. 1995). The surface areas of the blue-stained parts and the surface area of the left ventricle were measured on both sections and the ratios of AAR:LV, infarct:AAR and infarct:LV, expressed as percentages, were calculated and expressed as the mean of both sections. All measurements were done using a computerized morphometry system (Quantimet 570C, Leica, Cambridge, UK; Smits et al. 1992).
Histochemistry
For histological examination, tissue sections were deparaffinized and stained with Haematoxylin and Eosin. To localize calcium phosphate crystals, sections were stained using von Kossa staining (Bills et al. 1974). The same computerized morphometry system was used to measure the relative surface area of the calcified regions to the infarcted area.
Statistical analysis
All parameters are expressed as means ±S.E.M. Infarct sizes and maximal changes in +dP/dt evoked by dobutamine and volume loading were evaluated using Student's unpaired t test. The dose–response curves for dobutamine were compared using a two-way ANOVA and a post hoc Bonferonni t test. Parameters serially obtained by echocardiography were compared using an ANOVA for repeated measures and a post hoc Fisher's t test to identify the time-related and between-group differences. P values 
0.05 were regarded as statistically significant.
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Results |
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A total of 102 animals were used for this study, of which 82 (
80%) survived the entire protocol. Nine animals died during or shortly after sham operation, IR or PO surgery because of complications due to anaesthesia, arrhythmia or bleeding. Six animals died between 3 and 7 days after surgery, of which two PO animals had a ruptured heart and the other four (1 sham operated, 3 IR) died for unknown reasons. Five animals died between 2 and 8 weeks after IR or PO (2 sham operated, 2 IR, 1 PO). A total of 70 animals were used for the cardiac contractility experiments, of which seven animals were excluded because of difficulties in passing the aortic valves with the catheter tip, and two animals because they had died just before measurement due to complications with anaesthesia (1 sham operated, 1 IR).
Morphometric characteristics
Table 1 summarizes morphometric characteristics of the different groups of mice at the different time points in this study. Body weight was slightly decreased 1 day after surgery, but was increased in all groups (sham operated, IR and PO) at later time points. Ventricular weight and ventricular weight:body weight ratio were slightly, but insignificantly increased 2 weeks after IR compared to sham operation at that time point.
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Myocardial infarct size
One day after IR the area at risk (AAR) was 47 ± 2% of the left ventricular area. The percentage of the AAR that was identified as infarcted area was 51 ± 8%, meaning that 21 ± 4% of the left ventricle was infarcted area (Table 1). The magnitude of infarcted area:left ventricle ratio did not differ at 2 and 8 weeks after IR, but was considerably less than in the PO group.
As shown by the AZAN staining in Fig. 1A, B, D and E, the ventricular wall of mice subjected to the IR protocol consisted of viable endo- and epicardial layers of myocytes and patchy distributed scar tissue. In contrast, 8 weeks after PO, the infarcted wall of the left ventricle was thinned, with an almost transmural appearance of granulation tissue (Fig. 1G and H).
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In the majority of animals subjected to IR a process of calcification occurred in the infarcted area of the ventricular wall. Calcium deposits were macroscopically observed as fine, white granules or clumps. By Haematoxylin and Eosin staining they appeared as basophilic, clumped and amorphous granules lying in a pattern of previous cardiomyocytes and encircled by fibrous tissue. The calcium crystals were stained black by the von Kossa staining (Fig. 1C and F) and appeared at a frequency of 9/13 animals (69%) in the 2 week reperfusion group and 8/11 animals (73%) in the 8 week IR group. In the calcified hearts, the size of the calcified area was 25 ± 5% of the infarcted area in the 2 week IR group and 38 ± 5% of the infarcted area in the 8 week IR group. The calcification of the myocardial healing area was specific for the IR protocol because no calcification was observed in mice subjected to PO (Fig. 1I).
Echocardiography
The results of the in vivo echocardiographic measurements are given in Table 2. The comparison of the echocardiographic parameters at week 0 indicates that baseline values of EDV and ESV were somewhat greater in the PO group than in the sham-operated or IR groups. This is probably due to normal time-dependent biological variation given the fact that the mice used for the PO series of experiments were not simultaneously purchased. Compared to the baseline value, the EDV was significantly increased at 2 and 8 weeks after IR while this was not the case in the sham-operated mice. However, when compared to the PO group, the dilatory remodelling response to the IR injury was relatively small (40 ± 15% for IR versus 250 ± 70% for PO, Fig. 2). The time-dependent changes in EDV were paralleled by those in ESV 8 weeks after IR. However, cardiac function, as assessed by stroke volume (SV), ejection fraction (EF) and fractional shortening (FS), was not significantly altered 2 and 8 weeks after IR. In contrast, the geometrical changes in the PO group had significant functional consequences for SV, EF and FS (Fig. 2). The echocardiographic measurements also identified a small but significant thickening of the anterior wall (AW) at 2 and 8 weeks after IR, especially during systole. At 8 weeks after IR the posterior wall (PW) thickness was significantly increased as well. After PO the affected AW became very thin, whereas the PW showed a comparable hypertrophic response as observed 8 weeks after IR.
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Figure 3 presents LV function as evaluated in sham-operated, IR and PO groups at the different time points by measuring systolic blood pressure, the rate of left ventricular pressure development +dP/dt and heart rate (HR). Under basal conditions, +dP/dt did not differ between sham-operated, IR and PO groups. Nor did systolic blood pressures differ at baseline between sham-operated, IR and PO groups (74 ± 2 71 ± 2 and 72 ± 2 mmHg, respectively). Baseline HR values were significantly (P < 0.01) higher in the IR group than in sham-operated mice 1 day after reperfusion. When hearts were stimulated with dobutamine, +dP/dt levels increased in a dose-dependent manner in sham-operated animals, whereas the increase was blunted in IR animals at 1 day and 2 weeks after reperfusion (Fig. 3A). Dose–response curves for heart rate were comparable between groups. One day after IR, the increase in +dP/dt was significantly smaller (2456 ± 475 mmHg s–1) when compared to increments observed in the sham-operated group (5939 ± 928 mmHg s–1, P= 0.004). The blunted response was still present 2 weeks after IR (IR, 3174 ± 1066 versus sham, 7487 ± 1209 mmHg s–1, P= 0.01). In contrast, 8 weeks after IR, the contractility response to dobutamine was nearly restored to control levels (5828 ± 735 mmHg s–1 in IR versus 6620 ± 735 mmHg s–1 in sham-operated mice). At this time point, the contractile response to dobutamine in the PO group was significantly blunted.
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To examine whether the amount of calcification was associated with deficits in cardiac function, infarct size was plotted against the maximum +dP/dt responses to dobutamine in the 2 and 8 week IR groups (Fig. 4). The subgroup of mice with the largest calcified LV areas is indicated separately in this figure. The figure shows that although the mice with the largest amount of calcification were among those with the largest infarct size, no obvious relation to cardiac contractility was observed.
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Discussion |
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The degree of cardiac injury and survival rate is related to the duration of the ischaemic stimulus. In the present study, we chose a commonly used time frame of 30 min of ischaemia, and the survival rate was more than 80% at 8 weeks after IR.
In a study by Michael et al. (1999) it was described that following a 2 h ischaemic period the survival rate was 60% after 24 h and only 45% several weeks after reperfusion. In that study, left ventricular infarct size was about 30% and did not differ from infarct sizes found after permanent occlusion. In the present study, following the shorter 30 min ischaemic period, left ventricular infarct size was 21% at 1 day after IR. Two and 8 weeks after IR the LV infarct size was smaller (about 13%). This time-related difference in infarct size is most likely to be a consequence of the technique used to assess infarct size. Staining by TTC is based on the ability of living cells to reduce TTC to an insoluble red pigment. It cannot be excluded that 24 h after IR some of the cardiomyocytes were unable to metabolize TTC because they were in a hibernating state. Later on these cells may have regenerated to vital cardiomyocytes, which may explain the reduced infarct size as detected at 2 and 8 weeks after IR (Ausma et al. 1995; Vanoverschelde & Melin, 2001).
As shown in Fig. 1, permanent occlusion of the LAD in the PO model resulted in large transmural infarcts with thinning of the left ventricular wall and did not involve the septum and right ventricle. In contrast, in the IR model, infarcts were never transmural, but were characterized by a patchy distribution of granulation and scar tissue localized between an endo- and epicardial layer of vital cardiomyocytes.
At 2 and 8 weeks after IR we observed in about 70% of the animals pronounced calcified regions in the left ventricular wall that were surrounded by granulation and fibrous scar tissue. This phenomenon was completely absent in the PO animals.
Dystrophic calcium deposition appears in many pathological conditions due to passive precipitation of calcium and phosphates. In cardiovascular diseases this process is most frequently described in atherosclerosis, in which arterial plaque calcification occurs, and in degenerative diseases of the heart valves (David & Ivanov, 2003; Doherty et al. 2003). To our knowledge only two reports have been published about calcification in relation to reperfusion. A case study of (Tseng et al. 2000) reported acute calcification following transient ligation of the rodent middle cerebral artery, while Jennische (1984) showed postischaemic calcification in skeletal muscle of the rat. However, following myocardial ischaemia–reperfusion, tissue calcification has not been documented.
Lipids, apoptotic bodies and necrotic debris in the lesion-healing area may play a role in the nucleation of calcium hydroxyapatite crystals (Proudfoot et al. 2000). When blood flow is restored after ischaemia, debris of death cells may accumulate with calcium and phosphates from the blood before the inflammatory cells infiltrate the damaged tissue. After permanent occlusion of the area at risk, blood flow is not restored and so the disposition of calcium crystals is prevented, enabling the inflammatory cells to clear the necrotic debris. The present study was not designed to clarify the mechanisms of this aspect of lesion healing. We observed that the animals with the largest area of calcification were among those that had the largest infarct size (Fig. 4). However, the calcification process did not seem to have a negative impact on cardiac function because it returned to normal 8 weeks after IR. Further studies are necessary to investigate this issue in more depth.
Cardiac contractility was measured in order to characterize the evolution of cardiac function over time after ischaemia–reperfusion. Baseline heart rates were slightly elevated 24 h after IR compared to sham-operated animals. This was probably due to neurohumoral compensation following the acute IR injury. Baseline heart rates did not differ between sham-operated and IR mice at 2 and 8 weeks after surgery, suggesting a normalization of this response.
Baseline +dP/dt levels were not different between the IR and sham-operated mice at any time point. Also, baseline +dP/dt values obtained 8 weeks after PO were not different from those found in the sham-operated group, despite the increase in lung weights, which suggests signs of congestive heart failure. In contrast, other studies have reported decreased +dP/dt values after PO in baseline conditions (Patten et al. 1998; Lutgens et al. 1999). Differences in anaesthetic regimens and other experimental circumstances may explain these discrepancies. To obtain a better insight into the physiological consequences of IR injury, contractility changes were measured while the heart was stressed with dobutamine or a volume load. In comparison to sham-operated mice, cardiac contractility responses to dobutamine were reduced 1 day and 2 weeks after IR. At 8 weeks after IR, but not after PO, responses to dobutamine and volume loading were nearly restored. The recovery of cardiac contractility at 8 weeks after IR occurred simultaneously with morphological adaptations as determined by echocardiography and was paralleled by a significant increase in ventricular weight.
Part of this hypertrophic response is due to normal physiological growth. However, the enlargement of the end-diastolic volume (40% in IR versus 20% in sham-operated mice) and thickening of the posterior wall (23% in IR versus 13% in sham-operated mice) suggest an eccentric hypertrophic response to IR injury. Early signs of this process were already detected at 2 weeks after IR, as suggested by the positive correlation between infarct size and ventricular weight. The remodelling response may be too small at that time point to compensate for the reduced cardiac contractility response.
The process of dilatation was much smaller after IR than after PO. Eight weeks after PO the end-diastolic volume was increased by a factor of 2.5. Despite the enlargement of the ventricular cavity, stroke volume and ejection fraction were significantly reduced because the infarcted and thinned myocardial wall remained fully akinetic. These functional impairments, as detected by echocardiography, are in agreement with those previously obtained by direct ascending aortic blood flow measurements in this model (Janssen et al. 2002).
We conclude that in our mouse model, long-term cardiac consequences following ischaemia–reperfusion are different from those observed after permanent ischaemia. Contractility of the heart was depressed for at least 2 weeks after IR, but was restored after 8 weeks. Given the significant negative correlation between infarct size and cardiac contractility, the functional differences between the IR model and the PO model are most likely to be of a quantitative nature. After reoxygenation of the ischaemic heart, calcification, hypertrophy and minor dilatation characterized the lesion healing process. However, the gross architecture of the ventricular wall was preserved. This aspect differed qualitatively from the permanent occlusion model. When reperfusion was not established, the ischaemic area was not calcified, but completely replaced by connective tissue. In addition, the ventricular wall was severely dilated and loss of cardiac function was permanent.
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P < 0.01. B, change in cardiac contractility (+dP/dt) under volume loading (2.5 ml min–1 Ringer solution) in sham (
), IR (•) and PO groups (
) at 2 and 8 weeks (n= 7–10 per group). Results are expressed as means ±S.E.M.
P < 0.05.